Impact of rotavirus vaccine on admissions due to acute gastroenteritis and rotavirus gastroenteritis in Israel.

AIM: We examined the impact of insertion of the Rotavirus vaccine (RVV) into the Israeli National Immunisation Programme (NIP) on hospitalisations due to both acute gastroenteritis (AGE) and Rotavirus gastroenteritis (RVGE) in children. METHODS: We retrospectively analysed the medical records of children aged <5 years admitted with a diagnosis of AGE between 2008 and 2016 in two children's hospitals in central Israel. Clinical, laboratory, microbiological data and RV immunisation status were retrieved. Data were compared before and after the introduction of the RVV into the NIP. RESULTS: A total of 2042 children were admitted with AGE. Hospitalisations due to AGE and RVGE decreased from 3310 to 1950 and from 1027 to 585 per 100 000 admissions, respectively, after the RVV (relative risk reduction (RRR) of 41% and 43%, respectively). RV remained the most common pathogen in both study periods. There was no significant difference in the clinical course between immunised and non-immunised children admitted with RVGE. CONCLUSION: The introduction of the RVV to the NIP significantly reduced the admissions due to both AGE and RVGE in children <5 years. However, RV is still the most common agent for admissions due to AGE in this age group.

Protective effect of soluble Klotho in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass support-A pilot study.

OBJECTIVE: The Klotho protein family plays important roles in several metabolic pathways. Soluble Klotho has been recently put forward as an antiaging protein, demonstrating renal and cardiovascular protective traits. Cardiopulmonary bypass (CPB) support during cardiac surgery has been implicated in several adverse outcomes in pediatric and adult patients. Our goal was to assess whether serum Klotho levels can be used to predict outcomes in children undergoing cardiac surgery with CPB due to congenital heart defects (CHDs). METHODS: This prospective study was conducted on pediatric patients admitted to two Pediatric Cardiac Intensive Care Units, between 2012 and 2018. All patients were born with CHD and underwent corrective surgery with CPB. Sequential blood samples were analyzed by enzyme-linked immunosorbent assay for soluble Klotho levels at baseline, 2, 6, and 24 h after surgery. The association between Klotho levels and several demographic, intraoperative, and postoperative clinical and laboratory parameters was studied. RESULTS: Twenty-nine children undergoing cardiac surgery with CPB support were included. Serum Klotho levels were shown to significantly decrease 2 h after surgery and increase to baseline levels after 6 h (p < .001 and p < .05, respectively). Patients with low Klotho levels 2 h after surgery were at a 32-fold higher risk for developing postoperative complications (p = .015, odds ratio < 0.03). Moreover, Klotho levels at each of the four time points were lower in patients who developed postoperative complications. CONCLUSIONS: Cardiac surgery with CPB results in a significant decrease of serum Klotho levels 2 h after surgery in pediatric patients with CHDs, which can be used to predict development of postoperative complications in this patient population.

STAT3 isoforms differentially affect ACE2 expression: A potential target for COVID-19 therapy.

The SARS-coronavirus 2 is the aetiologic agent COVID-19. ACE2 has been identified as a cell entry receptor for the virus. Therefore, trying to understand how the gene is controlled has become a major goal. We silenced the expression of STAT3α and STAT3ß, and found that while silencing STAT3α causes an increase in ACE2 expression, silencing STAT3ß causes the opposite effect. Studying the role of STAT3 in ACE2 expression will shed light on the molecular events that contribute to the progression of the disease and that the different roles of STAT3α and STAT3ß in that context must be taken in consideration. Our results place STAT3 in line with additional potential therapeutic targets for treating COVID-19 patients.

Treatment Outcomes of Stenotrophomonas maltophilia Bacteremia in Critically Ill Children: A Multicenter Experience.

OBJECTIVES: Stenotrophomonas maltophilia is a gram-negative opportunistic bacterium that may cause a myriad of clinical diseases in immunocompromised individuals. We aimed to describe the clinical characteristics, risk factors, mortality, and treatment of S. maltophilia bacteremia in critically ill children, a topic on which data are sparse. DESIGN: A multicenter observational retrospective study in which medical charts of critically ill children with S. maltophilia bacteremia were reviewed between 2012 and 2017. SETTING: Data were collected from each of the four largest PICUs nationwide, allocated in tertiary medical centers to which children with complex conditions are referred regularly. PATIENTS: A total of 68 suitable cases of S. maltophilia bacteremia were retrieved and reviewed. MEASUREMENTS AND MAIN RESULTS: The total occurrence rate of S. maltophilia isolation had increased significantly during the study period (r = 0.65; p = 0.02). The crude mortality was 42%, and the attributed mortality was 18%. Significant risk factors for mortality were a longer length of hospital stay prior to infection (33 d in nonsurvivors vs 28 in survivors; p = 0.03), a nosocomial source of infection (p = 0.02), presentation with septic shock (p < 0.001), and treatment with chemotherapy (p = 0.007) or carbapenem antibiotics (p = 0.05) prior to culture retrieval. On multivariate analysis, septic shock (odds ratio, 14.6; 95% CI, 1.45-147.05; p = 0.023) and being treated with chemotherapy prior to infection (odds ratio, 5.2; 95% CI, 1.59-17.19; p = 0.006)] were associated with mortality. The combination of ciprofloxacin, trimethoprim-sulfamethoxazole, and minocycline resulted in the longest survival time (p < 0.01). CONCLUSIONS: The significant attributed mortality associated with S. maltophilia bacteremia in critically ill children calls for an aggressive therapeutic approach. The findings of this investigation favor a combination of trimethoprim-sulfamethoxazole, ciprofloxacin, and minocycline.

[POSTGRADUATE TRAINING IS OUR SPECIALTY].

BACKGROUND: In recent years, following public expectations for high quality medical care and a teaching system that can adapt to public needs, changes are being implemented in medical education. The Scientific Council of the Israeli Medical Association (IMA) is responsible, under the Physicians Ordinance, for the planning and supervision of the physicians' specialization system in Israel and promotes post graduate medical education of the highest quality for the advancement of medicine in Israel. In this issue, we highlight the key goals of medical education: knowledge acquisition, skills imparting and application of professional values, as well as the different tasks the Scientific Council has undertaken in order to advance them. This issue includes reports discussing amendments to specialization programs, creation of new specialties, changes to board certification examinations and accrediting and overseeing professional training. In addition, the issue will emphasize the significant changes being made in medical education in Israel while implementing Competency Based Medical Education (CBME).

[POSTGRADUATE MEDICAL EDUCATION ACCREDITATION IN ISRAEL].

INTRODUCTION: Accreditation of Post-Graduate Medical Education permits medical institutions to train residents, allowing them to achieve specialist certification. An accreditation system usually employs several tools such as site-visits, information gathering and occasionally self-evaluation, to determine adherence to pre-defined standards. The Scientific Council of the Israeli Medical Association is entrusted by law on this accreditation system in Israel. In our article, we briefly review the Post-Graduate Medical Education accreditation system in Israel and a number of pivotal challenges faced by the Scientific Council in this field in the 21st century. These challenges include the adaptation to different medical settings such as community based clinics and medical arrays, the adaptation of tools used for accreditation, new methods for up to date information gathering and updated structure of site-visit teams. A significant future challenge will be adapting the accreditation system to the new Competency Based Medical Education model of residency promoted in Israel by the Scientific Council.

Elevated Baseline Cortisol Levels Are Predictive of Bad Outcomes in Critically Ill Children.

OBJECTIVE: The definition of an adequate adrenal response in critically ill children continues to be controversial. We aimed to evaluate the cortisol levels at baseline and after adrenocorticotropin (ACTH) stimulation and determine their association to clinical outcome of critically ill children. METHODS: All children who underwent an ACTH test in the pediatric intensive care unit (PICU) in a tertiary medical center between 2006 and 2013 were included in the study. Data on age, sex, diagnosis, vasoactive-inotropic score, length of pediatric intensive care unit stay, and mortality were obtained. Laboratory variables included hematologic and chemistry data, arterial lactate, and total plasma cortisol levels at baseline and after ACTH stimulation. RESULTS: Ninety-nine patients (61 males; median [range] age, 2 [0-204] months) were enrolled. The mortality rate of children with a baseline cortisol level of 600 nmol/L or greater was 36% (12/33 patients) versus 18% (12/66 patients) for children with a baseline cortisol level of less than 600 nmol/L (odds ratio, 2.6 [95% confidence interval, 1-6.6]; P = 0.05). There was a positive correlation between baseline cortisol and lactate levels (r = 0.40, P < 0.0001), vasoactive-inotropic scores (r = 0.24, P = 0.02), and mortality (P = 0.05). There was no correlation between peak cortisol measured at the ACTH test or the delta increment of cortisol from baseline and mortality. CONCLUSIONS: A high baseline cortisol level in critically ill children was associated with more severe illness, higher lactate level, and a higher mortality rate. Routine baseline cortisol assessment is recommended to identify patients at high mortality risk.

Role of vasopressin and terlipressin in refractory shock compared to conventional therapy in the neonatal and pediatric population: a systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Vasopressin (AVP) and terlipressin (TP) have been used as last-line therapy in refractory shock in children. However, the efficacy and safety profiles of AVP and TP have not been determined in pediatric refractory shock of different origins. We aimed to assess the efficacy and safety of the addition of AVP/TP therapy in pediatric refractory shock of all causes compared to conventional therapy with fluid resuscitation and vasopressor and inotropic therapy. METHODS: We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) comparing AVP and TP to conventional therapy. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched up to February 2016. The systematic review included all reports of AVP/TP use in the pediatric population. Reports of clinical trials were pooled using random-effects models and TSA. Main outcomes were mortality and tissue ischemia. RESULTS: Three randomized controlled trials and five "before-and-after clinical" trials (without comparator) met the inclusion criteria. Among 224 neonates and children (aged 0 to 18 years) with refractory shock, 152 received therapy with AVP or TP. Pooled analyses showed no association between AVP/TP treatment and mortality (relative risk (RR),1.19; 95% confidence interval (CI), 0.71-2.00), length of stay in the pediatric intensive care unit (PICU) (mean difference (MD), -3.58 days; 95% CI, -9.05 to 1.83), and tissue ischemia (RR, 1.48; 95% CI, 0.47-4.62). In TSA, no significant effect on mortality and risk for developing tissue ischemia was observed with AVP/TP therapy. CONCLUSION: Our results emphasize the lack of observed benefit for AVP/TP in terms of mortality and length of stay in the PICU, and suggest an increased risk for ischemic events. Our TSA suggests that further large studies are necessary to demonstrate and establish benefits of AVP/TP in children. PROSPERO registry: CRD42016035872.

Micro-RNA-208a, -208b, and -499 as Biomarkers for Myocardial Damage After Cardiac Surgery in Children.

OBJECTIVES: To test the hypothesis that cardiac-enriched micro-RNAs can serve as accurate biomarkers that reflect myocardial injury and to predict the postoperative course following pediatric cardiac surgery. Micro-RNAs have emerged as plasma biomarkers for many pathologic states. We aimed to quantify preoperative and postoperative plasma levels of cardiac-enriched micro-RNA-208a, -208b, and -499 in children undergoing cardiac surgery and to evaluate correlations between their levels, the extent of myocardial damage, and the postoperative clinical course. DESIGN: PICU. PATIENTS: Thirty pediatric patients that underwent open heart surgery for the correction of congenital heart defects between January 2012 to July 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At 12 hours post surgery, the plasma levels of the micro-RNAs increased by 300- to 4,000-fold. At 24 hours, their levels decreased but remained significantly higher than before surgery. Micro-RNA levels were associated with troponin levels, longer cardiopulmonary bypass and aortic crossclamp times, maximal postoperative aspartate aminotransferase levels, and delayed hospital discharge. CONCLUSIONS: Circulating micro-RNA-208a, -208b, and -499 are detectable in the plasma of children undergoing cardiac surgery and may serve as novel biomarkers for monitoring and forecasting postoperative myocardial injury and recovery.

Immunisation led to a major reduction in paediatric patients hospitalised because of the varicella infection in Israel.

AIM: The varicella-zoster virus causes infections that are often mild but can cause substantial morbidity and mortality in otherwise healthy children. We examined trends in varicella-related hospitalisations before and after the implementation of a national two-dose varicella vaccination programme in Israel in September 2008. METHODS: This retrospective chart review, performed at three tertiary care paediatric hospitals in greater Tel Aviv, compared data from 2004 to 2008 and 2009 to 2012, before and after the varicella programme was launched. It included all children to the age of 18 who were hospitalised for conditions associated with the varicella infection. RESULTS: After the vaccination programme was introduced, the number of children hospitalised for varicella fell by 63% (p < 0.5), from 38.9 to 14.5 per 10 000, and there was a 75% reduction in children aged one to six. During the same period, the percentage of hospitalised children who were immunocompromised rose from 9.7% to 18.4% (p < 0.05). The most common complications were soft-tissue infections (60%), and the most prevalent pathogens were Group A ß-haemolytic streptococcus (53%) and Staphylococcus aureus (32%). CONCLUSION: The introduction of a two-dose immunisation programme dramatically decreased the varicella burden in Israel, leading to a major reduction in hospitalisation admissions linked to the infection.

Acute Childhood Encephalitis at 2 Tertiary Care Children's Hospitals in Israel: Etiology and Clinical Characteristics.

OBJECTIVES: The clinical characteristics, pathogens, and outcome were analyzed to investigate the etiology of acute pediatric encephalitis in 2 tertiary pediatric medical centers in Israel. METHODS: A retrospective study among children aged 1 month to 18 years hospitalized with the diagnosis of acute encephalitis between January 1999 and December 2009. Data on presenting symptoms, clinical findings, microbiological, virologic, electroencephalographic and neuroimaging studies, laboratory results, and hospital course were retrieved from the medical records and the computerized microbiology database. RESULTS: Forty-four children were included. An etiologic agent was identified in 11 (25%): Mycoplasma pneumoniae (n = 2), enterovirus (n = 3), herpes simplex virus (HSV) (n = 1), Epstein-Barr virus (n = 2), human herpes virus 6 (n = 1), influenza virus type A (n = 1), and varicella zoster virus (n = 1). Presenting features included fever (90% of patients), seizures (39%), focal neurological signs (18%), and decreased consciousness (67%). Diagnostic findings included pleocytosis in the cerebrospinal fluid (76% of patients), electroencephalographic abnormalities (78%), and neuroimaging abnormalities (34%). All patients were treated with acyclovir until negative result for HSV polymerase chain reaction was received from cerebrospinal fluid, the child with HSV encephalitis was treated with intravenous acyclovir for 3 weeks. The outcomes at the time of discharge were: normal (66%), motor difficulties (14%), global neurological deficits (7%), visual defects (2%), and hearing impairment (2%) and no deaths. CONCLUSIONS: The etiology of acute encephalitis remains unknown in the majority of cases. There was no correlation between adverse outcome and a specific etiologic agent. The high morbidity rate may suggest that current therapeutic modalities may not be sufficient.

Skin Necrosis and Purpura Fulminans in Children With and Without Thrombophilia--A Tertiary Center's Experience.

Purpura fulminans (PF) is a very rare clinicopathologic skin disorder comprising dermal microvascular thrombosis associated with perivascular hemorrhage of multiple origins. It may occur as the presenting symptom of severe congenital deficiency of protein C (PC) or protein S (PS) during the newborn period, or later in life following oral anticoagulant therapy with vitamin K antagonists, or of sepsis that may be associated with disseminated intravascular coagulation. Treatment consists of anticoagulants and PC concentrates during acute episodes. We report our experience in the diagnosis and management of pediatric PF. The medical records of the 6 children aged 2-16 years (median: 5 years) who presented with PF to our tertiary care center between 1996 and 2013 were studied. The thrombophilia workup revealed either the presence of congenital homozygous PC deficiency, prothrombotic polymorphisms (factor V Leiden and FIIG20210A heterozygosity), acquired PC/PS deficiency, or no discernible thrombophilia. The skin necrosis resolved following conservative fresh-frozen plasma/anticoagulant therapy in 2 cases, whereas 3 children required interventional plastic surgery. The sixth case, a 10-year-old child with severe PC deficiency, heterozygous factor V Leiden, and FIIG20210A, received recombinant activated PC. PF in childhood is rare and has multiple etiologies. Understanding of the variable pathogenesis and risk factors will facilitate diagnosis and appropriate clinical management.

The many etiologies of neonatal hypocalcemic seizures.

Seizures during the neonatal period have a broad differential diagnosis. Unlike in developing countries where hypovitaminosis D and hypocalcemia constitutes a major cause of infantile seizures, the number of neonatal seizures attributed to hypocalcemia in developed countries has decreased dramatically due to the improvement of infant formulas and vitamin D supplementation. In these countries, most infants that present with hypocalcemic seizures have underlying endocrinological etiologies rather than dietary insufficiencies. Here, we describe 3 cases of neonatal seizures due to hypocalcemia. Although the symptoms and calcium concentrations at presentation were similar in all 3 cases, the course of the disease and the final diagnosis for each were distinct. The cases are presented along with a brief review of the pathophysiology, differential diagnosis, and treatment of neonatal hypocalcemia.

The Safety of Pediatric Bedside Tracheostomy.

OBJECTIVE: Traditionally, pediatric tracheostomy has been viewed as a technically demanding procedure with a high complication rate, requiring the routine use of a formal operating room. Pediatric bedside tracheostomy in an intensive care unit (ICU) setting has not been widely reported, in contrast to the widespread adult bedside ICU tracheostomy. Transport of these critically ill, multiple life support systems dependent patients can be technically difficult, labor intensive, and potentially risky for these patients. Our study aimed to demonstrate the safety and efficacy of bedside tracheostomy in the pediatric ICU. MATERIALS AND METHODS: A retrospective analysis of all pediatric patients undergoing tracheostomy at a tertiary care center, between 1st of January 2013 and 31st of December 2019. RESULTS: During the study period, 117 pediatric patients underwent tracheostomy, 57 (48.7%) were performed bedside while 60 (51.3%) were performed in the operating room. Patients' ages ranged from 2 weeks to 17 years of age, with a median age of 16 months. No case of bedside tracheostomy necessitated a shift to the operating room. There was no difference in 30-day morbidity and mortality between the 2 groups. CONCLUSIONS: Our results suggest that pediatric open bedside tracheostomy in an ICU setting is a safe procedure, with similar complications and outcomes compared to tracheostomy performed in the operating room.

Pediatric parapneumonic empyema: risk factors, clinical characteristics, microbiology, and management.

OBJECTIVE: Pediatric empyema is increasing in incidence and continues to be a source of morbidity in children. Our objective was to determine the risk factors, clinical characteristics, distribution of the pathogens, and outcome of pediatric empyema in 2 Israeli pediatric medical centers. METHODS: This was a retrospective case-control study on children aged 2 months to 18 years hospitalized with community-acquired pneumonia (CAP) in the pre-Prevnar era (2000-2009). Demographic data, presenting symptoms, physical examination findings, imaging studies, laboratory results, hospital course, medical treatment, and surgical interventions were reviewed from medical records and computerized microbiology databases. RESULTS: One hundred ninety-one children comprised of 47 (24.9%) with parapneumonic empyema and 144(75.4%) without empyema. The symptoms and course of the children with empyema were substantially worse compared with patients without empyema. The most prevalent pathogen was Streptococcus pneumonia. The most common pneumococcal serotype was serotype 5, and 86% of the recovered S. pneumoniae were susceptible to penicillin. Children with empyema most commonly presented with prolonged fever, dyspnea (51%), and chest pain (17%). Forty-five children with empyema (98%) required a chest tube, fibrinolysis, or decortication with video-assisted thoracoscopy (VATS). Hospitalization stay was similar for children with empyema who underwent VATS and those who were treated conventionally. CONCLUSIONS: The most prevalent pathogen in children with CAP with and without empyema is S. pneumoniae. Children with empyema experience significantly more morbidity than did patients with CAP alone. In our experience, VATS apparently does not shorten the duration of hospitalization compared with conventional treatment. Immunization may affect the incidence of pediatric empyema and should be studied prospectively.

Thrombocytopenia and Bloodstream Infection: Incidence and Implication on Length of Stay in the Pediatric Intensive Care Unit.

The incidence and prognosis of thrombocytopenia in critically ill patients with bloodstream infection (BSI) is not well delineated in the pediatric intensive care unit (PICU) setting. We assessed these variables in our PICU and sought to determine whether thrombocytopenia could serve as a prognostic marker for length of stay (LOS). The study was conducted at the medical PICU of a university hospital, on all critically ill pediatric patients consecutively admitted during a 3-year period. Patient surveillance and data collection have been used to identify the risk factors during the study period. The main outcomes were BSI incidence and implication on morbidity and LOS. Data from 2,349 PICU patients was analyzed. The overall incidence of BSI was 3.9% (93/2,349). Overall, 85 of 93 patients (91.4%) with BSI survived and 8 patients died (8.6% mortality rate). The overall incidence of thrombocytopenia among these 93 patients was 54.8% (51/93) and 100% (8/8) for the nonsurvivors. Out of the 85 survivors, 27 thrombocytopenic patients were hospitalized for >14 days versus 14 of nonthrombocytopenic patients ( p = 0.007). Thrombocytopenia was associated with borderline significance with an increased LOS (adjusted odds ratio = 3.00, 95% confidence interval: 0.93-9.71, p = 0.066). Thrombocytopenia is common in critically ill pediatric patients with BSI and constitutes a simple and readily available risk marker for PICU LOS.

Point of care testing in children undergoing cardiopulmonary bypass.

BACKGROUND: Excessive hemorrhage is a major complication after cardiac surgery requiring cardiopulmonary bypass (CPB). The aim of this study was to define the potential role of the cone and platelet analyzer (CPA) and the rotating thromboelastogram (ROTEM) point of care tests in children undergoing CPB. PROCEDURE: We prospectively studied 15 pediatric patients aged 1 month to 10 years. Blood count, blood coagulation tests (prothrombin time [PT], activated partial thromboplastin time, fibrinogen, thrombin time), CPA and ROTEM parameters were measured before and after CPB. Demographic and surgical data were recorded as were those on perioperative blood loss and blood product transfusion. RESULTS: Low body weight, longer duration on CPB and lower core body temperature were associated with an increased bleeding risk. The ROTEM test showed a significant prolongation of clotting time and decreased maximal clot firmness (MCF) postoperatively in children with increased bleeding. The coagulation parameters associated with increased bleeding were: prolonged PT, lower fibrinogen levels, prior to surgery, and lower MCF after surgery. CPA test findings were not associated with postoperative bleeding in our patients. CONCLUSIONS: CPA did not serve as a prognostic tool for predicting bleeding risk in children undergoing CPB. The change in ROTEM's post-CPB results associated with bleeding tendency, and they may predict for poorer clot formation and stability.