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The aim was to evaluate the incidence, treatment, surgery rate, and anthropometry at diagnosis of children with inflammatory bowel disease (IBD).MethodsPatients diagnosed between January 1, 2007 to December 31, 2009 in Eastern Denmark, Funen, and Aarhus were included from a background population of 668,056 children <15 years of age. For evaluation of incidence, treatment, and surgery rate, a subcohort from Eastern Denmark was extracted for comparison with a previously published population-based cohort from the same geographical area (1998–2006).ResultsIn all, 130 children with IBD: 65 with Crohn's disease (CD), 62 with ulcerative colitis (UC), and three with IBD unclassified (IBDU) were included. The mean incidence rates per 106 in 2007–2009 were: IBD: 6.4 (95% confidence interval [CI]: 5.4–7.7), CD: 3.2 (2.5–4.1), UC: 3.1 (2.4–4.0) and IBDU: 0.2 (0.05–0.5). Comparing the two cohorts from Eastern Denmark we found higher incidence rates for IBD (5.0 and 7.2 in 1998–2000 and 2007–2009, respectively, P = 0.02) and CD (2.3 versus 3.3, P = 0.04). Furthermore, we found a significant decrease in surgery rates (15.8/100 person-years versus 4.2, P = 0.02) and an increase in the rate of initiating immunomodulators (IM) within the first year (29.0/100 person-years versus 69.2, P < 0.001). IM use was associated with a trend towards a decreased surgery risk (relative risk [RR] 0.38; 0.15–1.0). Children with CD had poor nutritional status at diagnosis compared with the general pediatric population.ConclusionsOver the past 12 years we found an increase in the incidence of IBD in children, an increasing use of IM, and decreasing 1-year surgery rates. CD patients had poor nutritional status.

Background. Accumulation of extracellular water (ECW) is a major clinical manifestation of nephrotic syndrome (NS) in children. Bioimpedance spectroscopy (BIS) is a simple, noninvasive technique that reflects body water volumes. BIS can further measure cell membrane capacitance (CM), which may be altered in NS. The aims of the study were to explore how BIS measurements could reflect disease status in NS, while avoiding prediction equations which are often only validated in adult populations. Methods. The study involved 8 children (2-10 years) with active NS (ANS group), 5 of which were also studied at NS remission (NSR group), as well as 38 healthy children of similar age (HC group). BIS measurements determined resistances RINF, RE, and RI (reflecting total body water, extracellular water, and intracellular water) and CM. Also resistance indices based on height (H) were considered, RI = H2/R. Results. It was found that RE and RINF were significantly lower in the ANS group than in both NSR and HC groups (p < 0.001). Corresponding resistance indices were significantly higher in the ANS group than in the NSR (p < 0.01) and the HC (p < 0.05) groups, in accordance with elevated water volumes in NS patients. Indices of intracellular water were not significantly different between groups. CM was significantly lower in the ANS group than in NSR and HC groups (p < 0.05). Conclusion. BIS could distinguish children with active NS from well-treated and healthy children. Studies with more children are warranted.

Background Oedema, characterized by accumulation of extracellular water (ECW), is one of the major clinical manifestations in children suffering from nephrotic syndrome (NS). The lack of a simple, inexpensive and harmless method for assessing ECW may be solved by the use of the bioelectrical impedance analysis (BIA) technique. The aims of this study were to examine whether phase angle (PA), bioelectrical impedance vector analysis (BIVA) and the impedance ratio (IR) reflect change in disease status in children with NS. Methods Eight children (age range: 2–10 years) with active NS (ANS group) were enrolled. In five of these (ANS* subgroup), impedance was also measured at remission (NSR group). Thirty-eight healthy children (age range: 2–10 years) were included as healthy controls (HC group). Whole-body impedance was measured with a bioimpedance spectroscopy device (Xitron 4200) with surface electrodes placed on the wrist and ankle. Results Values of PA, BIVA and IR were found to be significantly lower ( p -value range < 0.001 to < 0.01) in the ANS patients compared to the HC and NSR groups. No significant differences were observed between the NSR and HC groups. Conclusion The studied parameters can be used to assess change in disease status in NS patients. Data were consistent with NS being associated with expansion of ECW.

Abstract Background Early-life antibiotic use can alter the intestinal flora and modify the risk of developing Crohn disease (CD), but rigorous epidemiological evidence is limited, with inconsistent results. Methods We identified all children born in Denmark from 1995 to 2009 and followed them from birth until death, emigration, a diagnosis of CD, or January 1, 2013. Using Cox regression, we assessed the association between antibiotic exposure in the first year of life and subsequent risk for CD, adjusting for sex, degree of urbanization, birth order, birth year, route of delivery, gestational age, smoking during pregnancy, intake of nonsteroidal anti-inflammatory drugs in the first year of life, and family history of CD. Results During a median 9.5 years (9.3 million total person-years), CD was diagnosed in 208 of 979,039 children. Antibiotic use in the first year of life was associated with a higher risk of CD (adjusted hazard ratio, 1.4; 95% confidence interval [CI], 1.1-1.8), with the highest risk with ≥6 courses of antibiotics (adjusted hazard ratio, 4.1; 95% CI, 2.0-8.5). A family history of CD did not modify these risk associations. The cumulative risk of CD at the 11th birthday for children exposed to antibiotics in their first year of life was 0.16‰ (95% CI, 0.11‰–0.22‰) compared to 0.11‰ (95% CI, 0.08‰–0.15‰) for children unexposed to antibiotics in their first year of life. Conclusions Antibiotic use in the first year of life is associated with a modestly increased risk for CD, although the absolute risk is very low.

Obesity is a strong predictor for metabolic associated fatty liver disease (MAFLD), which has been associated with decreased insulin like growth factor 1 (IGF-1). In obesity, weight loss increases growth hormone secretion, but this is not unequivocally associated with increases in serum IGF-1 and IGF binding protein-3 (IGFBP-3). We studied the changes in the IGF axis in relation to weight loss and improvement in insulin resistance in children with or without MALFD after 10 weeks of lifestyle intervention at a weight loss camp (WLC). We investigated 113 (66 females) Caucasian children with obesity, median age 12.4 (range 7.3–14.6) years, before and after 10 weeks of lifestyle intervention at a WLC. We investigated children who was either MAFLD positive ( n  = 54) or negative ( n  = 59) before and after WLC. Children with MAFLD had lower baseline IGF-1 (249 ± 112 vs 278 ± 107 µg/l, P  = 0.048), whereas the IGF-1/IGFBP-3 molar ratio was similar to children without MAFLD (19.4 ± 6.6 vs. 21.8 ± 6.6%, P  = 0.108). When all children were considered as one group, WLC decreased SDS-BMI and HOMA-IR ( P  < 0.001, both) and increased IGF-1 (264 ± 110 vs 285 ± 108 µg/l, P  < 0.001) and the IGF/IGFBP-3 molar ratio (20.7 ± 6.7 vs 22.4 ± 6.1%, P  < 0.001). When categorized according to liver status, IGF-1 increased significantly in children with MAFLD ( P  = 0.008) and tended to increase in children without MAFLD ( P  = 0.052).    Conclusions : Ten weeks of lifestyle intervention decreased insulin resistance and improved the IGF axis. We observed slight differences in the IGF axis in relation to MAFLD status. This suggests that the IGF axis is primarily influenced by insulin resistance rather than MAFLD status. What is New: • Weight loss decreases insulin resistance and subsequently increases the IGF axis in children with obesity. • Children with MAFLD had an aberration in the IGF axis compared to their MAFLD negative counter parts and the IGF axis was primarily influenced by the decreased BMI-SDS and insulin resistance, rather than MAFLD status. What is Known: • NAFLD has previously been associated with reduced serum IGF-1 concentrations. • Data on the impact of MAFLD and aberrations in the growth hormone and IGF axis and the effects of lifestyle interventions in children are limited.

Epidemiologic studies combining exposure and outcome data with the collection of biosamples are needed to study gene-environment interactions that might contribute to the etiology of complex diseases such as pediatric Crohn's disease (CD). Nationwide registries, including those in Denmark and other Scandinavian countries, provide efficient and reliable sources of data for epidemiological studies evaluating the environmental determinants of disease. We performed a pilot study to test the feasibility of collecting salivary DNA to augment registry data in established cases of pediatric CD and randomly selected, population-based controls. Cases of CD born after 1995 and residing in the central region of Denmark were identified through the Danish National Patient Registry and confirmed by using standard diagnostic criteria. Age- and gender-matched controls were selected at random through the civil registration system. Cases and controls were contacted by mail and telephone and invited to submit a saliva sample. DNA was extracted and genotyped for six CD-associated single-nucleotide polymorphisms (SNPs). A total of 53 cases of pediatric CD were invited, and 40 contributed a saliva sample (75% response rate). A total of 126 controls were invited, and 54 contributed a saliva sample (44% response rate). As expected, demographic characteristics did not differ between cases and controls. DNA was successfully isolated from 93 of 94 samples. Genotyping was performed with only 2% undetermined genotypes. For five of six SNPs known to be associated with CD, risk allele frequencies were higher in cases than controls. This pilot study strongly supports the feasibility of augmenting traditional epidemiological data from Danish population-based registries with the de novo collection of genetic information from population-based cases and controls. This will facilitate rigorous studies of gene-environment interactions in complex chronic conditions such as CD.

All stillbirths in 1985 and 1986 in three Danish counties were assessed in a perinatal audit. The aim was to investigate if departure from generally accepted standards of satisfactory perinatal care might have contributed to stillbirths, and also to investigate if differences in the structure of antenatal care and the delivery systems might have any influence on the rate of stillbirths. 119 cases were evaluated, 70 were classified as unavoidable deaths, in 48 cases a different treatment might have improved the infant's possibility of survival and in one case consensus was not reached. The most frequent cause of suboptimal care was inadequate antenatal care of obvious signs of intrauterine growth retardation. Directives for visitation between surgical and obstetric departments were essential to the rate of stillbirth. The results indicate that it might be possible to achieve a further decrease in the number of stillbirths by intensifying the postgraduate training of the professionals and by issueing guidelines for the sharing of care responsibilities.

Background Days alive without life support (DAWOLS) and similar outcomes that seek to summarise mortality and non-mortality experiences are increasingly used in critical care research. The use of these outcomes is challenged by different definitions and non-normal outcome distributions that complicate statistical analysis decisions. Methods We scrutinized the central methodological considerations when using DAWOLS and similar outcomes and provide a description and overview of the pros and cons of various statistical methods for analysis supplemented with a comparison of these methods using data from the COVID STEROID 2 randomised clinical trial. We focused on readily available regression models of increasing complexity (linear, hurdle-negative binomial, zero–one-inflated beta, and cumulative logistic regression models) that allow comparison of multiple treatment arms, adjustment for covariates and interaction terms to assess treatment effect heterogeneity. Results In general, the simpler models adequately estimated group means despite not fitting the data well enough to mimic the input data. The more complex models better fitted and thus better replicated the input data, although this came with increased complexity and uncertainty of estimates. While the more complex models can model separate components of the outcome distributions (i.e., the probability of having zero DAWOLS), this complexity means that the specification of interpretable priors in a Bayesian setting is difficult. Finally, we present multiple examples of how these outcomes may be visualised to aid assessment and interpretation. Conclusions This summary of central methodological considerations when using, defining, and analysing DAWOLS and similar outcomes may help researchers choose the definition and analysis method that best fits their planned studies. Trial registration COVID STEROID 2 trial, ClinicalTrials.gov: NCT04509973, ctri.nic.in: CTRI/2020/10/028731.

Adaptive features may increase flexibility and efficiency of clinical trials, and improve participants’ chances of being allocated to better interventions. Our objective is to provide thorough guidance on key methodological considerations for adaptive clinical trials. We provide an overview of key methodological considerations for clinical trials employing adaptive stopping, adaptive arm dropping, and response-adaptive randomization. We cover pros and cons of different decisions and provide guidance on using simulation to compare different adaptive trial designs. We focus on Bayesian multi-arm adaptive trials, although the same general considerations apply to frequentist adaptive trials. We provide guidance on 1) interventions and possible common control, 2) outcome selection, follow-up duration and model choice, 3) timing of adaptive analyses, 4) decision rules for adaptive stopping and arm dropping, 5) randomization strategies, 6) performance metrics, their prioritization, and arm selection strategies, and 7) simulations, assessment of performance under different scenarios, and reporting. Finally, we provide an example using a newly developed R simulation engine that may be used to evaluate and compare different adaptive trial designs. This overview may help trialists design better and more transparent adaptive clinical trials and to adequately compare them before initiation. •Adaptive clinical trials are flexible and adaptive features may increase trial efficiency and individual participants' chances of being allocated to superior interventions.•Adaptive trials come with increased complexity and not all adaptive features may always be beneficial.•We provide an overview of and guidance on key methodological considerations for clinical trials employing adaptive stopping, adaptive arm dropping, or response-adaptive randomization.•Further, we provide a simulation engine and example on how to compare adaptive trial designs using simulation.•This guidance paper may help trialists design and plan adaptive clinical trials.

Univentricular heart anomalies represent a group of severe congenital heart defects necessitating early surgical intervention in infancy. The Fontan procedure, the final stage of single-ventricle palliation, establishes a serial connection between systemic and pulmonary circulation by channeling venous return to the lungs. The absence of the subpulmonary ventricle in this peculiar circulation progressively eventuates in failure, primarily due to chronic elevation in inferior vena cava (IVC) pressure. This study experimentally validates the effectiveness of an intracorporeally-powered venous ejector pump (VEP) in reducing IVC pressure in Fontan patients. The VEP exploits a fraction of aortic flow to create a jet-venturi effect for the IVC, negating the external power requirement and driveline infections. An invitro Fontan mock-up circulation loop is developed and the impact of VEP design parameters and physiological conditions is assessed using both idealized and patient-specific total cavopulmonary connection (TCPC) phantoms. The VEP performance in reducing IVC pressure exhibited an inverse relationship with the cardiac output and extra-cardiac conduit (ECC) size and a proportional relationship with the transpulmonary pressure gradient (TPG) and mean arterial pressure (MAP). The ideal VEP with fail-safe features provided an IVC pressure drop of 1.82 ± 0.49, 2.45 ± 0.54, and 3.12 ± 0.43 mm Hg for TPG values of 6, 8, and 10 mm Hg, respectively, averaged over all ECC sizes and cardiac outputs. Furthermore, the arterial oxygen saturation was consistently maintained above 85% during full-assist mode. These results emphasize the potential utility of the VEP to mitigate elevated venous pressure in Fontan patients.