Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation.

OBJECTIVES: We investigated a patient with systemic juvenile idiopathic arthritis (sJIA) and recurrent macrophage activation syndrome (MAS) to discover genetic and immunological contributing factors. METHODS: Severe recurrent MAS motivated whole exome sequencing (WES) to identify genetic variants potentially involved in disease pathogenesis. In vitro peripheral blood mononuclear cell (PBMC) stimulations for cytokine expression and caspase-1 activity assays as well as NF-κB reporter luciferase assays were performed to functionally characterize variants. RESULTS: WES revealed an extremely rare heterozygous missense variant, c.482G>A, p.R161H in the CASP1 gene encoding pro-caspase-1. Lipopolysaccharide (LPS) stimulation of patient PBMCs induced high levels of IL-6 compared to controls, and activation of the NLRP3 inflammasome resulted in increased production of IL-1ß and IL-18 as well as significantly elevated caspase-1 activity. Constitutive and inducible levels of IL-18 and IFNγ in whole blood were markedly elevated. Expression of the CASP1 variant in an NF-κB reporter luciferase assay induced increased NF-κB activation in a RIP2-dependent manner. The disease course of the patient was complicated by severe recurrent MAS. However, dual IL-1 and IL-6 blockade caused disease remission. CONCLUSION: For the first time, we demonstrate the involvement of a CASP1 variant in sJIA and recurrent MAS. This variant is gain-of-function for both inflammasome and NF-κB activation leading to increased production of IL-6, IL-1ß and IL-18. Although dual IL-1 and IL-6 blockade may be beneficial in patients, in whom single treatment is not sufficient to control MAS, caution should be practiced, since interstitial lung disease may progress despite apparent clinical and biochemical remission.

Macrophage Markers Are Poorly Associated With Liver Histology in Children With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: We have previously demonstrated associations between the macrophage activation marker soluble (s)CD163 and histology of nonalcoholic fatty liver disease (NAFLD) in adults, and elevated sCD163 levels in children with obesity with NAFLD. Macrophage activation has, however, not been investigated in children with biopsy-proven NAFLD, which was the objective of the present study. METHODS: We used in-house enzyme-linked immunosorbent assays to measure sCD163 and the novel macrophage marker soluble mannose receptor (sMR) in a cross-sectional (n = 155) pediatric NAFLD cohort, and a cohort of NAFLD children (n = 36) undergoing a randomized trial by the probiotic VSL#3. We included 56 healthy nonobese children for comparison. RESULTS: Levels of sCD163 and sMR were higher in both of the NAFLD cohorts compared with controls (P < 0.001). In the cross-sectional cohort, sCD163 only showed trends toward association with ballooning (rho = 0.14, P = 0.08) and portal inflammation (rho = 0.17, P = 0.08). sMR showed similar associations with liver histology. In the VSL#3 cohort, sCD163 correlated inversely with steatosis (rho = -0.35, P = 0.04), and lobular (rho = -0.57, P < 0.001) and portal inflammation (rho = -0.38, P = 0.02); sMR was not associated with any histological scores. Neither sCD163 nor sMR changed significantly during intervention, and without association with NAFLD resolution. CONCLUSIONS: The macrophage activation markers sCD163 and sMR showed poor associations with liver histology in 2 different cohorts of children with biopsy-proven NAFLD, and none of the markers decreased during successful intervention. These results are in contrast with studies of adult NAFLD and may suggest a possibility of different roles for macrophages in the pathogenesis of adult and pediatric NAFLD.

Determination of the renal concentration capacity following intravenous administration of dDAVP in healthy humans.

The synthetic AVP analogue 1-desamino-8-d-arginine-vasopressin (dDAVP) is used for treatment of polyuric disorders. Lack of commercially available assays limits the usefulness of dDAVP as a diagnostic tool in the assessment of renal concentrating capacity. We aimed to develop a specific radioimmunoassay (RIA) for determination of plasma dDAVP (pdDAVP) in order to investigate the relationship between pdDAVP levels and urine osmolality (Uosm). Further, we aimed to determine the onset, duration, and maximum concentrating capacity following intravenous (i.v.) bolus dDAVP injection. The dDAVP assay was based on a well-established RIA for measurements of AVP. Fourteen healthy subjects (aged 15-18 years) participated. Blood and urine samples were collected prior to and after i.v. bolus of 0.03 µg/kg dDAVP. Diuresis and Uosm was measured for nine hours following dDAVP administration. PdDAVP and Uosm were analyzed.We established a specific RIA for the measurement of pdDAVP. All subjects reached maximal pdDAVP concentration (Cmax) 30 minutes following infusion, and a rise in Uosm after 60 minutes. Maximal Uosm varied between subjects, with no direct correlation to the achieved pdDAVP levels. We found no significant intra-individual variation between two dDAVP infusions and the effect was reproducible in terms of Cmax and maximal Uosm. We characterized the relationship between pdDAVP and Uosm after dDAVP bolus injection in healthy adolescents using our dDAVP assay. Maximal Uosm achieved correlated with the baseline Uosm levels and seemed unrelated to achieved pdDAVP levels. The urine concentrating response was maintained at least eight hours.

No immediate effect on urodynamic parameters during transcutaneous electrical nerve stimulation (TENS) in children with overactive bladder and daytime incontinence-A randomized, double-blind, placebo-controlled study.

AIM: To evaluate the immediate effect on natural fill urodynamic parameters and bladder function during transcutaneous electrical nerve stimulation (TENS) in children with overactive bladder (OAB) and daytime urinary incontinence (DUI). MEETHODS: In this double-blind, placebo-controlled study, 24 children with severe OAB and DUI (mean age 8.5 ± 1.2 years) underwent 48-h natural fill urodynamics. After 24 h of baseline investigation, the children were randomized to either active continuous TENS (n = 12) or placebo TENS (n = 12) over the sacral S2-S3 outflow. The urodynamic recordings were analyzed manually for three different bladder contraction patterns resulting in a void. The number of bladder contractions not leading to a void was also calculated. Maximum voided volume (MVV) and average voided volume (AVV) were identified for both the baseline and the intervention day. RESULTS: We found that TENS had no immediate objective effect on bladder capacity. The difference (before minus after treatment) in MVV/EBC in the active TENS group = 0.03 ± 0.23 versus placebo TENS group = -0.01 ± 0.10 (P = 0.61). Also, there was no significant difference in the proportion of different bladder contraction types between the two groups. TENS did not significantly influence the number of bladder contractions not leading to a void. Results are presented as mean ± SD. CONCLUSION: There is no immediate objective effect of TENS on bladder activity assessed by natural fill urodynamics in children with OAB and DUI.

Combination treatment of nocturnal enuresis with desmopressin and indomethacin.

BACKGROUND: We investigated the effect of combining indomethacin and desmopressin in treating children with monosymptomatic nocturnal enuresis (MNE) and desmopressin-resistant nocturnal polyuria. METHODS: Twenty-three children with MNE, nocturnal polyuria, and partial or no response to desmopressin were recruited from incontinence clinics of our tertiary referral center. We used a randomized single-arm crossover placebo-controlled study design consisting of two 3-week treatment periods with a combination of desmopressin (0.4 mg) and indomethacin (50 mg) or desmopressin and placebo at bedtime. Home recordings at baseline and for the final 2 weeks of each treatment period were performed and included nocturnal urine output measurements. The number of dry nights achieved and reduction in the nocturnal urine output were the main effect parameters. Student's t test and Pearson's correlation coefficient were used for statistical analysis. RESULTS: The addition of indomethacin to desmopressin significantly reduced nocturnal urine output (from 324 ± 14 ml to 258 ± 13 ml, p < 0.001). This did not lead to more dry nights in all children, and we found no statistically significant reduction in enuresis frequency (from 68 % ± 0.1 to 56 % ± 0.1, p = 0.24). CONCLUSIONS: Addition of indomethacin to desmopressin can further reduce nocturnal urine output in children with MNE and desmopressin-resistant nocturnal polyuria. The combination treatment does not, however, improve outcome in terms of frequency of nights with enuresis. The dissociation of antidiuretic and antienuretic effect may reflect nocturnal bladder reservoir dysfunction in children who present with normal daytime bladder function.

Outcome of a standardized approach to childhood urinary symptoms-long-term follow-up of 720 patients.

AIMS: To investigate the relevance of enuresis subtyping for selection of treatment modality and for long-term outcome in a large consecutive patient cohort. MATERIALS AND METHODS: We included all patients referred for urinary incontinence during a 5-year period but excluding recurrent urinary tract infections (UTI). Type and severity of incontinence, prior history, results of examinations performed, number of visits, and effect of all treatments provided, were included in a clinical database. RESULTS: Seven hundred twenty children aged 4-16 years (mean 8.5 ± 2.2 years, 239 girls) were included in the analysis (42% with monosymptomatic (MNE), 55% with non-MNE, and 3% with isolated daytime incontinence). Initial evaluation revealed only few underlying causes (one neurological and eight anatomical). Investigations showed significant differences between MNE and non-MNE patients as both maximal voided volume and nocturnal urine volume was lower in non-MNE patients (P < 0.001). Follow-up for average 1,587 days (3.4 years) was performed in 660 (92%) patients. A higher number of visits and a longer treatment period were needed for non-MNE patients (on average 4.7 ± 2.8 visits) than MNE patients (3.1 ± 1.6 visits, P < 0.001). The most common treatment regimen that resulted in dryness in both MNE (40%) and non-MNE (36%) was the alarm system. Interestingly, of the 539 patients who initially were referred due to desmopressin resistance 177 (33%) of these were dry on desmopressin monotherapy. CONCLUSIONS: The study indicated that MNE and non-MNE are two distinct disease entities with different optimal treatments and showed that the latter patients are more difficult and time-consuming to manage.

Two nights of home polysomnography in healthy 7-14-year-old children - Feasibility and intraindividual variability.

OBJECTIVE: Attended polysomnography (PSG) is the gold standard for childhood sleep evaluation. There is, however, only limited information regarding repeated ambulatory PSG in children. We aimed to test whether in hospital attached level 2 home PSG is feasible and reproducible in healthy children. METHODS: We recruited healthy children aged 7-14 years to undergo two nights of full level 2 PSG. The PSG equipment was attached at the hospital on the day of the sleep test and all recordings were performed at home. Subjective sleep quality, nocturnal urine production, sleep time and number of awakenings were documented for a week in connection to the first PSG night. RESULTS: Thirty-three children were recruited of whom 32 children (aged 11 ± 2.1 years) underwent two nights of PSG. All 64 PSGs were technically adequate for sleep evaluation. We found mean sleep efficiency of 94% and mean total sleep time of 8.4 h. Sleep stages distribution with 5.9% N1, 46.8% N2, 24.3% N3 and 22.8% REM sleep. We found poorer subjective sleep quality, more self-reported awakenings, and shorter total sleep time on nights with PSG compared to nights without PSG with no differences between PSG study nights. No differences in nocturnal urine production were found between nights with and without PSG. The comparison of PSG variables between the two PSG nights revealed no first night effect. CONCLUSIONS: Type 2 PSG recording is feasible for sleep evaluation in children 7-14 years of age producing good data quality. We found no first night effect on PSG variables. www. CLINICALTRIALS: gov Registration number: NCT03477812.

Evaluation of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis: A Single Center Experience.

Objectives: Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile arthritis (sJIA), and early diagnosis is critical for survival. The objective of this study was to evaluate the 2016 MAS classification criteria in a Danish sJIA cohort and to compare different sets of criteria for the early identification of MAS including the HLH-2004 diagnostic guidelines, MS score, and the ferritin/ESR ratio. Methods: Data was extracted from medical charts of 32 patients with sJIA from a single Danish paediatric rheumatology center diagnosed between January 2014 and June 2021. Patients who met the 2016 MAS classification criteria were classified as having MAS. From a receiver operating characteristic (ROC) plot, the area under the curve (AUC) was calculated for the prediction of patients with MAS according to the 2016 MAS classification criteria using either MS score or the ferritin/ESR ratio. Results: Of the cohort, eight (25%) patients were classified as having MAS according to the 2016 MAS classification criteria compared to only three (9.4%) patients fulfilling the HLH-2004 diagnostic guidelines, all of which had recurrent MAS. The ferritin/ESR ratio showed the highest sensitivity (100%) but the lowest specificity (72.2%). In comparison, the MS score had a higher specificity (90.9%) for the identification of MAS according to the 2016 classification criteria. In our cohort, the most optimal cut-off point for the ferritin/ESR ratio was ≥19.4 (sensitivity: 100%, specificity: 72.2%) and ≥ -1.5 for the MS score (sensitivity: 71.4%, specificity: 91.7%), respectively. Conclusion: The 2016 MAS classification criteria were a valuable tool in the discrimination of sJIA with and without MAS. The HLH-2004 diagnostic guidelines showed the lowest sensitivity, ferritin/ESR ratio, and the lowest specificity compared to the MS score where an acceptable high sensitivity and specificity was found.

Eliciting Information Needs of Child Patients: Adapting the Kano Model to the Design of mHealth Applications.

BACKGROUND: Health care services are increasingly being digitized, but extant literature shows that digital technologies and applications are often developed without careful consideration of user needs. Research is needed to identify and investigate best-in-class methods to support user-centered design of mHealth applications. OBJECTIVES: The article investigates how the Kano model can be adapted and used for the purpose of eliciting child patients' information needs during the design phase of mHealth application development. The aim is to demonstrate its applicability for collecting and analyzing patient-centered data that are key to designing technology-supported solutions for health management. METHODS: The article is based on a mixed-methods case study, which includes interviews with 21 patients aged 6 to 18. Structured interviews are analyzed based on prescriptions of the Kano model. Semi-structured interviews about child patients' information needs are analyzed thematically. RESULTS: The results demonstrate several improvements to the Kano model that take into account the difficulties of effectively communicating with child patients. The combination of two types of interviews offers unique insights into the what, how, and why of patients' needs. Adaptation of the Kano model, simplification of response options, and participation of child patients' parents in interviews facilitate data collection. CONCLUSION: The article shows how the Kano model can be adapted to provide an effective means of eliciting child patients' needs. Adapting the model by combining structured and semi-structured interviews makes it a powerful tool in designing mHealth applications.

Increased nocturnal blood pressure in enuretic children with polyuria.

PURPOSE: We investigated the association between nocturnal blood pressure and urine production in children with enuresis. MATERIALS AND METHODS: A total of 39 consecutive children with a mean age of 9.8 years (range 6.2 to 14.9) with monosymptomatic nocturnal enuresis completed a bladder diary, including 2 weeks of basic documentation and 2 with desmopressin titration from 120 to 240 microg sublingually. Arterial blood pressure was measured every 30 minutes during 24 hours and during 4 additional nights using an ambulatory blood pressure monitor. Furthermore, 10 healthy children were recruited into the study who completed a bladder diary for 5 days while measuring arterial blood pressures with documentation of all intake and voided volumes. RESULTS: Patients with nocturnal polyuria had significantly higher nocturnal mean arterial pressure than patients without polyuria and controls (p <0.05). Furthermore, a positive correlation was seen between nocturnal urine output and nocturnal mean arterial pressure (r = 0.32, p <0.001). Nocturnal urine output was significantly higher during wet nights than dry nights (p <0.001). However, no significant difference was found in mean arterial pressure between wet and dry nights. CONCLUSIONS: Nocturnal mean arterial pressure was significantly higher in children with enuresis with polyuria than in children without polyuria. There was a significant positive correlation between average nocturnal mean arterial pressure and nocturnal urine volume in the whole study. The association between nocturnal blood pressure and urine volume, and the role of blood pressure should be investigated in a larger group of children with enuresis who have nocturnal polyuria.

Transcutaneous electrical nerve stimulation for refractory daytime urinary urge incontinence.

PURPOSE: We studied the effect of transcutaneous electrical nerve stimulation in children with overactive bladder and treatment refractory daytime urinary incontinence. MATERIALS AND METHODS: We recruited 27 children 5 to 14 years old with daytime urge incontinence refractory to timer assisted standard urotherapy and anticholinergics who had normal urinalysis, and unremarkable urinary tract ultrasound and physical examination. Study exclusion criteria were bladder underactivity, lower urinary tract obstruction, ongoing defecation disorders, lower urinary tract surgery and previous transcutaneous electrical nerve stimulation. After a 2-week run-in of standard urotherapy the children underwent natural fill ambulatory urodynamics to confirm detrusor overactivity. Subsequently they were randomly allocated to 4 weeks of 2 hours of daily active or placebo S2-S3 transcutaneous electrical nerve stimulation. The severity of incontinence and urgency, and 48-hour bladder diaries were recorded before randomization and during intervention week 4. Children withdrew from anticholinergics throughout the study period. RESULTS: Two children were excluded from randomization due to urodynamic signs of lower urinary tract obstruction. After 4 weeks of intervention 8 children (61%) in the active group showed a significant decrease in incontinence severity but this occurred in only 2 (17%) in the sham treated group (p <0.05). The active group had a significantly greater decrease in daily incontinence episodes compared to the sham treated group (p <0.01). Transcutaneous electrical nerve stimulation did not alter maximal and average voided volumes. CONCLUSIONS: Sacral transcutaneous electrical nerve stimulation seems superior to placebo for refractory daytime incontinence in children with overactive bladder. This effect does not seem to be a consequence of improved bladder reservoir function.

A Danish population-based cohort study of desmopressin use in adults with nocturia or nocturnal enuresis.

OBJECTIVE: This study investigated how desmopressin is prescribed to adults in Denmark. METHODS: All adult users of desmopressin over an 8-year period were identified from the Danish National Prescription Registry. Adult patients with nocturia or nocturnal enuresis (NE) were identified by indication codes for "frequent nocturnal voiding" or "involuntary nocturnal voiding", respectively. Patient demographics, desmopressin formulation and dose, and concomitant medication were investigated. RESULTS: In all, 13 871 adults with nocturia and 2872 adults with chronic (i.e. >10 prescriptions) NE were given 102 547 and 43 712 desmopressin prescriptions, respectively. Across the entire patient cohort, 57% were women and mean patient age was 62 years. Over 40% of prescriptions were to elderly patients (≥65 years), and desmopressin use for adult enuresis increased with age. Orally disintegrating tablets were the most frequently used formulation (57%-65% of prescriptions), and a greater proportion of women than men used low-dose desmopressin (60 µg). Concomitant use of painkillers (opioids: 18%-26.7% of prescriptions; non-steroidal anti-inflammatory drugs: 14.2%-16.4% of prescriptions) and antidepressants (14.4%-18.1% of prescriptions) was common in both conditions, and 5.4%-9.2% of concomitant prescriptions were for overactive bladder medications. CONCLUSIONS: This study provides insights into desmopressin use among Danish adults. Nearly half the prescriptions were to patients aged ≥65 years, despite historical manufacturer recommendations that desmopressin be restricted to patients <65 years of age. NE is considered a childhood condition, but desmopressin use for adult NE increased with age. A greater proportion of desmopressin prescriptions to women than men were for the lowest dose, consistent with greater sensitivity to desmopressin in women.

Response to Early-onset Pamidronate Treatment in Chronic Nonbacterial Osteomyelitis: A Retrospective Single-center Study.

OBJECTIVES: Chronic nonbacterial osteomyelitis (CNO) is a sterile inflammatory bone disorder with an unpredictable disease course. The objective was to assess clinical and radiological disease activity in children with CNO including response to early-onset pamidronate treatment. METHODS: A single-center retrospective study was conducted of children fulfilling the Bristol Criteria for CNO. At the time of diagnosis, whole-body magnetic resonance imaging (WB-MRI) or local MRI was performed to assess radiological disease activity. Children with multifocal or spinal bone inflammation and clinical disease activity not responding to nonsteroidal antiinflammatory drugs were categorized as having extended CNO. Clinical disease activity was assessed annually. RESULTS: Fifty-one children were included. Median followup time was 4 years (interquartile range 3-7). Children categorized with extended CNO (n = 32) were treated in an early-onset 2-year pamidronate regimen. In extended CNO, WB-MRI was performed at time of diagnosis, and at years 1 and 2 in 88%, 84%, and 91% of cases, respectively. During the first year, the total number of radiologically active lesions and number of spinal lesions per patient declined (p = 0.01). Clinically inactive disease was recorded in 12/32 children (38%). However, 8/12 children (67%) experienced clinical relapse. In limited CNO (n = 19), 10/19 children (53%) presented with clinically inactive disease after 1 year and did not experience clinical relapse. CONCLUSION: Pamidronate might contribute to improvement in clinical and radiological disease activity in extended CNO, especially after 1 year of treatment. However, children with continuously active disease after 2 years of pamidronate treatment were seen.

The impact of daytime diuresis on voiding frequency and incontinence classification in children.

PURPOSE: Daytime voiding frequency is an important criterion in the classification of childhood incontinence. The aim of this study was to assess the relative impact of diuresis and bladder capacity on voiding frequency. MATERIALS AND METHODS: We analyzed data from 570 children 4 to 15 years old (median age 8.3 +/- 2.0 years) treated for urinary incontinence at a secondary referral center, and 87 healthy controls. Based on frequency-volume charts, daytime voiding frequency, age adjusted maximum voided volume, daytime diuresis and fluid intake were calculated. Children were classified according to voiding frequency into 3 groups-decreased (fewer than 3 voids daily), normal (3 to 7) and increased voiding frequency (more than 7). RESULTS: A total of 219 children had monosymptomatic enuresis, while 351 children presented with daytime symptoms. In children with daytime symptoms we found a significant difference between voiding frequency groups regarding daytime diuresis (decreased voiding frequency 12.3 +/- 4.1 ml/kg, normal 18.7 +/- 6.0 ml/kg, increased 31.1 +/- 9.8 ml/kg, p <0.001). In contrast, maximum voided volume observed/expected bladder capacity for age did not differ significantly between normal and increased frequency groups (72% +/- 25% vs 74% +/- 23%), compared to patients with decreased voiding frequency (89% +/- 30%, p <0.01). Also, in healthy children we found a positive correlation between voiding frequency and daytime diuresis, whereas maximum voided volume observed/expected bladder capacity for age did not correlate with voiding frequency. Furthermore, we observed a significant positive correlation between fluid intake and diuresis (r = 0.53, p <0.001). CONCLUSIONS: In healthy controls and children with incontinence daytime voiding frequency depends mainly on diuresis, and seems less influenced by bladder capacity. Diuresis should be taken into consideration when evaluating voiding frequency from frequency-volume charts in children.