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Background: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated., Methods: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination., Results: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based., Conclusions: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies., Methods: In this longitudinal questionnaire study, the National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ-39) was applied at baseline, two-year follow-up, and 4-year follow-up in patients with pathogenic CRB1 variants. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] Classical test theory was performed to obtain subdomain scores and in particular 'near activities' and 'total composite' scores. The Rasch analysis based on previous calibrations of the NEI VFQ-25 was applied to create visual functioning and socio-emotional subscales., Results: In total, 22 patients with a CRB1-associated retinal dystrophy were included, […] with a median age of 25.0 years (interquartile range: 13-31 years) at baseline and mean follow-up of 4.0 ± 0.3 years. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] A significant decline at 4 years was observed for 'near activities' (51.0 ± 23.8 vs 35.4 ± 14.7, p = 0.004) and 'total composite' (63.0 ± 13.1 vs 52.0 ± 12.1, p = 0.001) subdomain scores. For the Rasch-scaled scores, the 'visual functioning' scale significantly decreased after 2 years (-0.89 logits; p = 0.012), but not at 4-year follow-up (+0.01 logits; p = 0.975). [Correction added on 20 November 2023, after first online publication: In the preceding sentence, "…after 4 years…" has been corrected to "…after 2 years…" in this version.] The 'socio-emotional' scale also showed a significant decline after 2 years (-0.78 logits, p = 0.033) and 4 years (-0.83 logits, p = 0.021)., Conclusion: In the absence of an intervention, a decline in vision-related quality of life is present in patients with pathogenic CRB1 variants at 4-year follow-up. Patient-reported outcome measures should be included in future clinical trials, as they can be a potential indicator of disease progression and treatment efficacy., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: Phototherapy is used to treat atopic dermatitis (AD). Evidence for its efficacy, impact on quality of life, cost-effectiveness and short- and long-term safety with real-life usage is weak., Objectives: We established a taskforce to examine how phototherapy is currently being used as a treatment for AD across the United Kingdom and Europe to inform our understanding and guide future research into management of patients with AD using UV-based phototherapies., Methods: An anonymous electronic multiple-response survey exploring phototherapy prescribing practices and experience of phototherapy modalities was developed by the study authors and sent to members of phototherapy networks from the United Kingdom and Europe. Responses were received between February and July 2021., Results: About 144 respondents from 27 European countries completed the survey. NBUVB was the most widely used [n = 138 (96%)]. Home-based NBUVB was available in 8/27 countries (25/144 respondents, 17%). Oral psoralen-UVA (PUVA) was more widely available than bath PUVA (n = 106, 74% vs. n = 60, 42%) and used mainly in adult patients. 49/144 (34%) of respondents had access to UVA1. Phototherapy would be considered instead of systemic treatment in 96% of adults and 82% of children for NBUVB, versus 40% of adults and 3% of children for PUVA. Starting doses, standard dosing increments, length of treatment courses, lifetime limits for treatments and thresholds for performing annual skin assessments varied between responders., Conclusions: NBUVB was the most widely used phototherapy for AD in adult and paediatric patients, while PUVA and UVA1 were less used. Prescribing practices varied considerably, highlighting the lack of consensus practice in many different aspects of phototherapy for the treatment of AD in children and adults. This indicates that further studies are required to determine optimal phototherapeutic regimens for AD and informs our understanding of parameters that should be included in future high-quality randomized controlled trials (RCT) of phototherapy., (© 2023 European Academy of Dermatology and Venereology.)

Aims: A few studies suggested that epilepsy and antiepileptic drugs with sodium channel-blocking properties were independently associated with out-of-hospital cardiac arrest (OHCA). However, these findings have not yet been replicated., Methods: Using Danish registries, we conducted a nested case-control study in a cohort of individuals between 1 June 2001 and 31 December 2015. Cases were defined as OHCA from presumed cardiac causes, and were matched with non-OHCA-controls based on sex, and age on the date of OHCA. Exposure of interest was epilepsy or antiepileptic drug use. To study the association between individual antiepileptic drug use and the rate of OHCA, we compared each antiepileptic drug with valproic acid. Cox regression with time-dependent covariates was conducted to calculate hazard ratio (HR) and 95% confidence interval (CI)., Results: We identified 35 195 OHCA-cases and 351 950 matched non-OHCA controls. Epilepsy (cases: 3.58%, controls: 1.60%) was associated with increased rate of OHCA compared with the general population (HR: 1.76, 95%CI: 1.64-1.88) when common OHCA risk factors were taken into account. When we studied antiepileptic drug use, we found that 2 antiepileptic drugs without sodium channel blockage, clonazepam (HR: 1.88, 95%CI: 1.45-2.44) and pregabalin (HR: 1.33, 95%CI: 1.05-1.69), were associated with OHCA, whereas none of the antiepileptic drugs with sodium channel blockage were associated with OHCA., Conclusion: Epilepsy is associated with increased rate of OHCA. Our findings do not support a possible association between antiepileptic drugs with sodium channel-blocking properties and OHCA., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Conflicting results have been reported regarding the association between antidepressant use and out-of-hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA., Methods: We conducted a nationwide nested case-control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time-dependent exposure and time-dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately., Results: During the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high-dose citalopram (>20 mg) and high-dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27-1.69], HR:1.43 [95% CI:1.16-1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high-dose mirtazapine (>30; HR:1.59 [95% CI:1.18-2.14]) among the serotonin-norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05-1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors., Conclusion: Our findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: To investigate the impact of the OrCam MyEye 2.0 (OrCam) on the quality of life and rehabilitation needs in patients with advanced retinitis pigmentosa (RP) or cone-rod dystrophies (CRD). The OrCam is a wearable low-vision aid that converts visual information to auditive feedback (e.g. text-to-speech, barcode and facial recognition)., Methods: Patients with a clinical diagnosis of RP (n = 9, 45%) or CRD (n = 11; 55%), and a best-corrected visual acuity of ≤20/400 Snellen were invited to participate in this study. Questionnaires were administered at baseline and after 5.2 (standard deviation ± 1.5) weeks, which included the Dutch version of the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ), the Participation and Activity Inventory (PAI) and the OrCam Function Questionnaire (OFQ)., Results: Following OrCam testing, significant improvements were observed in the 'near activities' subscale of the NEI-VFQ (p < 0.001); the 'visual functioning' subscale of the re-engineered NEI-VFQ (p = 0.001); the 'reading' rehabilitation goal of the PAI (p = 0.005) and the overall score of the OFQ (p < 0.001). The observed changes in questionnaire scores did not differ between phenotypes. Advantages and limitations of the OrCam were reported by patients. Three patients (15%) continued rehabilitation with the OrCam after completion of this study., Conclusions: The OrCam mainly improves reading domains in patients with advanced stages of RP or CRD. Further improvements in the OrCam are needed to address current limitations, which may enhance its utility for patients with RP or CRD., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Aims: Medication non-adherence post-discharge is common among patients, especially those suffering from chronic medical conditions, and contributes to hospital admissions and mortality. This study aimed to evaluate the effect of the Cardiac Care Bridge (CCB) intervention on medication adherence post-discharge., Methods: We performed a secondary analysis of the CCB randomized single-blind trial, a study in patients ≥70 years, at high risk of functional loss and admitted to cardiology departments in six hospitals. In this multi-component intervention study, community nurses performed medication reconciliation and observed medication-related problems (MRPs) during post-discharge home visits, and pharmacists provided recommendations to resolve MRPs. Adherence to high-risk medications was measured using the proportion of days covered (PDC), using pharmacy refill data. Furthermore, MRPs were assessed in the intervention group., Results: For 198 (64.7%) of 306 CCB patients, data were available on adherence (mean age: 82 years; 58.9% of patients used a multidose drug dispensing [MDD] system). The mean PDC before admission was 92.3% in the intervention group (n = 99) and 88.5% in the control group (n = 99), decreasing to 85.2% and 84.1% post-discharge, respectively (unadjusted difference: -2.6% (95% CI -9.8 to 4.6, P = .473); adjusted difference -3.3 (95% CI -10.3 to 3.7, P = .353)). Post-hoc analysis indicated that a modest beneficial intervention effect may be restricted to MDD non-users (P interaction  = .085). In total, 77.0% of the patients had at least one MRP post-discharge., Conclusions: Our findings indicate that a multi-component intervention, including several components targeting medication adherence in older cardiac patients discharged from hospital back home, did not benefit their medication adherence levels. A modest positive effect on adherence may potentially exist in those patients not using an MDD system. This finding needs replication., (© 2021 British Pharmacological Society.)

Aim: There is an ongoing debate regarding the optimal timing of discontinuation of antipsychotic drugs for patients with first episode psychosis. Although most guidelines recommend maintenance therapy for at least 1 or 2 years after reaching remission, study results indicate that early discontinuation may be beneficial for at least a subsample of patients. To date, little is known about which medication strategies are applied in patients recovering from a first psychotic episode. In this study, we examined the beliefs and practices of clinicians on medication discontinuation., Methods: We performed a survey among 50 experienced Dutch psychiatrists to assess how often specific treatment strategies have been applied in the past 12 months, as well as their knowledge and expectations with respect to medication discontinuation., Results: Psychiatrists estimated that, after remission, they continued medication at the same dose for at least 12 months in 51.2% of cases, continued in a reduced dose in 33.8% of cases and discontinued medication in 9.1% of cases after 4.4 months of remission on average. Although the medication is discontinued in only a relatively small proportion of patients, almost half of all clinicians (45.9%) used this strategy at least once in the past 12 months., Conclusions: There is substantial practice variation in antipsychotic medication strategies after remission from a first psychotic episode. Future research on long-term effects of early medication discontinuation can guide clinicians in making evidence-based decisions when treating first-episode patients., (© 2021 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Glucocorticoids form the backbone of paediatric acute lymphoblastic leukaemia (ALL) treatment. Many studies have been performed on steroid resistance; however, few studies have addressed the relationship between dose, concentration and clinical response. The aim of the present study was to evaluate the pharmacokinetics of prednisolone in the treatment of paediatric ALL and the correlation with clinical parameters. A total of 1028 bound and unbound prednisolone plasma concentrations were available from 124 children (aged 0-18 years) with newly diagnosed ALL enrolled in the Dutch Childhood Oncology Group studies. A population pharmacokinetic model was developed and post hoc area under the curve (AUC) was tested against treatment outcome parameters. The pharmacokinetics of unbound prednisolone in plasma was best described with allometric scaling and saturable binding to proteins. Plasma protein binding decreased with age. The AUC of unbound prednisolone was not associated with any of the disease parameters or treatment outcomes. Unbound prednisolone plasma concentrations correlated with age. No effect of exposure on clinical treatment outcome parameters was observed and does not substantiate individualised dosing. Poor responders, high-risk and relapsed patients showed a trend towards lower exposure compared to good responders. However, the group of poor responders was small and requires further research., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background Off-target properties of ticagrelor might reduce microvascular injury and improve clinical outcome in patients with ST-segment-elevation myocardial infarction. The REDUCE-MVI (Evaluation of Microvascular Injury in Revascularized Patients with ST-Segment-Elevation Myocardial Infarction Treated With Ticagrelor Versus Prasugrel) trial reported no benefit of ticagrelor regarding microvascular function at 1 month. We now present the follow-up data up to 1.5 years. Methods and Results We randomized 110 patients with ST-segment-elevation myocardial infarction to either ticagrelor 90 mg twice daily or prasugrel 10 mg once a day. Platelet inhibition and peripheral endothelial function measurements including calculation of the reactive hyperemia index and clinical follow-up were obtained up to 1.5 years. Major adverse clinical events and bleedings were scored. An intention to treat and a per-protocol analysis were performed. There were no between-group differences in platelet inhibition and endothelial function. At 1 year the reactive hyperemia index in the ticagrelor group was 0.66±0.26 versus 0.61±0.28 in the prasugrel group ( P =0.31). Platelet inhibition was lower at 1 month versus 1 year in the total study population (61% [42%-81%] versus 83% [61%-95%]; P <0.001), and per-protocol platelet inhibition was higher in patients randomized to ticagrelor versus prasugrel at 1 year (91% [83%-97%] versus 82% [65%-92%]; P =0.002). There was an improvement in intention to treat endothelial function in patients randomized to ticagrelor ( P =0.03) but not in patients randomized to prasugrel ( P =0.88). Major adverse clinical events (10% versus 14%; P =0.54) and bleedings (47% versus 63%; P =0.10) were similar in the intention-to-treat analysis in both groups. Conclusions Platelet inhibition at 1 year was higher in the ticagrelor group, without an accompanying increase in bleedings. Endothelial function improved over time in ticagrelor patients, while it did not change in the prasugrel group. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique Identifier: NCT02422888.

Background & Aims: Despite high-risk behaviour, 10%-20% of HCV multiple exposed individuals remain uninfected (MEU), whilst the remainder become infected (MEI). We hypothesize that host factors play a role in HCV susceptibility. We aimed to identify polymorphisms in host genes that encode for proteins involved in viral entry: CD81, Scavenger receptor 1 (SR-1), Low-density lipoprotein receptor (LDL-R), Claudin-1 (CLDN1), Occludin (OCLN) and Niemann-Pick C1-like 1 (NPC1L1)., Methods: Multiple exposed infected and MEU from two observational cohorts were selected. From the MSM study of acute infection with HCV (MOSAIC), HIV-1 infected MEU cases (n = 30) and HIV-1 infected MEI controls (n = 32) were selected based on reported high-risk behaviour. From the Amsterdam Cohorts Studies (ACS) injecting drug users (IDU) cohort, MEU cases (n = 40) and MEI controls (n = 22) were selected who injected drugs for ≥2 years, in the nineties, when HCV incidence was high. Selected single nucleotide polymorphisms (SNPs) were determined by sequencing or SNP assays., Results: No associations were found for SNPs within genes coding for CD81, SR-1, Claudin-1 or Occludin between the MEU and MEI individuals from either cohort. We did observe a significant association for rs688 within the LDL-R gene with HCV infection (OR: 0.41 P = 0.001), however, LDL cholesterol levels did not vary between individuals carrying the differential SNPs. Additionally, a marginal significant effect was found for rs217434 and rs2072183 (OR: 2.07 P = 0.032 and OR: 1.76 P = 0.039, respectively) within NPC1L1., Conclusions: Our results demonstrate that the rs688 SNP within the LDL-R gene associates with HCV susceptibility through mucosal as well as intravenous exposure., (© 2018 The Authors. Liver International Published by John Wiley & Sons Ltd.)