Pediatrics

The effect of follow-up after a negative double-blinded placebo-controlled cow's milk challenge on successful reintroduction Abstract Cow's milk allergy is a common food allergy in children with an incidence of 1–3%. The gold standard to diagnose cow's milk allergy is a double-blinded placebo-controlled food challenge (DBPCFC). Previous studies show that reintroduction of cow's milk is unsuccessful in 10–12% of patients. The aim of this retrospective study is to evaluate the effect of follow-up on the reintroduction of cow's milk. We analyzed the data of patients with a negative DBPCFC for cow's milk between 2014 and 2016 in three different departments. Questionnaires were used to compare the three ways of follow-up (no follow-up, follow-up in person or by telephone). Of the 336 children with a negative DBPCFC for cow's milk, 128 questionnaires (41%) were returned. Reintroduction of cow's milk was unsuccessful in 13.3% of the patients. There was no significant difference found between children with (73.8%) or without (26.2%) follow-up, or between follow-up by phone or personally. Whether this finding is caused by small numbers within this retrospective study should be investigated in future prospective studies. Conclusion: Follow-up does not influence the reintroduction success rate of cow's milk after a negative double-blinded placebo-controlled food challenge. What is Known: Diagnosis of cow's milk allergy by double-blinded placebo-controlled food challenge is the gold standard. • After a negative double-blinded placebo-controlled food challenge, reintroduction of cow's milk in the child's diet is unsuccessful in 10–12% of the children. • Recurrence of symptoms, aversion to the examined food, and fear are seen as the main reasons for unsuccessful introduction. What is New: • Reintroduction after a negative double-blinded placebo-controlled food challenge is not influenced by different ways of follow-up.

Laryngoscope burn risk in neonatal intubation Abstract Laryngoscope burns in neonatal intubation Following burns during neonatal intubation, we mounted an in vitro study of laryngoscopes to determine the temperatures reached during clinical use. The temperature of 10 different bulb laryngoscopes heads and two fibre optic heads were measured with a thermocouple, once opened, and upon closing. Within 60 s, all ten laryngoscopes, with light-bulb sources, had gained significant heat to cause thermal injury to neonatal skin. Laryngoscopes with LED light source and fibre optic heads did not. Conclusion: We recommend that the bulb laryngoscope blade, if used, is not left open prior to intubation and that it is closed between intubation attempts. What is Known: • The preterm epidermis is particularly vulnerable to injury. What is New: • Bulb laryngoscope light bulbs consistently reach temperatures sufficient to burn neonatal skin in less than 100 s in an in vitro study. • Bulb light safety advice should be incorporated into intubation guidelines.

Comparative evaluation of Airtraq™ and GlideScope® videolaryngoscopes for difficult pediatric intubation in a Pierre Robin manikin Abstract Airway management in children is associated with anatomical and physiological challenges compared with adults. Pierre Robin sequence (PRS) is a condition characterized by micrognathia, glossoptosis, and cleft palate and related to a difficult airway. Both the Airtraq™ and GlideScope® have never been previously directly compared in PRS. Our aim was to evaluate the performance of these two airway devices in a PRS manikin for ethical and practical reasons. Between April and July 2017, 26, pediatric intensive care clinical fellows or trainees from a tertiary pediatric center were recruited to participate. In this prospective and randomized crossover trial, all participants first set up the Airtraq™ and the GlideScope® and then used these videolaryngoscopes to intubate an AirSim® PRS manikin. Our primary outcome measure was the duration of the successful intubation attempt. Duration of the successful intubation attempt was 18.1 (14.2–34.9 [10.2–51.3]) s for the Airtraq™ compared to 31.1 (18.7–55.6 [6.2–119]) s for the GlideScope® (p = 0.045). Setup time was 50.0 ± 6.9 s for the Airtraq™ and 27.8 ± 8.6 s for the GlideScope® (p < 0.001). Conclusion: Even though setup time was longer, the characteristics of intubation performance were superior with the Airtraq™ relative to the GlideScope® in an AirSim® PRS manikin. What is Known: • Several case reports have described the successful use of Airtraq™ to intubate children with Pierre Robin sequence. • The GlideScope® has demonstrated similar rates of first-attempt successful intubation to flexible fiberoptic bronchoscopy in a Pierre Robin sequence manikin. What is New: • In the hands of pediatric non-airway specialists, the characteristics of intubation performance, including the duration of the successful intubation attempt, are superior with the Airtraq™ compared with the GlideScope® in a Pierre Robin sequence manikin. • Setup time for the Airtraq™ is, however, longer relative to that for the GlideScope®.

Developmental and behavioral problems in preschool-aged primary ciliary dyskinesia patients Abstract Primary ciliary dyskinesia (PCD) causes a broad spectrum of disease. This study aims to explore the developmental, behavioral, and social-emotional aspects of preschool-aged children with PCD. Fourteen PCD, 17 cystic fibrosis (CF) patients and 15 healthy subjects were enrolled. Developmental features of the participants were evaluated with Ages and Stages Questionnaire. Parents of participants filled out the Child Behavior Checklist (CBCL). The number of children screened positive for developmental delay was statistically higher in the PCD group. Higher numbers of children with PCD were screened positive for developmental delay in communication and problem-solving domains. Delay in fine motor skill domain was more common in children with PCD and CF compared to healthy subjects. There was no difference among the three groups in terms of gross motor and personal-social development. None of the children in all three groups was shown to have social-emotional problems. In CBCL, patients with CF had higher internalizing problem scores. Externalizing and total problem scores did not differ between the three groups. However, among PCD patients, children with developmental delay on more than one domain had higher externalizing and total problem scores. Conclusion: The current study revealed that positive screening for developmental delay is more common in preschool-aged PCD patients compared to patients with CF and healthy children. What is Known: • Intelligence scores of school-aged PCD patients are similar to healthy subjects despite their higher internalizing problem scores on Child Behavior Checklist (CBCL). • School-aged PCD patients exhibit higher hyperactivity and inattention findings. What is New: • Positive screening for developmental delay in communication, problem-solving and fine motor skills is more common in preschool-aged PCD patients. • Preschool-aged PCD patients screened positive for developmental delay in more than one domain have higher externalizing and total problem scores on CBCL.

Maternal phenylketonuria in Turkey: outcomes of 71 pregnancies and issues in management Abstract Untreated phenylketonuria (PKU) in pregnancy causes a severe embryopathy called maternal PKU syndrome. Here, we aimed to assess management issues and pregnancy outcomes in the first published series of PKU pregnancies from the developing world. Data were collected retrospectively in a single center from 71 pregnancies and 45 live births of 32 women with PKU, 11 of whom were diagnosed in adulthood after having an affected child. Microcephaly, intellectual disability, and dysmorphic facies were more prevalent in offspring of untreated than treated pregnancies with classical PKU (100% vs. 0%, 91% vs. 0%, and 73% vs. 23% with p < 0.001, p < 0.001, and p = 0.037, respectively). In treated pregnancies, phenylalanine levels were higher during weeks 6–14 than other periods of gestation (4.38 vs. 3.93, 2.00 and 2.28 mg/dl; p < 0.05). Poor compliance correlated with higher phenylalanine levels (ρ = − 0.64, p = 0.019) and fluctuations (ρ = − 0.66, p = 0.014). Conclusion: More frequent phenylalanine measurements during late first trimester are crucial to improve outcomes in treated pregnancies. In order to prevent untreated pregnancies via detecting undiagnosed adults, countries where significantly many women of childbearing age were not screened as newborns may consider pre-pregnancy PKU screening. Microcephaly in the newborn should prompt screening for PKU in the mother. What Is Known •Untreated phenylketonuria during pregnancy causes maternal phenylketonuria syndrome in the newborn. •Effective treatment throughout pregnancy can prevent adverse fetal outcomes. What Is New: •Metabolic control is related to frequency of follow-up and worsens during late first trimester. Closer follow-up during this period may improve metabolic control. •In order to prevent untreated pregnancies, pre-pregnancy phenylketonuria screening may be considered if many women of childbearing age were not screened as newborns.

Prediction of prolonged ventilator dependence in preterm infants Abstract Volutrauma is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Our aims were to identify risk factors in the first 24 h for prolonged ventilator dependence and assess volume delivery and carbon dioxide levels in infants with evolving BPD. A retrospective study was undertaken of 41 infants born at less than 32 weeks of gestational age (GA). A higher tidal volume, minute volume and resistance and a lower GA, birth weight and compliance were associated with a significantly higher risk of ventilator dependence at 28 days. The strongest relationships were with birth weight (area under the receiver operating characteristic curve, AUROC = 0.771) and GA (AUROC = 0.813). Tidal volume remained significantly higher after adjusting for GA in those who remained ventilator dependent at 28 days. The 18 who remained ventilator dependent at 28 days had increased mean carbon dioxide (PCO2) levels with increasing age from a mean of 41 mmHg in the first 24 h to 65 mmHg at 28 days PMA (p < 0.001). The increase in PCO2 occurred despite increases in peak inflation pressures (p < 0.001), tidal volumes (p = 0.002) and minute volumes (p < 0.001). Conclusion: These results suggest that initial volutrauma may contribute to the development of chronic ventilator dependence. What is Known: • In prematurely born infants, excessive tidal volumes are important in the pathogenesis of bronchopulmonary dysplasia (BPD), but a tidal volume that is too low will increase the risk of atelectasis, work of breathing and energy expenditure. What is New: • A high tidal volume in the first 24 h was associated with an increased risk of ventilator dependence at 28 days, which remained significant after adjusting for gestational age. Carbon dioxide levels significantly increased over the first month despite increased pressures and volumes in those who remained ventilator dependent.

Care for children with severe chronic skin diseases Abstract In this study, the care for children with a severe chronic skin disease in our national expert center of pediatric dermatology was evaluated. Patients and their parents were questioned by using existing questionnaires: 50 pediatric patients completed the modified "my positive health" questionnaire of Huber and 51 parents completed Pelentsov parental needs scale. Nineteen involved professionals answered a questionnaire with open boxes. Parents of children with a variety of chronic skin diseases and young adult patients were interviewed to find out what an optimal approach would look like according to them. Children with a severe chronic and/or congenital skin disorder score high on the "my positive health" questionnaire, indicating they are able to adapt and self-manage. Their highest median score was measured for the dimension "quality of life." Their parents expect improvement of "working with health care professionals," more specifically they want them to adopt a more holistic approach throughout the patient's life. Structured interviews showed they expect that a multidisciplinary team of care providers determine together with the patient and its family—in advance—which care is needed, at what time and by whom. The interviewed professionals indicated adoption of a holistic multidisciplinary approach as the single largest improvement to achieve better care. Conclusion: Although these children with a severe chronic and/or congenital skin disease were able to adapt and self-manage, they need a more personalized integrative multidisciplinary and systematic transmural approach covering all aspects of life during their lifetime. What is Known: • Severe skin disorders affect the child and its family in several ways. In our expert center, we try to optimize the care for these children through a multidisciplinary approach. What is New: • To our knowledge, no English publication describes the requirements for good care for pediatric patients with severe chronic skin disorders and how to optimize this care. We evaluated the health status of children with severe chronic skin disorders and the strengths and weaknesses of past and current care by questioning these children, their parents, adult patients, and involved professionals.

The triglycerides and glucose index is associated with elevated blood pressure in apparently healthy children and adolescents Abstract Prevalence of elevated blood pressure in pediatric population has been increasing worldwide. Thus, the aim of this study was to examine whether the triglycerides and glucose (TyG) index is associated with the presence of prehypertension or hypertension in children and adolescents. Apparently healthy children aged 6 to 15 years were enrolled in a population-based cross-sectional study. Participants were allocated into groups with normal blood pressure (NBP), prehypertension, and hypertension. Smoking, alcohol intake, pregnancy, previous diagnosis of diabetes, kidney, hepatic, or endocrine diseases were exclusion criteria. NBP was defined by systolic and/or diastolic blood pressure < 90th percentile, prehypertension by systolic and/or diastolic blood pressure ≥ 90th < 95th percentile, and hypertension by systolic and/or diastolic blood pressure ≥ 95th percentile, according to age, sex, and height percentiles. A total of 3589 children were enrolled, 1748 (49%) girls and 1841 (51%) boys, and allocated into groups with NBP (n = 2874), prehypertension (n = 271), and hypertension (n = 444). The multiple logistic regression analysis stratified by age and adjusted by the Z-score/SDS of body mass index and waist circumference showed that elevated TyG index was significantly associated with prehypertension (OR = 1.48; 95% CI: 1.08–2.05) and hypertension (OR = 1.63; 95% CI: 1.26–2.11). Conclusion: The results of the present study shows that the elevated TyG index is significantly associated with the presence of prehypertension and hypertension in children and adolescents. What is Known: • Prevalence of elevated blood pressure in children and adolescents has been increasing worldwide. • Insulin resistance plays a key role in the pathogenesis of hypertension. What is New: • The elevated TyG index is significantly associated with the presence of prehypertension in children aged 6–9 years and adolescents aged 10–15 years. • The elevated TyG index is significantly associated with the presence of hypertension in children aged 6–9 years and adolescents aged 10–15 years.

Comparison of cranial ultrasound and MRI for detecting BRAIN injury in extremely preterm infants and correlation with neurological outcomes at 1 and 3 years Abstract This study aimed to investigate the accuracy of different grades of brain injuries on serial and term equivalent age (TEA)-cranial ultrasound imaging (cUS) as compared to TEA magnetic resonance imaging (MRI) in extremely preterm infants < 28 weeks, and determine the predictive value of imaging abnormalities on neurodevelopmental outcome at 1 and 3 years. Seventy-five infants were included in the study. Severe TEA-cUS injury had high positive predictive value-PPV (100%) for predicting severe MRI injury compared to mild to moderate TEA-cUS injury or severe injury on worst cranial ultrasound scan. Absence of moderate to severe injury on TEA cUS or worst serial cUS was a good predictor of a normal MRI (negative predictive values > 93%). Severe grade 3 injuries on TEA-US had high predictive values in predicting abnormal neurodevelopment at both 1 and 3 years of age (PPV 100%). All grades of MRI and worst serial cUS injuries poorly predicted abnormal neurodevelopment at 1 and 3 years. Absence of an injury either on a cranial ultrasound or an MRI did not predict a normal outcome. Multiple logistic regression did not show a significant correlation between imaging injury and neurodevelopmental outcomes. Conclusion: This study demonstrates that TEA cUS can reliably identify severe brain abnormalities that would be seen on MRI imaging and positively predict abnormal neurodevelopment at both 1 and 3 years. Although MRI can pick up more subtle abnormalities that may be missed on cUS, their predictive value on neurodevelopmental impairment is poor. Normal cUS and MRI scan may not exclude abnormal neurodevelopment. Routine TEA-MRI scan provides limited benefit in predicting abnormal neurodevelopment in extremely preterm infants. What is Known: • Preterm neonates are at increased risk of white matter and other brain injuries, which may be associated with adverse neurodevelopmental outcome. • MRI is the most accurate method in detecting white matter injuries. What is New: • TEA-cUS can reliably detect severe brain injuries on MRI, but not mild/moderate lesions as well as abnormal neurodevelopment at 1 and 3 years. • TEA-MRI brain injury is poor in predicting abnormal neurodevelopment at 1 and 3 years and normal cUS or MRI brain injury may not guarantee normal neurodevelopment.

Accelerometer-based physical activity levels, fundamental movement skills and weight status in British preschool children from a deprived area Abstract Preschool children are recommended to participate in a minimum of 180-min physical activity (PA) per day to enhance their development and overall health. Low PA and increased obesity are thought to be linked to low mastery of fundamental movement skills (FMS) in preschool children. This study sought to investigate whether FMS influences PA levels and weight status in preschool children, in an area of low socioeconomic status. Secondary aims of this study were to determine whether gender or day of the week affected the primary outcomes. One hundred eighty-five preschool children aged 3–4 years old, participated in the study. FMS proficiency was determined using the Test of Gross Motor Development-2. PA was determined using triaxial accelerometry over a 4-day period. None of the samples met the recommended 180 min of PA. There were no significant differences in PA or weight status between preschool children with high, medium or low FMS mastery (P < 0.05). There were also no significant correlations between overall FMS and moderate to vigorous PA during the week or weekend days. Conclusion: Girls scored significantly greater at the hop, leap, and skip (locomotor skills) and the boys significantly higher at the kick (object control) (P < 0.05). There were no significant differences in PA or weight status between preschool children with high, medium, or low FMS mastery, possibly because FMS mastery had not developed to a high enough level to affect PA and FMS are considered independent of physical fitness and physical features, such as weight and height. What is Known: •FMS are commonly developed in early childhood, providing the building blocks for future motor skills, good health and lifelong PA. •No study to date has measured FMS, PA levels and weight status in preschool children, to determine whether FMS competency influences PA levels and weight status in preschool children, in an area of low SES. What is New: •FMS competency did not appear to influence the level of PA or weight status in this sample of UK preschool children from a low SES area. •PA and FMS may not be fully established and consequently not strongly linked at the ages of 3–4 years, therefore, the preschool years could be influential in providing a window to maximise input of good/optimal development of motor competence before the proficiency barrier sets in and we need remedial intervention.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Critical Care Medicine

Causes of Death in Status Epilepticus Objectives: To determine the causes of death in patients with status epilepticus. To analyze the relative contributions of seizure etiology, seizure refractoriness, use of mechanical ventilation, anesthetic drugs for seizure control, and medical complications to in-hospital and 90-day mortality, hospital length of stay, and discharge disposition. Design: Retrospective cohort. Setting: Single-center neuroscience ICU. Participants: Patients with status epilepticus were identified by retrospective search of electronic database from January 1, 2011, to December 31, 2016. Interventions: Review of electronic medical records. Measurements and Main Results: Demographics, clinical characteristics, treatments, and outcomes were collected. Univariable and multivariable logistic regression analysis were used to determine whether the use of anesthetic drugs, mechanical ventilation, Status Epilepticus Severity Score, refractoriness of seizures, etiology of seizures, or medical complications were associated with in-hospital, 90-day mortality or discharge disposition. Among 244 patients with status epilepticus (mean age was 64 yr [interquartile range, 42–76], 55% male, median Status Epilepticus Severity Score 3 [interquartile range, 2–4]), 24 received anesthetic drug infusions for seizure control. In-hospital and 90-day mortality rates were 9.2% and 19.2%, respectively. Death was preceded by withdrawal of life-sustaining treatment in 19 patients (86.3%) and cardiac arrest in three (13.7%). Only Status Epilepticus Severity Score was associated with in-hospital and 90-day mortality, whereas the use of anesthetic drugs for seizure control, mechanical ventilation, medical complications, etiology, and refractoriness of seizures were not. Hospital length of stay was longer in patients with medical complications (p = 0.0091), refractory seizures (p = 0.0077), and in those who required anesthetic drugs for seizure control (p = 0.0035). Patients who had refractory seizures were less likely to be discharged home (odds ratio, 0.295; CI, 0.143–0.608; p = 0.0009). Conclusions: In this cohort, death primarily resulted from the underlying neurologic disease and withdrawal of life-sustaining treatment and not from our treatment choices. Use of anesthetic drugs, medical complications, and mechanical ventilation were not associated with in-hospital and 90-day mortality. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: maximilianohawkes@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Association of Elevated Plasma Interleukin 18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome Objective: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial. Design: Retrospective analysis of randomized controlled clinical trial. Setting: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis. Patients: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population. Interventions: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge. Measurements and Main Results: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7–3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5–3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however. Conclusions: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial. Drs. Rogers, Hunninghake, Matthay, Steingrub, Wheeler, and Baron helped with conception and design. Dr. Guan, Dr. Trtchounian, Ms. Kozikowski, Ms. DeSouza, Ms. Mogan, Dr. Liu, and Dr. Nakahira helped with experimental procedures. Drs. Rogers, Hunninghake, Kaimal, Desai, and Baron helped with analysis and interpretation. Drs. Rogers, Hunninghake, Kaimal, Desai, Liu, Matthay, Steingrub, Yoon, Nakahira, Choi, and Baron helped with manuscript preparation and revision. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) R01 HL112747, HL111024, HL51856, HL55330, Global Research Laboratory grant number 2016K1A1A2910779, K23 HL125663, NIH/National Center for Advancing Translational Sciences KL2-TR-002385, and NHLBI ARDS Network investigators. Drs. Rogers and Hunninghake, Ms. Kozikowski, Ms. DeSouza, and Drs. Liu, Matthay, Steingrub, Nakahira, Choi, and Baron received support for article research from National Institutes of Health (NIH). Dr. Hunninghake received funding from consulting for Genentech, Boehringer-Ingelheim, the Gerson Lehrman Group, and Mistubishi Chemical for work unrelated to this submission. Ms. Kozikowski's institution received funding from Brigham and Womens Hospital. Ms. DeSouza disclosed work for hire. Dr. Liu's institution received funding from NHLBI, National Institute of Diabetes and Digestive and Kidney Disease, and she received funding from National Policy Forum on Critical Care and Acute Renal Failure, Achaogen (consultant), Durect (consultant), Theravance (consultant), Quark (consultant), Potrero Med (consultant), Amgen (stockholder), and Baxter (presenter at sponsored meeting). Dr. Matthay's institution received funding from Bayer Pharmaceuticals, Department of Defense, GlaxoSmithKline, and he received other support from CSL Behring, Roche-Genentec, Quark Pharmaceuticals, Boerhinger-Ingelheim, Cerus Therapeutics, and NHLBI. Dr. Choi's institution received funding from NIH; he received funding from Teva Pharmaceuticals; and he disclosed that he is a cofounder, stock holder, and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide, and he has a use patent on carbon monoxide. Dr. Baron's institution received funding from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: ajrogers@stanford.edu; rbaron@partners.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Multi-Compartment Profiling of Bacterial and Host Metabolites Identifies Intestinal Dysbiosis and Its Functional Consequences in the Critically Ill Child Objectives: Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children. Design: Prospective multicenter cohort study. Setting: Three U.K.-based PICUs. Patients: Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55). Interventions: Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls. Measurements and Main Results: Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = –0.2; p = 0.037). Conclusions: Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. Profiling of bacterial metabolites in fecal and urine samples may support identification and treatment of intestinal dysbiosis in critical illness. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drs. Wijeyesekera and Wagner contributed equally. Dr. Wijeyesekera developed and supervised the metabolic profiling strategy, undertook data analysis, and wrote the article. Dr. Wagner developed and supervised the microbial profiling strategy, undertook data analysis, and wrote the article. Dr. De Goffau analyzed the microbial data and co-wrote the article. Ms. Thurston undertook sample processing and data analysis. Drs. Rodrigues Sabino and Zaher, Ms. White, Ms. Ridout, and Dr. Valla undertook sample processing, data collection, and analysis. Dr. Meyer undertook data analysis. Drs. Peters, Branco, Torok, Meyer, and Klein contributed to protocol development, supervised data analysis, and co-wrote the article. Dr. Parkhill developed the microbial profiling protocol, supervised all aspects of the microbial data analysis, and co-wrote the article. Drs. Frost and Holmes developed the metabolic profiling protocol, supervised all aspects of the metabolic data analysis, and co-wrote the article. Dr. Pathan conceived and supervised the study and wrote the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Aspects of the work were funded by an Imperial College Biomedical Research Centre award (to Drs. Holmes and Pathan), the Evelyn Trust (to Drs. Parkhill and Pathan), a Wellcome Trust Core Informatics Award (to Dr. Parkhill), Great Ormond Street Hospital Children's Charity (to Drs. Peters and Ramnarayan), and a Levi-Montalcini award from the European Society of Intensive Care Medicine (to Dr. Pathan). The research was supported by the National Institute for Health Research Biomedical Research Centres based at Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Great Ormond Street Hospital NHS Foundation Trust, Imperial College Healthcare NHS Trust, and Imperial College London. Dr. Rodrigues Sabino's institution received funding from National Institute for Health Research Imperial Biomedical Research Centre Institute of Translational Medicine and Therapeutics Call for Experimental Medicine Proposals. Dr. Valla received funding from Baxter and Nutricia. Dr. Meyer received funding from academic lectures for Danone, Nestle and Mead Johnson, and from the Mead Johnson Allergy Advisory Board. Dr. Frost's institution received funding from Nestle and Heptares, and he received support for article research from Research Councils UK and Bill & Melinda Gates Foundation. Drs. Frost, Parkhill, and Pathan received support for article research from Wellcome Trust/Charity Open Access Fund. Dr. Parkhill's institution received funding from Wellcome Trust, and he received funding from Next Gen Diagnostics Llc. Dr. Pathan's institution received funding from European Society of Intensive Care Medicine, Evelyn Trust, and Wellcome Trust. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Nazima Pathan, FRCPCH, PhD, Department of Paediatrics, University of Cambridge, Level 8, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom. E-mail: np409@cam.ac.uk Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Interprofessional Shared Decision-Making in the ICU: A Systematic Review and Recommendations From an Expert Panel Objectives: There is growing recognition that high-quality care for patients and families in the ICU requires exemplary interprofessional collaboration and communication. One important aspect is how the ICU team makes complex decisions. However, no recommendations have been published on interprofessional shared decision-making. The aim of this project is to use systematic review and normative analysis by experts to examine existing evidence regarding interprofessional shared decision-making, describe its principles and provide ICU clinicians with recommendations regarding its implementation. Data Sources: We conducted a systematic review using MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and Cochrane databases and used normative analyses to formulate recommendations regarding interprofessional shared decision-making. Study Selection: Three authors screened titles and abstracts in duplicate. Data Synthesis: Four papers assessing the effect of interprofessional shared decision-making on quality of care were identified, suggesting that interprofessional shared decision-making is associated with improved processes and outcomes. Five recommendations, largely based on expert opinion, were developed: 1) interprofessional shared decision-making is a collaborative process among clinicians that allows for shared decisions regarding important treatment questions; 2) clinicians should consider engaging in interprofessional shared decision-making to promote the most appropriate and balanced decisions; 3) clinicians and hospitals should implement strategies to foster an ICU climate oriented toward interprofessional shared decision-making; 4) clinicians implementing interprofessional shared decision-making should consider incorporating a structured approach; and 5) further studies are needed to evaluate and improve the quality of interprofessional shared decision-making in ICUs. Conclusions: Clinicians should consider an interprofessional shared decision-making model that allows for the exchange of information, deliberation, and joint attainment of important treatment decisions. Drs. Michalsen, Ganz, White, Jensen, Metaxa, Latour, Truog, and Curtis conceptualized the article. Drs. Michalsen, Long, and Ganz reviewed the literature. All authors drafted and revised the article for important intellectual content as well as final approval for the version submitted. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Dr. DeKeyser Ganz's institution received funding from the Israel Institute of Health Policy Research, and she received funding from the Israel Higher Education Commission. Dr. Metaxa received funding from European Society of Intensive Care Medicine. Dr. Truog received funding from Covance (Data Safety Monitoring Committee) and Sanofi (Data Safety Monitoring Committees). Dr. Kesecioglu reports receiving honorarium from Xenios A.G. The remaining authors have disclosed that they do not have any potential conflicts of interest. Ethical standards: This research does not involve human participants or animals. For information regarding this article, E-mail: jrc@u.washington.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Outcome Prediction in Postanoxic Coma With Deep Learning Objectives: Visual assessment of the electroencephalogram by experienced clinical neurophysiologists allows reliable outcome prediction of approximately half of all comatose patients after cardiac arrest. Deep neural networks hold promise to achieve similar or even better performance, being more objective and consistent. Design: Prospective cohort study. Setting: Medical ICU of five teaching hospitals in the Netherlands. Patients: Eight-hundred ninety-five consecutive comatose patients after cardiac arrest. Interventions: None. Measurements and Main Results: Continuous electroencephalogram was recorded during the first 3 days after cardiac arrest. Functional outcome at 6 months was classified as good (Cerebral Performance Category 1–2) or poor (Cerebral Performance Category 3–5). We trained a convolutional neural network, with a VGG architecture (introduced by the Oxford Visual Geometry Group), to predict neurologic outcome at 12 and 24 hours after cardiac arrest using electroencephalogram epochs and outcome labels as inputs. Output of the network was the probability of good outcome. Data from two hospitals were used for training and internal validation (n = 661). Eighty percent of these data was used for training and cross-validation, the remaining 20% for independent internal validation. Data from the other three hospitals were used for external validation (n = 234). Prediction of poor outcome was most accurate at 12 hours, with a sensitivity in the external validation set of 58% (95% CI, 51–65%) at false positive rate of 0% (CI, 0–7%). Good outcome could be predicted at 12 hours with a sensitivity of 48% (CI, 45–51%) at a false positive rate of 5% (CI, 0–15%) in the external validation set. Conclusions: Deep learning of electroencephalogram signals outperforms any previously reported outcome predictor of coma after cardiac arrest, including visual electroencephalogram assessment by trained electroencephalogram experts. Our approach offers the potential for objective and real time, bedside insight in the neurologic prognosis of comatose patients after cardiac arrest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http:/journals.lww.com/ccmjournal). Dr. van Putten is co-founder of Clinical Science Systems, a supplier of electroencephalogram systems for Medisch Spectrum Twente. The remaining authors have disclosed that they do not have any conflicts of interest. This work was performed in Medisch Spectrum Twente, Rijnstate Hospital, St. Antonius Hospital, University Medical Center Groningen and VieCuri Medical Center, The Netherlands. For information regarding this article, E-mail: m.tjepkema-cloostermans@mst.nl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial Objectives: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. Design: Prospective, randomized, controlled study. Setting: Thirty-three hospitals in China. Patients: A total of 710 adults 18–75 years old with severe community-acquired pneumonia. Interventions: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. Measurements and Main Results: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9–21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4–15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). Conclusions: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by a Tianjin Science and Technology committee grant (14ZXLJSY00230) and National Natural Science Foundation of China (81630001,81490533). Drs. X. Yu and Zhi Liu disclosed work for hire. Dr. B. Zhang disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx. Unique identifier: ChiCTR-TRC-13003534. For information regarding this article, E-mail: bai.chunxue@zs-hospital.sh.cn; shanghongcai@126.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Intracranial Hypertension and Cerebral Perfusion Pressure Insults in Adult Hypertensive Intraventricular Hemorrhage: Occurrence and Associations With Outcome Objectives: Elevated intracranial pressure and inadequate cerebral perfusion pressure may contribute to poor outcomes in hypertensive intraventricular hemorrhage. We characterized the occurrence of elevated intracranial pressure and low cerebral perfusion pressure in obstructive intraventricular hemorrhage requiring extraventricular drainage. Design: Prospective observational cohort. Setting: ICUs of 73 academic hospitals. Patients: Four hundred ninety-nine patients enrolled in the CLEAR III trial, a multicenter, randomized study to determine if extraventricular drainage plus intraventricular alteplase improved outcome versus extraventricular drainage plus saline. Interventions: Intracranial pressure and cerebral perfusion pressure were recorded every 4 hours, analyzed over a range of thresholds, as single readings or spans (≥ 2) of readings after adjustment for intracerebral hemorrhage severity. Impact on 30- and 180-days modified Rankin Scale scores was assessed, and receiver operating curves were analyzed to identify optimal thresholds. Measurements and Main Results: Of 21,954 intracranial pressure readings, median interquartile range 12 mm Hg (8–16), 9.7% were greater than 20 mm Hg and 1.8% were greater than 30 mm Hg. Proportion of intracranial pressure readings from greater than 18 to greater than 30 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 70 mm Hg were associated with day-30 mortality and partially mitigated by intraventricular alteplase. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and intracranial pressure greater than 20 mm Hg in spans were associated with both 30-day mortality and 180-day mortality. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 60 mm Hg were associated with poor day-30 modified Rankin Scale, whereas cerebral perfusion pressure less than 65 and less than 75 mm Hg were associated with poor day-180 modified Rankin Scale. Conclusions: Elevated intracranial pressure and inadequate cerebral perfusion pressure are not infrequent during extraventricular drainage for severe intraventricular hemorrhage, and level and duration predict higher short-term mortality and long-term mortality. Burden of low cerebral perfusion pressure was also associated with poor short- and long-term outcomes and may be more significant than intracranial pressure. Adverse consequences of intracranial pressure-time burden and cerebral perfusion pressure-time burden should be tested prospectively as potential thresholds for therapeutic intervention. A full list of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III). Investigators are available in Appendix 1 (Supplemental Digital Content 9, http://links.lww.com/CCM/E727). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Institutes of Health grants 5U01NS062851 for Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III). Genentech assisted by donating the study drug. Dr. Ziai received funding from C. R. Bard, Headsense, and NINDS. Drs. Ziai, Thompson, and Mayo, Ms. McBee, Dr. Ullman, Ms. Lane, and Drs. Awad and Hanley received support for article research from National Institutes of Health (NIH). Drs. Thompson's and Award's institutions received funding from the NIH. Ms. McBee's, Ms. Lane's, and Dr. Hanley's institutions received funding from NIH/NINDS 5U01NS062851, NIH/NINDS 1U01NS08082, and Genentech (drug donation). Ms. McBee, Dr. Ullman, Ms. Lane, and Drs. Awad and Hanley disclosed off-label product use of alteplase. Dr. Ullman's institution received funding from NIH/NINDS. Dr. Awad received funding from expert reviews and medicolegal opinions. Dr. Hanley received funding from BrainScope, Neurotrope, Portola Pharmaceuticals, Op2Lysis, HeadSense, and Medtronic. Dr. Ziai, Ms. McBee, Ms. Lane, and Drs. Awad and Hanley are supported by grant 5U01NS062851. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: weziai@jhmi.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Limiting Treatment in Intensive Care: Contributions and Limits of Ethics Consultation No abstract available

Impact of Critical Care Point-of-Care Ultrasound Short-Courses on Trainee Competence Objectives: Competence in point-of-care ultrasound is recommended/mandated by several critical care specialties. Although doctors commonly attend point-of-care ultrasound short-courses for introductory training, there is little follow-up data on whether they eventually attain competence. This study was done to determine the impact of point-of-care ultrasound short-courses on point-of-care ultrasound competence. Design: Web-based survey. Setting: Follow-up after point-of-care ultrasound short-courses in the Asia-Pacific region. Subjects: Doctors who attended a point-of-care ultrasound short-course between December 2015 and February 2018. Interventions: Each subject was emailed a questionnaire on or after 6 months following their short-course. They were asked if they had performed at least 30 structured point-of-care ultrasound scans and/or reached point-of-care ultrasound competence and their perceived reasons/challenges/barriers. They were also asked if they used point-of-care ultrasound as a clinical diagnostic aid. Measurements and Main Results: The response rate was 74.9% (182/243). Among the 182 respondents, only 12 (6.6%) had attained competence in their chosen point-of-care ultrasound modality, attributing their success to self-motivation and time management. For the remaining doctors who did not attain competence (170/182, 93.4%), the common reasons were lack of time, change of priorities, and less commonly, difficulties in accessing an ultrasound machine/supervisor. Common suggestions to improve short-courses included requests for scanning practice on acutely ill ICU patients and prior information on the challenges regarding point-of-care ultrasound competence. Suggestions to improve competence pathways included regular supervision and protected learning time. All 12 credentialled doctors regularly used point-of-care ultrasound as a clinical diagnostic aid. Of the 170 noncredentialled doctors, 123 (72.4%) reported performing unsupervised point-of-care ultrasound for clinical management, either sporadically (42/170, 24.7%) or regularly (81/170, 47.7%). Conclusions: In this survey of doctors attending point-of-care ultrasound short-courses in Australasia, the majority of doctors did not attain competence. However, the practice of unsupervised point-of-care ultrasound use by noncredentialled doctors was common. Further research into effective strategies to improve point-of-care ultrasound competence is required. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rrarvind@hotmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Why Understanding Sepsis Endotypes Is Important for Steroid Trials in Septic Shock? No abstract available

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Endoscopic Ultrasound

EUS-directed transgastric access to the excluded stomach to facilitate pancreaticobiliary interventions in patients with Roux-en-Y gastric bypass anatomy Robert A Moran, Saowanee Ngamruengphong, Omid Sanaei, Lea Fayad, Vikesk K Singh, Vivek Kumbhari, Mouen A Khashab Endoscopic Ultrasound 2019 8(3):139-145

Recent developments in hepatopancreatobiliary EUS Irina M Cazacu, Ben S Singh, Adrian Saftoiu, Manoop S Bhutani Endoscopic Ultrasound 2019 8(3):146-150 The last American College of Gastroenterology's (ACG) annual meeting was held in Philadelphia on October 5–10, 2018 and showcased a wide variety of the latest and upcoming research within the field of Gastroenterology. This article will present the advancements and research regarding endoscopic ultrasound (EUS) presented at this year's meeting with focus on hepatopancreatobiliary indications. Seventy studies related to EUS were presented; however, case reports and video forum presentations were excluded from this review. Many endosonographers investigated various aspects of EUS such as the tissue acquisition and diagnostic yields of fine-needle biopsies, the application of interventional EUS, and various novel techniques to advance the role of EUS. It would be very difficult to discuss all of the abstracts presented in details; however, we commend and encourage all endosonographers who presented at ACG to continue advancing research and development in EUS.

EUS-guided drainage: Summary of therapeutic EUS consortium meeting Michel Kahaleh, Everson L. A. Artifon, Manuel Perez-Miranda, Monica Gaidhane, Carlos Rondon, Martin Freeman, Rajeev Attam, Takao Itoi, Marc Giovannini Endoscopic Ultrasound 2019 8(3):151-160 EUS-guided drainage is a safe and efficacious endoscopic technique for biliary, pancreatic, and gallbladder decompression. Recent literature has described many successful procedural techniques and devices to achieve EUS-guided drainage. This consortium gathering advanced endoscopists with expertise in both ultrasonography and therapeutic endoscopy, discuss the introduction to learning several EUS-guided drainage approaches, devices, and technology involved, possible obstacles to certain procedural and all potential complications.

Imaging of infracolic and pelvic compartment by linear EUS Malay Sharma, Amol Patil, Avinash Kumar, Amit Pathak, Piyush Somani, Srijaya S Sreesh, Chittapuram Srinivasan Rameshbabu Endoscopic Ultrasound 2019 8(3):161-171 The peritoneal cavity is subdivided into supracolic and infracolic compartments by transverse mesocolon, which attaches the colon to the posterior abdominal wall. Infracolic compartment is subdivided into right and left compartment by small bowel mesentery. Left infracolic space freely communicates with pelvic compartment. The infracolic compartment contains the coils of small bowel which is separated from paracolic gutter on either side by ascending and descending colon. Pelvic compartment mainly contains bladder, rectum and genital organ (prostate, seminal vesicle in male and uterus in female). The evaluation of different compartments of peritoneum is gaining importance in multimodality imaging. It has become essential that clinicians and endosonographers thoroughly understand the peritoneal spaces and the ligaments and mesenteries that form their boundaries in order to localize disease to a particular peritoneal/subperitoneal space and formulate a differential diagnosis on the basis of that location. In this article we describe the applied EUS anatomy of peritoneal ligaments, infracolic and pelvic compartments of peritoneum and there technique of imaging from stomach, duodenum, sigmoid colon and rectum. Imaging from stomach images the infracolic compartment through transverse mesocolon, imaging from duodenum images the infracolic compartment through the mesentery and imaging from rectum and sigmoid images the infracolic and pelvic compartments through the sigmoid mesocolon and pelvic peritoneum.

Direct endoscopic necrosectomy at the time of transmural stent placement results in earlier resolution of complex walled-off pancreatic necrosis: Results from a large multicenter United States trial Linda Yan, Andrew Dargan, Jose Nieto, Reem Z Shariaha, Kenneth F Binmoeller, Douglas G Adler, Michael DeSimone, Tyler Berzin, Mandeep Swahney, Peter V Draganov, Dennis J Yang, David L Diehl, Lillian Wang, Asma Ghulab, Nausharwan Butt, Ali A Siddiqui Endoscopic Ultrasound 2019 8(3):172-179 Background and Objectives: EUS-guided drainage, and direct endoscopic necrosectomy (DEN) of walled-off necrosis (WON) using a lumen-apposing metal stent (LAMS) is safe and effective. Early debridement of WON may improve overall clinical outcomes. The aim of this study is to perform a multicenter retrospective study to compare the clinical outcomes and predictors of success for endoscopic drainage of WON with LAMS followed by immediate or delayed DEN performed at standard intervals. Methods: Patients with WON managed by EUS-guided drainage with LAMS were divided into 2 groups: (1) those that underwent immediate DEN at the time of stent placement and (2) those that underwent delayed DEN 1 week after stent placement. DEN was subsequently performed every 1–2 week (s). Technical success (successful placement of LAMS), adverse events (AEs), and clinical success (complete resolution of the WON) were evaluated. Results: Totally, 271 patients underwent WON drainage with LAMS: 69 who underwent immediate DEN and 202 who underwent delayed DEN. The technical success for LAMS placement was 100% in both groups. There was no significant difference in the overall procedural AEs between the immediate and delayed DEN groups (P = 7.2% vs. 9.4%; P = 0.81). Stent dislodgement during index endoscopy occurred in three patients in the immediate DEN group compared to zero in the delayed DEN group (P = 0.016); all three dislodgements occurred during necrosectomy. Clinical success for WON resolution in the immediate DEN group was 91.3% compared to 86.1% in the delayed DEN group (P = 0.3). The mean number of necrosectomy sessions for WON resolution was significantly lower in the immediate DEN group compared to the delayed DEN group (3.1 vs. 3.9, P < 0.001). Performing DEN at the time of stent placement was an independent predictor for resolution of WON with lesser number of DEN sessions (odds ratio 2.3; P = 0.004). Conclusions: DEN at the time of initial stent placement reduces the number of necrosectomy sessions required for successful clinical resolution of WON.

Performance characteristics of EUS-FNA biopsy for adrenal lesions: A meta-analysis Suhag Patel, Raxitkumar Jinjuvadia, Anupama Devara, Paul H Naylor, Mohammad Anees, Kartikkumar Jinjuvadia, Mohammad Al-Haddad Endoscopic Ultrasound 2019 8(3):180-187 Background and Objective: The role of EUS-FNA biopsy (EUS-FNAB) for detection of metastatic lesions (mets) to adrenals has not been evaluated systematically. Our aim is to systematically evaluate the performance characteristics of EUS-FNAB in detecting metastasis to the adrenal glands. Materials and Methods: We performed a systematic search on PubMed and OvidSP from January 1990 to July 2016 using various search terms for EUS and adrenal lesion. Only articles published in English literature were included in the study. Studies with fewer than 10 patients were excluded from the study. Publication bias was assessed using Begg-Mazumdar test and visual inspection of funnel plots. Results: Eight studies including 360 adrenal lesions that underwent EUS-FNAB were identified. Of these, 137 FNABs were conclusive for malignancy. Sensitivity of EUS-FNAB in detecting metastasis to the adrenals was 95% (95% confidence interval [CI]: 90%–98%) and specificity was 99% (95% CI: 96%–100%). Pooled positivity of EUS-FNAB in detecting lung cancer metastasis to the adrenals was 44% (95% CI: 31.5%–57.3%). No evidence of publication bias was noted. Conclusion: Our study demonstrates that EUS-FNAB is highly sensitive and specific in detecting metastasis to adrenals. It also shows that up to about half of the patients with lung cancer and adrenal lesions on imaging have metastasis, a finding with profound implications on lung cancer staging and treatment.

The underutilization of EUS-guided biliary drainage: Perception of endoscopists in the East and West Won Jae Yoon, Do Hyun Park, Jun Ho Choi, Sunguk Jang, Jason Samarasena, Tae Hoon Lee, Woo Hyun Paik, Dongwook Oh, Tae Jun Song, Joon Hyuk Choi, Kazuo Hara, Takuji Iwashita, Manuel Perez-Miranda, John G Lee, Enrique Vazquez-Sequeiros, Itaru Naitoh, Juan J Vila, William R Brugge, Mamoru Takenaka, Sang Soo Lee, Dong-Wan Seo, Sung Koo Lee, Myung-Hwan Kim Endoscopic Ultrasound 2019 8(3):188-193 Background and Objectives: EUS-guided biliary drainage (EUS-BD) is increasingly utilized to manage unresectable malignant biliary obstruction after a failed ERCP. However, there is no data on how endoscopists perceive EUS-BD. The aim of this study was to investigate the perception of endoscopists on EUS-BD. Patients and Methods: A survey questionnaire of six topics with 22 survey statements was developed. A total of 17 pancreatobiliary endoscopists (10 from East and 7 from West) were invited to survey. The participants were asked to answer the multiple choice questionnaire and give comments. The opinions of the participants for individual survey statements were assessed using 5-point Likert scale. Results: All participants completed the survey. The endoscopists had a trend to perceive EUS-BD as a procedure indicated after a failed ERCP. Various EUS-BD methods were regarded as having different efficacy and safety. The superiority of EUS-BD over percutaneous transhepatic BD (PTBD) with regard to efficacy, procedure-related adverse events, and unscheduled re-intervention was not in agreement. Conclusions: EUS-BD was not yet perceived as the initial procedure to relieve the unresectable malignant biliary obstruction. Various EUS-BD methods were regarded as having different efficacy and safety. The superiority of EUS-BD over PTBD was not in agreement. Refining the procedure, developing dedicated devices, and gaining expertise in the procedure are necessary to popularize EUS-BD.

Discontinuation of proton pump inhibitor use reduces the number of endoscopic procedures required for resolution of walled-off pancreatic necrosis Patrick C Powers, Ali Siddiqui, Reem Z Sharaiha, Grace Yang, Enad Dawod, Aleksey A Novikov, Amy Javia, Cynthia Edirisuriya, Arish Noor, Tayebah Mumtaz, Usama Iqbal, David E Loren, Thomas E Kowalski, Natalie Cosgrove, Yordano Alicea, Amy Tyberg, Iman Andalib, Michel Kahaleh, Douglas G Adler Endoscopic Ultrasound 2019 8(3):194-198 Background and Objectives: Endoscopic drainage/debridement of symptomatic walled off necrosis (WON) using lumen-apposing metal stents (LAMS) is both safe and effective. While endoscopic management of WON is the standard approach to treatment, the ideal concomitant medical therapy remains unclear. The purpose of this study was to further elucidate the effect of proton pump inhibitor (PPIs) therapy on the technical and clinical success of endoscopic treatment of WON. Methods: Two hundred and seventy-two patients in 8 centers with WON managed by endoscopic drainage using LAMS were evaluated. Patients were followed for at least 6 months following treatment. The patients were divided into two groups: Those that used PPIs continuously during the therapy and those not on PPIs continuously during the interval of therapy. Outcomes included but were not limited to technical success, clinical success, number of procedures performed, and adverse events. Results: From 2013 to 2016, 272 patients underwent WON drainage with successful transmural LAMS placement. The two groups were split evenly into PPI users and non-PPI users, and matched in regards to demographics, etiology of pancreatitis, WON size, and location. There was no difference in the technical success between the two groups (100% vs. 98.8%, P = 1), or in clinical success rates (78.7% vs. 77.9%). There was a significant difference in the required number of direct endoscopic necrosectomies to achieve clinical success in the PPI vs. non-PPI group (3.2 vs. 4.6 respectively, P < 0.01). There were significantly more cases of stent occlusion in the non-PPI group vs. PPI group (9.5% vs. 20.1% P = 0.012), but all other documented adverse events were not significantly different. Conclusion: Discontinuing PPIs during endoscopic drainage and necrosectomy of symptomatic WON appears to reduce the number of endoscopic procedures required to achieve resolution. Continuous PPI results in higher rates of early stent occlusion.

Drainage of the right liver under EUS guidance: A bridge technique allowing drainage of the right liver through the left liver into the stomach or jejunum Fabrice Caillol, Coline Bosshardt, Sylvia Reimao, Ellen Francioni, Christian Pesenti, Erwan Bories, Jean Philippe Ratone, Marc Giovannini Endoscopic Ultrasound 2019 8(3):199-203 Background and Objective: EUS-guided biliary drainage is now comparable to percutaneous drainage. This technique can be used in cases of complex drainage of the hilum, mainly for salvage therapy to drain the left liver. In cases of inaccessible papilla or altered anatomy, EUS-guided biliary drainage for hilar stenosis of the liver could be used as the first approach. However, this technique has limited applicability for the right liver. In this feasibility study, we reported drainage of the right liver using the bridge technique and hepaticogastrostomy. Patients and Methods: This retrospective study was based on a prospective registry from January 2013 to February 2017. Patients with inaccessible papilla due to altered anatomy or duodenal invasion and drainage under EUS guidance and bridge technique without previous biliary drainage were included in the study. The bridge technique was used to place an uncovered biliary stent between the right and left liver. The left liver was drained with a hepaticogastrostomy. Results: Twelve patients were included in the study. Stenosis was Type II for nine, IIIA for two, and Type IV for one patient. Technical and clinical success was 100% and 83%, respectively. Morbidity was 33% (four patients), including three with abdominal pain managed conservatively and one with a percutaneous salvage drainage. Postoperative mortality was 8% (uncontrolled sepsis). The mean survival was 6 months. Chemotherapy could be administered in 70% (seven) patients in cases of clinical success. Conclusion: The bridge technique under EUS guidance could be a first alternative for draining malignant hilar stenosis in cases of the inaccessible papilla.

Endobronchial ultrasound-guided transbronchial needle aspiration under general anesthesia versus bronchoscopist-directed deep sedation: A retrospective analysis Christian G Cornelissen, Johanna Dapper, Michael Dreher, Tobias Müller Endoscopic Ultrasound 2019 8(3):204-208 Background: Different sedation strategies are used during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnostic workup of lung cancer including general anesthesia (GA) and moderate sedation. However, no data are available about EBUS-TBNA under deep sedation (DS) with fiberoptic intubation directed by the investigator. Materials and Methods: A retrospective analysis of EBUS-TBNAs under GA (n = 160) or DS (n = 105) was performed. Results: Unadjusted diagnostic yield did not differ significantly between the groups (GA: 42.5% vs. DS: 53.3%P= 0.1018). Similar results were obtained when only patients with a final diagnosis of malignancy were analyzed (GA: 53.6% vs. DS: 61.5%P= 0.2675). Adverse events (AEs) occurred more often under DS (GA: 27.5% vs. DS: 59.1%P< 0.0001) due to more sedation-related problems whereas severe AEs tended to be higher under GA (GA: 7.5% vs. DS: 1.9%P= 0.0523). Conclusion: In summary, our data show that the diagnostic yield and the complication rate of EBUS-TBNA performed under DS are similar compared to GA. Hence, in an appropriate setting, EBUS-TBNA can be performed safely under DS.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Tropical Biomedicine

Nationwide seroprevalence, spatial distribution and risk factors of Leishmania in Jordan Mohammad M Obaidat, Amira A Roess Asian Pacific Journal of Tropical Biomedicine 2019 9(6):227-231 Objective: To explore the seroprevalence, spatial distribution and risk factors for Leishmania seropositivity in Jordan. Methods: Blood samples from 872 apparently healthy participants were randomly selected from 11 governorates in Jordan and tested for anti-Leishmania K39 IgG. Risk factors (animal ownership and agriculture practices) and demographic data were also collected using pre-tested and validated questionnaire. Results: Overall, 2.52% of participants were seropositive for Leishmania spp. Participants living in the Jordan Valley plateau had significantly greater odds (adjusted odds ratio = 3.70, 95% CI 1.37-9.93) of seropositivity than those living in the Highlands after adjustment for age. Conclusions: This study supports the intermittent reports of cutaneous leishmaniasis outbreaks in the Jordan Valley. Vector control measures in the Jordan Valley should be considered, including insecticide treated bed nets, sugar baits and using flowering plants to attract and trap Phlebotomus papatasi sand flies. Active surveillance in the Jordan Valley is also recommended in light of this and other reports.

Establishment of an early warning system for cutaneous leishmaniasis in Fars province, Iran Marjan Zare, Abbas Rezaianzadeh, Hamidreza Tabatabaee, Hossain Faramarzi, Mohsen Aliakbarpour, Mostafa Ebrahimi Asian Pacific Journal of Tropical Biomedicine 2019 9(6):232-239 Objective: To establish an early warning system for cutaneous leishmaniasis in Fars province, Iran in 2016. Methods: Time-series data were recorded from 29 201 cutaneous leishmaniasis cases in 25 cities of Fars province from 2010 to 2015 and were used to fit and predict the cases using time-series models. Different models were compared via Akaike information criterion/ Bayesian information criterion statistics, residual analysis, autocorrelation function, and partial autocorrelation function sample/model. To decide on an outbreak, four endemic scores were evaluated including mean, median, mean + 2 standard deviations, and median + interquartile range of the past five years. Patients whose symptoms of cutaneous leishmaniasis began from 1 January 2010 to 31 December 2015 were included, and there were no exclusion criteria. Results: Regarding four statistically significant endemic values, four different cutaneous leishmaniasis space-time outbreaks were detected in 2016. The accuracy of all four endemic values was statistically significant (P<0.05). Conclusions: This study presents a protocol to set early warning systems regarding time and space features of cutaneous leishmaniasis in four steps: (i) to define endemic values based on which we could verify if there is an outbreak, (ii) to set different time-series models to forecast cutaneous leishmaniasis in future, (iii) to compare the forecasts with endemic values and decide on space-time outbreaks, and (iv) to set an alarm to health managers.

Trigonella foenum-graecum seed extract modulates expression of lipid metabolism- related genes in HepG2 cells Maryam Mohammad-Sadeghipour, Mehdi Mahmoodi, Soudeh Khanamani Falahati-pour, Alireza Khoshdel, Mohammad Ali Fahmidehkar, Mohammad Reza Mirzaei, Mojgan Noroozi Karimabad, Mohammad Reza Hajizadeh Asian Pacific Journal of Tropical Biomedicine 2019 9(6):240-248 Objective: To investigate anti-dyslipidemic effects of hydroalcoholic fenugreek seed extracts, diosgenin, and 4-OH-Ile on HepG2 cell line. Methods: HepG2 cells were treated with hydroalcoholic fenugreek seed extracts, diosgenin, 4-OH-Ile, and orlistat. IC20 was calculated using the MTT method. The cells were then pre-treated with IC20 concentrations for 24 and 48 h. Real time PCR was employed to measure expression of liver X receptor alpha (LXR α ), sterol regulatory element-binding protein-1C (SREBP-1C), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), fibroblast growth factor 21 (FGF21), peroxisome proliferator-activated receptor gamma (PPAR γ ), and low-density lipoprotein receptor (LDLR). Results: The results showed that LXR α (P=0.003, P<0.001), SREBP-1C (P<0.001, P<0.001), ACC (P=0.002, P=0.006), and FAS (P<0.001, P<0.001) were downregulated significantly, while FGF21 (P<0.001, P<0.001), PPAR 7 (P=0.004, P<0.001), and LDLR (P<0.001, P<0.001) were upregulated significantly in HepG2 cells treated with the IC20 of hydroalcoholic fenugreek seed extracts, diosgenin, 4-OH-Ile, and orlistat in 24 and 48 h, respectively. Conclusions: Hydroalcoholic fenugreek seed extracts, diosgenin, and 4-OH-Ile significantly modulate the expression of some important lipid metabolism related genes, which is similar to orlistat. Trigonella foenum-graecum seed extract or its derivatives should be further investigated for their dyslipidemia effects and its complications.

Methanolic extract of Abrus precatorius promotes breast cancer MDA-MB-231 cell death by inducing cell cycle arrest at G0/G1 and upregulating Bax Wan Suriyani Wan-Ibrahim, Norzila Ismail, Siti Farhanah Mohd-Salleh, Aidy Irman Yajid, Michael Pak-Kai Wong, Mohd Nizam Md Hashim Asian Pacific Journal of Tropical Biomedicine 2019 9(6):249-256 Objective: To determine the anti-proliferative activity of Abrus precatorius (A. precatorius) leaf extracts and their effect on cell death. Methods: A. precatorius leaves were extracted successively with hexane, ethyl acetate and methanol by Soxhlet extraction. Aqueous extract was prepared by decoction at 50 C. Extracts of A. precatorius leaves were used to treat selected cancer and normal cell lines for 72 h. Furthermore, 3-(4,5-dimethyl thiazol-2-yl) 2,5-diphenyl tetrazolium bromide assay was performed to determine cell viability. Analysis of cell cycle arrest, apoptosis assay and apoptosis protein expressions were determined by flow cytometry. Results: Methanolic extract of A. precatorius leaves showed the lowest IC50 on MDA-MB-231 cells at (26.40±5.40) μg/mL. Flow cytometry analysis revealed that cell arrest occurred at G0/ G1 phase and the apoptosis assay showed the occurrence of early apoptosis at 48 h in MDA-MB-231 cells treated with methanolic extract of A. precatorius leaves. Methanolic extract of A. precatorius leaves induced apoptosis by upregulation of Bax, p53 and caspase-3 and downregulation of Bcl-2. Conclusions: Methanolic extract of A. precatorius leaves promotes MDA-MB-231 cell death by inducing cell cycle arrest and apoptosis possibly via the mitochondrial-related pathway.

A new angiotensin-converting enzyme inhibitor from Peperomia pellucida (L.) Kunth Islamudin Ahmad, Neneng Siti Silfi Ambarwati, Berna Elya, Hanita Omar, Kamarza Mulia, Arry Yanuar, Osamu Negishi, Abdul Mun´im Asian Pacific Journal of Tropical Biomedicine 2019 9(6):257-262 Objective: To isolate, identify, and evaluate a new angiotensin-converting enzyme inhibitor from Peperomia pellucida (L.) Kunth herbs. Methods: A dried sample of Peperomia pellucida herb was successively macerated with n-hexane and ethyl acetate. The ethyl acetate extract solution was evaporated to obtain the crude extract. Vacuum liquid column chromatography and thin layer chromatography were performed to obtain two pure compounds. Then, both compounds were elucidated and identified using the spectroscopic method. Angiotensin-converting enzyme inhibitory activity studies of both compounds were determined using angiotensin-converting enzyme kit WST-1 with spectrophotometer microplate reader 96-well at 450 nm wavelength. Results: Two bioactive compounds were successfully isolated from Peperomia pellucida herb, including a new compound of 2,3,5-trimethoxy-9-(12,14,15-trimethoxybenzyl)-1H-indene and pellucidin A. Both compounds demonstrated angiotensin-converting enzyme inhibitory activity, with IC50 values of 72 μM (27.95 μg/mL) and 11 μM (4.4 μg/mL), respectively. Conclusions: In the present study, two active angiotensin-converting enzyme inhibitors were successfully isolated and purified from Peperomia pellucida which is used as an antihypertensive in traditional medicine, and support its use as an angiotensin-converting enzyme-inhibiting drug.

Gene set enrichment analysis of alpha-glucosidase inhibitors from Ficus benghalensis Pukar Khanal, BM Patil Asian Pacific Journal of Tropical Biomedicine 2019 9(6):263-270 Objective: To identify alpha-glucosidase inhibitors from Ficus benghalensis and analyze gene set enrichment of regulated protein molecules. Methods: The phytoconstituents of Ficus benghalensis were queried for inhibitors of alpha-glucosidase, also identified as aldose reductase inhibitors. Druglikeness score, absorption, distribution, metabolism, excretion and toxicity profile, biological spectrum, and gene expression were predicated for each compound. Docking study was performed to predict the binding affinity with alpha-glucosidase and aldose reductase and compared with clinically proven molecules. Kyoto Encyclopedia of Genes and Genomes pathway analysis was performed for the regulated genes to identify the modulated pathways. Results: Apigenin, 3,4’,5,7-tetrahydroxy-3’-methoxyflavone, and kaempferol were identified as inhibitors of alpha-glucosidase and aldose reductase. Kaempferol was predicted to possess the highest binding affinity with both targets. The p53 signaling pathway was predicted to modulate the majority of protein molecules in diabetes mellitus. All the alpha-glucosidase inhibitors were also predicted as membrane integrity agonist and anti-mutagenic compounds. Conclusions: The current study indicates alpha-glucosidase inhibitors from Ficus benghalensis can act as aldose reductase inhibitors after absorption from the intestinal tract. Furthermore, these phytoconstituents are involved in the regulation of numerous protein molecules and pathways. Hence, the anti-diabetic efficacies of these compounds are due to their action on multiple protein molecules and synergistic effects which should be confirmed by future investigations.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com