Factors Associated with the Quality and Transparency of National Guidelines: A Mixed-Methods Study.

We assessed the methodological quality and transparency of all the national clinical practice guidelines that were published in Croatia up until 2017 and explored the factors associated with their quality rating. An in-depth quantitative and qualitative analysis was performed using rigorous methodology. We evaluated the guidelines using a validated AGREE II instrument with four raters; we used multiple linear regressions to identify the predictors of quality; and two focus groups, including guideline developers, to further explore the guideline development process. The majority of the guidelines (N = 74) were developed by medical societies. The guidelines' quality was rated low: the median standardized AGREE II score was low, 36% (IQR 28-42), and so were the overall-assessments. The aspects of the guidelines that were rated best were the "clarity of presentation" and the "scope and purpose" (median ≥ 59%); however, the other four domains received very low scores (15-33%). Overall, the guideline quality did not improve over time. The guidelines that were developed by medical societies scored significantly worse than those developed by governmental, or unofficial working groups (12-43% per domain). In focus group discussions, inadequate methodology, a lack of implementation systems in place, a lack of awareness about editorial independence, and broader expertise/perspectives in working groups were identified as factors behind the low scores. The factors identified as affecting the quality of the national guidelines may help stakeholders who are developing interventions and education programs aimed at improving guideline quality worldwide.

Miscibility of rock and ice in the interiors of water worlds.

Super-Earths and sub-Neptunes are the most common planet types in our galaxy. A subset of these planets is predicted to be water worlds, bodies that are rich in water and poor in hydrogen gas. The interior structures of water worlds have been assumed to consist of water surrounding a rocky mantle and iron core. In small planets, water and rock form distinct layers with limited incorporation of water into silicate phases, but these materials may interact differently during the growth and evolution of water worlds due to greater interior pressures and temperatures. Here, we use density functional molecular dynamics (DFT-MD) simulations to study the miscibility and interactions of enstatite (MgSiO3), a major end-member silicate phase, and water (H2O) at extreme conditions in water world interiors. We explore pressures ranging from 30 to 120 GPa and temperatures from 500 to 8000 K. Our results demonstrate that enstatite and water are miscible in all proportions if the temperature exceeds the melting point of MgSiO3. Furthermore, we performed smoothed particle hydrodynamics simulations to demonstrate that the conditions necessary for rock-water miscibility are reached during giant impacts between water-rich bodies of 0.7-4.7 Earth masses. Our simulations lead to water worlds that include a mixed layer of rock and water.

A suicide attempt by ingestion of oleander leaves and treatment with digoxin-specific Fab antibody fragments.

Natural cardiac glycosides have positive inotropic heart effects but at high, toxic doses they can cause life-threatening cardiac arrhythmias. Here we present the first Croatian case of a 16-year-old girl who attempted suicide by eating dried oleander leaves, which contain natural cardiac glycosides, and her treatment with a specific antidote. The girl presented with an oedema of the uvula indicating local toxicity, severe bradycardia, first-degree atrioventricular block, drowsiness, and vomiting. Having taken her medical history, we started treatment with atropine, intravenous infusion of dextrose-saline solution and gastroprotection, but it was not successful. Then we introduced digoxin-specific Fab antibody fragments and within two hours, the patient's sinus rhythm returned to normal. Cases of self-poisoning with this oleander are common in South-East Asia, because it is often used as a medicinal herb, and digoxin-specific Fab fragments have already been reported as effective antidote against oleander poisoning there. Our case has taught us that it is important to have this drug in the hospital pharmacy both for digitalis and oleander poisoning.

Percutaneous Endoscopic Gastrostomy Tubes Can Be Considered Safe in Children: A Single-Center 11-Year Retrospective Analysis.

Background and Objectives: When the human body is disabled to naturally ingest food through the mouth, enteral or parenteral nutritional support should be started. Percutaneous gastrostomy (PEG) is a flexible feeding tube that is inserted into the stomach through the abdominal wall in patients who will need long-term enteral nutrient intake. The aim of this study is to analyze clinical characteristic of children at the time of PEG placement as well as to determine indications, complications and outcomes associated with PEG at the Department of Pediatrics of the University Hospital of Split. Materials and Methods: Retrospective analysis of the medical records of patients treated from 2010 to 2020 was performed. The following data were collected from medical records: age, gender, information about nasogastric feeding before PEG placement, indication for PEG insertion, duration of PEG, procedure-related complications and treatment outcomes. Malnutrition was determined according to the z-score range for BMI for age and sex. According to the indication for PEG placement, patients were divided into five categories: central nervous system (CNS) diseases, neuromuscular diseases, genetic disorders, metabolic diseases, and group of children with polytrauma. Results: A total of 40 patients with median age of 110 months were included in study. At the time of PEG placement, most patients had deviations in body weight and height compared to expected values for age and sex. The most common underlying diagnoses were diseases of the central nervous system. Minor complications were found in 13 (35%) of patients. One patient (2.7%) developed major complication (gastrocolic fistula) and consequently underwent reoperation. The median duration of PEG in patients with complications before the need for replacement was 27 months, and in patients without complications, 43 months. Conclusions: Negative deviations of z-score body weight, body height, and body mass index could indicate the need for possible earlier placement of PEG. PEG can be considered as a safe therapeutic option in children since PEG-related complications, mostly in minor forms, were found in a small number of patients.

Effectiveness of a Daily Rounding Checklist on Processes of Care and Outcomes in Diverse Pediatric Intensive Care Units Across the World.

BACKGROUND: Implementation of checklists has been shown to be effective in improving patient safety. This study aims to evaluate the effectiveness of implementation of a checklist for daily care processes into clinical practice of pediatric intensive care units (PICUs) with limited resources. METHODS: Prospective before-after study in eight PICUs from China, Congo, Croatia, Fiji, and India after implementation of a daily checklist into the ICU rounds. RESULTS: Seven hundred and thirty-five patients from eight centers were enrolled between 2015 and 2017. Baseline stage had 292 patients and post-implementation 443. The ICU length of stay post-implementation decreased significantly [9.4 (4-15.5) vs. 7.3 (3.4-13.4) days, p = 0.01], with a nominal improvement in the hospital length of stay [15.4 (8.4-25) vs. 12.6 (7.5-24.4) days, p = 0.055]. The hospital mortality and ICU mortality between baseline group and post-implementation group did not show a significant difference, 14.4% vs. 11.3%; p = 0.22 for each. There was a variable impact of checklist implementation on adherence to various processes of care recommendations. A decreased exposure in days was noticed for; mechanical ventilation from 42.6% to 33.8%, p < 0.01; central line from 31.3% to 25.3%, p < 0.01; and urinary catheter from 30.6% to 24.4%, p < 0.01. Although there was an increased utilization of antimicrobials (89.9-93.2%, p < 0.01). CONCLUSIONS: Checklists for the treatment of acute illness and injury in the PICU setting marginally impacted the outcome and processes of care. The intervention led to increasing adherence with guidelines in multiple ICU processes and led to decreased length of stay.

Feather foreign body caused periparotid and peritonsillar abscess in a 9-month-old girl.

Migratory foreign body appeared to be bird feather, caused peritonsillar and periparotid abscess in a nine-month-old infant. Patient presented painful, tender and fluctuating red neck mass on the left neck region II, and refusal of oral intake, with no fever. Azithromycin was introduced four days before presentation for suspected urinary tract infection. ENT examination revealed left peritonsillar abscess; ultrasound confirmed periparotid abscess, MSCT verified both diagnoses. Under general anaesthesia, we performed abscess incision, after pus drainage, small foreign body spontaneously came through the wound. After washing it with saline, it appeared like a bird feather. Subsequently, peritonsillar abscess was incised and drained. After 24-hour postoperative care on pediatric intensive care unit, the patient continued three-day parenteral antibiotic treatment on the otolaryngology department; it was discharged with a recommendation to continue seven days of oral antibiotic therapy. Suggested mechanism was ingestion of bird feather from stuffed bedding, that got trapped in the tonsillar crypt. Afterwards, it started to migrate through the neck tissue. Households with children younger than three years should not have feather stuffed clothes or beddings.

Germline AGO2 mutations impair RNA interference and human neurological development.

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.

Research methodology used in the 50 most cited articles in the field of pediatrics: types of studies that become citation classics.

BACKGROUND: One of the frequently used methods for assessing research trends and the impact of published scientific literature in a particular discipline is citation analysis. Journals may strive to improve their metrics by choosing manuscripts and study designs that are more likely to be cited. The aim of this study was to identify the 50 most-cited articles in the field of pediatrics, analyze their study design and other characteristics of those articles, and assess the prevalence of systematic reviews among them. METHODS: In December 2017, we searched Web of Science (WoS) for all articles published in the field of pediatrics. Two authors screened articles independently and in the further analysis included 50 articles with the highest number of citations. To avoid bias for scientific papers published earlier, the citation density was calculated. We also analyzed Journal Impact Factor (JIF) of journals where citation classics were published. RESULTS: The citation density in top 50 cited articles in the field of pediatrics ranged from 33.16 to 432.8, with the average of 119.95. Most of the articles reported clinical science. Median 2016 JIF for journals that published them was 6.226 (range: 2.778 to 72.406). Half of the top 10 highly cited articles in pediatrics were published in a journal with JIF below 5. Most of the studies among the citation classics in pediatrics were cross-sectional studies (N = 22), followed by non-systematic narrative reviews (N = 10), randomized controlled trials (N = 5), cohort studies (N = 5), systematic reviews (N = 2), case-control studies (N = 2), case reports (N = 2), and there was one study protocol and one expert opinion. CONCLUSION: Few randomized controlled trials and systematic reviews were among citation classics in the field of pediatrics. Articles that use observational research methodology, and are published in journals with lower impact factors, can become citation classics.

Characteristics of Children with Diabetic Ketoacidosis Treated in Pediatric Intensive Care Unit: Two-Center Cross-Sectional Study in Croatia.

Background and objective: There is an increasing risk of type 1 diabetes mellitus (T1D) among children in Croatia. Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with T1D, with cerebral edema as the most severe complication. Since early recognition of cerebral edema leads to a better outcome, it is important that patients with moderate or severe DKA are closely monitored and treated in pediatric intensive care units (PICUs). The aim of this study is to investigate clinical and laboratory parameters, as well as complications in children treated in PICUs because of DKA. Materials and methods: Patients treated due to DKA in the PICU of the University Hospitals of Split and Osijek from 2013 to 2017 were included in this study. Retrospectively collected data included age, gender, clinical signs and symptoms, and various laboratory parameters. After dividing subjects into two groups: Newly diagnosed with T1D (NT1D) and previously diagnosed with T1D (PT1D), collected data were compared between the two groups. Results: A total of 82 patients were enrolled. Those with NT1D were more often treated in the PICU, with two of them developing cerebral edema. Dehydration was the most frequent clinical sign, found in 95% of patients at admission. Decreased consciousness level was found in 41.5% of patients, with majority of them being somnolent. No difference was found between NT1D and PT1D. Additionally, there was no significant difference regarding laboratory data at admission. Conclusions: More children with NT1D required treatment in the PICU due to DKA with two of them developing cerebral edema. Since cerebral edema is a life-threatening condition, treatment of patients with moderate or severe DKA in PICUs will provide necessary monitoring enabling early recognition, treatment, and better treatment outcome. To minimize the incidence of DKA among patients with NT1D, it is important to continuously carry out public health education programs aimed at early identification of signs and symptoms of T1D.

Association of Appendicitis, Helicobacter Pylori Positive Gastritis and Thrombotic Thrombocytopenic Purpura in an Adolescent.

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) in children is a rare life-threatening syndrome, characterized by microangiopathic hemolytic anemia, thrombocytopenia with renal dysfunction, neurologic symptoms, and fever. TTP is usually caused by deficient activity of von Willebrand factor cleaving protease (ADAMTS13), due to either gene mutations or acquired via anti-ADAMTS13 autoantibodies. It can be triggered by bone marrow or solid organ transplantation, cardiothoracic-, abdominal-, and orthopedic surgeries, infections including very rarely Helicobacter pylori infection. CASE REPORT Here we report a case of a 16-year-old male with TTP, who presented with thrombocytopenia before an appendectomy. Seven days after surgery, our patient started to vomit, developed melena, and was admitted to our pediatric intensive care unit (PICU) with clinical presentation of shock. Gastroscopy revealed H. pylori positive hemorrhagic gastritis. The patient was treated by erythrocyte transfusions, fresh frozen plasma, human albumin, glucose-electrolyte solutions, vitamin K, platelet transfusion before implantation of central venous catheter, and antibiotics. After 36 hours, we started plasma exchange (PEX). Blood tests showed deficiency of ADAMTS13. Due to the presence of anti-ADAMTS13 autoantibodies, rituximab was administered. Due to generalized tonic-clonic seizures, he was artificially ventilated. Brain MR angiography showed small ischemic cerebro-vascular insult in the arteria cerebri media region. Despite immunosuppressive therapy and PEX, the patient did not improve completely until the H. pylori infection was eradicated. After which, he recovered completely. CONCLUSIONS We present a rare case of TTP accompanied with appendicitis and gastritis caused by H. pylori, where TTP improvement was dependent on H. pylori infection eradication.

Thrombocytopenic purpura following envenomation by the nose-horned viper (Vipera ammodytes ammodytes): Two case reports.

RATIONALE: Two clinical cases are reported of envenomation by the nose-horned viper (Vipera ammodytes ammodytes) venom of a 9-year-old boy and of an 84-year-old woman. PATIENT CONCERNS: Both patients had been bitten on their extremities by such a snake in August near Split, a town in southern Croatia. DIAGNOSES: Clinical manifestation of envenomation was severe in the case of the boy, being characterized by a severe coagulopathy. This was only just apparent in the case of the elderly woman, who suffered extensive local edema and hematoma at the site of the bite, together with a neurotoxic effect-bilateral ptosis. This was the first occasion of thrombocytopenic purpura being observed in patients envenomed by nose-horned viper venom. This unexpected clinical finding was characterized by an unusually profound thrombocytopenia of 5 and 10 × 10/L platelets of the respective patients on their admission to the hospital, together with purpura, observed on the face and thorax of both individuals. In the most serious cases, such pathology can be life threatening if not promptly recognized and treated. INTERVENTIONS: The patients recovered quickly on receiving the specific antivenom along with all the usual supportive treatments. OUTCOMES: No serious sequels were noticed at the moment of discharge. LESSONS: Our finding constitutes an important message to clinicians to consider the possibility of such complications in the case of nose-horned viper envenomation.

Emotional and behavioral outcomes and quality of life in school-age children born as late preterm: retrospective cohort study.

Aim To determine the effect of late preterm birth and treatment at the intensive care unit (ICU) on school-age children's emotional and behavioral problems and quality of life (QoL). METHODS: Emotional and behavioral problems and QoL were investigated in 6-12-year-olds who were born late preterm at the University Hospital Center Split in the period from January 2002 to March 2008. The study included 126 late preterm children treated in ICU (LP-ICU group), 127 late preterm children not treated in ICU (LP-non-ICU group), and 131 full-term children treated in ICU (FT-ICU group). Emotional and behavioral difficulties were assessed using the Child Behavior Checklist. QoL was evaluated with the Royal Alexandra Hospital for Children Measure of Function questionnaire. The data was collected via telephone interview with mothers during 2014. RESULTS: Late preterm children had a nearly 5-fold risk for internalizing problems in comparison with FT-ICU children (OR 4.76, 95% confidence interval [CI] 2.37-9.56 and OR 4.82, 95% CI 2.25-10.37 in LP-ICU and LP-non-ICU children, respectively). They also had a greater risk for externalizing problems (OR 3.08, 95% CI 1.44-6.61 and OR 2.68, 95% CI 1.14-6.28, respectively) and total problems (OR 6.29, 95% CI 2.86-13.83 and OR 7.38, 95% CI 3.08-17.69, respectively) and a considerably increased risk for lower QoL (OR 12.79, 95% CI 5.56-29.41 and OR 5.05, 95% CI 2.04-12.48, respectively). CONCLUSION: Children born late preterm had a greater risk for emotional and behavioral problems and lower QoL during childhood than their full-term born peers and they experienced serious health problems upon birth.

Late preterm birth is a strong predictor of maternal stress later in life: Retrospective cohort study in school-aged children.

AIM: The aim of this study was to compare the level of stress in mothers of school-aged children born late preterm and admitted to the intensive care unit (ICU) with the level of maternal stress if a child was born late preterm and not admitted to the ICU as well as if a full-term child was admitted to the ICU. METHODS: In this retrospective cohort study the data were gathered via telephone interview with mothers. The Parenting Stress Index/Short Form was used to determine the level of stress in mothers. Background demographic characteristics, medically relevant variables, and the level of stress were tested using the chi-square test and Kruskal-Wallis test. Logistic regression was used in order to identify predictors of significant level of stress. RESULTS: Mothers of late preterm born children who were admitted to the ICU, as well as mothers of late preterm children who were not admitted had higher level of stress compared to mothers of full-term children. Namely, mothers of late preterm born children admitted to the ICU had 18-fold increase in risk for significant level of total stress (OR = 18.09; 95% CI 8.55 to 38.26) while 24-fold greater risk was observed in mothers of late preterm children who were not admitted to the ICU (OR = 24.05; 95% CI 10.66 to 54.26) in comparison to mothers of full-term born children. CONCLUSION: Results indicate that preterm birth and its complications are associated with a higher level of stress in mothers, that persists to school age.

Lab-score is a valuable predictor of serious bacterial infection in infants admitted to hospital.

Parents frequently bring their children to the Emergency Department (ED) because of the fever without apparent source (FWAS). To avoid possible complications, it is important to recognize serious bacterial infection (SBI) as early as possible. Various tests, including different clinical scores and scales, are used in the laboratory evaluation of patients. However, it is still impossible to predict the presence of SBI with complete certainty. Galetto-Lacour et al. developed and validated a risk index score, named Lab-score. Lab-score is based on the three predictive variables independently associated with SBI: procalcitonin (PCT), C-reactive protein (CRP), and urinary dipstick. The objective of this study was to assess the performance of the Lab-score in predicting SBI in well-appearing infants ≤ 180 days of age with FWAS, who presented to ED and were hospitalized with suspicion of having SBI. Based on this study findings, white blood cells count (WBC), CRP, PCT, and lab-score ≥ 3 were confirmed as useful biomarkers for differentiation between SBI and non-SBI. Also, receiver operating characteristic curve (ROC) analysis confirmed that all of them were useful for differentiation between SBI and non-SBI patients with the highest area under curve (AUC) calculated for the Lab-score. The results of this research confirmed its value, with calculated sensitivity of 67.7% and specificity of 98.6% in prediction of SBI in infants aged ≤ 180 days. Its value was even better in infants aged ≤ 90 days with sensitivity of 75% and specificity of 97.7%. In conclusion, we demonstrated the high value of lab-score in detecting SBI in infants under 6 months of age with FWAS.

Effects of immune modulation therapy in the first Croatian infant diagnosed with Pompe disease: a 3-year follow-up study.

Pompe disease is a storage disorder characterized by deficient or absent activity of the enzyme acid alpha-glucosidase. As a result of ineffective metabolism, glycogen accumulates in muscle tissues. Patients with a classic infantile-onset form present by the first few months of life with hypertrophic cardiomyopathy and muscle weakness. If left untreated, these patients rapidly die of cardiorespiratory failure. A cross-reactive immunological material (CRIM)-negative status is predictive of high anti-alglucosidase alpha antibody titers. However, CRIM-positive patients also sometimes develop robust antibody titers. High antibody titers complicate therapeutic management, and those patients have a worse clinical outcome of enzyme replacement therapy (ERT).Four years ago, we successfully used an immune modulation therapy (IMT) protocol in a CRIM-positive infantile-onset patient with Pompe disease in whom ERT had to be discontinued because of severe infusion-associated reactions. She was found to be positive for anti-alglucosidase alpha antibodies. IMT (rituximab, methotrexate, and intravenous gammaglobulin) was started, and ERT was safely reintroduced during the IMT induction phase without any complications. Antibodies disappeared; IMT was tapered and discontinued; and cardiomyopathy steadily improved. During more than 3 years of follow-up, she remained ventilator dependent, and no gains in motor skills were noticed. The antibodies are still undetectable, and no adverse reactions associated with IMT had occurred. The cardiomyopathy is gradually increasing, but there is still ~ 50 % reduction as compared with the highest value measured. Although the reversal of clinical decline in our CRIM-positive and antibody-positive infant cannot be solely attributed to IMT, this protocol proved itself efficient and safe.

The correlation of changes of the optic nerve diameter in the acute retrobulbar neuritis with the brain changes in multiple sclerosis.

The aim of this paper is to compare diameter of healthy and affected optic nerve determined by ultrasound with brain lesions in acute retrobulbar neuritis in patients with multiple sclerosis. In this prospective study 20 patients with multiple sclerosis and acute retrobulbar neuritis were examined. Optic nerve diameter was measured by ultrasound. Brain lesions were detected by magnetic resonance. Correlation between demyelinating lesions of the brain in multiple sclerosis and optic nerve diameter was tested by Kruskal-Wallis test. Significant difference in diameter between healthy and affected optic nerve in acute retrobulbar neuritis was found. Demyelinating brain changes examined by magnetic resonance revealed periventricular lesions, subcortical lesions and lesions in corpus callosum. There is statistically significant correlation between optic nerve diameter and number of brain lesions in multiple sclerosis, p < 0.05. Diameter of optic nerve in retrobulbar neuritis measured by ultrasound correlates with brain lesions detected by magnetic resonance in multiple sclerosis.