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Previous studies evaluating the risk of spontaneous abortions following exposure to macrolides reported controversial results. The goal of the current study was to examine the risk for spontaneous abortions following exposure to macrolides during pregnancy. We conducted a population-based retrospective cohort study by linking three computerized databases: Clalit Health Services drug dispensation database, Soroka Medical Center (SMC) birth database, and SMC hospitalizations database. Multivariate time-varying Cox regressions were performed and adjusted for suspected confounders and known risk factors for spontaneous abortions. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. A secondary analysis was performed to assess the association between exposure to macrolides in terms of the defined daily dose dispensed and spontaneous abortions. The study cohort included 65,457 pregnancies that ended at Soroka Medical Center between 2004 and 2009, of which 6508 (9.9%) resulted in a spontaneous abortion. A total of 825 (1.26%) pregnancies were exposed to macrolides during the exposure period. Exposure to macrolides was not associated with spontaneous abortions as a group (adjusted HR 1.00 95% CI 0.77-1.31) or as specific medications. There was no evidence of a dose-response relationship between exposure to macrolides and spontaneous abortions. In conclusion, this population-based retrospective cohort study did not detect an increased risk for spontaneous abortion following exposure to macrolides during the first trimester of pregnancy., (© 2024, The American College of Clinical Pharmacology.)

Background and Aims: Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy., Methods: KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes., Results: KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P < .0001, LQT1-SupRep vs. WT, P = ns). Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour., Conclusions: This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Genome-wide association studies have reported a correlation between a SNP of the RING finger E3 ubiquitin protein ligase rififylin (RFFL) and QT interval variability in humans (Newton-Cheh et al., 2009). Previously, we have shown that RFFL downregulates expression and function of the human-like ether-a-go-go-related gene potassium channel and corresponding rapidly activating delayed rectifier potassium current (I Kr ) in adult rabbit ventricular cardiomyocytes. Here, we report that RFFL also affects the transient outward current (I to ), but in a peculiar way. RFFL overexpression in adult rabbit ventricular cardiomyocytes significantly decreases the contribution of its fast component (I to,f ) from 35% to 21% and increases the contribution of its slow component (I to,s ) from 65% to 79%. Since I to,f in rabbits is mainly conducted by Kv4.3, we investigated the effect of RFFL on Kv4.3 expressed in HEK293A cells. We found that RFFL overexpression reduced Kv4.3 expression and corresponding I to,f in a RING domain-dependent manner in the presence or absence of its accessory subunit Kv channel-interacting protein 2. On the other hand, RFFL overexpression in Kv1.4-expressing HEK cells leads to an increase in both Kv1.4 expression level and I to,s , similarly in a RING domain-dependent manner. Our physiologically detailed rabbit ventricular myocyte computational model shows that these yin and yang effects of RFFL overexpression on I to,f, and I to,s affect phase 1 of the action potential waveform and slightly decrease its duration in addition to suppressing I Kr . Thus, RFFL modifies cardiac repolarization reserve via ubiquitination of multiple proteins that differently affect various potassium channels and cardiac action potential duration., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A growing body of literature reports associations between exposure to particulate matter with aerodynamic diameters ≤2.5 μm (PM 2.5 ) and 2.5-10 μm (PM 10-2.5 ) during pregnancy and preterm birth (PTB). However, the role of ambient temperature in PM-PTB associations was rarely investigated. In Israel, we used Maccabi Healthcare Services data to establish a population-based cohort of 381,265 singleton births reaching 24-42 weeks' gestation and birth weight of 500-5000 g (2004-2015). Daily PM and ambient temperature predictions from a satellite-based spatiotemporal model, at a 1 × 1 km spatial resolution, were linked to the date of birth and maternal residence. Mixed effects Cox regression models, adjusted for covariates, with a random intercept at the mother level were used to assess associations between mean exposure during pregnancy and PTB. We found that exposure to PM 2.5 was positively associated with PTB when the average exposure during pregnancy was either low (first quintile) or high (fifth quintile), compared to exposure in the 2nd-4th quintiles, with hazard ratios (HRs) 1.18 (95% confidence interval [CI], 1.13-1.24) and 1.07 (95% CI, 1.02-1.12), respectively. The results revealed effect modification of temperature. For mothers exposed to low (below median) average temperature during pregnancy, HRs of PTB were 0.93 (95% CI, 0.87-1.00) and 1.21 (95% CI, 1.14-1.29) for the first and fifth PM 2.5 quintiles, respectively, when compared to the 2nd-4th quintiles. However, a reverse trend was indicated for high-temperature pregnancies, where the corresponding HRs were 1.48 (95% CI, 1.39-1.58) and 0.92, (95% CI, 0.96-0.98). In conclusion, consideration of climatic factors can provide new insights into the risk of PTB as a result of exposure to PM 2.5 during pregnancy., Competing Interests: Declaration of competing interest The authors declare they have nothing to disclose., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Studies have suggested an association between particulate matter (PM) air pollution and certain congenital anomalies (CAs). However, most studies assumed a linear concentration-response relation and were based on anomalies that were ascertained at birth or up to 1 year of age. We investigated associations between exposures to PM during the first trimester of pregnancy and CAs in 9 organ systems using birth and childhood follow-up data from a leading health care provider in Israel. We conducted a retrospective population-based cohort study among 396,334 births, 2004-2015. Daily PM data at a 1 × 1 km spatial grid were obtained from a satellite-derived prediction models and were linked to the mothers' residential addresses at birth. Adjusted odds ratios (ORs) were estimated with logistic regression models using exposure levels as either continuous or categorical variables. We captured 57,638 isolated CAs with estimated prevalence of 96 and 136 anomalies per 1000 births in the first year of life and by age 6 years, respectively. Analysis of continuous PM with diameter < 2.5 μm (PM 2.5 ) indicated a supra-linear relation with anomalies in the circulatory, respiratory, digestive, genital and integument systems (79 % of CAs). The slope of the concentration-response function was positive and steepest for PM 2.5 lower than the median concentration (21.5 μg/m 3 ) and had a less steep or negative slope at higher levels. Similar trends were observed for PM 2.5 quartiles. For example, for cardiac anomalies, the ORs were 1.09 (95 % confidence interval: 1.02, 1.15), 1.04 (0.98, 1.10) and 1.00 (0.94, 1.07) for births in the second, third and fourth quartiles, respectively, when compared to the first quartile. In sum, this study adds new evidence for adverse effects of air pollution on neonatal health even with low-level air pollution. Information on late diagnosis of children with anomalies is important in evaluating the burden of disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a 12-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age., Competing Interests: BB, KM, ES, EM, YC, NT, YL, LS, TK, AK, PB, ZQ, PC, PD, DT, Fd, BC, JS, GK No competing interests declared, (© 2023, Baggett, Murphy, Sengun et al.)

Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca 2+ release is essential to boost energy production in ventricular cardiomyocytes (VCMs) and match increased metabolic demand. Mitochondria from female hearts exhibit lower mito-[Ca 2+ ] 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-Ca 2+ accumulation, thereby reducing ROS production and stress-induced intracellular Ca 2+ mishandling. Experiments using mitochondria-targeted biosensors confirmed lower mito-ROS and mito-[Ca 2+ ] in female rat VCMs challenged with β-adrenergic agonist isoproterenol compared to males. Biochemical studies revealed decreased mitochondria Ca 2+ 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 Ca 2+ release in response to ISO. Conversely, shRNA-mediated knockdown of COX7RP in female VCMs reduced supercomplexes and increased mito-ROS, promoting intracellular Ca 2+ 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-[Ca 2+ ] limits mito-ROS under stress conditions and lowers propensity to pro-arrhythmic spontaneous SR Ca 2+ release. We conclude that sexual dimorphism in mito-Ca 2+ handling and ETC organization may contribute to cardioprotection in healthy premenopausal females., (© 2023. The Author(s).)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Shaked et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2022 British Pharmacological Society.)

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., (© 2021 John Wiley & Sons Ltd.)

Background: A growing body of literature reports associations between exposure to particulate matter with diameter ≤2.5 μm (PM 2.5 ) during pregnancy and birth outcomes. However, findings are inconsistent across studies., Objectives: To assess the association between PM 2.5 and birth outcomes of fetal growth in a cohort with high prevalence of siblings by multilevel models accounting for geographical- and mother-level correlations., Methods: In Israel, we used Maccabi Healthcare Services data to establish a population-based cohort of 381,265 singleton births reaching 24-42 weeks' gestation and birth weight of 500-5000 g (2004-2015). Daily PM 2.5 predictions from a satellite-based spatiotemporal model were linked to the date of birth and maternal residence. We generated mean PM 2.5 values for the entire pregnancy and for exposure periods during pregnancy. Associations between exposure and birth outcomes were modeled by using multilevel logistic regression with random effects for maternal locality of residence, administrative census area (ACA) and mother., Results: In fully adjusted models with a mother-level random intercept only, a 10-μg/m 3 increase in PM 2.5 over the entire pregnancy was positively associated with term low birth weight (TLBW) (Odds ratio, OR = 1.25, 95% confidence interval, CI: 1.09,1.43) and small for gestational age (SGA) (OR = 1.15, 95% CI: 1.06,1.26). Locality- and ACA-level effects accounted for <0.4% of the variance while mother-level effects explained ∼50% of the variability. Associations varied by exposure period, infants' sex, birth order, and maternal pre-pregnancy BMI., Conclusions: Consideration of mother-level variability in a region with high fertility rates provides new insights on the strength of associations between PM 2.5 and birth outcomes., (Copyright © 2022. Published by Elsevier Inc.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

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., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Treatment of bacterial infections currently focuses on choosing an antibiotic that matches a pathogen's susceptibility, with less attention paid to the risk that even susceptibility-matched treatments can fail as a result of resistance emerging in response to treatment. Combining whole-genome sequencing of 1113 pre- and posttreatment bacterial isolates with machine-learning analysis of 140,349 urinary tract infections and 7365 wound infections, we found that treatment-induced emergence of resistance could be predicted and minimized at the individual-patient level. Emergence of resistance was common and driven not by de novo resistance evolution but by rapid reinfection with a different strain resistant to the prescribed antibiotic. As most infections are seeded from a patient's own microbiota, these resistance-gaining recurrences can be predicted using the patient's past infection history and minimized by machine learning-personalized antibiotic recommendations, offering a means to reduce the emergence and spread of resistant pathogens.

Background: Maternal post-partum depression is one of the most common medical complications around childbirth. One of its consequences is a possible association with children's receipt of preventive health care, including immunization. This study aimed to explore the association between maternal postpartum depression and children's immunization rates., Methods: A retrospective cohort study of Maccabi Healthcare Services (HMO) members comparing immunization rates between children born between 2006 and 2019 to mothers with post-partum depression and children born to mothers with no documented depression. Post-partum depression was assessed by Edinburgh Postnatal Depression Scale, a 10-item questionnaire considered the screening tool of choice in Israel for early Post-partum detection. 1:1 matching was conducted according to criteria: age of the mother ± 2 years, child's year of birth, the newborn baby's gender, the baby's birth order and socioeconomic index. The primary outcome was defined as non-vaccination and the exposure was defined as depression. A sub-analysis was performed, comparing immunization rates of children born to mothers treated with antidepressant medications to rates of children born to untreated mothers., Results: A total of 709 subjects in the exposed cohort (children born to mothers with post-partum depression symptoms) and 681 subjects in the matched cohort were analyzed. The relative risks among children born to depressed mothers compared with children born to healthy mothers for not receiving any vaccine at 2 months, three doses of pertussis vaccine up to 7 months and four doses of DTaP-Hib-IPV vaccine up to 18 months were 1.15 (95% CI 0.74-1.78), 1.11 (95% CI 0.94-1.31) and 0.82 (95% CI 0.56-1.95), respectively. The relative risks among 139 infants born to treated mothers compared with 570 infants born to untreated mothers for not receiving any vaccine at 2 months, three doses of pertussis vaccine up to 7 months and four doses of DTaP-Hib-IPV vaccine up to 18 months were 1.28 (0.64-2.54), 0.78 (0.57-1.06) and 0.42 (0.17-1.03), respectively., Conclusion: We found no significant association between maternal post-partum depression and uptake of child Immunization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zaikin, Koren, Chodick and Grossman.)

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 (Ca v α1c), 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kabakov, Sengun, Lu, Roder, Bronk, Baggett, Turan, Moshal and Koren.)

Background: The severity of nausea and vomiting of pregnancy (NVP) correlates with pregnancy complications. This study aimed to confirm the measurement and structural invariance of the 24 h Pregnancy-Unique Quantification of Emesis and Nausea (PUQE-24) regarding parity and observation time among pregnant women during the first trimester., Methods: Questionnaires including the PUQE-24 and the Health-Related Quality of Life for Nausea and Vomiting during Pregnancy (NVP-QOL) questionnaire were distributed to pregnant women from 10 to 13 weeks of gestation who were attending antenatal clinics. There were 382 respondents, and of these, 129 responded to the PUQE-24 again one week later., Results: Confirmatory factor analysis of this single factor model showed a good fit with the data: CFI = 1.000. The PUQE-24 factor and NVP-QOL factor were strongly correlated ( r = 82). Configural, measurement, and structural invariance of the factor structure of the PUQE items were confirmed between primiparas and multiparas as well as at the test and retest observation occasions., Conclusion: The findings suggested that using the PUQE-24 among pregnant women in the first trimester was robust in its factor structure. The PUQE-24 may be a promising tool as an easy and robust measure of the severity of nausea and vomiting among pregnant women.

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 χ 2 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., (© 2021 British Pharmacological Society.)

Cnidium officinale Makino is a perennial plant, a member of the Umbelliferae family. Cnidium root has traditionally been used as a medicinal herb. It has analgesic, antiinflammatory, antipyretic, antibacterial, antispasmodic, vasodilatory, hypertensive, and sedative effects. However, there are no studies of reproductive toxicity in humans. Therefore, this study aimed to prospectively evaluate the fetal and neonatal outcomes in the children of women who inadvertently used Cnidium root during pregnancy. In a prospective cohort study design, 111 singleton pregnant women taking Cnidium root for various reasons, and 219 age-matched singleton pregnant women unexposed to any herbal agent (unexposed group), were followed up until delivery. In the exposed group, Cnidium root was indicated as controlling cough and cold in 54.1% of patients, at the maximal dose of 12,000 mg/day between 1 day to 12.4 weeks of gestation. Fetal outcomes, including birth weight and 1- and 5-min Apgar score, were similar for the two groups. There were four babies born with major malformations in the exposed group vs. 14 in the unexposed group (OR = 0.5; 95% CI 0.2-1.6; p = 0.190). The gestational age, length, and head circumference were relatively shorter among babies born in the exposed group. Even after adjusting for gender, there was a tenfold increase in the frequency of shorter newborns (<2SD) in the exposed group (OR = 10.1; 95% CI 1.2-87.6; p = 0.019). Our study suggests that Cnidium root is not a major human teratogen. Whether lesser gestational ages at birth and shorter birth lengths are clinically relevant after exposure to Cnidium remains to be elucidated in further studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2021. The Author(s).)

Objective: Isotretinoin is among the most notorious human teratogens, documented originally as causing up to 30% of malformations. This systematic review and meta-analysis aimed to evaluate the rates of major malformation (MM) among isotretinoin-exposed pregnant women over the years through a systematic review and meta-analysis., Methods: Eligible studies were searched and identified using various databases. Single-arm meta-analysis and meta-analysis of odd ratios among controlled studies were performed using Review Manager version 5.3., Results: Ten eligible studies that combined 2,783 isotretinoin-exposed women were included in our study. The rate of MM weighted for the sample size was 15%. Three studies that included an unexposed comparison group were eligible for the meta-analysis. The pooled odds ratio of MM for isotretinoin-exposed women was 3.76. After 2006, the pooled odds ratio of MM for isotretinoin exposure was significantly lower at 1.04., Conclusion: The current rate of MM in isotretinoin-exposed women was substantially lower after 2006.

Background: This study examined the effectiveness of a birth preparation course on coping with childbirth among primigravid ultra-orthodox Jewish women in Israel. Methods: In total, 130 ultra-orthodox 25-35-week primigravid women were divided into a study ( n = 100, participated in birth preparation courses) and a control ( n = 30, did not participate in the courses) group. A questionnaire was delivered three times: T 1 -before the course/delivery, T 2 -two-three days after delivery, and T 3 -a month after delivery. Results: At T 3 , self-efficacy among the study group was higher than in the control group. Differences in self-efficacy were found over time regardless of the group (F (2,246) = 12.83, p < 0.001), as a time-group interaction effect (F (2,246) = 10.20, p < 0.01). Self-efficacy in the study group (Mean, M = 3.40, Standard deviation, SD = 0.63 at T 1 ) dropped to M = 3.06, SD = 0.76 at T 2 and rose to M = 3.34, SD = 0.64 at T 3 . In the control group, self-efficacy (M = 3.53, SD = 0.56 at T 1 ) dropped to M = 3.26, SD = 0.63 at T 2 and to M = 2.95, SD = 0.76 at T 3 . Discussion: The childbirth preparation course was found to be effective in raising self-efficacy among primigravid ultra-orthodox religious women when compared to the control group.

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.

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.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

Objectives: Our objective was to estimate the likelihood of abnormal development among institutionalized children, addressing either the risk in general, or the risk for fetal alcohol spectrum disorder (FASD)., Methods: Narrative review of studies measuring developmental effects of these populations. We identified all systematic reviews and meta analyses dealing with the associations between institutionalization of children and their neurodevelopment in general, or between institunalization of children and their likelihood of suffering from FASD., Results: a) In a published meta-analysis the mean IQ/DQ was 84 among institutionalized children, as compared to 104 among children raised in families. Favorable caregiver-child ratios appeared to have a protective effect, whereas longer stays in institutions had a detrimental effect on IQ/ DQ. b) A further meta- analysis has shown a positive impact of adoption on children's cognitive development with adopted children's displaying remarkably normal cognitive competence as compared to their non-adopted peers.c) The overall pooled prevalence was 6% (60 per 1,000, 95% CI 38-85) for full blown fetal alcohol syndrome (FAS), and 16.9% (95% CI 109-238 per 1,000) for the whole range of FASD.d) The estimated prevalence of FASD was 10-40 fold higher than the 7.7 per 1000 in the general population., Conclusions: A large proportion of adopted institutionalized children may not follow a normal developmental trajectory. If not afflicted by FASD, there is a positive impact of adoption on children's cognitive development and in general they are comparable to their non- adopted peers., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Fetal alcohol spectrum disorder (FASD) has been recently estimated to afflict up to 5% of American children. Most of these children exhibit different degrees of symptomatology of disruptive behaviors. Yet, there has been very little research on the efficacy and safety of pharmacological modalities, limited mostly to stimulants for attention deficit hyperactive disorder or second generation atypical antipsychotics for aggression. Recently, the use of cannabinoids has been described for symptoms related to autistic spectrum disorder with apparent favorable effects, as well as for other disruptive behaviors. The objective of our study was to follow up in a retrospective case series the effect of cannabis in children and young adults diagnosed with FASD. Methods: In two children and three FASD young adults with severe disruptive behavior, changes in behavior after cannabis use were measured by the parent version of the Nisonger Child Behavior Rating Form. Results: In all five cases, there was a highly statistical decrease in the disruptive behavior score from 18±1.0 before cannabis use to 6±2.1 after introduction of cannabis ( p =0.0002). Discussion: In children and young adults with FASD, cannabis, mostly cannabidiol (CBD), has been associated with a marked and statistically significant improvement in serious disruptive behavior. These cases suggest that the efficacy and safety of CBD should be tested in well-controlled studies., Competing Interests: No competing financial interests exist., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

This article has been withdrawn as the request of the author(s) and/or Editors. The Publisher apologizes for any inconvenience this may cause., (Copyright © 2020. Published by Elsevier Ltd.)

Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral condition found in 5-10% of school-age children and in 2-5% of adults. Stimulants affecting the dopaminergic, noradrenergic and/or serotonergic systems are commonly used for treatment in children and adults, including women of childbearing age. The data on the effects of stimulants (methylphenidate and amphetamines) in pregnancy are generally reassuring, but methylphenidate might slightly increase the rate of cardiac malformations and of spontaneous abortions, while amphetamines might slightly increase the risk for premature birth, low birth weight and other pregnancy complications. Bupropion, a dopamine and norepinephrine reuptake inhibitor, when used as an antidepressant, appears to be safe in pregnancy. The data on the use of atomoxetine, guanfacine and clonidine in pregnancy are scarce. Importantly, there are practically no data on the long-term neurodevelopmental effects of most of these drugs. The published data on the development of children born to methamphetamineabusing women may be misleading since these women generally use other drugs, including alcohol, and the home environment where the child is raised may not be optimal. The treating physician should judge the need for treatment during pregnancy in relation to the severity of the clinical symptoms. If needed, methylphenidate is preferred over amphetamines because breast feeding is possible. If one uses non-stimulant medications, bupropion seems to be the preferred drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

There is no other example in human teratology where, after more than 40 epidemiological studies, repeated meta-analyses and thousands of pregnancies, the fetal safety or risk of an agent has not been verified and settled. The objectives of the present review were to identify and discuss sources of bias that may lead clinicians and scientists to believe that SRIs cause malformation or other adverse outcomes, where, in fact, they may not. The present study highlights sources of bias that may explain why children exposed in utero to SRI exhibit higher rates of congenital malformations, mostly cardiovascular and other complications. It appears that pregnant women treated for depression and anxiety are distinctively different from healthy women in numerous covariates, which may confound pregnancy outcomes. Acknowledging and adjusting for these sources of bias are critical before one selects to withhold therapy for moderate or severe cases of depression and anxiety in pregnancy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current I Na and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on I Na We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca 2+ and Na + homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Turan et al.)

Objective: To investigate coronary endothelial protection of a small-conductance calcium-activated potassium (SK) channel activator against a period of cardioplegic-hypoxia and reoxygenation (CP-H/R) injury in mice and patients with diabetes (DM) and those without diabetes (nondiabetic [ND])., Methods: Mouse small coronary arteries/heart endothelial cells (MHECs) and human coronary arterial endothelial cells (HCAECs) were dissected from the harvested hearts of mice (n = 16/group) and from discarded right atrial tissue samples of patients with DM and without DM (n = 8/group). The SK current density of MHECs was measured. The in vitro small arteries/arterioles, MHECs, and HCAECs were subjected to 60 minutes of CP hypoxia, followed by 60 minutes of oxygenation. Vessels were treated with or without the selective SK activator NS309 for 5 minutes before and during CP hypoxia., Results: DM and/or CP-H/R significantly inhibited the total SK currents of MHECs and HCAECs and significantly diminished the mouse coronary relaxation response to NS309. Administration of NS309 immediately before and during CP hypoxia significantly improved the recovery of coronary endothelial function, as demonstrated by increased relaxation responses to adenosine 5'-diphosphate and substance P compared with those seen in controls (P < .05). This protective effect was more pronounced in vessels from ND mice and patients compared with DM mice and patients (P < .05). Cell surface membrane SK3 expression was significantly reduced after hypoxia, whereas cytosolic SK3 expression was greater than that of the sham control group (P < .05)., Conclusions: Application of NS309 immediately before and during CP hypoxia protects mouse and human coronary microvasculature against CP-H/R injury, but this effect is diminished in the diabetic coronary microvasculature. SK inhibition/inactivation and/or internalization/redistribution may contribute to CP-H/R-induced coronary endothelial and vascular relaxation dysfunction., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Background: End stage renal disease (ESRD) describes the most severe stage of chronic kidney disease (CKD), when patients need dialysis or renal transplant. There is often a delay in recognizing, diagnosing, and treating the various etiologies of CKD. The objective of the present study was to employ machine learning algorithms to develop a prediction model for progression to ESRD based on a large-scale multidimensional database., Methods: This study analyzed 10,000,000 medical insurance claims from 550,000 patient records using a commercial health insurance database. Inclusion criteria were patients over the age of 18 diagnosed with CKD Stages 1-4. We compiled 240 predictor candidates, divided into six feature groups: demographics, chronic conditions, diagnosis and procedure features, medication features, medical costs, and episode counts. We used a feature embedding method based on implementation of the Word2Vec algorithm to further capture temporal information for the three main components of the data: diagnosis, procedures, and medications. For the analysis, we used the gradient boosting tree algorithm (XGBoost implementation)., Results: The C-statistic for the model was 0.93 [(0.916-0.943) 95% confidence interval], with a sensitivity of 0.715 and specificity of 0.958. Positive Predictive Value (PPV) was 0.517, and Negative Predictive Value (NPV) was 0.981. For the top 1 percentile of patients identified by our model, the PPV was 1.0. In addition, for the top 5 percentile of patients identified by our model, the PPV was 0.71. All the results above were tested on the test data only, and the threshold used to obtain these results was 0.1. Notable features contributing to the model were chronic heart and ischemic heart disease as a comorbidity, patient age, and number of hypertensive crisis events., Conclusions: When a patient is approaching the threshold of ESRD risk, a warning message can be sent electronically to the physician, who will initiate a referral for a nephrology consultation to ensure an investigation to hasten the establishment of a diagnosis and initiate management and therapy when appropriate.

Background: Patient satisfaction with the quality of health care services is complex with many known factors impacting upon satisfaction, among them the choice of physician. Previous studies examined characteristics of a woman's choice of gynecologist, but information regarding reasons for these choices among women of Ethiopian descent is lacking. The objective of this study was to identify characteristics related preference of an obstetrician-gynecologist based on gender among women of Ethiopian descent., Method: Analysis of anonymous self-reported questionnaire distributed to 500 women of Ethiopian descent who visited an obstetrician-gynecologist at least once in the past three years (Mean age 29.5; SD = 8.2). Trust in physician was examined using the TPS scale; service quality was checked using the SERVQUAL; and the 5Qs model was used to measure patient's satisfaction of health care., Results: Very religious (84.1%) and religious (53.6%) women of Ethiopian descent were more likely to prefer a female obstetrician-gynecologist compared to traditional (39.3%) or secular (34.4%) women (p < 0.001). Participants had higher probability to prefer a male gynecologist if they had more employment hours (OR = 3.57, 95% CI = 1.72-7.42, p < 0.001), and the responsiveness of the physician was less important to them (OR = 0.77, 95% CI = 0.60-0.99, p < 0.05). Age of participants, country of birth, years in Israel, family status, being a mother, education or health status were not associated with choosing a female obstetrician-gynecologist. Religious women would prefer to wait longer for a female gynecologist due to modesty imperatives, even at the cost of compromising their health as a result of waiting longer., Conclusions: The findings of this research highlight the importance of accessibility to female obstetrician-gynecologists for women of Ethiopian descent and demonstrate that determinants in the host population rather than immigrant's past culture, affect the women's decision. This study demonstrates the importance of the health care system in Israel to enable more female obstetrician-gynecologists to treat women of Ethiopian descent., Competing Interests: The authors declare no conflict of interest.

Although dementia affects roughly 50 million people worldwide, its etiology is largely unknown. Recent studies have found a link between hypermagnesemia, hypomagnesemia, and increased risk of dementia. In this study, we explore the link between serum magnesium levels and the prevalence of dementia following the adoption of desalinated water (DSW) in Israel. DSW contains no magnesium, and relying on it for drinking water can lead to an increased incidence of hypomagnesia. Our objective was to analyze in a treat-control context how the switch to desalinated drinking water affected serum magnesium concentrations and the prevalence of dementia. We selected two cities which differed in terms of their access to underground aquifers but were otherwise similar. Rehovot has no underground water and uses over 90% DSW, whereas Kfar Saba relies almost entirely on its own aquifers. The cities are otherwise relatively similar in terms of their demographic composition. Using medical records for all subjects insured by the Maccabi Health Services in Rehovot (n = 23,991) and Kfar Saba (n = 20,541), we examined mean serum concentrations of Mg in the period prior to desalination (2001-2006) and post-desalination (2007-2018). Dementia prevalence is taken from 2007 to 2020 for the same coverage population. Serum magnesium levels were significantly lower in Rehovot following the switch to DSW (2.067 ± 0.21 pre-desalination and 2.059 ± 0.216 post-desalination, p < 0.01). In contrast, serum magnesium levels increased in Kfar Saba, which continued to rely on groundwater (2.008 ± 0.179 vs. 2.067 ± 0.206, p < 0.01). The prevalence of dementia was similar in the two cities (488/20,541, 2.37% in Rehovot and 613/23,991, 2.55% in Kfar Saba). In this ecological study, the adoption of DSW was associated with a significant decrease in serum magnesium concentrations. However, this change was not associated with a higher prevalence of dementia. While this association study cannot rule out some effect of hypomagnesemia on dementia morbidity, it suggests that the effect, if it exists, is relatively small.

Background: High magnesium intake has been associated with a decreased risk of dementia. In contrast, other research has found that both low and high serum magnesium levels were associated with an increased risk of Alzheimer's disease and mixed dementia. Hence, presently the role of magnesium levels in dementia is unclear., Objective: To investigate a possible association between serum magnesium concentrations and dementia in a large population-based sample., Methods: Maccabi Healthcare Service in Israel provides healthcare to over 2 million citizens. Maccabi maintains a registry with approximately 26,000 diagnosed dementia patients. We focused on patients of both sexes with Alzheimer's disease or mixed dementia aged 65 or older, excluding patients with clinical diagnoses that could affect serum magnesium level, or with other causes of cognitive decline. Our control group consisted of patients of the same age and sex without dementia., Results: No significant differences were found in mean, mode, and median magnesium levels between the dementia and control groups. However, there were marginally but significantly more cases with low magnesium levels among dementia patients than among controls: A total of 9.4% of tests done in patients with dementia and 7.81% done in non-dementia subjects were hypomagnesemic ( p  <  0.00001)., Conclusion: Despite similar means and medians of serum magnesium in dementia and controls, the proportion of lower than normal magnesium test results was slightly higher among dementia patients. It is possible that patients with dementia have more episodes of hypomagnesemia than controls, despite similar overall mean levels of magnesium., Competing Interests: The authors have no conflict of interest to report., (© 2020 – IOS Press and the authors. All rights reserved.)

Introduction: 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., Areas Covered: 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., Expert Opinion: 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.

Cardiac small conductance Ca 2+ -activated K + (SK) channels are activated solely by Ca 2+ , but the SK current (I SK ) is inwardly rectified. However, the impact of inward rectification in shaping action potentials (APs) in ventricular cardiomyocytes under β-adrenergic stimulation or in disease states remains undefined. Two processes underlie this inward rectification: an intrinsic rectification caused by an electrostatic energy barrier from positively charged amino acids at the inner pore and a voltage-dependent Ca 2+ /Mg 2+ block. Thus, Ca 2+ has a biphasic effect on I SK , activating at low [Ca 2+ ] yet inhibiting I SK at high [Ca 2+ ]. We examined the effect of I SK rectification on APs in rat cardiomyocytes by simultaneously recording whole-cell apamin-sensitive currents and Ca 2+ transients during an AP waveform and developed a computer model of SK channels with rectification features. The typical profile of I SK during AP clamp included an initial peak (mean 1.6 pA/pF) followed by decay to the point that submembrane [Ca 2+ ] reached ∼10 μM. During the rest of the AP stimulus, I SK either plateaued or gradually increased as the cell repolarized and submembrane [Ca 2+ ] decreased further. We used a six-state gating model combined with intrinsic and Ca 2+ /Mg 2+ -dependent rectification to simulate I SK and investigated the relative contributions of each type of rectification to AP shape. This SK channel model replicates key features of I SK recording during AP clamp showing that intrinsic rectification limits I SK at high V m during the early and plateau phase of APs. Furthermore, the initial rise of Ca 2+ transients activates, but higher [Ca 2+ ] blocks SK channels, yielding a transient outward-like I SK trajectory. During the decay phase of Ca 2+ , the Ca 2+ -dependent block is released, causing I SK to rise again and contribute to repolarization. Therefore, I SK is an important repolarizing current, and the rectification characteristics of an SK channel determine its impact on early, plateau, and repolarization phases of APs., (Copyright © 2020 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

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 I Kr ; LQT2), KCNE1 (KCNE1-G52R, decreased I Ks ; 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 I Kr -blocking (LQT5) or I K1 /I Ks -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 I Ks 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 (I Kr blockade in LQT5 and I K1 and I Ks 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., (© 2020 The British Pharmacological Society.)

Background: Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I NaL ) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs., Methods: We tested the effects of the selective I NaL blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca 2+ imaging, and computer modeling., Results: GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7/14 hearts in control versus 1/14 hearts at 100 nmol/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca 2+ -mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol/L, n=7/12 and 100 nmol/L n=8/12 hearts without EADs and PVTs). Confocal Ca 2+ imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca 2+ transient duration via accelerating Na + /Ca 2+ exchanger (I NCX )-mediated Ca 2+ efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I NaL potentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na + (Na i ) that decreases the depolarizing I NCX thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K + channels (I Ks ), suggesting important roles of I NaL in regulating Na i ., Conclusions: Selective I NaL blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na i . Graphic Abstract: A graphic abstract is available for this article.

Background: Diabetic (DM) inactivation of small conductance calcium-activated potassium (SK) channels contributes to coronary endothelial dysfunction. However, the mechanisms responsible for this down-regulation of endothelial SK channels are poorly understood. Thus, we hypothesized that the altered metabolic signaling in diabetes regulates endothelial SK channels and human coronary microvascular function., Methods: Human atrial tissue, coronary arterioles and coronary artery endothelial cells (HCAECs) obtained from DM and non-diabetic (ND) patients (n = 12/group) undergoing cardiac surgery were used to analyze metabolic alterations, endothelial SK channel function, coronary microvascular reactivity and SK gene/protein expression/localization., Results: The relaxation response of DM coronary arterioles to the selective SK channel activator SKA-31 and calcium ionophore A23187 was significantly decreased compared to that of ND arterioles (p < 0.05). Diabetes increases the level of NADH and the NADH/NAD + ratio in human myocardium and HCAECs (p < 0.05). Increase in intracellular NADH (100 μM) in the HCAECs caused a significant decrease in endothelial SK channel currents (p < 0.05), whereas, intracellular application of NAD + (500 μM) increased the endothelial SK channel currents (p < 0.05). Mitochondrial reactive oxygen species (mROS) of HCAECs and NADPH oxidase (NOX) and PKC protein expression in the human myocardium and coronary microvasculature were increased respectively (p < 0.05)., Conclusions: Diabetes is associated with metabolic changes in the human myocardium, coronary microvasculature and HCAECs. Endothelial SK channel function is regulated by the metabolite pyridine nucleotides, NADH and NAD + , suggesting that metabolic regulation of endothelial SK channels may contribute to coronary endothelial dysfunction in the DM patients with diabetes., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)