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Background: Hepatitis C virus (HCV) is a major cause of chronic liver disease, in which liver stiffness increases. Liver stiffness measurements (LSM) are therefore essential in diagnosing liver diseases and predicting disease development. The study objective was to perform a comprehensive prospective assessment of the liver before, after and 4 years after treatment for HCV, including an assessment of the long-term outcome of fibrosis, steatosis and inflammation., Methods and Findings: Patients eligible for HCV treatment were included prospectively in 2018 ( n  = 47). Liver stiffness was measured using transient elastography and 2D shear-wave elastography (SWE). Blood tests, B-mode ultrasound (US) and SWE, were performed before, after (end of treatment [EOT]), 3 months after (EOT3) and 4 years after treatment (4Y). At the final visit, we added attenuation imaging and shear-wave dispersion slope (SWDS) measurements to assess steatosis and inflammation. Three months after treatment, the sustained virologic response rate was 93%. The median liver stiffness for baseline, EOT, EOT3 and 4Y was 8.1, 5.9, 5.6 and 6.3 kPa, respectively. There was a significant reduction in liver stiffness from baseline to EOT, and from EOT to EOT3. After 4 years, the mean attenuation coefficient (AC) was 0.58 dB/cm/MHz, and the mean SWDS value was 14.3 (m/s)/kHz., Conclusion: The treatment for HCV was highly effective. Measurements of liver stiffness decreased significantly after treatment and remained low after 4 years. AC measurements indicated low levels of liver steatosis. Shear-wave dispersion values indicated inflammation of the liver, but the clinical implication is undetermined and should be explored in larger studies.Clinicaltrials.gov: NCT03434470., Abbreviations: AC: attenuation coefficient; APRI: aspartate aminotransferase to platelet ratio index; ATI: attenuation imaging; cACLD: compensated advanced chronic liver disease; CAP: controlled attenuation parameter; FIB-4: Fibrosis-4 Index for liver fibrosis; HCC: hepatocellular carcinoma; LSM: liver stiffness measurement; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; SWDS: shear-wave dispersion slope; SWE: shear-wave elastography; US: ultrasound.

Background: Antibiotic resistance is an increasing global threat, accelerated by both misuse and overuse of antibiotics. Most antibiotics to humans are prescribed in primary care, commonly for respiratory symptoms, and there is a need for research on the usage of and outcomes after antibiotic treatment to counteract antibiotic resistance., Objective: To evaluate symptom duration, treatment length, and adverse events of antibiotic treatment in children., Design and Setting: Observational study at four out-of-hours services and one paediatric emergency clinic in Norwegian emergency primary care., Subjects: 266 children aged 0 to 6 years with fever or respiratory symptoms., Main Outcome Measures: Duration of symptoms and absenteeism from kindergarten/school, treatment length, and reported adverse events., Results: There were no differences in duration of symptoms, fever or absenteeism when comparing the groups prescribed (30.8%) and not prescribed (69.2%) antibiotics. This lack of difference remained when analysing the subgroup with otitis media.In the group prescribed antibiotics, 84.5% of parents reported giving antibiotics for 5-7 days, and 50.7% reported no difficulties. Adverse events of antibiotics were reported in 42.3% of the cases, the vast majority being gastrointestinal disturbances., Conclusion: Children with fever or respiratory symptoms experience similar duration of symptoms and absenteeism regardless of antibiotic treatment. A substantial number of parents reported adverse events when the child received antibiotics. Several parents experienced additional difficulties with the treatment, some ending treatment within day 4., Trial Registration Number: NCT02496559; Results.

Aim: To examine whether biochemical surveillance vs clinical observation of term infants with prolonged rupture of membranes as a risk factor for early-onset sepsis is associated with differences in patient trajectories in maternity and neonatal intensive care units., Methods: A retrospective study of live-born infants with gestational age ≥ 37 + 0 weeks born after prolonged rupture of membranes (≥24 h) in four Norwegian hospitals 2017-2019. Two hospitals used biochemical surveillance, and two used predominantly clinical observation to identify early-onset sepsis cases., Results: The biochemical surveillance hospitals had more C-reactive protein measurements (p < 0.001), neonatal intensive care unit admissions (p < 0.001) and antibiotic treatment (p < 0.001). Hospitals using predominantly clinical observation initiated antibiotic treatment earlier in infants with suspected early-onset sepsis (p = 0.04) but not in infants fulfilling early-onset sepsis diagnostic criteria (p = 0.09). There was no difference in antibiotic treatment duration (p = 0.59), fraction of infants fulfilling early-onset sepsis diagnostic criteria (p = 0.49) or length of hospitalisation (p = 0.30), and no early-onset sepsis-related adverse outcomes., Conclusion: The biochemical surveillance hospitals had more C-reactive protein measurements, but there was no difference in antibiotic treatment duration, early-onset sepsis cases, length of hospitalisation or adverse outcomes. Personnel resources needed for clinical surveillance should be weighed against the limitation of potentially painful procedures., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Purpose:  Liver elastography is increasingly being applied in screening for and follow-up of pediatric liver disease, and has been shown to correlate well with fibrosis staging through liver biopsy. Because time is of the essence when examining children, we wanted to evaluate if a reliable result can be achieved with fewer acquisitions., Materials and Methods:  243 healthy children aged 4-17 years were examined after three hours of fasting. Participants were divided into four age groups: 4-7 years; 8-11 years; 12-14 years and 15-17 years. Both two-dimensional shear wave elastography (2D-SWE; GE Logiq E9) and point shear wave elastography (pSWE; Samsung RS80A with Prestige) were performed in all participants, while transient elastography (TE, Fibroscan) was performed in a subset of 87 children aged 8-17 years. Median liver stiffness measurement (LSM) values of 3, 4, 5, 6, 7, and 8 acquisitions were compared with the median value of 10 acquisitions (reference standard). Comparison was performed for all participants together as well as within every specific age group. We investigated both the intraclass correlation coefficient (ICC) with absolute agreement and all outliers more than 10 %, 20 % or ≥ 0.5 or 1.0 kPa from the median of 10 acquisitions., Results:  For all three systems there was no significant difference between three and ten acquisitions, with ICCs ≥ 0.97. All systems needed 4 acquisitions to achieve no LSM deviating ≥ 1.0 kPa of a median of ten. To achieve no LSM deviating ≥ 20 % of a median of ten acquisitions, pSWE and TE needed 4 acquisitions, while 2D-SWE required 6 acquisitions., Conclusion:  Our results contradict recommendations of 10 acquisitions for pSWE and TE and only 3 for 2D-SWE., Competing Interests: OHG did consultancy for GE and Samsung in 2017., (Thieme. All rights reserved.)

Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin., Methods: We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin., Results: At baseline, the median (range) ELF test was 9.3 (7.5-12.9) and median LSM 1.26 m/s (0.66-3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p  = 0.005, vs . 0.12 point/year, 95% CI [0.03, 0.21], p  = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86)., Conclusions: ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC., Lay Summary: Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk., Competing Interests: W. Rosenberg is one of the inventors and patent holders of the ELF test. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest.

Background & Aims: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters., Methods: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted., Results: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa., Conclusions: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In cases of infants with yellow colouration, both the sclerae and the skin should be examined. The top priority is to rule out conjugated hyperbilirubinaemia, which may be a symptom of biliary atresia. Children with this condition will first develop yellow sclerae, and will have jaundice that continues beyond the first two weeks of life. Although discoloured stools are a classic sign of biliary atresia, they are not always present. Children over two weeks of age with yellow skin should therefore be assessed immediately, regardless of the colour of the stool.

The aim of the study described here was to characterize three different liver elastography methods in primary sclerosing cholangitis (PSC) patients, for the first time exploring 2-D shear wave elastography (2-D-SWE) in PSC patients and its putative advantages over point shear wave elastography (pSWE). Sixty-six adult PSC patients (51 males, 77%) underwent liver elastography: Transient elastography (TE), pSWE and 2-D-SWE were applied head-to-head after B-mode ultrasonography and blood tests. Liver stiffness measurements (LSMs) by pSWE yielded lower values than those by TE; 2-D-SWE had less steep slope but was overall not significantly different from TE. Correlation between LSMs by pSWE and TE was excellent (intraclass correlation coefficient = 0.92); correlation for 2-D-SWE with either pSWE or TE was moderate but improved with exclusion of overweight individuals. LSMs correlated with the Enhanced Liver Fibrosis test (ELF) across all scanner systems. Our study indicates that LSM by different systems is feasible in PSC patients and that 2-D-SWE tends to underestimate stiffness compared with TE., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To determine serum C-reactive protein (CRP) concentrations in healthy term-born infants shortly after birth., Methods: We sampled blood from 182 infants along with the routine neonatal screening programme at 48-72 hours of age from consecutively recruited healthy infants without signs of infection and a gestational age (GA) of at least 37 weeks. The blood was stored at minus 20°C until analysis in one assay after the end of the study., Results: The CRP levels were positively skewed. The median concentration was 5.0 mg/L, 48.9% of the neonates had values <5.0 mg/L, 19.8% ≥10.0 mg/L, 7.1% ≥20.0 mg/L and 1.1% (2 neonates) >30 mg/L. The CRP level was positively related to GA and duration of labour, slightly higher in boys than girls and after vaginal compared to Caesarean delivery., Conclusion: In healthy neonates born at term, the CRP concentrations did not vary substantially with various common perinatal clinical conditions, and levels above 30 mg/L were uncommon at two to three days of age., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: Noninvasive tests for the evaluation of liver fibrosis are particularly helpful in children to avoid general anesthesia and potential complications of invasive tests. We aimed to establish reference values for 2 different elastography methods in a head-to-head comparison for children and adolescents 4 to 17 years, using transient elastography as common reference in a subset., Methods: A total of 243 healthy participants aged 4 to 17 years were examined by a single observer with a full liver B-mode scan before elastography, following a minimum of 3 hours fasting. Liver stiffness measurements (LSMs) using 2-dimensional shear wave elastography (2D-SWE, GE Logiq E9) and point shear wave elastography (pSWE, Samsung RS80A with Prestige) were performed in all participants, and compared to transient elastography (TE, FibroScan) in a subset (n = 87). Interobserver agreement was evaluated in 50 children aged 4 to 17 years., Results: Valid measurements were obtained in 242 of 243 (99.6%) subjects for 2D-SWE, 238 of 243 (97.9%) for pSWE, and in 83 of 87 (95.4%) for TE. Median liver stiffness overall was 3.3 (interquartile range [IQR] 2.7-4.3), 4.1 (IQR 3.6-4.7), and 4.1 kPa (IQR 3.5-4.6) for 2D-SWE, pSWE, and TE, respectively. Intraclass correlation coefficients between observers were 0.84 and 0.83 for 2D-SWE and pSWE, respectively. LSM values were significantly lower for 2D-SWE compared to pSWE and TE, and increased with advancing age. Higher LSM values in males were observed in adolescents., Conclusions: All methods showed excellent feasibility. 2D-SWE showed significantly lower LSM values than pSWE and TE, and lower failure rate compared to TE. Our results further indicate an age and sex effect on LSM values.

Objective: Establishing normal liver stiffness (LS) values in healthy livers is a prerequisite to differentiate normal from pathological LS values. Our aim was to define normal LS using two novel elastography methods head-to-head and to assess the number of measurements, variability and reproducibility., Materials and Methods: We evaluated shear wave elastography (SWE) methods integrated in Samsung RS80A and GE S8 by obtaining LS measurements (LSM) in 100 healthy subjects (20-70 years). Transient Elastography (TE) was used as reference method. Data were analyzed according to age, sex, BMI and 5 vs. 10 measurements. All subjects underwent B-mode ultrasound examination and lab tests to exclude liver pathology. Interobserver variation was evaluated in a subset (n = 24)., Results: Both methods showed excellent feasibility, measuring LS in all subjects. LSM-mean for GE S8 2D-SWE was higher compared to TE (4.5±0.8 kPa vs. 4.2±1.1, p<0.001) and Samsung RS80A (4.1±0.8 kPa, p<0.001). Both methods showed low intra- and interobserver variation. LSM-mean was significantly higher in males than females using 2D-SWE, while a similar trend for Samsung SWE did not reach significance. No method demonstrated statistical significant difference in LSM across age and BMI groups nor between LSM-mean based on 5 vs. 10 measurements., Conclusion: LSM was performed with high reproducibility in healthy adult livers. LSM-mean was significantly higher for GE S8 2D-SWE compared to Samsung RS80A and TE in healthy livers. Males had higher LSM than females. No method demonstrated statistical significant difference in LSM-mean across age- and non-obese BMI groups. Our results indicate that five LSM may be sufficient for reliable results., Competing Interests: The authors have declared that no competing interests exist.

This study aimed to assess and validate the repeatability and agreement of quantitative elastography of novel shear wave methods on four individual tissue-mimicking liver fibrosis phantoms with different known Young's modulus. We used GE Logiq E9 2D-SWE, Philips iU22 ARFI (pSWE), Samsung TS80A SWE (pSWE), Hitachi Ascendus (SWM) and Transient Elastography (TE). Two individual investigators performed all measurements non-continued and in parallel. The methods were evaluated for inter- and intraobserver variability by intraclass correlation, coefficient of variation and limits of agreement using the median elastography value. All systems used in this study provided high repeatability in quantitative measurements in a liver fibrosis phantom and excellent inter- and intraclass correlations. All four elastography platforms showed excellent intra-and interobserver agreement (interclass correlation 0.981-1.000 and intraclass correlation 0.987-1.000) and no significant difference in mean elasticity measurements for all systems, except for TE on phantom 4. All four liver fibrosis phantoms could be differentiated by quantitative elastography, by all platforms (p<0.001). In the Bland-Altman analysis the differences in measurements were larger for the phantoms with higher Young's modulus. All platforms had a coefficient of variation in the range 0.00-0.21 for all four phantoms, equivalent to low variance and high repeatability.

Objectives: Acute respiratory infections and fever among children are highly prevalent in primary care. It is challenging to distinguish between viral and bacterial infections. Norway has a relatively low prescription rate of antibiotics, but it is still regarded as too high as the antimicrobial resistance is increasing. The aim of the study was to identify predictors for prescribing antibiotics or referral to hospital among children., Design: Secondary analysis of a randomised controlled study., Setting: 4 out-of-hours services and 1 paediatric emergency clinic in Norwegian primary care., Participants: 401 children aged 0-6 years with respiratory symptoms and/or fever visiting the out-of-hours services., Outcomes: 2 main outcome variables were registered: antibiotic prescription and referral to hospital., Results: The total prescription rate of antibiotics was 23%, phenoxymethylpenicillin was used in 67% of the cases. Findings on ear examination (OR 4.62; 95% CI 2.35 to 9.10), parents' assessment that the child has a bacterial infection (OR 2.45; 95% CI 1.17 to 5.13) and a C reactive protein (CRP) value >20 mg/L (OR 3.57; 95% CI 1.43 to 8.83) were significantly associated with prescription of antibiotics. Vomiting in the past 24 hours was negatively associated with prescription (OR 0.26; 95% CI 0.13 to 0.53). The main predictors significantly associated with referral to hospital were respiratory rate (OR 1.07; 95% CI 1.03 to 1.12), oxygen saturation <95% (OR 3.39; 95% CI 1.02 to 11.23), signs on auscultation (OR 5.57; 95% CI 1.96 to 15.84) and the parents' assessment before the consultation that the child needs hospitalisation (OR 414; 95% CI 26 to 6624)., Conclusions: CRP values >20 mg/L, findings on ear examination, use of paracetamol and no vomiting in the past 24 hours were significantly associated with antibiotic prescription. Affected respiration was a predictor for referral to hospital. The parents' assessment was also significantly associated with the outcomes., Trial Registration Number: NCT02496559; Results., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Point shear wave elastography (pSWE) is an ultrasound-based method for non-invasive quantification of liver fibrosis. The objective of this study was to explore liver pSWE in patients with primary sclerosing cholangitis (PSC) for assessment of fibrosis. Fifty-five non-transplant patients with PSC (38 males, 17 females; mean age: 46.4 y) were included and compared with 24 matched controls. Median (range) PSC duration was 8.1 (0-33) y. Ultrasonographic scanning followed by liver stiffness measurement by pSWE was performed using a conventional ultrasound system (Philips iU22). Signs of liver fibrosis on B-mode were identified in 21 patients (38%). Splenomegaly was found in 19 patients (35%) and ascites in two patients (4%). Successful pSWE measurements were achieved in the right liver lobe of all individuals and in the left liver lobe of 36 patients (65.5%). PSC patients had significantly higher median shear wave velocity (SWV) than controls in the right liver (median [range] SWV 1.26 [0.73-2.57] m/s vs. 1.09 [0.88-1.25] m/s, p < 0.001). SWV measured in the left liver lobe and spleen did not differ between PSC patients and controls. Our findings indicate that PSC patients have increased median SWV, indicating more fibrosis compared with controls; however, a wide range of SWV values were obtained among PSC patients, possibly reflecting the various stages in disease development., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of preconsultation C reactive protein (CRP) screening on antibiotic prescribing and referral to hospital in Norwegian primary care settings with low prevalence of serious infections., Design: Randomised controlled observational study at out-of-hours services in Norway., Setting: Primary care., Participants: 401 children (0-6 years) with fever and/or respiratory symptoms were recruited from 5 different out-of-hours services (including 1 paediatric emergency clinic) in 2013-2015., Intervention: Data were collected from questionnaires and clinical examination results. Every third child was randomised to a CRP test before the consultation; for the rest, the doctor ordered a CRP test if considered necessary., Outcome Measures: Main outcome variables were prescription of antibiotics and referral to hospital., Results: In the group pretested with CRP, the antibiotic prescription rate was 26%, compared with 22% in the control group. In the group pretested with CRP, 5% were admitted to hospital, compared with 9% in the control group. These differences were not statistically significant. The main predictors for ordering a CRP test were parents' assessment of seriousness of the illness and the child's temperature. Paediatricians ordered CRP tests less frequently than did other doctors (9% vs 56%, p<0.001)., Conclusions: Preconsultation screening with CRP of children presenting to out-of-hours services with fever and/or respiratory symptoms does not significantly affect the prescription of antibiotics or referral to hospital., Trial Registration Number: NCT02496559; Results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)