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Aim: To evaluate Corrected QT (QTc) interval prolongation (QTcP) in paediatric patients treated with voriconazole (VRC) and identify its associated risk factors in this setting.Methods: Clinical, VRC-related and QTc interval data were collected retrospectively from the electronic medical records of VRC-treated paediatric patients attending a large tertiary medical centre in 2011-2016 who underwent electrocardiography before and during therapy. Paired comparison of QTc intervals before and during VRC treatment was performed, adjusted for concurrent medications, electrolyte disturbances and co-morbidities.Results: Fifty-five patients (mean age 10.1 ± 5.4 years) met the inclusion criteria; 34 had an oncologic or hemato-oncologic diagnosis. Mean QTc interval was 402.8 ± 27.9 msec before VRC treatment and 440.0 ± 45.3 msec on treatment (p < 0.001). During treatment, 38 patients (61.8%) had QTcP ≥30 msec and 17 (30.9%), QTcP ≥60 msec; 10 patients (18.2%) had QTc ≥500 msec of whom one acquired torsades de pointes. On multivariate analysis, older age (p = 0.025), lower potassium level (p = 0.025) and longer baseline QTc (0.032) were associated QTcP ≥60 msec, but not daily or cumulative dose of VRC.Conclusion: This study demonstrated a high rate of clinically significant QTcP in VRC-treated children. Proper QTc monitoring, together with laboratory monitoring and electrolyte imbalance correction, is important to prevent cardiac arrhythmias in this patient population. [ABSTRACT FROM AUTHOR]

Background: Over the years, reports have associated fluoroquinolones (FQ) with seizures. The incidence and whether FQ compared to non-epileptogenic antibiotic are associated with increased risk of seizures has yet to be examined., Methods: A retrospective observational study of hospitalized patients treated with FQ (ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin) or macrolides (MA: azithromycin or roxithromycin) between January 2009 and January 2021 in a large tertiary academic medical centre. The outcome was the occurrence of a seizure during treatment. The Naranjo scale was used to assess causality between FQ treatment and seizures. Comparative analysis was conducted using propensity score matching to correct for possible bias due to non-random selection, followed by inverse probability weighting (IPW) to estimate the difference in seizure risk between FQ and MA., Results: Overall, 52 722 patients were treated with FQ during a total of 178 982 days. Mean age was 65 (±19) years and 47% were females. Thirty-three patients (0.06%) experienced a seizure, yielding an incidence of 1:5422 treatment days. Causality was deemed probable and possible among 9/33 and 24/33, respectively. The MA group composed of 8522 patients treated during 17 954 treatment days. Mean age was 65 (±21) years, 49% were females. Six (0.07%) patients experienced each a single seizure. IPW estimated OR for seizures among the FQ versus MA group was 1.44 (95%CI 0.59-3.5, P = 0.42)., Discussion: The incidence of FQ associated seizures among hospitalized patients is low and the risk did not significantly exceed that under macrolides. Our results provide evidence for clinicians and decision-makers when balancing fluoroquinolones risks and benefits., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: In Israel, coverage of health needs is delivered by four health maintenance organizations (HMOs), which are budgeted by the government according to the recommendations of the National Drug Formulary (NDF) Committee. For medications not listed in the NDF, individuals may request to cover the costs by the HMO Exemptions Committee (DEC). The objectives of the current study, a first of its kind, are to document the DEC decision process, to identify its components and to determine the decisions' clinical outcome., Methods: This retrospective cohort study included all members (≥ age 18) of the Maccabi Healthcare Service (MHS) who submitted a request to the DEC between June 2017 and December 2018. Collected data include patient demographics, clinical information and components of the decision process. Decision success (i.e., clinical outcome correlated with DEC decision) was determined by clinical outcome over at least one-year follow-up., Results: A total of 335 requests were included. Strong evidence and rare disease were positively associated with approvals, while the availability of alternative treatments and costs were negatively associated. The majority of decisions (75%) met predicted clinical outcomes. Only estimated costs were found to be associated with decision success., Conclusions: Factors that reduce the potential costs of a requested drug are significantly associated with higher odds for drug approval, but only when the evidence supports potential benefit., (© 2024. The Author(s).)

Background: In-utero phthalate exposure was shown to be associated with shortened anogenital distance (AGD) in male newborns, but findings among female are inconsistent. While phthalate exposure among pregnant women in Israel is widespread, no study has examined the association with offspring AGD. The objective of the current study was to investigate the association between maternal phthalates urinary concentration and offspring AGD at time of delivery among a birth cohort in Israel., Methods: We measured spot urinary concentration of monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) among women presenting to the delivery room at Shamir Medical Center in Israel. Birthweight, length and AGD were measured in all newborns using a standardized protocol. Each AGD measurement was adjusted to weight (ano-genital index). Confounders included socio-demographic characteristics, comorbidities and obstetrical history. Univariate and multivariate analyses assessed the associations between phthalates, confounders and AGD., Results: Overall, 193 mother and infant were analyzed. All newborns were born at term and had normal Apgar scores. Mean maternal age was 32 ± 4.7 years old. Mean birth weight and pregnancy week were 3183 ± 498 g and 39 ± 1.3, respectively. Median (IQR) urinary phthalate concentration adjusted to creatinine (ug/g) were 3.96 (2.2-6.6), 1.22 (0.7-2), 10.84 (7-20.4), 6.36 (3.3-11.2) and 0.64 (0.4-1.1) for MBP, MBzP, MECPP, MEHHP and MEOHP, respectively. Univariate comparison showed a significant association between higher than median MBzP concentration, higher Ano-Fourchetal index (AFI: 4.4 vs. 4.1, p = 0.037) and Ano-clitoral index (ACI: 11.5 vs. 10.4, p = 0.032) in infants. Total urinary phthalates concentration ≥26.25 μg/g was significantly associated with smaller penile width index (3.5 vs. 3.7, p = 0.022), higher ACI (11.6 vs. 10.3, p = 0.013) and a trend towards significance for higher AFI (4.3 vs. 4.1, p = 0.055). Following multivariate linear regression only PWI remained significantly associated with total phthalate urinary concentration., Conclusions: Maternal urinary phthalates concentration at delivery were not associated with female AGD, but total urinary phthalate concentration were inversely associated with penile width., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Matitiahu Berkovich reports financial support and equipment, drugs, or supplies were provided by Environment and Health Fund. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: Cidofovir (CDV), a nucleoside phosphonate analogue, exhibits activity against severe cytomegalovirus and adenoviral (ADV) infection. Nevertheless, reports of elevated nephrotoxicity rates limited its use to highly vulnerable cases, mainly immunocompromised children with fulminant infection. Limited data exists regarding CDV safety in immunocompetent children., Objective: To evaluate CDV-related toxicity, mainly nephrotoxicity, in immunocompetent children with severe ADV/cytomegalovirus infection., Methods: We conducted a retrospective review of medical records for all immunocompetent children under 18 years of age treated with intravenous CDV from January 2005 to December 2019., Results: Among the 23 patients identified, 21 were diagnosed with severe ADV infection. Median age was 15 months. Twenty-one (91%) children were admitted to the pediatric intensive care unit. Eighteen patients (78%) received standard CDV protocol (5 mg/kg CDV weekly for 2 weeks), 4 (17%) according to nephroprotective low-dose protocol and 1 patient transitioned. The median duration of CDV treatment was 14 days (range: 1-21 days). All patients received hyperhydration and probenecid with each infusion. Acute kidney injury was recorded in 1 patient (with concurrent septic shock) during CDV treatment. Two children exhibited acute kidney injury before CDV initiation, but renal function normalized during CDV treatment. One patient developed transient neutropenia (600 cells/L), apparently as a result of sepsis. No other major adverse effects were noted. Mortality rate was 3/23 (13%), unrelated to CDV toxicity., Conclusions: Our findings suggest that CDV-related nephrotoxicity rate in immunocompetent children may be lower than previously reported, perhaps lower than in the severely immunocompromised population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by vocal and motor tics and other comorbidities. Clinical recommendations for the use of medical cannabis are established, yet further guidance is needed. The aim of this study was to describe the experience of patients with TS with medical cannabis. Materials and Methods: TS patients were recruited from a registry of patients ("Tikun Olam" company). Questionnaires were answered before and after 6 months of treatment. Patients were divided into two groups: (A) patients who responded and (B) patients who did not respond to the follow-up questionnaire. In group A, an analysis was made to evaluate the presence and frequency of motor and vocal tics. The patients' general mood, employment status, quality of life, and comorbidities were also included in the analysis. Results: Seventy patients were identified. The tetrahydrocannabinol and cannabidiol mean daily dose was 123 and 50.5 mg, respectively. In group A, a statistically significant improvement was identified in quality of life ( p <0.005), employment status ( p =0.027), and in the reduction of the number of medications ( p <0.005). Sixty-seven percent and 89% of patients with obsessive-compulsive disorder and anxiety comorbidities, respectively, reported an improvement. No statistically significant improvement was identified in motor tics ( p =0.375), vocal tics ( p >0.999), tics frequency ( p =0.062), or general mood ( p =0.129). The most frequent adverse effects were dizziness ( n =4) and increased appetite ( n =3). Conclusion: Subjective reports from TS patients suggest that medical cannabis may improve their quality of life and comorbidities. More studies are needed to evaluate the efficacy and safety of medical cannabis. Registry in the MOH: https://www.moh.gov.sg/ (Trial number: 0185-19-ASF).

Previous studies have established a relationship between bacterial proteins and autoimmune diseases through several mechanisms. Infective endocarditis is known for its immunological phenomena, and the presence of antineutrophil cytoplasmic antibodies (ANCA) antibodies has been previously demonstrated in several infectious diseases. This retrospective, comparative, and descriptive study examined the relationship between infective endocarditis and the presence of ANCA antibodies. Ninety infective endocarditis cases were included in the study and tested for ANCA antibodies. The prevalence of ANCA positivity was determined, along with the differences in characteristics and prognosis between infective endocarditis patients with positive and negative serology for ANCA antibodies. The results showed that the characteristics of endocarditis patients who underwent ANCA serology testing were similar to those who did not, except for a higher prevalence of central line and chronic kidney disease in patients with ANCA serology (6.7% compared to 1.1% and 25.6% compared to 12.9%, respectively). Of the 90 endocarditis patients tested for ANCA serology, 18% were ANCA-positive, consistent with other prospective studies. There were no statistically significant differences in the primary outcome, six-month and one-year mortality, between patients with positive and negative ANCA serology. Similarly, in the secondary outcomes of acute kidney injury, heart surgery, and days of hospitalization, there were no statistically significant differences between patients with positive and negative ANCA serology. However, there were statistically significant differences in certain characteristics between the two groups. Patients with positive ANCA serology were found to have a higher prevalence of Enterococcus involvement (29.4% compared to 9.6% with P-value 0.046) and Q fever (23.5% compared to 4.1% P-value 0.02%). In contrast, patients with negative ANCA serology had a higher prevalence of fever (73% compared to 41% P-value 0.033)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ozeri et al.)

Background: Enteroviruses (EV) comprise the single most common cause of aseptic meningitis with variable geographical and temporal epidemiology. While EV-PCR in CSF is considered a gold standard for diagnosis, it is not-uncommon to use stool EV as a surrogate. Our aim was to assess the clinical significance of EV-PCR-positive CSF and stool in the investigation of patients with neurological symptoms., Methods: In this retrospective study from Sheba Medical centre, the largest tertiary hospital in Israel, we collected demographic, clinical and laboratory data of patients with EV-PCR-positive between 2016 and 2020. A comparison between various combinations of EV-PCR-positive CSF and stool was conducted. Data regarding EV strain-type and cycle threshold (Ct) were crossed with clinical symptoms and temporal kinetics., Results: Between 2016-2020, 448 CSF samples with positive EV-PCR were recorded from unique patients, the vast majority of which were diagnosed with meningitis (98%, 443/448). Unlike the diverse strain types of EV background activity, meningitis-related EV showed a clear epidemic pattern. In comparison with the EV CSF+/Stool+ group, the EV CSF-/Stool+ group had frequently more alternative pathogens detected and a higher stool Ct-value. Clinically, EV CSF-/Stool+ patients were less febrile and more lethargic and convulsive., Discussion: The comparison of the EV CSF+/Stool+ and CSF-/Stool+ groups suggests that putative diagnosis of EV meningitis is prudent in the febrile, non-lethargic non-convulsive patients with an EV-PCR-positive stool. Otherwise, the detection of stool EV only, in a non-epidemic setup, especially with a high Ct-value, may be incidental and mandate a continuous diagnostic effort for an alternative culprit., 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.)

Despite a favorable effect of imatinib on glucose metabolism in animal models, human reports are inconsistent. We retrospectively studied the long-term effect of imatinib on fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), LDL-cholesterol (LDL), and triglycerides (TGs) in a large HMO cohort of patients initiating therapy. In patients with diabetes ( n  = 118), significant reductions in HbA1c (0.53%, IQR 0.09, 1.19; p  < .001) and FPG (10.2 mg/dL, IQR -3.5, 32.2; p  < .001), independent of demographics and of glucose-lowering drugs utilization, were observed during the first year of imatinib treatment. Significant reductions in LDL (17.8 mg/dL, IQR -1.3, 34.0; p  < .001) and TG (25.0 mg/dL, IQR -2.3, 58.3; p  < .001), also independent of demographics and of statin utilization, were evident in the entire cohort ( n  = 611) during the first imatinib year. All reductions persisted during the second treatment year. To conclude, imatinib is associated with durable metabolic benefits, which may guide TKI choice in patients with cardiovascular co-morbidities.

Background: Polychlorinated biphenyls (PCBs) are persistent organic pollutants banned for use worldwide. Due to their biodegradation resistance, they accumulate along the food chain and in the environment. Maternal exposure to PCBs may affect the fetus and the infant. PCBs are immunotoxic and may damage the developing immune system. PCBs are associated with elevated IgE antibodies in cord blood and are considered to be predictive of atopic reactions. Several studies on the association between prenatal exposure to PCBs and atopic reactions were previously published, albeit with conflicting results. Objectives: To examine the association between maternal PCBs levels and atopic reactions in their offspring. Methods: During the years 2013-2015, a prospective birth cohort was recruited at the delivery rooms of Shamir Medical Center (Assaf Harofeh) and "Dana Dwek" Children's Hospital. Four PCBs congeners were investigated: PCBs 118, 138, 153, and 180. In 2019, when children reached the age of 4-6 years, mothers were interviewed using the ISAAC questionnaire to assess symptoms of atopic reactions, including asthma, allergic rhinitis, and atopic dermatitis. Results: One hundred and fifty mother-child dyads were analyzed. No significant differences were found in the median serum PCBs concentrations of each studied congener or total PCBs for asthma, allergic rhinitis, atopic dermatitis diagnosis, or parent-reported symptoms. No association was found between exposure to total PCBs and the risk for asthma symptoms or diagnosis, adjusted to maternal age and family member with atopic condition: aOR = 0.94, 95%CI: (0.88; 0.99). No association was observed between each studied PCB congener and asthma symptoms or diagnosis. The same results were found also for other studied outcomes-allergic rhinitis and atopic dermatitis. Conclusion: Our study joins a series of previous studies that attempt to shed light on environmental exposures in utero as influencing factors for atopic conditions in children. Our results reflect the complexity of the pathophysiology of these phenomena. No relationship between maternal serum PCBs levels was demonstrated for asthma, allergic rhinitis, or atopic dermatitis. However, additional multi-participant studies, with longer, spanning into later pediatric age follow up are needed., 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 Berlin, Flor-Hirsch, Kohn, Brik, Keidar, Livne, Marom, Ovental, Mandel, Lubetzky, Factor-Litvak, Tovbin, Betser, Moskovich, Hazan, Britzi, Gueta, Berkovitch, Matok and Hamiel.)

Importance: Lamotrigine use during breastfeeding has significantly increased in the recent years, whereas breast milk lamotrigine pharmacokinetics data are still sparse. Objectives: To assess lamotrigine exposure in breastfed infants by monitoring maternal serum and breast milk concentrations. Methods: Breastfeeding women treated with lamotrigine were recruited to this study. Maternal trough breast milk and serum samples were collected, and additional breast milk samples were collected 1, 3, 6, 9, 12 hours after lamotrigine consumption. Trough breast milk/serum ratios (M/S ratio) and breast milk area under the curve (AUC) values were calculated. Results: Twenty-one breastfeeding women were recruited to this study, and the final dataset was based on the samples collected from 17 women. Lamotrigine trough serum and mother's milk concentrations were 5.1 ± 3.3 mg/L and 3.1 ± 1.9 mg/L, respectively (mean ± standard deviation). The trough M/S ratio of lamotrigine was 0.66 ± 0.22. The lamotrigine breast milk average AUC was 41.7 ± 24.6 mg·h/L. The estimated infant dose of lamotrigine was 0.52 ± 0.31 mg/kg/day and 0.26 ± 0.15 mg/kg/day for fully and partially breastfed infants, respectively. Significant correlation was found between the maternal lamotrigine serum trough concentrations and the breast milk parameters: trough breast milk concentrations (Spearman's rho = 0.986, p  < 0.0001) and breast milk AUC values (Spearman's rho = 0.941, p  < 0.0001). No significant correlation was found between the maternal lamotrigine daily dose and serum trough concentrations, breast milk trough concentrations, and breast milk AUC values (Spearman's rho = 0.294, 0.285, and 0.438, p  = 0.252, 0.396, and 0.078, respectively). Conclusion and Relevance: High correlation between the maternal lamotrigine trough serum concentrations and the breast milk AUC values was found, implying that monitoring the maternal lamotrigine serum concentrations can be useful for prediction of exposure of infants to lamotrigine through the breast milk. The trial was registered in the Israeli trials registry MOH&#95;2021-09-05&#95;010243 at September 5, 2021 Retrospectively registered https://my.health.gov.il/CliniTrials.

Aims: Papaverine is indicated for abdominal pain of various aetiologies. However, data on maternal and foetal safety following gestational exposure are lacking. The aim was to examine whether first trimester exposure to papaverine is associated with increased risk for major malformation and whether gestational exposure at any stage is associated with increased risk for preterm delivery, lower birthweight, small for gestational age, caesarean section (CS), lower Apgar score and perinatal death., Methods: A retrospective comparative study consisted of pregnant women treated with papaverine between February 2010 and October 2019 at a large tertiary center. The control group comprised of livebirth deliveries randomly selected from the institutional obstetric database., Results: The study group consisted of 498 pregnancies, which resulted in 537/544 (98.7%) live births, of whom 46/537 (8.6%) were exposed during the first trimester. The control group consisted of 498 pregnancies and 514 live births. Rate of major malformations did not differ between study group (2/46, 4.3%) and control (25/315, 4.9%, P = .67). Papaverine exposure was associated with higher rate of preterm delivery (22.3 vs. 10.3%, P < .001), CS (35.9 vs. 24.1%, P < .001) and lower birth weight (3207 vs. 3246 g, P = .02). Adjustment for treatment indication demonstrated that these remained significant only when given for obstetrical/surgical aetiologies. Comparable rates were observed for the remaining outcomes., Conclusions: Short-term gestational exposure to papaverine adjusted for indication was not associated with preterm deliveries, CS, lower birthweight, small for gestational age or perinatal death. Rate of major malformations among 46 first trimester exposures was comparable to controls., (© 2021 British Pharmacological Society.)

Background: Caffeine citrate is the most frequently used medication in preterm neonates for the prevention of apnea of prematurity. There is no accepted consensus regarding the optimal caffeine citrate dosing. In this study, we evaluate clinical responses of premature neonates to standard-dose caffeine citrate treatment., Methods: A prospective observational study conducted at the NICU at Sheba Medical Center (3/2016-2/2017). The study population included preterm neonates born at a gestational age (GA) < 33 weeks and treated with caffeine citrate according to the local NICU protocol., Results: The study cohort included 66 preterm neonates of GA < 33 weeks. Thirty infants were defined as responders and 36 as nonresponders to 7.5 mg/kg caffeine citrate treatment, and they required a further dose increase to 10 mg/kg. Infants in the nonresponders group were born at earlier GA than responders (29 vs. 31 weeks, respectively, P = 0.004). The nonresponders required a significantly longer hospital stay (56 vs. 46 days, P = 0.014), and longer supplemental oxygen support (18 vs 2 days, P = 0.008)., Conclusions: Caffeine citrate initiation at higher doses is safe and does not require routine serum levels monitoring. It might be more effective for controlling apnea of prematurity in preterm neonates born ≤29 weeks of gestation., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: Primary spontaneous pneumothorax (PSP) commonly occurs in adolescents. PSP symptoms can mimic cardiac event. We aimed to examine electrocardiography (ECG) changes that accompanied PSP in relation to side and size of pneumothorax.A retrospectively reviewed 57 adolescents presented with PSP and underwent a cardiac evaluation.Overall, 49 patients (86%) were male, median age of 16 years. Of these, 1 patient had a known mitral valve prolapse. In 56 patients the initial episode of PSP was unilateral (16 left sided and 40 right sided), and 1 was bilateral. The main initial symptom was chest pain or dyspnea and chest pain 66.6% and 33.3% respectively. Small pneumothorax was right and left sided in 1and 8 patients respectively, medium right (n = 8) medium left (n = 22), large right (n = 7) and large left (n = 10). One additional patient had medium bilateral pneumothorax. ECG findings were abnormal in 12 patients (21%) and included ST elevation in 5 patients, inverted T wave in 2 patients, incomplete right bundle branch block in 2 patients, poor R wave progression, left axis deviation and low QRS voltage in 1 patient each. Only 2 patients had abnormal echocardiography findings, MPV (n = 1) and minimal mitral and tricuspid regurgitation (n = 1). Serum troponin-T levels were normal in all patients.ECG changes were found in 21% among pediatric patients with PSP. No correlation was observed between ECG changes and side/size of pneumothorax. It is important to rule out pneumothorax among children presented with chest pain, dyspnea and ECG changes., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: To determine whether oral potassium chloride (KCI) therapy with concomitant anticholinergic exposure among hospitalized patients is associated with an excess risk for upper gastrointestinal bleeding (UGIB)., Methods: A retrospective controlled study among hospitalized patients between January 2007 and April 2019 who were treated with oral KCI. Patients were divided into two groups: with or without concomitant exposure to agents with anticholinergic activity. Outcome was defined as any UGIB., Results: The final sample included 13 728 subjects who received oral KCI treatment, of them 3542 (25.8%) had at least one documented overlap with an anticholinergic agent. Mean age was 67.6 (±17.2) and 6893 (50.2%) were females. Median KCI dose was 2.4 g (interquartile range [IQR] 1.2-5.4, n = 9416) with the majority (90.4%) being treated with the wax-matrix form (Slow-K). Twenty-six (0.2%) patients experienced an UGIB event. Univariate analysis demonstrated a significantly higher rate of UGIB among patients concomitantly treated with oral KCI and anticholinergics (0.3%) compared to those without anticholinergic exposure (0.1%, P = 0.018), with median 7 days (IQR 3-16.8) from first KCI dose to bleeding event. Multivariate analysis demonstrated that concomitant anticholinergic exposure (Odds Ratio 2.48, 95% Confidence Interval 1.11-6.51, P = 0.022) and anticoagulation treatment among patients with hemato-oncologic disease (OR 6.61, 95% CI 1.96-22.25, P = 0.002) were significantly associated with UGIB., Conclusion: Hospitalized patients treated concomitantly with oral KCI and anticholinergic agents have significantly increased risk for UGIB., (© 2020 British Pharmacological Society.)

Background: Uninterrupted drug therapy during acute illness is often associated with pharmacokinetic and pharmacodynamic variations. Among warfarin treated patients, these changes are reflected in the INR. However, in the case of direct oral anticoagulants (DOACs), given that routine laboratory monitoring is not recommended, these changes may result in unforeseen thromboembolic or bleeding events., Objectives: To determine the rate of thromboembolic (TEE) and bleeding events associated with uninterrupted DOAC compared to warfarin treatment during acute illness., Methods: A retrospective cohort study of patients treated with DOACs or warfarin, both at steady state, who were hospitalized for acute illness. Primary outcome was any TEE or major bleeding requiring re-hospitalization within one month from discharge. Secondary outcome was a composite of major bleeding and clinically relevant non-major bleeding (CRNMB) events., Results: A total of 410 patients continued oral anticoagulant treatment during their hospitalization, of whom 191 (46.6%) were on DOACs and 219 (53.4%) on warfarin, with a total of 18 (4.4%) events. Rates of TEE and major bleeding events did not differ between DOACs and warfarin treated patients (0.9% vs. 0.5% and 0.5% vs. 1%, respectively). Similarly, rate of secondary outcome was comparable between DOACs (4.7%) and warfarin (2.7%, p = 0.29). Sub-analyses demonstrated significantly higher rates among rivaroxaban (10.4%) treated patients compared to warfarin (p = 0.03)., Conclusion: Uninterrupted treatment with DOACs during acute illness is not associated with increased risk for re-hospitalizations due to bleeding or thromboembolic events compared to warfarin. Our results suggest a higher bleeding rate among rivaroxaban treated patients at high bleeding risk., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pyroglutamic acid (PGA) is a compound that accumulates during oxidative stress and hence, elevated levels may be associated with poor prognosis in patients with infection or sepsis. To examine this hypothesis, patients presenting with acute infection were recruited in the emergency department and prospectively followed for 30 days. Sport urine samples were quantified for PGA. Outcomes were mortality and composite outcome of death or organ failure. Thirty two (32%) patients had qSOFA≥2. Median urine PGA was 22.9 (IQR 17.64, 33.53) µmol/mmol creatinine. Four patients demonstrated PGA values ≥ 63 µmol/mmol creatinine. Univariate analysis showed that PGA concentration ≥ 75 th percentile (i.e. 33.53 µmol/mmol creatinine) was associated with higher rates of in-hospital mortality (p = 0.041) with similar trend for PGA ≥ 63 µmol/mmol creatinine (p = 0.04). However, multivariate analysis showed that PGA was not associated with worse outcomes, whereas heart rate was associated with both composite outcomes (HR 1.0, p = 0.008 and HR 1.02, p = 0.001 for composite outcome with 30 days and in-hospital mortality, respectively). Among low risk patients, high PGA levels were consistently associated with worse outcomes. In conclusion, urine PGA concentration was not associated with worse outcomes among septic patients. Nevertheless, future studies should evaluate this association in larger cohorts.

Background: Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described., Methods: A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline., Results: A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae., Conclusion: In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made., (© 2019 Wiley Periodicals, Inc.)

Introduction: The tight regulation of the cytokine network during macrophage activation is of prime importance to enable a fast and potent innate immune response against exogenous pathogens. The inflammation mediating ubiquitin-like protein HLA-F adjacent transcript number 10 (FAT10) was shown to be transcriptionally regulated by and also regulate the nuclear factor-κB (NFκB) signaling pathway. However, very little is known about the regulation of FAT10 gene expression during macrophage activation., Results: RNA sequencing of interferon (IFN)γ-stimulated mouse peritoneal macrophages analyzed by ingenuity pathway analysis revealed significant involvement of tumor necrosis factor receptor 1 (TNFR1) signaling in addition to IFNγ signaling. Subsequently, IFNγ robustly upregulated FAT10 expression compared to a milder induction seen with TNFα or lipopolysaccharide (LPS) stimulation. While low dose IFNγ with TNFα synergistically elevated FAT10 expression, preincubation of macrophages with IFNγ strongly augmented TNFα-induced FAT10 expression. Moreover, a short preincubation with IFNγ, which did not elevate FAT10, was sufficient to potentiate the induction of FAT10 by TNFα. A double augmentation mechanism of TNFα signaling was demonstrated, where IFNγ rapidly induced the expression of TNFα and TNFR1, which further augmented the induction of TNFα and TNFR1 expression by TNFα. Importantly, the induction of FAT10 by IFNγ in macrophages from TNFα-deficient or TNFR1-deficient mice was completely inhibited compared to macrophages from wild type (WT) mice. Finally, we show that TNFα-induced FAT10 expression is dependent on NFκB signaling., Conclusion: IFNγ potentiates the TNFα/TNFR1 signaling pathway to induce FAT10 expression in mouse macrophages, mediated through NFκB network., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

5-oxoprolinemia (pyroglutamic acid, PGA) in the absence of acetaminophen use has been rarely reported as a cause for high anion gap metabolic acidosis. We investigated the prevalence and risk factors for elevated PGA concentrations among hospitalized patients with high anion gap metabolic acidosis: We prospectively enrolled patients with high anion gap metabolic acidosis hospitalized in the department of medicine. For each patient we collected the main diagnosis, concurrent medications and laboratory parameters. Spot urine samples were tested for PGA concentration. Levels ≥63 µmol/mmol creatinine were considered elevated. Overall, forty patients were prospectively followed. Mean age was 66.9 (17.9) years. Four (6.3%) patients had a high urine PGA level and demonstrated also lower blood pH (7.2 vs 7.3, p = 0.05) and lower serum lactate concentration (17.5 mg/dl vs 23.0 mg/dl, p = 0.04). Additionally, the high PGA level group consisted of more patients with septic shock [2/4 (50%) vs 3/36 (8.3%)] with a trend towards significance (p = 0.07). In conclusion, PGA might have a role in patients with septic shock and acidosis. Being a treatable condition, PGA should be taken into consideration particularly when no other cause for high anion gap is identified.

Background and Aims: Discontinuation of thiopurine analogues is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant. We aimed to determine drug elimination and immune re-constitution following thiopurine cessation., Methods: The elimination kinetics of 6-thioguanine nucleotides (6-TGN) were determined in nine inflammatory bowel disease [IBD] patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 [TSST1] or anti-CD3 [OKT3]-induced CD4+ T-cell proliferation, following an initial exposure to TSST1 and 6-mercaptopurine [6MP], separately or combined., Results: All patients discontinuing thiopurines displayed first-order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days [interquartile range 5.9-8.4]. Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent polyclonal or Vβ2+-preferential stimulation. By contrast, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vβ2+clonal response to further stimulation [p = 0.008], whereas overall response to further non-Vβ2-selective stimulation with OKT3 was unaltered [p = 0.9]., Conclusions: Upon 6MP/azathioprine discontinuation, a 6-TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.

Background: Adverse drug events (ADEs) are a major cause of morbidity and mortality worldwide. Hence, identifying and monitoring ADEs is of utmost importance. The Trigger Tool introduced by the Institute of Healthcare Improvement in the United States has been used in various countries worldwide, but has yet to be validated in Israel., Objectives: To validate the international Trigger Tool in Israel and to compare the results with those generated in various countries., Methods: A retrospective descriptive correlative analysis surveying four general hospitals in Israel from different geographical regions was conducted. Patient medical charts (n=960) were screened for 17 established triggers and confirmed for the presence of an ADE. Trigger incidence was compared to the actual ADE rate. Further comparison among countries was conducted using published literature describing Trigger Tool validation in various countries., Results: A total of 421 triggers in 279 hospitalizations were identified, of which 75 ADEs in 72 hospitalizations (7.5%) were confirmed. In addition, two ADEs were identified by chart review only. Mean positive predictive value was 17.81% and overall sensitivity was 97%. We found 1.54 ADEs for every 100 hospitalization days, 7.8 ADEs per 100 admissions, and 1.81 ADEs for every 1000 doses of medication. Of the 77 ADEs identified, 22.7% were defined as preventable., Conclusions: Our results support the Trigger Tool validity in Israel as a standardized method. Further studies should evaluate between hospital and region differences in ADE rate, in particular for the preventable events.

Competing Interests: Competing interests: None declared.

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Elderly patients are exposed to increased number of medications, often with no proof of a positive benefit/risk ratio. Unfortunately, this trend does not spare those with limited life expectancy, including end-stage cancer patients who require only palliative treatment. For many medications in this subpopulation, the risk of adverse drug events outweighs the possible benefits and yet, many are still poly-medicated during their last year of life., Aim: To describe the extent of polypharmacy among end-stage cancer patients, at the time of admission to homecare hospice., Methods: A retrospective chart review of 202 patients admitted to Homecare Hospice of the Israel Cancer Association and died before January 2015., Results: Average lifespan from admission until death was 39.2 ± 5.4 days. 63% died within the first month, 89% within 3 months. Excluding oncological treatments, 181 (90%) and 46 (23%) patients were treated with ≥ 6 and ≥ 12 drugs for chronic diseases, respectively. Two months before death, 32 (16%) patients were treated with ≥ 3 blood pressure lowering drugs, 62 (31%) with statins and 48 (23%) with aspirin., Conclusion: Though not representative of the whole end-stage cancer patient population, our study demonstrates that these patients are exposed to extensive polypharmacy. Most of these medications could have probably been safely de-prescribed much earlier in the course of the malignant disease. Considering the prolonged trust-based relationship with their patients, the family physicians are those who should be encouraged to implement the palliative approach and reduce polypharmacy much before reaching hospice settings., (© 2018 John Wiley & Sons Ltd.)

We describe herein a 61-year-old woman who presented with fever, night sweats and cough. The diagnosis of pneumonia was established, but with symptom recurrence following antibiotic therapy, further diagnostics were performed. Biopsy via bronchoscopy revealed cryptogenic organizing pneumonia, and later on follow-up, a selective IgG immune deficiency was also diagnosed. Initial treatment of high-dose glucocorticoid therapy induced remission, but with dose reduction recurrence was observed. Intravenous immune globulin treatment was initiated and induced a successful clinical and radiological remission. Few cases of cryptogenic organizing pneumonia and hypogammaglobulinemia have been reported. To our knowledge, this is the fourth case described of cryptogenic organizing pneumonia with a hypogammaglobulinemia state and the first reported case of a selective immune deficiency state treated successfully with intravenous immune globulins.

The authors review a case of an Indian tourist couple both presenting a clinical picture of intermittent fever, thrombocytopenia and relative leukopenia several days after their arrival to israel. The diagnosis of Plasmodium vivax (P.vivax) malaria was established in both patients and antimalarial treatment with chloroquine was initiated. Shortly after initiating the treatment, the husband developed clinical acute respiratory distress syndrome (ARDS). With symptomatic treatment, the patient recovered within few days. The diagnosis of P. vivax was confirmed by PCR, and was shown to be a single infection with no Plasmodium falciparum as co-infection. Although P. vivax is considered as having a benign course, in contrast to P. falciparum infections, in recent years there have been an increased number of reports of complicated P. vivax malaria, mainly ARDS. Physicians should be aware of the possible complicated course of P. vivax malaria.

Cancer-related cachexia and anorexia are present in more than 80% of patients with malignancies. The pathophysiology is not fully known and during the past several years major attention was attributed to the function of secreted cytokines, such as TNF-alpha, as a fundamental part of the process. In the attempt to prevent the weight loss, which in many cases causes the patients' death, many studies have been conducted where the effect of the cytokine TNF-alpha was blocked. This article presents two different studies from the past several years where the effect was inhibited by two different methods: one by the monoclonal antibody Infliximab and the other by blocking the TNF-alpha receptor with Etanercept. Both were double-blinded and the patients were randomly divided into arms, with the control group treated with placebo. In both groups, primary and secondary outcomes were defined, however, in the end, no statistical significance was achieved. In conclusion, cancer-related cachexia and anorexia are not the result of one cytokine by itself and blocking it causes only a minimal change without any statistical significance in cancer patients. It is reasonable to assume that the body adaptation to the tumor, which results in cachexia, is due to several mediators working together rather than a single major mediator.