Urinary biomarkers associated with acute kidney injury in pediatric mechanical circulatory support patients.

BACKGROUND: In patients requiring mechanical circulatory support (MCS), the incidence of acute kidney injury (AKI) is between 37 and 63%. In this study, we performed an exploratory analysis evaluating the relationship of multiple urine biomarkers with AKI development in pediatric MCS patients. METHODS: This is a single center retrospective study in a pediatric cohort receiving MCS from August 2014 to November 2020. We measured 14 urine biomarkers of kidney injury on day 1 following MCS initiation and analyzed their association with development of AKI in the first 7 days of MCS initiation. RESULTS: Sixty patients met inclusion criteria. Patients with AKI were more likely to be supported by venoarterial extracorporeal membrane oxygenation (65% vs. 8.3%, p < 0.001), compared to the no AKI group and less likely to have ventricular assist devices (10% vs. 50%, p < 0.001). There was a significant increase in the median urine albumin and urine osteoactivin in the AKI group, compared to the no AKI group (p = 0.020 and p = 0.018, respectively). When normalized to urine creatinine (UCr), an increased log osteoactivin/UCr was associated with higher odds of AKI development (OR: 2.05; 95% CI: 1.07, 4.44; p = 0.028), and higher log epidermal growth factor (EGF)/UCr (OR: 0.41; 95% CI: 0.15, 0.96) was associated with decreased odds of AKI. CONCLUSIONS: Early increase in urine osteoactivin is associated with AKI development within 7 days of MCS initiation in pediatric patients. Contrary, an increased urine EGF is associated with kidney protection. A higher resolution version of the Graphical abstract is available as Supplementary information.

Antineurofascin IgG2-associated paediatric autoimmune nodopathy.

In this case series of four paediatric patients, we present the first described cases of immunotherapy-responsive autoimmune nodopathy with IgG2 antineurofascin antibodies. In three cases, the antineurofascin antibodies were predominantly of the IgG2 subclass, a novel finding in comparison to previously described adult cases where IgG4 and/or IgG1/3 have typically been described. One patient had low signal for IgG2 with predominant IgG1 and IgG4 antibodies, a pattern commonly seen in adult patients. Two patients had antibodies targeting all three neurofascin isoforms (155, 186, and 140), whereas antibodies in the sera from the third targeted only the nodal isoforms 186 and 140, and the fourth patient only neurofascin 155. The three patients with IgG2 predominant antibodies appear to be responsive to intravenous immunoglobulin (IVIG) to varying degrees thus far, whereas the patient with IgG1/4 antibodies had poor response to IVIG but good response to steroids. Although the full clinical significance of IgG2 predominant antineurofascin antibodies in the context of childhood polyneuropathy remains unclear, emerging evidence of serological-phenotypic correlation may inform prognostication and therapeutic decision-making, warranting further study into this area. WHAT THIS PAPER ADDS: Paediatric immunotherapy-responsive nodopathies were associated with antineurofascin antibodies predominantly of the IgG2 subclass in 3 out of 4 patients. Identification of antibodies and understanding their phenotypic relevance could predict response to treatment and guide therapeutic decision-making in children.

Optimized Infliximab Induction Predicts Better Long-Term Clinical and Biomarker Outcomes Compared to Standard Induction Dosing.

OBJECTIVES: To evaluate the efficacy of standard and optimized infliximab induction dosing in attaining corticosteroid (CS) free clinical remission at week 52 and the effect that post-induction trough levels have on long-term outcome. METHODS: Inflammatory bowel disease (IBD) patients ≤18 years commenced on infliximab between August 1, 2016, and August 1, 2018, from Vancouver, Canada, and Glasgow, Scotland, were included. The Glasgow cohort followed standard induction while the Vancouver cohort undertook induction optimization based on clinical, biomarker, and proactive infliximab trough levels. Baseline characteristics and laboratory values were documented. RESULTS: In total, 140 children were included [median age 14.1 years (interquartile range (IQR) 12.0-16.0)]; 54% male. CS-free clinical remission at week 52 was higher in the optimized group compared to the standard cohort [65/78 (83%) vs. 32/62 (52%), P < 0.001]. Combined CS-free clinical and biomarker remission (CRP < 5 mg/L) was also higher in the optimized compared to the standard cohort [65/78 (83%) vs 25/62 (40%), P < 0.001]. The median post-induction trough level was higher in children who were in CS-free clinical remission at week 52 [3.6 mg/L (1.5-7.1)] vs. those who were not [2.0 mg/L (0.8-4.1), P = 0.04]. The odds of attaining a therapeutic post-induction trough level were almost 4-fold higher in the optimized group than the standard cohort (OR 3.97, 95% CI: 1.89-8.68, P < 0.001). CONCLUSIONS: Standard infliximab induction resulted in less favorable long-term outcomes for pediatric IBD patients. Optimizing induction using clinical, biomarker, and proactive trough levels resulted in higher post-induction trough levels and a greater odds of attaining long-term clinical remission.

Epstein-Barr Virus Status and Subsequent Thiopurine Exposure Within a Paediatric Inflammatory Bowel Disease Population.

ABSTRACT: The use of thiopurine therapy in Epstein-Barr virus (EBV)-naïve inflammatory bowel disease (IBD) patients remains controversial due to a risk of EBV-associated complications. We evaluated EBV status and outcomes within our paediatric IBD population over an 8-year period; finding that 217 of 409 (53%) screened patients were seropositive for EBV at IBD diagnosis; that thiopurines were used in 189 of 217 (87%) seropositive and 159 of 192 (83%) seronegative patients (P = 0.22); and that 7 of 192 (4%) previously seronegative patients subsequently tested positive for EBV with 6 of 7 (86%) patients having concurrently recorded thiopurine use. All six patients continued thiopurine with/without a period of cessation; no EBV-associated lymphoproliferative disorders/serious complications were recorded within our cohort. A significant proportion of our patients would not receive thiopurine therapy should their use be avoided in EBV-negative patients (47%) or seronegative males (30%). The small but significant risks of thiopurine treatment must be balanced against the potential benefits of successful IBD management; further research into this is required.

The deadly gap: Understanding suicide among veterans transitioning out of the military.

In the period following separation from the military, service members face the challenge of transitioning to a post-military civilian life. Some evidence suggests these transitioning Veterans are at higher risk for suicide compared with both the broader Veteran population and the United States public, yet they often do not receive adequate support and resources. In this review, we use the Three-Step Theory of suicide to outline characteristics of transitioning Veterans and the transition process that may affect suicide risk. We then highlight relevant services available to this specific subgroup of Veterans and make recommendations that address barriers to care. Cumulatively, this literature suggests transitioning Veterans fall within a "deadly gap" between the end of their military service and transition into civilian life. This "deadly gap" consists of limited psychiatric services and increased suicide risk factors which together may explain the increase in suicide during this transition period.

The association of childhood trauma with sleep disturbances and risk of suicide in US veterans.

BACKGROUND: Sleep dysregulation is prevalent among veterans and is associated with increased risk of suicidal ideation and behaviors. A confluence of risk factors have been identified to date that contribute to increase risk for suicidal behavior. How these risk factors including childhood trauma, comorbid psychopathology, impulsivity, and hostility together with sleep disturbance contribute to suicide risk remains an open question. These factors have never been examined simultaneously in a unified mediation model, as investigated in the present study, to determine their relative contribution to suicide risk. METHODS: Veterans (N = 105) were recruited across 3-groups, including Major Depressive Disorder (MDD) with/without a history of a suicide attempt (n = 35 and n = 37, respectively), and non-psychiatric controls, who had no history of mental illness or suicidal behavior (n = 33). The participants were assessed using validated self-report assessments with in-depth phenotyping for relevant risk factors associated with suicidal behavior including childhood adversity, depression severity, impulsivity, hostility, and sleep quality. These factors were included in mediation models using path analysis. RESULTS: Across all subjects including those with MDD and non-psychiatric controls, mediation analysis showed that higher levels of childhood trauma had an indirect effect on poor sleep quality (p = 0.001). This effect was orthogonal, being independently mediated by both MDD psychopathology (p = 0.003), and higher traits of impulsivity (p = 0.001) and hostility (p = 0.015). Amongst MDD veterans, childhood trauma was directly associated with increased suicide risk (p = 0.034), irrespective of their severity of depression, or their degree of hostility and impulsivity. LIMITATIONS: include use of self-report data, and the inability to establish causal inferences with cross-sectional design. CONCLUSION: Childhood adversity as a significant pre-deployment risk factor for disturbed sleep and elevated suicide risk, potentially important for incorporation in clinical practice for suicide.

Protocol for a multinational risk-stratified randomised controlled trial in paediatric Crohn's disease: methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or high risk for aggressive disease course.

INTRODUCTION: Immunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn's disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups. AIMS: To compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation. METHODS AND ANALYSIS: REDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6-17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk). ETHICS AND DISSEMINATION: ClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access. TRIAL REGISTRATION NUMBER: NCT02852694; Pre-results.

A Decade of Varicella Screening Within a Paediatric Inflammatory Bowel Disease Population.

INTRODUCTION: Increased risk of opportunistic infection-e.g., varicella zoster infection-secondary to therapies is a cause of morbidity in inflammatory bowel disease [IBD] patients. The UK vaccination schedule does not include varicella immunisation. We aimed to evaluate the varicella screening and immunisation programme in a paediatric IBD population. METHODS: Data regarding IBD diagnosis, varicella status, and consequent immunisations/treatment interventions were collected retrospectively from the records of patients diagnosed with IBD over a 10-year period [2009-2018]. RESULTS: In all, 520 IBD patients were diagnosed; 505/520 [97%] had varicella testing; 46/505 [9%] were naïve. Of 501 patients, 391[78%] were tested before or within 7 days of diagnosis; this increased in the second 5-year period compared with the first (229/268 [85%] versus 162/233 [70%]; p <0.00001). Median diagnosis age of naïve patients was lower [8.3 years versus 12.8 years; p <0.00001]. Where vaccination was feasible, 21/31 [68%] had two and 7/31 [23%] one immunisation. Prednisolone induction led to lower rates of vaccination (5/13 [39%] versus 23/33 [70%] for other induction therapies; p =0.02). Of 28 vaccinated patients, 5 [18%] had suspected breakthrough varicella; and 6/18 [33%] unimmunised patients required post-exposure prophylaxis or treatment for varicella. Immunisation was associated with a decrease in patients requiring post-exposure prophylaxis (0/28 [0%] versus 5/18 [28%]; p =0.0006) and varicella-related hospital admission (1/28 [4%] versus 4/18 [22%]; p =0.01). CONCLUSIONS: High rates of varicella screening and immunisation within a PIBD population are possible, resulting in a reduction in hospital admissions for varicella treatment. Varicella immunisation may be of increasing importance within the PIBD population with the emergence of novel therapeutic strategies.

Clinician Responses to Pediatric Lipid Screens Suggestive of Severe Dyslipidemia.

Objectives: To measure case detection and response time of severe pediatric dyslipidemia, defined as non-high-density lipoprotein cholesterol (HDL-C) ≥190 mg/dL on the initial screening panel. Although low adherence to guidelines recommending universal pediatric lipid screening is well-documented, it is unknown how clinicians respond to pediatric lipid screening results suggestive of severe dyslipidemia. Study design: This study is a single-institution, retrospective review of patients 0-18 years of age with initial lipid panels completed from January 1, 2010, to June 30, 2018. A chart review was conducted on all patients with non-HDL-C ≥190 mg/dL to determine indication(s) for the initial lipid panel, specialty of ordering clinician, type of action taken to an abnormal result (repeat laboratory tests, treatment, and/or referral), time from result to clinician action, and diagnosis. Results: There were 16 860 initial lipid panels that met the inclusion criteria; 178 (1.1%) had non-HDL-C ≥190 mg/dL, indicating severe dyslipidemia. The most common indication for screening was universal screening (52%). For all lipid panels with non-HDL ≥190 mg/dL, a clinician action was documented for 47% within 7 days and 69% within 30 days. No follow-up action was documented in 18 (9%). A clinical diagnosis of familial hypercholesterolemia was the most common diagnosis, in 24% of patients. Conclusions: The majority of lipid panels with non-HDL-C ≥190 mg/dL had some action documented, although the actions varied. Universal screening was the most common indication for testing, clarifying its significance in identifying severe dyslipidemia. Further education and improved management protocols may help responses to severe dyslipidemia in children at high risk for premature cardiovascular disease.

Prehabilitation: The Impact of Preoperative Exclusive Enteral Nutrition on Paediatric Patients With Crohn Disease.

Exclusive enteral nutrition (EEN) is effective in inducing remission in paediatric Crohn Disease (CD) and has been shown to reduce inflammation and improve outcomes in adult CD patients when used before resectional surgery. This retrospective study demonstrates that preoperative EEN is achievable in paediatric CD patients undergoing right hemicolectomy and is associated with positive peri-operative outcomes. Seventeen patients (8 who received preoperative EEN and 9 who did not) were included in the study. Six of 8 (75.0%) managed EEN orally; 1 via nasogastric tube and another via a previously sited gastrostomy. Use of preoperative EEN was associated with a decreased rate of moderate/severe disease on resection pathology (5/8 [62.5%] vs 9/9 [100%]; P = 0.04). Larger studies are required to determine the wider potential benefits of preoperative EEN on postoperative outcomes within paediatric practice.

Using a Steroid-sparing Tool in Paediatric Inflammatory Bowel Disease to Evaluate Steroid Use and Dependency.

OBJECTIVES: The aim of the study was to evaluate the use of steroids within the paediatric inflammatory bowel disease (PIBD) population at a tertiary paediatric centre over a year; to identify cases of steroid dependency; and assess factors associated with steroid excess. METHODS: The prevalent PIBD population (May 1, 2017-April 30, 2018) were reviewed. Data were collected retrospectively from patient records and entered into an online steroid assessment tool (modified for paediatrics). RESULTS: A total of 229 patients (181 Crohn disease, 31 ulcerative colitis [UC], and 17 inflammatory bowel disease-unclassified) were included. Of the 229 patients 38 (16.6%) received oral steroids; 12 of 38 (31.6%) receiving >3-month course. Eleven of 38 (28.9%) received >1 steroid course (maximum 2). Of the 229 patients 37 (16.2%) had exclusive enteral nutrition, with 26 of 37 (11.4% total cohort) avoiding steroid use during the study period.Quiescent disease activity had a negative correlation with steroid use (11/127 [8.7%] vs 27/102 [26.5%] P < 0.01), and steroid dependency (3/127 [2.4%] vs 12/102 [11.8%] P < 0.01). Patients with UC were more likely to be steroid dependent (5/31 [16.1%] UC vs 10/198 [5.1%]; P = 0.02); as were network-managed patients (8/11 [72.7%] vs 7/27 [25.9%]; P = 0.01). Fourteen of 15 (93.3%) of steroid-dependent patients had active steroid sparing strategies in place (eg, commencement, switching, or optimization of therapies). CONCLUSIONS: We have described rates of steroid use and dependency within our PIBD population. Exclusive enteral nutrition served as a steroid sparing tool in 11.4% of the total cohort. Replication of this study in other paediatric centres would allow comparative analysis.

BMPR1A mutation-positive juvenile polyposis syndrome and atrial septal defect: coincidence or association?

We describe the case of a 16-year-old male patient with BMPR1A mutation and incidentally detected atrial septal defect (ASD). This patient was diagnosed with BMPR1A mutation through genetic testing and was attending for routine surveillance endoscopy when ASD was incidentally diagnosed. He was referred to cardiology outpatient clinic with plans for elective ASD closure. Through this case report we aim to discuss the pathophysiology of juvenile polyposis syndrome (JPS), highlight what we believe to be a novel presentation of comorbid BMPR1A mutation and ASD and hypothesise that patients with BMPR1A mutation and JPS may be at risk of previously unrecognised cardiovascular complications analogous to the previous association of SMAD4 JPS and cardiac abnormalities.

On (3)H beta-particle and (60)Co gamma irradiation of aqueous systems.

The chemistry of water and aqueous solutions is very different after irradiation with (3)H beta particles and high-energy electrons or (60)Co gamma rays. The greater the linear energy transfer (LET) of the medium for (3)H beta particles compared to high-energy electrons or (60)Co gamma rays leads to an increased local concentration of reactants. There is an increased amount of intratrack chemistry, which reduces the escape yield of and OH by about 50%, but increases the yield of H(2) by about 50% and of H(2)O(2) by about 35%. Analysis of stochastic-diffusion kinetic calculations employing simulated track structures reveals that the yield of H(2) produced by diffusion-kinetic processes increases significantly for (3)H beta particles compared to (60)Co gamma radiation, while production of H(2) by sub-picosecond processes is essentially the same. In both (3)H beta-particle and (60)Co gamma radiolysis, the reactions + and are equally important in the production of H(2). In the former case, each reaction has a yield of approximately 0.18, and in the latter a yield of approximately 0.08. In neutral water, the reaction (H + H) is negligible. The yield of Fe(III) in (3)H beta-particle radiolysis of the Fricke dosimeter is much smaller than in radiolysis with more energetic electrons. Simulations show that this change is primarily due to the reduced escape yield of H, formed from the scavenging of by the bulk H(3)O(+) of the acid. The chemical differences observed in experiments, and in calculations, reflect the underlying structure of the electron tracks: Examination of the track structure simulations demonstrates that primary events are considerably more well-separated in high-energy electron tracks compared to (3)H beta-particle tracks.