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Background Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn’s disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52. Methods Pre- [n = 86], and 10–14-week post-treatment [n = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [n = 48; five 5-mg/kg infusions over 22 weeks] or CONV [n = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes [FC] with |log2FC| > 0.5 after false discovery rate adjustment were considered significant. Results FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins [including oncostatin-M, TNFSF14, HGF and TGF-α], and higher clinical disease activity, C-reactive protein and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52. Conclusion FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation. Trial registration number NCT02517684.

ObjectiveIn newly diagnosed paediatric patients with moderate-to-severe Crohn’s disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment.DesignIn this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3–17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI Results100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004).ConclusionsFL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy.Trial registration numberClinicalTrials.gov Registry (NCT02517684).

Background Recently, we established that First-line infliximab (FL-IFX) was superior to conventional treatment (CONV) in achieving and maintaining clinical remission in newly diagnosed paediatric patients with moderate-to-severe Crohn’s disease (CD) (PMID: 33384335). Selection of patients eligible for FL-IFX can be corroborated by combining clinical criteria with immunological biomarkers relating to the patients’ underlying immunopathology. Therefore, we investigated differential effects of FL-IFX and CONV induction treatment on serum inflammatory protein concentrations and assessed whether stratification of CD patients according to baseline serum profiles of IFX-modulated proteins relates to maintaining remission at week 52. Methods In the TISKIDS randomised controlled trial, newly diagnosed therapy-naïve CD patients with a weighted paediatric CD activity index (wPCDAI) >40 were included. FL-IFX consisted of 5 IFX infusions (5 mg/kg) combined with azathioprine (AZA) maintenance treatment. CONV treatment consisted of induction therapy with Exclusive Enteral Nutrition or oral prednisolone combined with AZA maintenance. Serum samples of 48 FL-IFX and 43 CONV patients, collected at time of diagnosis and after 10–14 weeks of induction treatment, were available. Concentrations of 92 inflammatory proteins were determined with Olink Proteomics® proximity extension technology. Hierarchical clustering was performed to stratify patients according to their serum immune profiles. Clinical disease remission was defined as wPCDAI Results At baseline, prior to therapy, clinical disease characteristics and serum inflammatory protein concentrations did not significantly differ between FL-IFX and CONV treated patients. After 10–14 weeks, FL-IFX reduced 28 proteins and enhanced 2 proteins while CONV treatment reduced 13 proteins and enhanced 1 protein. Eighteen proteins were differentially regulated by FL-IFX only. Hierarchical clustering of patients based on their baseline profiles of the 30 IFX-modulated proteins revealed 2 patient clusters. The CD-hi cluster had an increased abundance of 24/30 proteins amongst which Oncostatin-M, TNFSF14, HGF and TGF-alpha and higher clinical inflammatory parameters compared to the CD-lo cluster. Crucially, both baseline inflammatory protein profile and type of induction therapy significantly determined whether patients reached clinical disease remission without treatment escalation at week 52; with CD-hi patients having the lowest change. Conclusion FL-IFX achieves stronger reduction and modulates more proteins than CONV treatment. Stratification of patients according to profiles of IFX-modulated proteins discerns patients with a lower chance of reaching clinical remission without treatment escalation at week 52.

Antibodies directed to tumour necrosis factor-α (TNF-α) are very effective in treating paediatric Crohn’s disease (CD). Over the last few years, research has provided important new insights into how to optimise this treatment’s effectiveness. Research on predictors for anti-TNF treatment responsiveness has revealed potential markers, but data on their accuracy in paediatric CD patients are lagging behind. Also, new evidence has become available on the safety profile of anti-TNF antibodies that suggests the assumed increased malignancy risk seen in patients on anti-TNF and thiopurine combination treatment may be linked more to thiopurine use and not to anti-TNF treatment. In addition, the early results of CT-P13, an infliximab biosimilar, in CD patients confirm the expected similarity with its originator. Thus, the effectiveness of anti-TNF antibody treatment is slowly improving, its malignancy risk is lower than assumed, and its costs are reduced by the introduction of equally effective biosimilars. Together, these trends allow for a more prominent role for anti-TNF antibodies in future treatment of paediatric CD.

Aim: To determine differences in surgical procedures and clinical characteristics at the time of surgery between native bicuspid aortic valves (BAV) and tricuspid aortic valves (TAV) in patients being followed up after aortic valve surgery (AVS). Methods: In this retrospective cohort study in a non-academic hospital, we identified patients who had a surgeon’s report of the number of native valve cusps and were still being followed up. We selected patients with BAV and TAV, and used multivariable regression analyses to identify associations between BAV-TAV and pre-specified clinical characteristics. Results: Of 439 patients, 140 had BAV (32%) and 299 TAV (68%). BAV patients were younger at the time of surgery (mean age 58.6 ± 13 years) than TAV patients (69.1 ± 12 years, p < 0.001) and were more often male (64% vs 53%; p = 0.029). Cardiovascular risk factors were less prevalent in BAV than in TAV patients at the time of surgery (hypertension (31% vs 55%), hypercholesterolaemia (29% vs 58%) and diabetes (7% vs 16%); all p < 0.005). Concomitant coronary artery bypass grafting (CABG) was performed less often in BAV than in TAV patients (14% vs 39%, p < 0.001), even when adjusted for confounders (adjusted odds ratio (adj.OR) 0.45; 95% CI: 0.25–0.83). In contrast, surgery of the proximal aorta was performed more often (31% vs 11%, respectively, p < 0.001; adj.OR 2.3; 95% CI: 1.3–4.0). Conclusions: Whereas mechanical stress is the supposed major driver of valvulopathy towards AVS in BAV, prevalent cardiovascular risk factors are a suspected driver towards the requirement for AVS and concomitant CABG in TAV, an observation based on surgical determination of the number of valve cusps.

Background & Aims Mucosal healing (MH) has become a goal of therapy for Crohn’s disease (CD), but frequent endoscopies are not feasible. We aimed to develop and validate a non-invasive index to assess mucosal inflammation in children with CD. Methods We collected data from the multi-center prospective ImageKids study, in which children with CD underwent ileocolonoscopy with magnetic resonance enterography. We investigated the association of pediatric CD activity index (PCDAI) items and laboratory test results with the simple endoscopic score for CD (SESCD). We used these data in a blended mathematical judgmental clinimetric approach to develop a weighted categorized index to identify children with CD who have MH, which we called the MINI index. We validated the index using data from 3 independent patient cohorts. The derivation and validation cohorts included 154 and 168 children, respectively (age 14.1 ± 2.5 years and 14.2 ± 3.9 years), of whom 16% and 36% had MH (defined as SESCD Results In multivariable models, the stooling item of the PCDAI, erythrocyte sedimentation rate, and level of fecal calprotectin were associated with SESCD (all P Conclusions We developed an index to non-invasively assess mucosal inflammation in children with CD. This index, identifies children with MH with high sensitivity and specificity. The added benefit of MINI over measurement of fecal calprotectin was small but significant, especially for patients with concentrations of fecal calprotectin from 100 to 599 μg/g. ClinicalTrials.gov no: NCT01881490 .

Background In newly diagnosed paediatric Crohn’s disease (CD) patients current guidelines instruct to start exclusive enteral nutrition (EEN) or oral prednisolone in combination with immunomodulators to achieve remission. Infliximab (IFX) is proven to be highly effective in paediatric CD patients, but mostly used once patients are refractory, the so-called step-up (SU) treatment strategy. However, evidence is emerging IFX is more effective if initiated earlier in the disease course. We investigated whether initiation of IFX directly after diagnosis of moderate-to-severe CD, i.e. top-down (TD) treatment, results in a higher long-term remission rate compared with SU treatment. Methods For this international randomised controlled trial (RCT) patients aged 3–17 years, with new-onset, untreated CD with weighted paediatric CD activity index (wPCDAI) >40 were included. TD treatment consisted of 5 IFX (CT-P13) infusions of 5 mg/kg (0, 2, 6, 14, 22 weeks) combined with azathioprine (AZA). After 5 infusions, IFX was stopped while continuing AZA. SU treatment consisted of induction therapy with EEN or oral prednisolone combined with AZA as a maintenance treatment. In both groups, IFX could be (re)started on predefined conditions. The primary endpoint of this study was sustained clinical remission (wPCDAI Results 100 patients were included in 12 centres. Three out of 100 patients did not start with the study after randomisation (n = 97; 49 TD vs. 48 SU). At 52 weeks, 21/48 (44%) of TD patients were in clinical remission without a need for treatment intensification or surgery, while in the SU group this number was significantly lower (8/48, p = 0.004). After induction therapy, IFX was (re)started in 19/49 (39%) TD patients compared with 30/48 (62%) SU patients within 52 weeks (p = 0.019). At week 10, significantly more TD (27/44, 61%) than SU treated patients (17/44, 39%) were in clinical remission (p = 0.033). Fifty-seven of 97 consented to endoscopy at week 10. Endoscopic remission rates were higher in TD (16/27 [59%], median SES-CD 1 [IQR 0–5]) than SU treated patients (5/30 [17%], median SES-CD 6 [IQR 3–16], p = 0.001). Similarly, low faecal calprotectin levels were more frequent in the TD group (n = 75; TD 21/40 [53%] vs. SU 9/35 [26%], p = 0.027). Conclusion We are the first to compare TD IFX to SU treatment in an RCT of paediatric CD patients. TD treatment was superior to SU in achieving sustained clinical remission. Therefore, we advise to start IFX directly after diagnosis in moderate-to-severe paediatric Crohn’s disease patients.

Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy.

Background Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. This is an updated version of a Cochrane Review previously published in 2017. Objectives To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there is a sound biological rationale for its use. Search methods For the latest update we searched the following databases on 3 February 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 31 January 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We imposed no language restrictions and contacted researchers to identify continuing or unpublished studies. Selection criteria Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptics, antipyretics or recognised Central Nervous System active agents with each other, placebo, or no treatment. Data collection and analysis For the original review, two review authors independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding, and exclusions. For the 2016 update, a third review author checked all original inclusions, data analyses, and updated the search. For the 2020 update, one review author updated the search and performed the data analysis following a peer-review process with the original review authors. We assessed seizure recurrence at 6, 12, 18, 24, 36, 48 months, and where data were available at age 5 to 6 years along with recorded adverse effects. We evaluated the presence of publication bias using funnel plots. Main results We included 42 articles describing 32 randomised trials, with 4431 randomised participants used in the analysis of this review. We analysed 15 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbital, phenytoin, valproate, pyridoxine, ibuprofen, or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, paracetamol, or placebo; nor for continuous phenobarbital versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam. There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment at six months (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.48 to 0.85; 6 studies, 1151 participants; moderate-certainty evidence), 12 months (RR 0.69, 95% CI 0.56 to 0.84; 8 studies, 1416 participants; moderate-certainty evidence), 18 months (RR 0.37, 95% CI 0.23 to 0.60; 1 study, 289 participants; low-certainty evidence), 24 months (RR 0.73, 95% CI 0.56 to 0.95; 4 studies, 739 participants; high-certainty evidence), 36 months (RR 0.58, 95% CI 0.40 to 0.85; 1 study, 139 participants; low-certainty evidence), 48 months (RR 0.36, 95% CI 0.15 to 0.89; 1 study, 110 participants; moderate-certainty evidence), with no benefit at 60 to 72 months (RR 0.08, 95% CI 0.00 to 1.31; 1 study, 60 participants; very low-certainty evidence). Phenobarbital versus placebo or no treatment reduced seizures at six months (RR 0.59, 95% CI 0.42 to 0.83; 6 studies, 833 participants; moderate-certainty evidence), 12 months (RR 0.54, 95% CI 0.42 to 0.70; 7 studies, 807 participants; low-certainty evidence), and 24 months (RR 0.69, 95% CI 0.53 to 0.89; 3 studies, 533 participants; moderate-certainty evidence), but not at 18 months (RR 0.77, 95% CI 0.56 to 1.05; 2 studies, 264 participants) or 60 to 72 months follow-up (RR 1.50, 95% CI 0.61 to 3.69; 1 study, 60 participants; very low-certainty evidence). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64; 1 study, 60 participants; low-certainty evidence), an effect found against an extremely high (83.3%) recurrence rate in the controls, a result that needs replication. When compared to intermittent diazepam, intermittent oral melatonin did not significantly reduce seizures at six months (RR 0.45, 95% CI 0.18 to 1.15; 1 study, 60 participants; very-low certainty evidence). When compared to placebo, intermittent oral levetiracetam significantly reduced recurrent seizures at 12 months (RR 0.27, 95% CI 0.15 to 0.52; 1 study, 115 participants; very low-certainty evidence). The recording of adverse effects was variable. Two studies reported lower comprehension scores in phenobarbital-treated children. Adverse effects were recorded in up to 30% of children in the phenobarbital-treated groups and 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbital versus placebo (seven studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months. There were too few studies to identify publication bias for the other comparisons. The methodological quality of most of the included studies was low or very low. Methods of randomisation and allocation concealment often did not meet current standards, and 'treatment versus no treatment' was more commonly seen than 'treatment versus placebo', leading to obvious risks of bias. AUTHORS' CONCLUSIONS: We found reduced recurrence rates for intermittent diazepam and continuous phenobarbital, with adverse effects in up to 30% of children. The apparent benefit for clobazam treatment in one trial needs to be replicated. Levetiracetam also shows benefit with a good safety profile; however, further study is required. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management, and, most importantly, the benign nature of the phenomenon.

Introduction Crohn's disease (CD) is a chronic inflammatory disease predominantly affecting the gastrointestinal tract. CD usually requires lifelong medication and is accompanied by severe complications, such as fistulae and strictures, resulting in surgery. Infliximab (IFX) is very effective for treating paediatric patients with CD, but is currently only registered for therapy refractory patients—the so-called step-up strategy. We hypothesise that using IFX first-line, that is, top-down, will give more mucosal healing, fewer relapses, less complications, need for surgery and hospitalisation. Methods and analysis This international multicentre open-label randomised controlled trial includes children, aged 3–17 years, with new-onset, untreated CD with moderate-to-severe disease activity (weighted Paediatric Crohn's Disease Activity Index (wPCDAI)>40). Eligible patients will be randomised to top-down or step-up treatment. Top-down treatment consists of 5 IFX infusions combined with azathioprine (AZA). After these 5 infusions, patients will continue AZA. Patients randomised to step-up will receive standard induction treatment, either oral prednisolone or exclusive enteral nutrition, combined with AZA as maintenance treatment. The primary outcome is clinical remission (wPCDAI

Background: After aortic valve replacement (AVR), bicuspid aortic valve (BAV) patients continue to be at risk of aortic complications. Therefore, knowledge of native valve anatomy is important for follow-up. We aimed to determine the extent of which the presence of BAV disease is known in a regional post-AVR population. Methods: The Electronical Medical Record system was used to collect all patients under follow-up after AVR. We documented their clinical data and used the operative report to determine valve phenotype; lacking reports were retrieved. Results: We identified 560 patients who underwent AVR between 1971 and 2012, with a median of 6.2 years follow-up postoperatively. Mean age at surgery was 66 years (SD13.2 years), and 319 patients (57%) were male. In 29 cases (5%), an operative report was not available and in 85 patients (16%) the report lacked a description of valve phenotype. In 446 patients, a surgeon's description of native valve was available: 299 patients (67%) had tricuspid aortic valve, 140 (31%) BAV, and 3 (1%) quadricuspid aortic valve. In 4 patients (1%) the description was non-conclusive. In 66/140 BAV patients the surgeon's diagnosis was not reported back to the referring cardiologist, which corresponded with 12% of all 560 AVR patients. Another 21% of these 560 lacked a clear description of native valve anatomy: no report, no native valve description or an unclear valve description. Conclusions: Native valve anatomy was not known in one-third of AVR patients under follow-up, which included almost half of the BAV patients. This lack of knowledge withholds patients from appropriate ascending aorta surveillance. (C) 2016 Elsevier Ireland Ltd. All rights reserved

We report a case of a 39-year-old female with a ventricular septal defect (VSD) and a giant appendiform aneurysm of the membranous septum, illustrated by echocardiography and magnetic resonance imaging. From the literature a short review of the prevalence of spontaneous closure of VSDs together with the possible complications of persisting VSDs is presented. Since patients stay at risk in later years, follow-up at regular intervals is advised.