Publications by authors named "Ilan Youngster"

66 Publications

Presence of SARS-CoV-2 RNA on playground surfaces and water fountains.

Epidemiol Infect 2021 03 8;149:e67. Epub 2021 Mar 8.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The possibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission by fomites or environmental surfaces has been suggested. It is unclear if SARS-CoV-2 can be detected in outdoor public areas. The objective of the current study was to assess the presence of SARS-CoV-2 in environmental samples collected at public playgrounds and water fountains, in a country with high disease prevalence. Environmental samples were collected from six cities in central Israel. Samples were collected from drinking fountains and high-touch recreational equipment at playgrounds. Sterile pre-moistened swabs were used to collect the samples, put in viral transfer media and transferred to the laboratory. Viral detection was achieved by real-time reverse transcriptase-polymerase chain reaction, targeting four genes. Forty-three samples were collected from playground equipment and 25 samples from water fountains. Two of the 43 (4.6%) samples from playground equipment and one (4%) sample from a drinking fountain tested positive. It is unclear whether the recovery of viral RNA on outdoor surfaces also indicates the possibility of acquiring the virus. Adherence to environmental and personal hygiene in urban settings seems prudent.
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http://dx.doi.org/10.1017/S0950268821000546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985893PMC
March 2021

Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial.

Gut 2021 Jan 18. Epub 2021 Jan 18.

Department of Public Health, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Objective: To examine the effectiveness of green-Mediterranean (MED) diet, further restricted in red/processed meat, and enriched with green plants and polyphenols on non-alcoholic fatty liver disease (NAFLD), reflected by intrahepatic fat (IHF) loss.

Design: For the DIRECT-PLUS 18-month randomized clinical trial, we assigned 294 participants with abdominal obesity/dyslipidaemia into healthy dietary guidelines (HDG), MED and green-MED weight-loss diet groups, all accompanied by physical activity. Both isocaloric MED groups consumed 28 g/day walnuts (+440 mg/day polyphenols provided). The green-MED group further consumed green tea (3-4 cups/day) and Mankai (a aquatic plant strain; 100 g/day frozen cubes) green shake (+1240 mg/day total polyphenols provided). IHF% 18-month changes were quantified continuously by proton magnetic resonance spectroscopy (MRS).

Results: Participants (age=51 years; 88% men; body mass index=31.3 kg/m; median IHF%=6.6%; mean=10.2%; 62% with NAFLD) had 89.8% 18-month retention-rate, and 78% had eligible follow-up MRS. Overall, NAFLD prevalence declined to: 54.8% (HDG), 47.9% (MED) and 31.5% (green-MED), p=0.012 between groups. Despite similar moderate weight-loss in both MED groups, green-MED group achieved almost double IHF% loss (-38.9% proportionally), as compared with MED (-19.6% proportionally; p=0.035 weight loss adjusted) and HDG (-12.2% proportionally; p<0.001). After 18 months, both MED groups had significantly higher total plasma polyphenol levels versus HDG, with higher detection of and 2-5-dihydroxybenzoic-acid in green-MED. Greater IHF% loss was independently associated with increased Mankai and walnuts intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, changes in microbiome composition (beta-diversity) and specific bacteria (p<0.05 for all).

Conclusion: The new suggested strategy of green-Mediterranean diet, amplified with green plant-based proteins/polyphenols as Mankai, green tea, and walnuts, and restricted in red/processed meat can double IHF loss than other healthy nutritional strategies and reduce NAFLD in half.

Trial Registration Number: NCT03020186.
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http://dx.doi.org/10.1136/gutjnl-2020-323106DOI Listing
January 2021

The prevalence and underreporting of needlestick injuries among hospital workers: a cross-sectional study.

Int J Qual Health Care 2021 Feb;33(1)

Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

Objective: Needlestick and sharps injuries (NSIs) are known occupational risks among health-care workers. Reporting these injuries is important for early prevention and management of blood-borne infections. We investigated the prevalence and characteristics of NSIs and underreporting among hospital workers (HWs) from different sectors.

Methods: A single-center cross-sectional study, involving an anonymous survey delivered to 2205 HWs. The survey included demographic information about the worker and information about training, injuries and reporting.

Results: Of the 844 HWs respondents (40%), NSIs occurred in 443 of them (53%); the majority were from needles (68%) and at bedside (51%). Significantly higher prevalences of injuries (P < 0.001) were noted among physicians (75%) and workers in their 40s (61%) and in the emergency and surgical departments (66% and 55%, respectively). NSIs were reported among 28% of workers who did not directly use needles. Underreporting was found in 46%, with a significant decrease in the report rate as the number of injuries increased (P < 0.001). Underreporting was significantly more common (P < 0.001) among physicians (59%), especially seniors (72%), workers without training about NSIs (59%), older age groups (56% in workers above 51 years, P = 0.003) and males (54%, P = 0.01). The highest underreporting rate was in injuries occurring in the operating room and the lowest in witnessed injuries occurring while passing a needle (82% vs. 31%, P < 0.001).

Conclusions: NSIs and underreporting are common among HWs from all sectors, including those who do not use needles. Improving preventive measures and reporting should be encouraged. We recommend reducing bedside procedures as possible and assigning two workers to procedures at risk for injuries, to increase the report rate.
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http://dx.doi.org/10.1093/intqhc/mzab009DOI Listing
February 2021

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.

Science 2021 02 10;371(6529):602-609. Epub 2020 Dec 10.

School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
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http://dx.doi.org/10.1126/science.abb5920DOI Listing
February 2021

Fever response to ibuprofen in viral and bacterial childhood infections.

Am J Emerg Med 2020 Nov 21. Epub 2020 Nov 21.

Pediatric Infectious Diseases Unit and the Center for Microbiome Research, Shamir Medical Center, Zerifin 70300, Israel; The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

Objective: to compare the antipyretic effects of ibuprofen in febrile children with serious bacterial infections (SBI), and children with a presumed viral infection.

Methods: A prospective cross- sectional study was conducted in a pediatric Emergency department between October 2018 and March 2020 for children aged 3 months to 4 years with a rectal temperature ≥ 38.5 °C. Patients received 10 mg/kg of ibuprofen oral suspension. Rectal temperature was measured 60 and 120 min after administration. Laboratory and imaging evaluations were performed for each study participant in order to identify serious bacterial infection.

Results: Ninety patients were included, of which 18 were diagnosed with serious bacterial infections. There was no significant difference in age, fever at presentation and duration of fever between the groups. No significant difference was noted in body temperature reduction at 60 and 120 min after ibuprofen administration (1.09 ± 0.75 °C vs 0.89 ± 0.58 °C, mean difference -0.12 °C, 95% CI -0.54-0.15 °C; 1.85 ± 0.53 °C vs 1.78 ± 0.83 °C, mean difference - 0.07 °C, 95% CI -0.49-0.36 °C, in the SBI and non-SBI groups respectively).

Conclusion: Fever response to Ibuprofen administration is not indicative of serious bacterial infections in children under 4 years of age. Larger prospective studies are required to define whether the lack of response to Ibuprofen has any impact on the management of febrile children.
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http://dx.doi.org/10.1016/j.ajem.2020.11.036DOI Listing
November 2020

The effect of green Mediterranean diet on cardiometabolic risk; a randomised controlled trial.

Heart 2020 Nov 23. Epub 2020 Nov 23.

Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

Background: A Mediterranean diet is favourable for cardiometabolic risk.

Objective: To examine the residual effect of a green Mediterranean diet, further enriched with green plant-based foods and lower meat intake, on cardiometabolic risk.

Methods: For the DIRECT-PLUS parallel, randomised clinical trial we assigned individuals with abdominal obesity/dyslipidaemia 1:1:1 into three diet groups: healthy dietary guidance (HDG), Mediterranean and green Mediterranean diet, all combined with physical activity. The Mediterranean diets were equally energy restricted and included 28 g/day walnuts. The green Mediterranean diet further included green tea (3-4 cups/day) and a (Mankai strain; 100 g/day frozen cubes) plant-based protein shake, which partially substituted animal protein. We examined the effect of the 6-month dietary induction weight loss phase on cardiometabolic state.

Results: Participants (n=294; age 51 years; body mass index 31.3 kg/m; waist circumference 109.7 cm; 88% men; 10 year Framingham risk score 4.7%) had a 6-month retention rate of 98.3%. Both Mediterranean diets achieved similar weight loss ((green Mediterranean -6.2 kg; Mediterranean -5.4 kg) vs the HDG group -1.5 kg; p<0.001), but the green Mediterranean group had a greater reduction in waist circumference (-8.6 cm) than the Mediterranean (-6.8 cm; p=0.033) and HDG (-4.3 cm; p<0.001) groups. Stratification by gender showed that these differences were significant only among men. Within 6 months the green Mediterranean group achieved greater decrease in low-density lipoprotein cholesterol (LDL-C; green Mediterranean -6.1 mg/dL (-3.7%), -2.3 (-0.8%), HDG -0.2 mg/dL (+1.8%); p=0.012 between extreme groups), diastolic blood pressure (green Mediterranean -7.2 mm Hg, Mediterranean -5.2 mm Hg, HDG -3.4 mm Hg; p=0.005 between extreme groups), and homeostatic model assessment for insulin resistance (green Mediterranean -0.77, Mediterranean -0.46, HDG -0.27; p=0.020 between extreme groups). The LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio decline was greater in the green Mediterranean group (-0.38) than in the Mediterranean (-0.21; p=0.021) and HDG (-0.14; p<0.001) groups. High-sensitivity C-reactive protein reduction was greater in the green Mediterranean group (-0.52 mg/L) than in the Mediterranean (-0.24 mg/L; p=0.023) and HDG (-0.15 mg/L; p=0.044) groups. The green Mediterranean group achieved a better improvement (-3.7% absolute risk reduction) in the 10-year Framingham Risk Score (Mediterranean-2.3%; p0.073, HDG-1.4%; p<0.001).

Conclusions: The green MED diet, supplemented with walnuts, green tea and Mankai and lower in meat/poultry, may amplify the beneficial cardiometabolic effects of Mediterranean diet.

Trial Registration Number: This study is registered under ClinicalTrials.gov Identifier no NCT03020186.
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http://dx.doi.org/10.1136/heartjnl-2020-317802DOI Listing
November 2020

Children discharged from an emergency department with bacteraemia had lower C-reactive protein and better outcomes than admissions.

Acta Paediatr 2020 Oct 30. Epub 2020 Oct 30.

Pediatric Emergency Unit, Shamir Medical Center, Zerifin, Israel.

Aim: To investigate whether there are common clinical findings in bacteraemic children that were discharged from the emergency department (ED) and to follow their clinical outcome.

Methods: A retrospective chart review of children above one-month-old with positive blood cultures obtained in Shamir Medical Center's ED between January 2011 and December 2019 was conducted.

Results: A total of 250 cases were analysed, of which 68 discharged after first evaluation. Streptococcus pneumonia was the most commonly isolated pathogen. Compared to children that were admitted when first evaluated in the ED, discharged children had lower C-reactive protein (mean 50.5 ± 62.8 vs 121.7 ± 113.2 mg/L, p < 0.001). Dyspnoea and being ill-looking were less prevalent among the latter (6.7% versus 35.1%, p = <0.001, 3.0% versus 22.2% p < 0.001, respectively), as were presence of Kingella kingae and other Gram-negative bacteria. Of the children hospitalised in our institution, the duration of hospitalisation was significantly lower than in those admitted during the first visit (6.3 ± 4.3 vs 9.0 ± 7.4 days, p = .002). None of the discharged children were admitted to paediatric intensive care unit.

Conclusion: Children with bacteraemia who were discharged home before knowing their positive blood cultures results had lower C-reactive protein and better outcome compared to those admitted on first evaluation in emergency department.
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http://dx.doi.org/10.1111/apa.15645DOI Listing
October 2020

Microbial signature in IgE-mediated food allergies.

Genome Med 2020 10 27;12(1):92. Epub 2020 Oct 27.

The Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.

Background: Multiple studies suggest a key role for gut microbiota in IgE-mediated food allergy (FA) development, but to date, none has studied it in the persistent state.

Methods: To characterize the gut microbiota composition and short-chain fatty acid (SCFAs) profiles associated with major food allergy groups, we recruited 233 patients with FA including milk (N = 66), sesame (N = 38), peanut (N = 71), and tree nuts (N = 58), and non-allergic controls (N = 58). DNA was isolated from fecal samples, and 16S rRNA gene sequences were analyzed. SCFAs in stool were analyzed from patients with a single allergy (N = 84) and controls (N = 31).

Results: The gut microbiota composition of allergic patients was significantly different compared to age-matched controls both in α-diversity and β-diversity. Distinct microbial signatures were noted for FA to different foods. Prevotella copri (P. copri) was the most overrepresented species in non-allergic controls. SCFAs levels were significantly higher in the non-allergic compared to the FA groups, whereas P. copri significantly correlated with all three SCFAs. We used these microbial differences to distinguish between FA patients and non-allergic healthy controls with an area under the curve of 0.90, and for the classification of FA patients according to their FA types using a supervised learning algorithm. Bacteroides and P. copri were identified as taxa potentially contributing to KEGG acetate-related pathways enriched in non-allergic compared to FA. In addition, overall pathway dissimilarities were found among different FAs.

Conclusions: Our results demonstrate a link between IgE-mediated FA and the composition and metabolic activity of the gut microbiota.
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http://dx.doi.org/10.1186/s13073-020-00789-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592384PMC
October 2020

Another step in the journey - from feces to regulated microbial therapeutics.

Authors:
Ilan Youngster

Clin Infect Dis 2020 Sep 22. Epub 2020 Sep 22.

Pediatric Infectious Diseases Unit, Shamir (Assaf Harofeh) Medical Center, Zerifin, Israel.

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http://dx.doi.org/10.1093/cid/ciaa1435DOI Listing
September 2020

Maternal vaccinations coverage and reasons for non-compliance - a cross-sectional observational study.

BMC Pregnancy Childbirth 2020 Sep 16;20(1):541. Epub 2020 Sep 16.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Maternal influenza and pertussis vaccinations have been proven safe and effective in reducing maternal and infant morbidity and mortality. Though recommended, not all pregnant women receive these important vaccines. We aimed to evaluate the vaccine coverage of maternal immunization in pregnancy for seasonal influenza and acellular pertussis and elucidate the reasons for non-vaccination among pregnant women. The secondary objective was to describe factors that affect vaccine uptake.

Methods: A cross sectional observational study using anonymous questionnaires distributed to women in the maternity ward or pregnant women hospitalized in the high-risk ward, between Nov 2017 and June 2018, In an Israeli tertiary hospital.

Results: Of 321 women approached, 313 were eligible, with a total of 290 women completing the questionnaire (92.6%). We found a 75.9% (95% CI 71-81) and 34.5% (95% CI 29-40) vaccination rate for pertussis and influenza vaccines, respectively. The most prominent reason for not receiving the pertussis vaccine was being under-informed (24%). Influenza vaccine was not received mainly due to concerns about vaccine efficacy (28%). Other factors influencing vaccine uptake included education, prior childbirth and vaccine recommendations made by the provider.

Conclusion: Although maternal vaccination of pertussis and influenza is officially recommended, vaccine uptake is suboptimal. Our study suggests a central role for medical providers in diminishing the concerns about safety and efficacy, and presents novel factors influencing compliance rates, like seasonality and number of prior births.
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http://dx.doi.org/10.1186/s12884-020-03243-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493363PMC
September 2020

Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain.

Gastroenterology 2021 Jan 26;160(1):158-173.e10. Epub 2020 Aug 26.

Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Harvard T.H. Chan School of Public Health, Cambridge, Massachusetts. Electronic address:

Background & Aims: We evaluated the efficacy and safety of diet-modulated autologous fecal microbiota transplantation (aFMT) for treatment of weight regain after the weight-loss phase.

Methods: In the DIRECT PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols-Unprocessed) weight-loss trial (May 2017 through July 2018), abdominally obese or dyslipidemic participants in Israel were randomly assigned to healthy dietary guidelines, Mediterranean diet, and green-Mediterranean diet weight-loss groups. All groups received free gym membership and physical activity guidelines. Both isocaloric Mediterranean groups consumed 28 g/d walnuts (+440 mg/d polyphenols provided). The green-Mediterranean dieters also consumed green tea (3-4 cups/d) and a Wolffia globosa (Mankai strain, 100 g/d) green shake (+800 mg/d polyphenols provided). After 6 months (weight-loss phase), 90 eligible participants (mean age, 52 years; mean weight loss, 8.3 kg) provided a fecal sample that was processed into aFMT by frozen, opaque, and odorless capsules. The participants were then randomly assigned to groups that received 100 capsules containing their own fecal microbiota or placebo until month 14. The primary outcome was regain of the lost weight over the expected weight-regain phase (months 6-14). Secondary outcomes were gastrointestinal symptoms, waist circumference, glycemic status, and changes in the gut microbiome, as measured by metagenomic sequencing and 16s ribosomal RNA. We validated the results in a parallel in vivo study of mice specifically fed with Mankai compared with control chow diet.

Results: Of the 90 participants in the aFMT trial, 96% ingested at least 80 of 100 oral aFMT or placebo frozen capsules during the transplantation period. No aFMT-related adverse events or symptoms were observed. For the primary outcome, although no significant differences in weight regain were observed among the participants in the different lifestyle interventions during months 6-14 (aFMT, 30.4% vs placebo, 40.6%; P = .28), aFMT significantly attenuated weight regain in the green-Mediterranean group (aFMT, 17.1%, vs placebo, 50%; P = .02), but not in the dietary guidelines (P = .57) or Mediterranean diet (P = .64) groups (P for the interaction = .03). Accordingly, aFMT attenuated waist circumference gain (aFMT, 1.89 cm vs placebo, 5.05 cm; P = .01) and insulin rebound (aFMT, -1.46 ± 3.6 μIU/mL vs placebo, 1.64 ± 4.7 μIU/mL; P = .04) in the green-Mediterranean group but not in the dietary guidelines or Mediterranean diet (P for the interaction = .04 and .03, respectively). The green-Mediterranean diet was the only intervention to induce a significant change in microbiome composition during the weight-loss phase, and to prompt preservation of weight-loss-associated specific bacteria and microbial metabolic pathways (mainly microbial sugar transport) after the aFMT. In mice, Mankai-modulated aFMT in the weight-loss phase compared with control diet aFMT, significantly prevented weight regain and resulted in better glucose tolerance during a high-fat diet-induced regain phase (all, P < .05).

Conclusions: Autologous FMT, collected during the weight-loss phase and administrated in the regain phase, might preserve weight loss and glycemic control, and is associated with specific microbiome signatures. A high-polyphenols, green plant-based or Mankai diet better optimizes the microbiome for an aFMT procedure. ClinicalTrials.gov number, NCT03020186.
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http://dx.doi.org/10.1053/j.gastro.2020.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755729PMC
January 2021

SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults.

JAMA 2020 Jun;323(22):2340-2341

The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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http://dx.doi.org/10.1001/jama.2020.8189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221856PMC
June 2020

Understanding Newborn Hepatitis B Immunization Refusal: One Size Does Not Fit All.

Isr Med Assoc J 2020 Mar;22(3):191-192

Pediatric Infectious Diseases Unit and the Center for Microbiome Research, Shamir Medical Center (Assaf Harofeh), Zerifin, Israel.

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March 2020

The genome of opportunistic fungal pathogen Fusarium oxysporum carries a unique set of lineage-specific chromosomes.

Commun Biol 2020 01 31;3(1):50. Epub 2020 Jan 31.

Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, 01003, USA.

Fusarium oxysporum is a cross-kingdom fungal pathogen that infects plants and humans. Horizontally transferred lineage-specific (LS) chromosomes were reported to determine host-specific pathogenicity among phytopathogenic F. oxysporum. However, the existence and functional importance of LS chromosomes among human pathogenic isolates are unknown. Here we report four unique LS chromosomes in a human pathogenic strain NRRL 32931, isolated from a leukemia patient. These LS chromosomes were devoid of housekeeping genes, but were significantly enriched in genes encoding metal ion transporters and cation transporters. Homologs of NRRL 32931 LS genes, including a homolog of ceruloplasmin and the genes that contribute to the expansion of the alkaline pH-responsive transcription factor PacC/Rim1p, were also present in the genome of NRRL 47514, a strain associated with Fusarium keratitis outbreak. This study provides the first evidence, to our knowledge, for genomic compartmentalization in two human pathogenic fungal genomes and suggests an important role of LS chromosomes in niche adaptation.
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http://dx.doi.org/10.1038/s42003-020-0770-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994591PMC
January 2020

Potential impact of removing metronidazole from treatment armamentarium of mild acute infection.

Future Microbiol 2019 11 8;14:1489-1495. Epub 2020 Jan 8.

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Recent guidelines recommended removing metronidazole as a therapeutic option for infections (CDI). However, superiority of vancomycin over metronidazole in mild CDI is not established and use of vancomycin might lead to emergence of vancomycin-resistant enterococci (VRE). A retrospective cohort study and efficacy analyses were conducted at Shamir Medical Center, Israel (2010-2015), among adults with acute CDI.  A total of 409 patients were enrolled. In multivariable analyses, metronidazole was noninferior to vancomycin for mild CDI, but vancomycin was an independent predictor for post-CDI VRE acquisition. A significant independent association was evident between treatment with vancomycin and, later, acquisition of VRE. In first episodes of mild acute CDI, metronidazole should be considered a valid therapeutic option.
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http://dx.doi.org/10.2217/fmb-2019-0157DOI Listing
November 2019

Nationwide epidemiology of early-onset sepsis in Israel 2010-2015, time to re-evaluate empiric treatment.

Acta Paediatr 2019 12 4;108(12):2192-2198. Epub 2019 Aug 4.

Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Aim: Early-onset neonatal sepsis (EOS) may lead to significant morbidity and mortality, yet the recommended antimicrobials have not changed for many years. We aimed to optimise EOS treatment by examining EOS pathogens, resistance rates and resistance risk factors.

Methods: A retrospective, nationwide cohort study analysing 2010-2015 EOS data in Israel.

Results: The 21 participating centres constitute 92% of the total birth cohort (around 180 000 live births/year). Of 549 EOS neonates (0.57/1000 live births), 306 (56%) and 243 (44%) were full-term and preterm, respectively (0.35 vs. 2.94 per/1000 live births). Gram-negative pathogens predominated, especially in preterms. Escherichia coli and Streptococcus agalactiae were most common pathogens (0.2 and 0.19 per 1000 live births, respectively). In 277 Gram-negatives, 16%, 14%, 8% and 3% were gentamicin-resistant, extended-spectrum beta-lactamase (ESBL)-positive, gentamicin-resistant and ESBL-positive, and amikacin-resistant, respectively; preterms had higher resistance rates. No risk factors for antimicrobial resistance were identified. Mortality was reported in 21% of Gram-negative EOS versus 7% of Gram-positive EOS [OR 3.4 (95% CI 1.8-6.2), p < 0.01].

Conclusion: In this nationwide study, EOS was caused predominantly by Gram-negatives, with high gentamicin resistance and ESBL phenotype rates, without identifiable resistance risk factors. As EOS is life-threatening, modification of empiric therapy for amikacin-based regimens should be considered, mainly in preterms.
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http://dx.doi.org/10.1111/apa.14889DOI Listing
December 2019

A Green-Mediterranean Diet, Supplemented with Mankai Duckweed, Preserves Iron-Homeostasis in Humans and Is Efficient in Reversal of Anemia in Rats.

J Nutr 2019 06;149(6):1004-1011

Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Background: Decreased dietary meat may deplete iron stores, as plant-derived iron bioavailability is typically limited.

Objectives: We explored the effect of a low-meat Mediterranean (green-MED) diet, supplemented with Wolffia globosa duckweed (Mankai: rich in protein and iron) as a food source for humans, on iron status. We further examined the iron bioavailability of Mankai in rats.

Methods: Two hundred and ninety-four abdominally obese/dyslipidemic [mean age = 51.1 y; body mass index (kg/m2) = 31.3; 88% men] nonanemic participants were randomly assigned to physical activity (PA), PA + MED diet, or PA + green-MED diet. Both isocaloric MED groups consumed 28 g walnuts/d and the low-meat green-MED group further consumed green tea (800 mL/d) and Mankai (100 g green shake/d). In a complementary animal experiment, after 44 d of an iron deficiency anemia-inducing diet, 50 female rats (age = 3 wk; Sprague Dawley strain) were randomly assigned into: iron-deficient diet (vehicle), or vehicle + iso-iron: ferrous gluconate (FG) 14, Mankai 50, and Mankai 80 versions (1.7 mg · kg-1 · d-1 elemental iron), or FG9.5 and Mankai 50-C version (1.15 mg · kg-1 · d-1 elemental iron). The specific primary aim for both studies was changes in iron homeostasis parameters.

Results: After 6 mo of intervention, iron status trajectory did not differ between the PA and PA + MED groups. Hemoglobin modestly increased in the PA + green-MED group (0.23 g/dL) compared with PA (-0.1 g/dL; P < 0.001) and PA + MED (-0.1 g/dL; P < 0.001). Serum iron and serum transferrin saturation increased in the PA + green-MED group compared with the PA group (8.21 μg/dL compared with -5.23 μg/dL and 2.39% compared with -1.15%, respectively; P < 0.05 for both comparisons), as did folic acid (P = 0.011). In rats, hemoglobin decreased from 15.7 to 9.4 mg/dL after 44 d of diet-induced anemia. After depletion treatment, the vehicle-treated group had a further decrease of 1.3 mg/dL, whereas hemoglobin concentrations in both FG and Mankai iso-iron treatments similarly rebounded (FG14: +10.8 mg/dL, Mankai 50: +6.4 mg/dL, Mankai 80: +7.3 mg/dL; FG9.5: +5.1 mg/dL, Mankai 50-C: +7.1 mg/dL; P < 0.05 for all vs. the vehicle group).

Conclusions: In humans, a green-MED low-meat diet does not impair iron homeostasis. In rats, iron derived from Mankai (a green-plant protein source) is bioavailable and efficient in reversal of anemia. This trial was registered at clinicaltrials.gov as NCT03020186.
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http://dx.doi.org/10.1093/jn/nxy321DOI Listing
June 2019

Five years of fecal microbiota transplantation - an update of the Israeli experience.

World J Gastroenterol 2018 Dec;24(47):5403-5414

Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel.

Aim: To evaluate and describe the efficacy of fecal microbiota transplantation (FMT) for infection (CDI) in a national Israeli cohort.

Methods: All patients who received FMT for recurrent (recurrence within 8 wk of the previous treatment) or refractory CDI from 2013 through 2017 in all the five medical centers in Israel currently performing FMT were included. Stool donors were screened according to the Israeli Ministry of Health guidelines. Clinical and laboratory data of patients were collected from patients' medical files, and they included indications for FMT, risk factors for CDI and disease severity. Primary outcome was FMT success (at least 2 mo free of CDI-related diarrhea post-FMT). Secondary outcomes included initial response to FMT (cessation of diarrhea within 7 d) and recurrence at 6 mo.

Results: There were 111 FMTs for CDI, with a median age of 70 years [interquartile range (IQR): 53-82], and 42% (47) males. Fifty patients (45%) were treated the lower gastrointestinal (LGI, represented only by colonoscopy) route, 37 (33%) capsules, and 24 (22%) the upper gastrointestinal (UGI) route. The overall success rate was 87.4% (97 patients), with no significant difference between routes of administration ( = 0.338). In the univariant analysis, FMT success correlated with milder disease ( = 0.01), ambulatory setting ( < 0.05) and lower Charlson comorbidity score ( < 0.05). In the multivariant analysis, only severe CDI [odd ratio (OR) = 0.14, < 0.05] and inpatient FMT (OR = 0.19, < 0.05) were each independently inversely related to FMT success. There were 35 (32%) patients younger than 60 years of age, and 14 (40%) of them had a background of inflammatory bowel disease.

Conclusion: FMT is a safe and effective treatment for CDI, with capsules emerging as a successful and well-tolerated route. Severe CDI is less likely to respond to FMT.
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http://dx.doi.org/10.3748/wjg.v24.i47.5403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305536PMC
December 2018

Predictors of grade 3-5 vesicoureteral reflux in infants ≤ 2 months of age with pyelonephritis.

Pediatr Nephrol 2019 05 26;34(5):907-915. Epub 2018 Dec 26.

Department of Pediatrics, Assaf Harofeh Medical Center, 70300, Zerifin, Israel.

Background: This study aimed to assess predictors for grade 3-5 vesicoureteral reflux (VUR) in infants ≤ 2 months of age admitted for first urinary tract infection (UTI).

Methods: Retrospective cohort study of 195 infants ≤ 2 months admitted to a pediatric ward for first UTI between 2006 and 2017. Clinical, laboratory, and imaging data were collected from electronic medical charts. We examined associations between grade 3-5 VUR and different patient characteristics.

Results: Twenty infants (10%) were diagnosed with grade 3-5 VUR; all had fever. Infants with grade 3-5 VUR had higher blood neutrophil percentage (BNP) (65% vs. 46%, P < 0.001), higher neutrophil-to-lymphocyte ratio (NLR) (2.6 vs. 1.3, P < 0.001), more renal ultrasound abnormalities (prenatal 26% vs. 5%, P = 0.007; postnatal 84% vs. 55%, P = 0.015), and Pseudomonas UTI (15% vs. 1%, respectively, P < 0.001). NLR > 1.65 showed sensitivity 100% and specificity 61% for detecting grade 3-5 VUR. BNP > 53% showed sensitivity 100% and specificity 60% for detecting grade 3-5 VUR. BNP was the best single marker for grade 3-5 VUR with area under the curve (AUC) of 0.82 (95% CI 0.75-0.89). In a multivariate model, AUC for combination of BNP and hydronephrosis was 0.86 (95% CI 0.79-0.93, P = 0.007).

Conclusions: Infants ≤ 2 months of age admitted for a first UTI are at risk for grade 3-5 VUR and thus should undergo a voiding cystourethrography (VCUG) if their renal ultrasound is abnormal or if they have Pseudomonas UTI. Avoiding VCUG can be considered in afebrile infants and in infants with BNP < 53% or NLR < 1.65.
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http://dx.doi.org/10.1007/s00467-018-4167-0DOI Listing
May 2019

[THE EPIDEMIOLOGY OF CLOSTRIDIUM DIFFICILE INFECTIONS AND ASPECTS PERTAINING TO TREATMENT WITH VANCOMYCIN AT ASSAF HAROFEH MEDICAL CENTER].

Harefuah 2018 May;157(5):305-308

Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: The epidemiology of Clostridium difficile infections (CDI) have evolved dramatically in the past decade. Vancomycin is the treatment of choice for moderate to severe CDI. However, controlled comparative data pertaining to mild CDI is lacking. Furthermore, the potential impact of vancomycin treatment on subsequent vancomycin-resistant Enterococcus (VRE) isolation remains unknown.

Methods: A retrospective cohort analysis was executed at the Assaf Harofeh Medical Center, from 2013 to 2015. Adult patients (>18 years) with a first episode of acute CDI, determined per pre-established criteria, were enrolled. The efficacy of vancomycin vs. metronidazole among patients with mild CDI, and the independent association of oral vancomycin treatment during the acute CDI and later (up to 18 months) VRE isolation, was analyzed by logistic regression.

Results: A total of 260 patients with CDI were enrolled. The majority were elderly (75%), and 56% had moderate to severe disease. Among 75 patients with mild disease, no differences were observed in terms of clinical outcomes between vancomycin or metronidazole treatment. Metronidazole remained non-inferior even after incorporating a prediction score to control for confounders associated with being a "vancomycin case". In multivariable analysis, oral vancomycin treatment during the acute CDI was the strongest independent predictor for later isolation of VRE (aOR=74, p=0.004).

Conclusions: Our study suggests that metronidazole should remain the recommended treatment of choice for mild CDI, due to clinical non-inferiority and an apparent association between vancomycin therapy and subsequent VRE isolation on an individual patient level analysis.
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May 2018

Poor Immunogenicity, Not Vaccine Strain Egg Adaptation, May Explain the Low H3N2 Influenza Vaccine Effectiveness in 2012-2013.

Clin Infect Dis 2018 07;67(3):327-333

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, Massachusetts.

Background: Influenza vaccination aims to prevent infection by influenza virus and reduce associated morbidity and mortality; however, vaccine effectiveness (VE) can be modest, especially for subtype A(H3N2). Low VE has been attributed to mismatches between the vaccine and circulating influenza strains and to the vaccine's elicitation of protective immunity in only a subset of the population. The low H3N2 VE in the 2012-2013 season was attributed to egg-adaptive mutations that created antigenic mismatch between the actual vaccine strain (IVR-165) and both the intended vaccine strain (A/Victoria/361/2011) and the predominant circulating strains (clades 3C.2 and 3C.3).

Methods: We investigated the basis of low VE in 2012-2013 by determining whether vaccinated and unvaccinated individuals were infected by different viral strains and by assessing the serologic responses to IVR-165, A/Victoria/361/2011, and 3C.2 and 3C.3 strains in an adult cohort before and after vaccination.

Results: We found no significant genetic differences between the strains that infected vaccinated and unvaccinated individuals. Vaccination increased titers to A/Victoria/361/2011 and 3C.2 and 3C.3 representative strains as much as to IVR-165. These results are consistent with the hypothesis that vaccination boosted cross-reactive immune responses instead of specific responses against unique vaccine epitopes. Only approximately one-third of the cohort achieved a ≥4-fold increase in titer.

Conclusions: In contrast to analyses based on ferret studies, low H3N2 VE in 2012-2013 in adults does not appear to be due to egg adaptation of the vaccine strain. Instead, low VE might have been caused by low vaccine immunogenicity in a subset of the population.
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http://dx.doi.org/10.1093/cid/ciy097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051447PMC
July 2018

Strain Tracking Reveals the Determinants of Bacterial Engraftment in the Human Gut Following Fecal Microbiota Transplantation.

Cell Host Microbe 2018 Feb;23(2):229-240.e5

Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA; Finch Therapeutics, Somerville, MA, USA; Department of Biological Engineering, MIT, Cambridge, MA, USA. Electronic address:

Fecal microbiota transplantation (FMT) from healthy donor to patient is a treatment for microbiome-associated diseases. Although the success of FMT requires donor bacteria to engraft in the patient's gut, the forces governing engraftment in humans are unknown. Here we use an ongoing clinical experiment, the treatment of recurrent Clostridium difficile infection, to uncover the rules of engraftment in humans. We built a statistical model that predicts which bacterial species will engraft in a given host, and developed Strain Finder, a method to infer strain genotypes and track them over time. We find that engraftment can be predicted largely from the abundance and phylogeny of bacteria in the donor and the pre-FMT patient. Furthermore, donor strains within a species engraft in an all-or-nothing manner and previously undetected strains frequently colonize patients receiving FMT. We validated these findings for metabolic syndrome, suggesting that the same principles of engraftment extend to other indications.
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http://dx.doi.org/10.1016/j.chom.2018.01.003DOI Listing
February 2018

Fatal and Near-Fatal Non-allergic Reactions in Patients with Underlying Cardiac Disease Receiving Benzathine Penicillin G in Israel and Switzerland.

Front Pharmacol 2017 21;8:843. Epub 2017 Nov 21.

Pharmaceutical Division, Israeli Ministry of Health, Jerusalem, Israel.

Benzathine Penicillin G (BPG) is commonly used for treatment of penicillin-susceptible infections and secondary prevention of rheumatic fever. Death following administration of BPG is extremely rare-only a handful of cases have been described in the literature since the 1950's. In this case series from Israel and Switzerland, we describe nine cases of serious adverse reactions-six fatal reactions and three near-fatalities-occurring within minutes of receiving intramuscular BPG. Allergic reactions or faulty administration were not implicated in any of the cases; however, all patients had cardiac risk factors. This case series describes a relatively rare risk that should be borne in mind when prescribing BPG.
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http://dx.doi.org/10.3389/fphar.2017.00843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702457PMC
November 2017

Shivering in Febrile Children: Frequency and Usefulness in Predicting Serious Bacterial Infections - A Prospective Case-Control Study.

J Pediatr 2017 11 7;190:258-260.e1. Epub 2017 Sep 7.

Pediatric Emergency Unit, Assaf Harofeh Medical Center, Zerifin, Affiliated to the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

A prospective case-control study was conducted in a pediatric emergency department to describe the proportion of febrile children experiencing shivering and its clinical significance. Shivering was reported in 186 of 645 febrile children (28.8%). The rate of serious bacterial infection was similar in 86 children with shivering and 86 matched controls.
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http://dx.doi.org/10.1016/j.jpeds.2017.06.075DOI Listing
November 2017

Editorial: Making Fecal Microbiota Transplantation Easier to Swallow: Freeze-Dried Preparation for Recurrent Clostridium difficile Infections.

Am J Gastroenterol 2017 06;112(6):948-950

Edward Hines Jr. Veterans Affairs Hospital, Hines, IL, USA.

Fecal microbiota transplant (FMT) has emerged as an effective and increasingly popular therapy for recurrent Clostridium difficile infections in patients that have failed standard antimicrobial treatment. Patient access to FMT is hampered by the logistics of manufacturing, storing, and delivering the inocula. An observational study describes the development and clinical efficacy of freeze-dried FMT capsules for oral administration. While awaiting the emergence of defined bacterial therapeutics for Clostridium difficile infections, this refinement of FMT is an encouraging step toward simplifying FMT treatment. Randomized controlled trials are required to further establish the efficacy and safety of lyophilized FMT.
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http://dx.doi.org/10.1038/ajg.2017.91DOI Listing
June 2017

Antibiotic Use in Children - A Cross-National Analysis of 6 Countries.

J Pediatr 2017 03 21;182:239-244.e1. Epub 2016 Dec 21.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Objectives: To describe the rates of pediatric antibiotic use across 6 countries on 3 continents.

Study Design: Cross-national analysis of 7 pediatric cohorts in 6 countries (Germany, Italy, South Korea, Norway, Spain, and the US) was performed for 2008-2012. Antibiotic dispensings were identified and grouped into subclasses. We calculated the rates of antimicrobial prescriptions per person-year specific to each age group, comparing the rates across different countries.

Results: A total of 74 744 302 person-years from all participating centers were included in this analysis. Infants in South Korea had the highest rate of antimicrobial consumption, with 3.41 prescribed courses per child-year during the first 2 years of life. This compares with 1.6 in Lazio, Italy; 1.4 in Pedianet, Italy; 1.5 in Spain; 1.1 in the US; 1.0 in Germany; and 0.5 courses per child-year in Norway. Of antimicrobial prescriptions written in Norway, 64.8% were for first-line penicillins, compared with 38.2% in Germany, 31.8% in the US, 27.7% in Spain, 25.1% in the Italian Pedianet population, 9.8% in South Korea, and 8% in the Italian Lazio population.

Conclusions: We found substantial differences of up to 7.5-fold in pediatric antimicrobial use across several industrialized countries from Europe, Asia, and North America. These data reinforce the need to develop strategies to decrease the unnecessary use of antimicrobial agents.
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http://dx.doi.org/10.1016/j.jpeds.2016.11.027DOI Listing
March 2017

Recurrent Immune Thrombocytopenia After Influenza Vaccination: A Case Report.

Pediatrics 2016 12 8;138(6). Epub 2016 Nov 8.

Department of Pediatrics, Assaf Harofeh Medical Center, Zerifin, Israel; and.

Immune thrombocytopenia (ITP) is an isolated autoimmune condition, often preceded by a viral infection. Vaccines, mainly the measles-mumps-rubella vaccine, have also been associated with an increased risk of developing the disease. Although some case reports of ITP after influenza immunization in adults have been published, epidemiologic studies examining the role of the influenza vaccine as a trigger of ITP have not conclusively proven causality. We report a child with 3 occurrences of ITP, each within 1 week of receiving the influenza trivalent inactivated vaccine. He recovered fully in-between the episodes, and no further episodes have occurred since discontinuation of seasonal influenza vaccination. To the best of our knowledge, this report is the first showing, with high probability, the influenza vaccine as a cause for ITP in a pediatric patient.
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http://dx.doi.org/10.1542/peds.2016-0124DOI Listing
December 2016

Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection.

BMC Med 2016 09 9;14(1):134. Epub 2016 Sep 9.

Divisions of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.

Background: Fecal microbiota transplantation (FMT) has been shown to be safe and effective in treating refractory or relapsing C. difficile infection (CDI), but its use has been limited by practical barriers. We recently reported a small preliminary feasibility study using orally administered frozen fecal capsules. Following these early results, we now report our clinical experience in a large cohort with structured follow-up.

Methods: We prospectively followed a cohort of patients with recurrent or refractory CDI who were treated with frozen, encapsulated FMT at our institution. The primary endpoint was defined as clinical resolution whilst off antibiotics for CDI at 8 weeks after last capsule ingestion. Safety was defined as any FMT-related adverse event grade 2 or above.

Results: Overall, 180 patients aged 7-95 years with a minimal follow-up of 8 weeks were included in the analysis. CDI resolved in 82 % of patients after a single treatment, rising to a 91 % cure rate with two treatments. Three adverse events Grade 2 or above, deemed related or possibly related to FMT, were observed.

Conclusions: We confirm the effectiveness and safety of oral administration of frozen encapsulated fecal material, prepared from unrelated donors, in treating recurrent CDI. Randomized studies and FMT registries are still needed to ascertain long-term safety.
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http://dx.doi.org/10.1186/s12916-016-0680-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016994PMC
September 2016