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Summary: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016–2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92–5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07–7.59), Group A streptococcus (OR 2.73, 95% CI 1.13–6.09) and E. coli (OR 2.7, 95% CI 1.02–6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11–0.46), influenza B (OR 0.12, 95% CI 0.02–0.37) and RSV (OR 0.16, 95% CI: 0.06–0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23–0.72) and EBV (OR 0.71, 95% CI 0.56–0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

Abstract Background During the COVID‐19 pandemic, the first UK lockdown (March to May 2020) witnessed a dramatic reduction in children presenting to primary/emergency care, creating concern that fear of the virus was resulting in children presenting late. Methods An online survey was co‐developed with UK parents to understand the impact of the lockdown on parents' help‐seeking for, and care of, their sick/injured child(ren). The survey was advertised through social media and snowballing to parents whose children had been ill/injured during the lockdown. Analysis used descriptive statistics, SPSSv25 and thematic analysis. Results The survey was fully completed by 198 UK parents. The majority asked for help (144/198): from their family doctor (78), national helplines (48) or an Emergency Department (23). Most reported that their decision‐making had not changed, although how they sought help had changed. A few parents reported that the severity and duration of illness had increased because of uncertainty about and/or difficulty accessing services. Parents did not always report seeking help for symptoms rated red or amber by the Royal College of Paediatrics and Child Health. Parents reported accessing information through the internet or using information that they already had. Parent Contribution This was a collaboration with parents from survey development to dissemination, with two parents being integral members of our research team. Conclusions Our questionnaire was completed by parents who were not deterred from seeking help for their sick or injured children. Even for these parents, the lockdown changes to services created uncertainty about, and barriers to, accessing medical help for their children.

ObjectivesPneumonia is the most common bacterial infection in children at the emergency department (ED). Clinical prediction models for childhood pneumonia have been developed (using chest x-ray as their reference standard), but without implementation in clinical practice. Given current insights in the diagnostic limitations of chest x-ray, this study aims to validate these prediction models for a clinical diagnosis of pneumonia, and to explore their potential to guide decisions on antibiotic treatment at the ED.MethodsWe systematically identified clinical prediction models for childhood pneumonia and assessed their quality. We evaluated the validity of these models in two populations, using a clinical reference standard (1. definite/probable bacterial, 2. bacterial syndrome, 3. unknown bacterial/viral, 4. viral syndrome, 5. definite/probable viral), measuring performance by the ordinal c-statistic (ORC). Validation populations included prospectively collected data of children aged 1 month to 5 years attending the ED of Rotterdam (2012-2013) or Coventry (2005-2006) with fever and cough or dyspnoea.ResultsWe identified eight prediction models and could evaluate the validity of seven, with original good performance. In the Dutch population 22/248 (9%) had a bacterial infection, in Coventry 53/301 (17%), antibiotic prescription was 21% and 35% respectively. Three models predicted a higher risk in children with bacterial infections than in those with viral disease (ORC ≥0.55) and could identify children at low risk of bacterial infection.ConclusionsThree clinical prediction models for childhood pneumonia could discriminate fairly well between a clinical reference standard of bacterial versus viral infection. However, they all require the measurement of biomarkers, raising questions on the exact target population when implementing these models in clinical practice. Moreover, choosing optimal thresholds to guide antibiotic prescription is challenging and requires careful consideration of potential harms and benefits.

Molybdenum is an essential trace element, considered in recent work to be a promising 3D-printable biodegradable material for medical applications. Specifically, in our recent in vitro work, we were able to show that molybdenum is a material of high biocompatibility, sufficient stability, and uniform degradation. Thus, it seems to fulfill the optimal requirements for a resorbable osteosynthesis material. To confirm these results in a complex organism, we tested molybdenum against the gold standard titanium. For this purpose, we implanted either molybdenum or titanium implants into the nuchal folds of 48 Wistar rats. We examined all animals daily for clinical inflammatory parameters and euthanized one-third of the cohort after 12, 24, and 52 weeks, respectively. Subsequently, the tissues surrounding the samples, as well as the spleens, livers, and kidneys of all animals, were pathologically processed and examined. Subsequently, selected samples were examined metallographically. No significant increased inflammatory reaction of the material molybdenum versus titanium could be detected, either clinically or pathologically. The animals did not show any significant differences regarding their general condition or weight development. However, the introduced molybdenum platelets showed significantly less degradation than previously in the in vitro model. This is most likely due to the capsule formation, which has already been described for other implants.

BackgroundPoint-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability.Methods and findingsA cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics.ConclusionThere is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicians, and the role of diagnostic tests in the management of acute childhood infections.

BACKGROUND:The protection of breastfeeding against respiratory tract infections in the first year of life has often been suggested. Few studies examined the effect of breastfeeding on respiratory tract infections after infancy. OBJECTIVE:To examine the association between breastfeeding with lower respiratory tract infections (LRTI) and upper respiratory tract infections (URTI) after infancy up to 4 years of age (n = 5322). METHODS:This study was embedded in The Generation R study, a Dutch population-based prospective cohort study from fetal life until young adulthood. Information on breastfeeding duration (never;

Many postmenopausal women have vitamin D and calcium deficiency. Therefore, vitamin D and calcium supplementation is recommended for all patients with osteopenia and osteoporosis. We used an experimental rat model to test the hypothesis that induction of osteoporosis is more efficiently achieved in peripheral bone through combining ovariectomy with a unique multi-deficiencies diet (vitamin D depletion and deficient calcium, vitamin K and phosphorus). 14-week-old Sprague-Dawley rats served as controls to examine the initial bone status. 11 rats were bilaterally ovariectomized (OVX) and fed with multi-deficiencies diet. Three months later the treated group and the Sham group (n = 8) were euthanized. Bone biomechanical competence of the diaphyseal bone was examined on both, tibia and femur. Image analysis was performed on tibia via µCT, and on femur via histological analysis. Lower torsional stiffness indicated inferior mechanical competence of the tibia in 3 month OVX+Diet. Proximal metaphyseal region of the tibia showed a diminished bone tissue portion to total tissue in the µCT despite the increased total area as evaluated in both µCT and histology. Cortical bone showed higher porosity and smaller cross sectional thickness of the tibial diaphysis in the OVX+Diet rats. A lower ALP positive area and elevated serum level of RANKL exhibited the unbalanced cellular interaction in bone remodeling in the OVX+Diet rat after 3 month of treatment. Interestingly, more adipose tissue area in bone marrow indicated an effect of bone loss similar to that observed in osteoporotic patients. Nonetheless, the presence of osteoid and elevated serum level of PTH, BGP and Opn suggest the development of osteomalacia rather than an osteoporosis. As the treatment and fracture management of both osteoporotic and osteomalacia patients are clinically overlapping, this study provides a preclinical animal model to be utilized in local supplementation of minerals, drugs and growth factors in future fracture healing studies.