Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD):an analysis of a prospective multicentre cohort study

Background: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. Methods: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. Findings: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6–58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720–2473] vs 3440 [2939–4026]; p&lt;0·0001), BA.1 (107·3 [86·40–133·2] vs 648·9 [523·5–804·5]; p&lt;0·0001), and BA.4/5 (40·63 [31·99–51·60] vs 223·0 [183·1–271·4]; p&lt;0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5–16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8–10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08–2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79–0·95]; p=0·0028). Interpretation: Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. Funding: Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.</p

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p &lt;0.0001; 26.8 days [95% CI 26.2 – 27.5] vs 47.6 days [45.5 – 49.8], p &lt;0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p &lt;0.0001; 35.9 days [34.9 – 36.8] vs 58.0 days [55.0 – 61.3], p value &lt; 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.</p

Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma

Background: The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma.Methods: PXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.Results: PXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's epithelium, compared to squamous epithelium of these BE patients (P < 0.001), and RE patients (P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls (P = 0.037).Conclusions: PXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease

Predictors of quality of life among youths in foster care—a 5‑year prospective follow‑up study

Purpose Few studies have investigated possible predictors of positive outcomes for youths in foster care. The aim of this prospective follow-up study was to examine quality of life (QoL) among youths in foster care and to assess whether contextual and child factors predicted QoL. Methods Online questionnaires were completed by carers in Norway in 2012 (T1, n = 236, child age 6–12 years) and by youths and carers in 2017 (T2, n = 405, youth age 11–18 years). We received responses on 116 of the youths at both T1 and T2, and our final sample consisted of 525 youths with responses from T1 and/or T2. Child welfare caseworkers reported preplacement maltreatment and service use at T1. We assessed mental health and prosocial behavior at T1 by having carers complete the Strength and Difficulties Questionnaire and QoL at T2 with youth-reported KIDSCREEN-27. We analyzed the data using descriptive statistics, t-tests and multiple linear regressions, and we used multiple imputation to handle missing data. Results Youths in foster care had lower QoL across all dimensions compared to a Swedish general youth sample. QoL scores among our sample were similar to Norwegian youths with ill or substance abusing parents and to European norm data. Youths reported the highest QoL scores on the parent relations and autonomy dimension. Male gender, younger age, kinship care and prosocial behavior five years earlier predicted higher QoL. Conclusion Similar to other at-risk youths, youths in foster care seem to have lower QoL than the general Scandinavian population. Despite early adversities, they had good relations with their current carers. Adolescent girls seem especially vulnerable to low QoL and might need extra support to have good lives in foster care

Predictors of quality of life among youths in foster care—a 5-year prospective follow-up study

Abstract Purpose Few studies have investigated possible predictors of positive outcomes for youths in foster care. The aim of this prospective follow-up study was to examine quality of life (QoL) among youths in foster care and to assess whether contextual and child factors predicted QoL. Methods Online questionnaires were completed by carers in Norway in 2012 (T1, n = 236, child age 6–12 years) and by youths and carers in 2017 (T2, n = 405, youth age 11–18 years). We received responses on 116 of the youths at both T1 and T2, and our final sample consisted of 525 youths with responses from T1 and/or T2. Child welfare caseworkers reported preplacement maltreatment and service use at T1. We assessed mental health and prosocial behavior at T1 by having carers complete the Strength and Difficulties Questionnaire and QoL at T2 with youth-reported KIDSCREEN-27. We analyzed the data using descriptive statistics, t-tests and multiple linear regressions, and we used multiple imputation to handle missing data. Results Youths in foster care had lower QoL across all dimensions compared to a Swedish general youth sample. QoL scores among our sample were similar to Norwegian youths with ill or substance abusing parents and to European norm data. Youths reported the highest QoL scores on the parent relations and autonomy dimension. Male gender, younger age, kinship care and prosocial behavior five years earlier predicted higher QoL. Conclusion Similar to other at-risk youths, youths in foster care seem to have lower QoL than the general Scandinavian population. Despite early adversities, they had good relations with their current carers. Adolescent girls seem especially vulnerable to low QoL and might need extra support to have good lives in foster care. </jats:sec

Suppression-induced forgetting - Replication of Wiechert et al (2023) in the lab

Replication study, in which Wiechert et al.'s (2023) online TNT procedure is implemented in an in-person laboratory settin

Risankizumab and Certolizumab Pegol Dual-Targeted Therapy for Crohn’s Disease and Axial Spondyloarthritis: A Case Report

Introduction: Treatment of Crohn’s disease (CD) and axial spondyloarthritis (axSpA) is challenging, with CD refractory to anti-TNF antibodies. Here, we present for the first time a case treated with dual-targeted therapy (DTT) using the anti-IL-23 monoclonal risankizumab and the anti-TNF antibody certolizumab pegol. Case Presentation: Our patient initially presented with axSpA at the age of 27. Nine years later, CD was diagnosed by the age of 36. One year after the diagnosis of CD, a spontaneous ileal perforation occurred as part of a disease course refractory to multiple anti-TNF antibodies and intolerance to immunomodulators. However, the axSpA showed a response to the anti-TNF certolizumab pegol. After stopping certolizumab pegol, we enrolled the patient into the M15-991 induction trial (MOTIVATE) and the maintenance trial (FORTIFY) testing the anti-IL-23 antibody risankizumab versus placebo in CD with failure to prior biological therapy. As a result, risankizumab induced a CD response but failed to control the axSpA. Considering the CD refractory and the axSpA responding to anti-TNFs, we initiated a DTT with risankizumab and certolizumab pegol. Risankizumab and certolizumab pegol together improved both CD and axSpA. As adverse events, there were only two episodes of spontaneously resolving common colds during the 19-month reviewed period. Conclusion: DTT using risankizumab and certolizumab pegol is effective in CD and axSpA without serious adverse events in our patient. Combining biologicals that target specific pathways in immune-mediated diseases promises excellent potential in CD associated with extraintestinal manifestations

Replication of Wiechert et al (2023) - Study 1

Replication study, in which Wiechert et al.'s (2023) online TNT procedure is implemented in an in-person laboratory settin

Suppression-induced forgetting - Replication of Wiechert et al (2023) in the lab

This registration entails the details and adjustments of an in-lab replication of Wiechert et al.'s (2023) online administered TNT study

A case of intoxication with tea made from Digitalis purpurea

We present the case of a 34-year-old woman with recurrent depressive disorder who ingested purple foxglove with suicidal intent. She bought a foxglove plant (Digitalis purpurea) over the internet and used all of its leaves to make a tea that she then drank over a period of a few hours. Seventeen hours later, she developed abdominal pain, emesis and bradycardia and was admitted via the emergency department to the intensive care unit for further treatment and monitoring. The plasma digoxin concentration measured 3.53 nmol/l (therapeutic reference range 0.77-1.50 nmol/l) 21 hours after ingestion of the tea. She remained heamodynamically and neurologically stable, was treated with antiemetics and simple analgesia and did not require digoxin-specific antibodies. Despite normal renal function, her plasma digoxin half-life was prolonged (estimated 76 h), reflecting the long half-life of the parent compound digitoxin which is the main cardiac glycoside in Digitalis purpurea. She was transferred to psychiatric care 48 h after admission. In this report, we compare this case to other similar cases, which to date have only been rarely reported in the literature.</jats:p