Whole-exome sequencing for genetic diagnosis of idiopathic liver injury in children.

Genome-wide approaches, such as whole-exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter-individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric-onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually-curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case-level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously-reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.

Screening for functional gastrointestinal disorders in preterm infants up to 12 months of corrected age: a prospective cohort study.

Functional gastrointestinal disorders (FGIDs) are characterized by a variety of symptoms that are frequently age-dependent, chronic, or recurrent and are not explained by structural or biochemical abnormalities. There are studies in the literature reporting different results regarding the relationship between prematurity and FGIDs. The main objective of this study was to compare the frequency of FGIDs between preterm and term infants. The secondary objective was to evaluate whether there was any association between neonatal characteristics and development of FGIDs. A multicenter prospective cohort study that included preterm infants born before 37 weeks of gestation and healthy term infants was carried out. At 1, 2, 4, 6, 9, and 12 months of age, infants were assessed for the presence of FGIDs using the Rome IV criteria. In preterm infants, an additional follow-up visit was made at 12 months corrected age. 134 preterm and 104 term infants were enrolled in the study. Infantile colic, rumination syndrome, functional constipation, and infant dyschezia were more common in preterm infants. Incidence of other FGIDs (infant regurgitation, functional diarrhea and cyclic vomiting syndrome) were similar among preterm and term infants. Preterm infants who are exclusively breastfeed in the first 6 months of life have a lower incidence of infantile colic (18.8% vs 52.1%, p = 0.025). In terms of chronological age, FGIDs symptoms started later in preterm infants; this difference was statistically significant for infantile colic and regurgitation (median age 2 months vs 1 month, p < 0.001).   Conclusions: Preterm infants have a higher prevalence of FGIDs compared with term controls. Therefore, especially if they have gastrointestinal complaints, they should be screened for FGIDs. Possibly due to maturational differences, the time of occurrence of FGIDs may differ in preterm infants. Infantile colic incidence decreases with exclusive breastfeeding. What is Known: • The functional gastrointestinal disorders are a very common in infancy. • Data on preterm infants with FGIDs are currently very limited. What is New: • Preterm infants have a higher incidence of infantile colic, rumination syndrome, functional constipation and infant dyschezia when compared to term infants. • Preterm infants who are exclusively breastfed during the first 6 months of life experience a lower incidence of infantile colic.

Characteristics and outcomes of critically ill patients with covid-19 in Sakarya, Turkey: a single centre cohort study

Background/aim: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Turkey on March 10, 2020 and the number of the patients are increasing day by day. Coronavirus disease 2019 (Covid-19) has high mortality rates in intensive care units (ICUs). We aimed to describe the demographic characteristics, comorbidities, treatment protocols, and clinical outcomes among the critically ill patients admitted to the ICU of our hospital. Materials and methods: This cohort study included 103 consecutive patients who had laboratory confirmed Covid-19 and admitted to ICU of Sakarya University Training and Research Hospital between March 19 and April 13, 2020. The final date of the follow-up was April 18. Results: The mean age of the patients was 69.6 ± 14.1 years. Most of the patients had increased CRP (99%), serum ferritin (73.8%), d-dimer (82.5%), and hs-troponin levels (38.8%). 34 patients (33%) had lymphocytopenia, 24 patients (23.3%) had thrombocytopenia. 63 patients (61.2%) developed acute respiratory distress syndrome (ARDS), 31 patients (30.1%) had acute kidney injury, and 52 patients (50.5%) had multiple organ dysfunction syndrome (MODS) during follow-up. Sixty-two patients (60.2%) received mechanical ventilation. As of April 18, of the 103 patients, 52 (50.5%) had died, 30 (29.1%) had been discharged from the ICU, 21 (20.4%) were still in the ICU. Conclusions: Covid-19 has high mortality rates in ICU. Patients with elevated procalcitonin, hs-troponin, d-dimer, and CRP levels and lower platelet count at admission have higher mortality.

The relationship of extent of initial radiological involvement with the need of intensive care, mortality rates, and laboratory parameters in Covid-19

Background/aim: It is very important for the efficient use of limited capacity and the success of treatment to predict patients who may need ICU with high mortality rate in the Covid-19 outbreak. In our study, it was aimed to investigate the value of the radiological involvement on initial CT in demonstrating the ICU transfer and mortality rate of patients. Materials and methods: All PCR-positive patients were included in the study, whose CT, PCR, and laboratory values were obtained simultaneously at the time of first admission. Patients were divided into 4 groups in terms of the extent of radiological lesions. These groups were compared in terms of intensive care transfer needs and Covid-related mortality rates. Results: A total of 477 patients were included in the study. Ninety of them were group 0 (no lung involvement), 162 were group 1 (mild lesion), 89 were group 2 (moderate lesion), and 136 were group 3 (severe lung involvement). A significant relationship was found between the extensiveness of the radiological lesion on CT and admission to intensive care and mortality rate. As the initial radiological involvement amounts increased, the rate of ICU transfer and mortality increased. The mortality rates of the groups were 0%, 3%, 12.3%, and 12.5%, respectively, and the difference was significant (p < 0.001). Similarly, the ICU transfer rates of the groups were 2.2%, 5.6%, 13.5%, and 17.7%, respectively, and the difference was significant (p < 0.001). Conclusion: In conclusion, in our study, the strong relationship between the initial radiological extent assessment and the need for intensive care and mortality rates has been demonstrated, and we believe that our results will make a significant contribution to increase the success of the health system in predicting patients who may progress, helping clinicians and managing pandemics.

Screening for functional gastrointestinal disorders in children with epilepsy.

BACKGROUND AND AIM: We aimed to examine the frequency of functional gastrointestinal disorders (FGIDs) among pediatric patients with epilepsy and the association of FGIDs with epilepsy characteristics. MATERIAL AND METHODS: Patients with epilepsy aged between 4 and 18 years old were enrolled. Age- and sex-matched healthy children were taken as the control group. Children with cerebral palsy, history of abdominal surgery, gastrointestinal disorders, medication affecting gastrointestinal system motility, recent gastrointestinal infection, and those on the ketogenic diet were excluded from the study. Rome IV symptom-based criteria were used to screen FGIDs. Frequencies of FGIDs were compared between patients with epilepsy and controls. Additionally, epilepsy type, seizure frequency, and antiepileptic drug (AED) requirements were also compared between patients with and without FGIDs. RESULTS: During the study period, 78 children [41 girls, age between 4 and 17 years, mean ±â€¯standard deviation (SD): 11.5 ±â€¯4.3 years] with epilepsy were included in the study. The mean age at epilepsy onset was 7.8 ±â€¯3.7 years, and mean disease duration was 5.1 ±â€¯3.9 years. The most common epilepsy type was focal (74.3%), followed by generalized (25.7%). There was at least one of the FGIDs in 26 children in the patient group and 15 children in the control group (33.3% vs. 19.2%, p < 0.001). The most common FGID in the patient group was irritable bowel syndrome (IBS), which was significantly higher than the control group. While aerophagia and rumination syndrome were not seen in either group, cyclic vomiting syndrome was seen only in the patient group. When the patients with and without FGIDs were compared, there was no difference between the groups in terms of epilepsy type, frequency of seizure, type, and the number of drugs used. CONCLUSIONS: We found that children with epilepsy have a higher prevalence of FGIDs when compared with age- and sex-matched healthy controls. Our results suggest that children with epilepsy, especially complaining of gastrointestinal symptoms, should be screened for FGIDs.

Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

Hyaline fibromatosis syndrome (HFS), resulting from ANTXR2 mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious ANTXR2 mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-Cas9 ANTXR2 knockout, and compared with organoids from two healthy controls. The ANTXR2-deficient organoids displayed normal growth and polarity, compared to controls. Using an anthrax-toxin assay we showed that the c.155C>T mutation causes loss-of-function of ANTXR2 protein. An intrinsic defect of monolayer formation in patient-derived or ANTXR2KO organoids was not apparent, suggesting normal epithelial function. However, electron microscopy and second harmonic generation imaging showed abnormal collagen deposition in duodenal samples of these patients. Specifically, collagen VI, which is known to bind ANTXR2, was highly expressed in the duodenum of these patients. In conclusion, despite resistance to anthrax-toxin, epithelial cell function, and specifically monolayer formation, is intact in patients with HFS. Nevertheless, loss of ANTXR2-mediated signaling leads to collagen VI accumulation in the duodenum and abnormal extracellular matrix composition, which likely plays a role in development of PLE.

[Mortality prediction ability of phycians in intensive care units of Turkey (MOPAP)]. / Türkiye'de yogun bakim ünitelerinde hekimin mortaliteyi öngörebilme gücü.

INTRODUCTION: Intensive care physicians are increasingly involved in decision making about the prognosis of intensive care unit ICU patients. With this study; we aimed to evaluate the power of clinician foresight at prediction of mortality in patient at triage to intensive care and patient follow-up. MATERIALS AND METHODS: This study was conducted in ICUs located in various geographical regions of Turkey between January 1, 2017-April 30, 2017.The clinical research was planned as observational, multicenter, cross-sectional. RESULT: A total of 1169 intubated patients were followed in 37 different ICU. At the beginning of the follow-up we asked the physician who will follow the patient in the ICU to give a score for the probability of survival of the patients. Scoring included a total of 6 scores from 0 to 5, with the "0" the worst probability "5" being the best. According to this distribution, only 1 (0.9%) of 113 patients who were given 0 points survived. Three (6.1%) of 49 with the best score of 5 died. Survival rates were significantly different in each score group (r: -0.488; p<0.001). After the combined mortality estimation scores based on the clinical observations of the physicians (0 and 1 point score was combined as non-survive, 4 and 5 score was combined as survived) 320 of the 545 patients were estimated to be dead and 225 were predicted survival. Sensitivity and spesifity of scoring system to predict mortality was 91.56% (95% CI: 87.96-94.37), 76.89% (95% CI: 70.82-82.23) respectively. CONCLUSIONS: In this study, we concluded that the physicians who follow the patients in the ICU can predict the poor prognosis at the time of admission and the high mortality rate. The physician's opinion on mortality estimation should be considered in intensive care mortality scoring in addition to other laboratory and clinical parameters.

Clinical and histopathological features of immunoglobulin G4-associated autoimmune hepatitis in children.

BACKGROUND AND AIM: We aimed to examine the frequency and the characteristics of immunoglobulin G4 (IgG4)-associated autoimmune hepatitis among pediatric patients with autoimmune hepatitis. METHODS: Immunostaining for IgG and IgG4 was performed in liver biopsies of 40 pediatric patients with autoimmune hepatitis. The patients with more than 10 IgG4-positive plasma cells/high-power field were defined as IgG4-associated autoimmune hepatitis. Clinic, laboratory, and histopathological results were compared between groups. RESULTS: Among the 40 pediatric patients, 34 patients were type 1 and 6 patients were type 2 autoimmune hepatitis. Six patients (15%), four of the type 1 and two of the type 2 autoimmune hepatitis patients, were diagnosed with IgG4-associated autoimmune hepatitis. Clinical, laboratory, and histopathological data were initially similar in both forms. There was a positive correlation between IgG4-positive plasma cell count and degree of portal (r: 0.406, P: 0.009) and lobular inflammation (r: 0.37, P: 0.019), grade of interface hepatitis (r: 0.33, P: 0.03), and fibrosis (r: 0.318, P: 0.046). Time required for normalization of liver transaminases and serum IgG level was significantly shorter in IgG4-associated autoimmune hepatitis (3.3 ± 0.5 vs 6.6 ± 3.5 for alanine aminotransferase, 3.7 ± 0.8 vs 6.7 ± 1.2 for aspartate aminotransferase, 4.3 ± 1.2 vs 7.1 ± 2.7 for gamma-glutamyl transpeptidase, and 7.2 ± 3.1 vs 12.8 ± 4.5 for IgG). CONCLUSIONS: Immunoglobulin G4-associated autoimmune hepatitis can be found in pediatric age group and also in type 2 autoimmune hepatitis patients. As steroid response may be better in IgG4-associated autoimmune hepatitis, biopsy specimens should be evaluated for this entity at diagnosis.

As a Novel Procalcitonin Assay is Architect B∙R∙A∙H∙M∙S PCT; Comparison of Two Commercial Systems.

BACKGROUND: Procalcitonin (PCT) is the precursor structure of the calcitonin hormone with 116 amino acids. The measurement of serum procalcitonin is currently being safely used in community-acquired pneumonia, bacterial peritonitis and sepsis in the diagnosis, decision on the initiation of treatment, and follow-up of the response to treatment. In this study, it is aimed to compare PCT results obtained by the VIDAS PCT that makes measurements by the enzyme-dependent fluorescence (ELFA) method and Architect PCT method, a chemiluminescent microparticle immunoassay (CMIA) that has just been put into use, both of which are B∙R∙A∙H∙M∙S licensed and have method differences. METHODS: Serum samples of 109 patients from different clinics with a PCT request were included in the study. The sera were divided into two groups and the samples were immediately studied with two methods. Cohen's Kappa (κ) coefficient was used to determine concordance between the two methods. Other parameters were analyzed by the paired t-test, and their concordance was evaluated. RESULTS: In the concordance analysis study carried out by considering the significant cutoff value of 0.5 ng/mL in the clinical diagnosis of bacterial infections, the κ value was found to be 0.930, p < 0.001. Concordance was at an excellent level. Upon pairing and analyzing all the results regardless of the cutoff value, the Concordance Coefficient was found to be 0.958 (p < 0.001). It was observed that concordance was at an excellent level. CONCLUSIONS: Upon comparing the patient results obtained as a result of the study, it was observed that the concordance of the methods with each other was excellent. Larger and more comprehensive studies on this issue will be helpful.

Diaphragmatic thickness in chronic obstructive lung disease and relationship with clinical severity parameters

Background/aim: Sonographic assessment of diaphragm structure and function would be a useful clinical tool in patients with chronic obstructive pulmonary disease (COPD). Our aim was to determine the muscle thickness of the diaphragm and the usefulness of clinical practice in patients with COPD. Materials and methods: The diaphragmatic thickness of 34 COPD patients and 34 healthy subjects was measured during tidal volume (Tmin) and deep inspiration (Tmax) on both sides using a B-mode ultrasound. The body mass index and the modified Medical Research Council (mMRC) index values were reported. Results: There was no correlation among TminR (P = 0.134), TminL (P = 0.647), TmaxR (P = 0.721), and TmaxL (P = 0.905) between the patients with COPD and the control group. There was also no significant difference between diaphragmatic thickness and COPD severity, respiratory function (P = 0.410), and frequency of exacerbations (P = 0.881) and mMRC (P = 0.667). Conclusion: Diaphragmatic dysfunction in COPD is related to mobility restriction rather than muscle thickness.