Introduction: eHealth seems promising in addressing challenges in the provision of care for Huntington’s disease (HD) across Europe. By harnessing information and communication technologies,... Show moreIntroduction: eHealth seems promising in addressing challenges in the provision of care for Huntington’s disease (HD) across Europe. By harnessing information and communication technologies, eHealth can partially relocate care from specialized centers to the patients’ home, thereby increasing the availability and accessibility of specialty care services beyond regional borders. Previous research on eHealth (development) in HD is however limited, especially when it comes to including eHealth services specifically designed together with HD gene expansion carriers (HDGECs) and their partners to fit their needs and expectations. Methods: This article describes the qualitative human-centered design process and first evaluations of the Huntington Support App prototype: a web-app aimed to support the quality of life (QoL) of HDGECs and their partners in Europe. Prospective end-users, i.e., HDGECs, their partners, and healthcare providers (HCPs), from different countries were involved throughout the development process. Through interviews, we captured people’s experiences with the disease, quality of life (QoL), and eHealth. We translated their stories into design directions that were further co-designed and subsequently evaluated with the user groups. Results: The resulting prototype centralizes clear and reliable information on the disease, HD-related news and events, as well as direct contact possibilities with HCPs via an online walk-in hour or by scheduling an appointment. The app’s prototype was positively received and rated as (very) appealing, pleasant, easy to use and helpful by both HDGECs and partners. Discussion: By involving end-users in every step, we developed a healthcare app that meets relevant needs of individuals affected by HD and therefore may lead to high adoption and retention rates. As a result, the app provides lowthreshold access to reliable information and specialized care for HD in Europe. A description of the Huntington Support App as well as implications for further development of the app’s prototype are provided. Show less
Controlling the end-groups of biocompatible polymers is crucial for enabling polymer-based therapeutics and nanomedicine. Typically, end-group diversification is a challenging and time-consuming... Show moreControlling the end-groups of biocompatible polymers is crucial for enabling polymer-based therapeutics and nanomedicine. Typically, end-group diversification is a challenging and time-consuming endeavor, especially for polymers prepared via ionic polymerization mechanisms with limited functional group tolerance. In this study, we present a facile end-group diversification approach for poly(2-oxazoline)s (POx), enabling quick and reliable production of heterotelechelic polymers to facilitate POxylation. The approach relies on the careful tuning of reaction parameters to establish differential reactivity of a pentafluorobenzyl initiator fragment and the living oxazolinium chain-end, allowing the selective introduction of N-, S-, O-nucleophiles via the termination of the polymerization, and a consecutive nucleophilic para-fluoro substitution. The value of this approach for the accelerated development of nanomedicine is demonstrated through the synthesis of well-defined lipid-polymer conjugates and POx-polypeptide block-copolymers, which are well-suited for drug and gene delivery. Furthermore, we investigated the application of a lipid-POx conjugate for the formulation and delivery of mRNA-loaded lipid nanoparticles for immunization against the SARS-COV-2 virus, underscoring the value of POx as a biocompatible polymer platform. Show less
Moet in Nederland desinformatie strafbaar worden gesteld? In dit artikel wordt gekeken wat de laatste ontwikkelingen zijn van desinformatieregulering op het niveau van de Europese Unie. Daarnaast... Show moreMoet in Nederland desinformatie strafbaar worden gesteld? In dit artikel wordt gekeken wat de laatste ontwikkelingen zijn van desinformatieregulering op het niveau van de Europese Unie. Daarnaast wordt gekeken naar Franse wetgeving omtrent desinformatie en wordt belicht hoe de rol van de rechter daarin uiteindelijk zeer beperkt is omwille van de vrijheid van meningsuiting. Ten slotte wordt gewaarschuwd tegen een expliciete strafbaarstelling van desinformatie, bekeken vanuit de soft-lawaanpak van de EU en de hardere juridische aanpak van Frankrijk. Show less
Piqeur, F.; Banken, E.; Coolen, L.; Tanis, P.J.; Maas, M.; Roef, M.; ... ; Burger, J.W.A. 2024
Due to improvements in treatment for primary rectal cancer, the incidence of LRRC has decreased. However, 6–12% of patients will still develop a local recurrence. Treatment of patients with LRRC... Show moreDue to improvements in treatment for primary rectal cancer, the incidence of LRRC has decreased. However, 6–12% of patients will still develop a local recurrence. Treatment of patients with LRRC can be challenging, because of complex and heterogeneous disease presentation and scarce − often low-grade − data steering clinical decisions. Previous consensus guidelines have provided some direction regarding diagnosis and treatment, but no comprehensive guidelines encompassing all aspects of the clinical management of patients with LRRC are available to date. The treatment of LRRC requires a multidisciplinary approach and overarching expertise in all domains. This broad expertise is often limited to specific expert centres, with dedicated multidisciplinary teams treating LRRC. A comprehensive, narrative literature review was performed and used to develop the Dutch National Guideline for management of LRRC, in an attempt to guide decision making for clinicians, regarding the complete clinical pathway from diagnosis to surgery. Show less
Introduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases,... Show moreIntroduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.Materials and methods This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies.Results 169 irAEs were experienced by 86/143 patients (137 grades 1–2, 32 grades 3–4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597).Conclusion The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction. Show less
Yaykasli, K.O.; Schie, K.A. van; Toes, R.E.M.; Wuhrer, M.; Koeleman, C.A.M.; Bila, G.; ... ; Bilyy, R. 2024
Sepsis is a life-threatening condition with a rising disease burden worldwide. It is a multifactorial disease and is defined as a dysregulated host response to infection. Neutrophils have been... Show moreSepsis is a life-threatening condition with a rising disease burden worldwide. It is a multifactorial disease and is defined as a dysregulated host response to infection. Neutrophils have been shown to be involved in the pathogenesis of sepsis by exacerbating inflammation. However, the exact effector mechanism of action still remains a mystery. Changes in the glycosylation pattern of the immunoglobulin G (IgG) Fc region are described for several diseases including meningococcal sepsis. In this study, we investigated the possible contribution of neutrophils and neutrophil implication, potentially related to degranulation or neutrophil extracellular trap (NET) formation in changing the IgG Fc N-glycosylation pattern in a murine sepsis model. We have measured the serum level of cytokines/chemokines and immunoglobulins, the serum activity of neutrophil elastase (NE), and analyzed the IgG Fc glycosylation pattern by Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (LC-ESI-MS) and Lectin enzyme-linked immunosorbent assay (ELISA). We observed an increased activity of NE- and neutrophil-associated cytokines such as keratinocyte chemoattractant (KC) with the development of sepsis. Regarding the IgG Fc N-glycosylation, we observed an increase in fucosylation and α1,3-galactosylation and a decrease for sialyation. Interestingly, these changes were not uniform for all IgG subclasses. After depletion of neutrophils, we saw a change in the exposure of fucose and α2,6-linked sialic acid during the time course of our experimental sepsis model. In conclusion, neutrophils can influence changes in the IgG glycosylation pattern in experimental sepsis. Show less
Runhaar, J.; Özbulut, Ö; Kloppenburg, M.; Boers, M.; Bijlsma, J.W.J.; Bierma-Zeinstra, S.; CREDO expert group 2024
Objective To provide a set of diagnostic criteria for early-stage hip osteoarthritis (OA) in primary care, using signs and symptoms monitored over 2 years in individuals with hip pain and/or... Show moreObjective To provide a set of diagnostic criteria for early-stage hip osteoarthritis (OA) in primary care, using signs and symptoms monitored over 2 years in individuals with hip pain and/or stiffness. Additionally, the study aimed to see whether these factors were additive to factors based on baseline signs and symptoms only.Methods Data of the 543 persons with 735 symptomatic hips were collected from the prospective Cohort Hip and Cohort Knee cohort study. Using data from 5 to 10 years of follow-up, 24 experts (13 general practitioners, 11 secondary care physicians (6 rheumatologists and 5 orthopaedic surgeons)) inspected individuals’ medical data on the presence of clinically relevant hip OA. Their diagnoses are used as reference standards. Backward selection method was used to provide models using the factors from baseline to 2 years of follow-up. Additionally, new models were combined with previously published models, using same selection method. Area under the curve (AUC) was calculated after each removal of factors in the final combined models.Results Radiographic factors and high-sensitive C reactive protein did not end up in any model with change factors only. AUC value (SD) of the final obtained model of change factors was 0.70 (0.01). Adding newly defined factors to previously published models significantly (p<0.0001) increased the AUC value to 0.75 (0.01).Conclusion Final diagnostic criteria, consisting only of the factors obtained through history taking and physical examination, were able to detect early-stage hip OA associated with clinically relevant hip OA 5–10 years later, with ‘moderate’ precision. Show less
Wind, M.; Dekker, L.; Akker-van Marle, M.E. van den; Ballieux, B.E.P.B.; Cobbaert, C.M.; Rabelink, T.J.; ... ; Sueters, M. 2024
Objective: To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with... Show moreObjective: To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with suspected pre-eclampsia. Study design: Post-hoc analysis of a prospective cohort study. Main outcome measures: Primary outcome was the occurrence of pre-eclampsia in one and four weeks after presentation with suspected pre-eclampsia. Test characteristics with 95% confidence intervals (CI) were calculated on pre-eclampsia development in one and four weeks. Results: Twenty-three multiple pregnancies with suspected pre-eclampsia between 20 and 37 weeks gestation were included for analysis. Women who eventually developed pre-eclampsia had a significantly higher PCr (34.0 vs. 16.5, p = 0.015), sFlt-1 (17033 vs. 5270 pg/ml, p = 0.047) and sFlt-1/PlGF ratio (99 vs. 25, p = 0.033) at baseline. Furthermore, PCr ≥ 30 and sFlt-1/PlGF ratio > 38 was respectively seen in 1/16 (6.3 %) and 3/16 (18.8 %) of the women who did not develop pre-eclampsia. For predicting pre-eclampsia within one week the sFlt-1/PlGF ratio sensitivity was 75.0 % [95 % CI 19.4–99.4] and the negative predictive value 93.8 % [73.0–98.8], while no pre-eclampsia developed when PCr was < 30. Consequently, the combination of these tests did not lead to an improvement in test characteristics, with non-significant differences in positive predictive value (50.0 % [29.5–70.5] versus 80.0 % [37.3–96.4]) compared to PCr alone for pre-eclampsia development in one week. Conclusions: In addition to standard-of-care spot urine PCr measurements, this study has not been able to demonstrate that the sFlt-1/PlGF ratio cut-off 38 is of added value in the prediction of pre-eclampsia in multiple pregnancy. Show less
Hooge, M. de; Stal, R.; Sepriano, A.; Baraliakos, X.; Reijnierse, M.; Braun, J.; ... ; Ramiro, S. 2024
Objectives To assess the association of posterior element (PE) and facet joint (FJ) inflammation with subsequent new FJ ankylosis (FJA) on MRI, in patients with radiographic axial spondyloarthritis... Show moreObjectives To assess the association of posterior element (PE) and facet joint (FJ) inflammation with subsequent new FJ ankylosis (FJA) on MRI, in patients with radiographic axial spondyloarthritis (r-axSpA). Methods Patients from the Sensitive Imaging in Ankylosing Spondylitis cohort, inclusion criteria r-axSpA and ≥1 radiographic spinal syndesmophyte, were studied. MRI of the full spinal was performed at baseline, 1 and 2 years. PE/FJ inflammatory lesions and FJA were assessed per vertebral unit (VU) level by three readers. With multilevel time-lagged autoregressive generalised estimated equations, the association between PE/FJ inflammation and the subsequent development of FJA was investigated, taking the reader and VU levels into account. Results Out of the 58 patients with at least 2 reader scores available, mean age 49 (SD 10) years, 84% men, 59% had baseline PE inflammation, 24% had FJ inflammation and 26% had FJA. PE inflammation was more prevalent in the lower thoracic spine and FJ inflammation in the upper thoracic spine. VU with PE or FJ inflammation showed subsequent new FJA in two and one VU levels, respectively. The probability of developing FJA doubled with prior FJ inflammation. In multilevel analysis, FJ inflammation was associated with subsequent FJA (OR=3.8, 95% CI: 1.5 to 9.8), while no association was found between PE inflammation and new FJA (OR=1.2 (0.6–2.4)). Conclusions FJ inflammation is rare in severe r-axSpA, but when present, the likelihood of developing subsequent FJA is over three times higher compared with FJ without inflammation. This finding contributes to the understanding of the relationship between inflammation and ankylosis at the same anatomical location in patients with axSpA. Show less
BackgroundClostridioides difficile is a leading cause of infectious diarrhea in both humans and livestock. In particular, C. difficile strains belonging to sequence type (ST) 11 are common... Show moreBackgroundClostridioides difficile is a leading cause of infectious diarrhea in both humans and livestock. In particular, C. difficile strains belonging to sequence type (ST) 11 are common enteropathogens. The aim of this study was to determine the presence and genetic relatedness of C. difficile types in dairy cattle and calves.MethodDutch dairy farms were visited between February and December 2021. Feces was collected from adult dairy cattle and calves of two age categories (<4 weeks and 4 weeks-4 months). Fecal samples were also requested from dairy farmers, family members and employees. Fecal samples were cultured in an enrichment medium for 10–15 days and subcultured on solid media for capillary PCR ribotyping and whole genome sequencing.ResultsC. difficile was detected on 31 out of 157 (19.8%) dairy farms. The highest prevalence was found in calves <4 weeks (17.5%). None of the 99 human samples collected were positive. Thirty-seven cultured isolates belonged to 11 different PCR ribotypes (RT) of which RT695 (56.8%) and RT078/126 (16.2%) were most abundant. In the database of the Netherlands National Expertise Centre for C. difficile infections (CDI, >10.000 patient isolates), RT695 was found in only two patients with hospital-onset CDI, diagnosed in 2020 and 2021. Sequence analysis of 21C. difficile RT695 from cattle revealed that all isolates belonged to clade 5, ST11 and contained genes encoding toxin A, toxin B and binary toxin. RT695 strains carried antimicrobial resistance genes typically found in clade 5C. difficile. Groups of genetically related RT695 isolates were found between dairy farms, whereas identical strains were only present in individual farms.ConclusionsC. difficile was found in ∼20% of dairy farms with a predominance of the relatively unknown RT695. Isolates of RT695 belonged to the same clade and sequence type as RT078/126, which is recognized as an important zoonotic type. Show less
Grewal, N.; Idhrees, M.; Velayudhan, B.; Klautz, R.J.M.; Grewal, S. 2024
Abstract: Background: Thoracic aortopathy includes conditions like aortic aneurysms and dissections, posing significant management challenges. In India, care delivery is complicated by geographic... Show moreAbstract: Background: Thoracic aortopathy includes conditions like aortic aneurysms and dissections, posing significant management challenges. In India, care delivery is complicated by geographic vastness, financial constraints, and healthcare resource disparities. Telemedicine and digital health technologies offer promising solutions. Methods: A comprehensive review of literature and clinical experiences was conducted to explore the implementation of remote care strategies for thoracic aortopathy in India. The review included studies from 2000 to 2023 and insights from cardiothoracic specialists. Results: Remote care benefits include improved access to specialized expertise, enhanced patient engagement, and optimized resource utilization. Telemedicine enables consultations without travel, and remote monitoring facilitates early intervention. However, challenges like technology integration, digital literacy, patient engagement, privacy concerns, and regulatory compliance need addressing. Discussion: Telemedicine offers significant advantages but requires overcoming challenges to ensure effective, secure care. Careful planning for technology integration, patient education, robust privacy measures, and supportive regulatory policies are essential. Addressing these issues can bridge the healthcare access gap and improve outcomes in India’s diverse landscape. Show less
BackgroundNumerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal p...Show moreBackgroundNumerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal prognostic factor, or whether other risk factors become increasingly common with age. We aimed to address this question with a unique multimethod study design using state-of-the-art statistical and causal inference techniques on datasets of three large, randomised trials.MethodsIn this multimethod analysis, data from 1801 women participating in the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk endometrial cancer, 427 patients with high-intermediate risk endometrial cancer, and 660 patients with high-risk endometrial cancer. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable, a deep learning causal inference model called AutoCI was used.FindingsMedian follow-up as estimated using the reversed Kaplan-Meier method was 12·3 years (95% CI 11·9–12·6) for PORTEC-1, 10·5 years (10·2–10·7) for PORTEC-2, and 6·1 years (5·9–6·3) for PORTEC-3. Both overall recurrence and endometrial cancer-specific death significantly increased with age. Moreover, older women had a higher frequency of deep myometrial invasion, serous tumour histology, and p53-abnormal tumours. Age was an independent risk factor for both overall recurrence (hazard ratio [HR] 1·02 per year, 95% CI 1·01–1·04; p=0·0012) and endometrial cancer-specific death (HR 1·03 per year, 1·01–1·05; p=0·0012) and was identified as a significant causal variable.InterpretationThis study showed that advanced age was associated with more aggressive tumour features in women with endometrial cancer, and was independently and causally related to worse oncological outcomes. Therefore, our findings suggest that older women with endometrial cancer should not be excluded from diagnostic assessments, molecular testing, and adjuvant therapy based on their age alone. Show less
The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low-dose corticosteroids. Drug concentrations are monitored using... Show moreThe recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low-dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal toxicity, it might be more informative to monitor patients' immunological status rather than drug concentrations. We selected a panel of T-cell-based immune assays, which were used for immunomonitoring of 14 stable kidney transplantation patients. Whole blood was incubated with a T-cell stimulus, after which T-cell proliferation, T-cell activation marker expression and cytokine production were measured to study residual immune activity in vitro (before drug intake; drug added to the incubation) and ex vivo (after drug intake). T-cell proliferation was completely suppressed in all patients over the full day, while IL-2, IFN-γ, CD71, and CD154 showed fluctuations over the day with a strong inhibition (75%-25%) at 2 h post-dose. The level of inhibition was variable between patients and could not be related to pharmacokinetic parameters or the presence of regulatory or senescence immune cells. Moreover, the level of inhibition did not correlate with the in vitro tacrolimus drug effect as studied by incubating pre-dose blood samples with additional tacrolimus. Overall, IL-2, IFN-γ, CD71, and CD154 seem to be good markers to monitor residual immune activity of transplantation patients. To evaluate the correlation between these pharmacodynamic biomarkers and clinical outcome, prospective observational studies are needed. Show less
