The main aim of the present thesis is to investigate the authoritative role of the ancestors in matters of social cohesion, succession, inheritance, property ownership and gender norms. In... Show moreThe main aim of the present thesis is to investigate the authoritative role of the ancestors in matters of social cohesion, succession, inheritance, property ownership and gender norms. In particular the purpose is to ascertain whether religious sources concerning the cult of the ancestors can provide concrete evidence on how justice was actually administrated in Ancient Egypt. The title – Only the dead can tell us – derived indeed from the idea that this core of religious beliefs, which also included necromantic practices, can be invaluable for better understanding Ancient Egyptian society and justice. Show less
Heutz, J.W.; Looijen, A.E.M.; Kuijpers, J.H.S.A.M.; Schreurs, M.W.J.; Helm-van Mil, A.H.M. van der; Jong, P.H.P. de 2024
The mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid... Show moreThe mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid factor (RF) for modern treatment outcomes remains unknown. We aimed to investigate the prognostic value of IgA-ACPA and IgA-RF for treatment outcomes in an early arthritis population. IgA-ACPA/RF isotypes were measured in baseline sera from 480 inflammatory arthritis (IA) patients, who were included in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH). The tREACH trial was a multicentre, stratified, single-blinded trial with a treat-to-target approach. The prognostic value of IgA-ACPA/RF was determined by evaluating differences in (1) quick-attained (< 6 months after diagnosis) and persistent remission rates, (2) DMARD-free remission and (3) biological use between IA patients with and without IgA-ACPA/RF over 3 years of follow-up. IgA-ACPA was present in 23% of patients and overlapped with IgG-ACPA positivity in 94%. Similarly, IgA-RF overlapped with IgM-RF in 90% of patients. IgA-ACPA positivity was associated with lower DFR rates and more biological use, but this effect was largely mediated by the presence of IgG-ACPA, since this effect disappeared after stratification for IgG-ACPA (HR 0.6, 95%CI 0.2-1.6 for DFR). No differences were observed in ‘quick-attained and persistent remission’ rates and for IgA-RF. Their seems to be no additional value of IgA-ACPA and IgA-RF for modern, long-term clinical outcomes. The effects of IgA-ACPA seen in our study are largely mediated by the presence of IgG-ACPA. Based on these results, there is no rationale for measuring these isotypes in daily practice. Show less
Coronaviruses comprise seven human viruses, some of them the common cold viruses, only causing mild symptoms in healthy individuals, while SARS-CoV, MERS-CoV, and SARS-CoV-2 can potentially cause... Show moreCoronaviruses comprise seven human viruses, some of them the common cold viruses, only causing mild symptoms in healthy individuals, while SARS-CoV, MERS-CoV, and SARS-CoV-2 can potentially cause severe disease and deadly pneumonia. The outbreak of SARS-CoV-2 in 2019 and its rapid worldwide spread has made apparent the need for a fast response to newly emerging viruses and to have effective therapies available. Although vaccines against SARS-CoV-2 were developed at an unprecedented speed, early patients would have benefitted from antiviral drugs. The respiratory tract is the first entry point for coronaviruses, where epithelial cells are infected and also represent the first barrier of defense. Primary human airway epithelial cells that are cultured and differentiated at the air-liquid interface (HAE-ALI) represent an advanced cell culture model recapitulating the human lung epithelium better than mono-cell cultures. In this thesis, four research projects conducted during the PhD track, are described and discussed, which focussed mainly on SARS-CoV-2. Chapter 1 gives an introduction to the overall research topic of coronavirus biology and antiviral drug discovery, and the use of HAE-ALI to study both. Chapter 2 describes the characterization of SARS-oV-2 infection in HAE-ALI. Changes in the cellular composition, caused by culture time or drug treatment, impacted virus replication, and this correlated with the presence of the main susceptible cells, ciliated cells and goblet cells, as well as expression of virus cell-entry factors. Furthermore, the importance of having a diverse epithelium in the cultures was identified, where likely goblet cells play a supportive role in infection. The findings contribute to the understanding of the variable susceptibility to SARS-CoV-2 infection between individuals and across anatomical locations in the respiratory tract, and possibly in chronic lung diseases affecting the epithelium. Chapter 3 then aimed to conduct a comparative study between SARS-CoV, MERS-CoV, and SARS-CoV-2, and two common cold coronaviruses. We employed the HAE-ALI cell culture model to decipher differences in the epithelial transcriptional response upon coronavirus infection. RNA sequencing data showed limited expression of interferon genes in infections with SARS-CoV, MERS-CoV, and SARS-CoV-2, as opposed to the common cold coronaviruses, which corroborated previous studies showing suppression of interferon responses by the these three coronaviruses. Furthermore, SARSCoV-2 infection uniquely lacked the expression of a set of immediate early genes, which are expressed in response to stressors like infection. By utilizing the findings about one of these genes, NR4A1, an inhibitor was identified that blocks SARS-CoV-2 and MERS-CoV replication. Chapters 4 and 5 describe two antiviral drugs that efficiently block the replication of SARS-CoV-2 and other coronaviruses. The first, R-Propranolol, is part of a drug that is approved for the treatment of hemangioma (benign vascular tumor), besides various medical conditions like cardiovascular diseases. R-Propranolol was shown to reduce a proangiogenic factor, which was recently reported to be associated with an increased rate of severe lung pathology in COVID-19. Therefore, this drug could be an interesting candidate to investigate further as host-directed therapy to reduce vascular damage in COVID-19, caused by endothelial dysfunction and pathological angiogenesis. Additionally, a potent antiviral effect of R-Propranolol against SARS-CoV-2 and other coronaviruses was observed, which makes the drug an interesting antiviral with two potential angles of activity. Chapter 5 describes a class of host-directed antivirals, glucosidase inhibitors, which inhibit endoplasmic reticulum (ER) resident alpha-glucosidases, important for protein folding in the ER and quality control. Many viruses, including coronaviruses, use the host’s ER protein quality control machinery for their glycoproteins. For SARS-CoV-2, especially the spike protein, which is crucial for virus attachment and entry into the host cell, is heavily glycosylated and dependent on processing in the ER and Golgi. Several compounds were tested, belonging to two classes, iminosugars and cyclitols. While iminosugars have been studied for decades as potential antiviral drugs, we identified 1,6-epi-cyclophellitol cyclosulfate, a candidate of a new class of glucosidase inhibitors, as superior due to its high specificity for ER alpha-glucosidase II and potent antiviral efficacy. Inhibition of ER alphaglucosidases led to a reduction in spike protein generation and subsequently to a reduced production of infectious virus particles. In addition to SARS-CoV-2, 1,6-epi-cyclophellitol cyclosulfate also blocks the production of SARS-CoV and MERS-CoV progeny, rendering this class of compounds promising broad-spectrum antivirals. In the final chapter, the main findings of the research projects are discussed in the context of recently published studies. Furthermore, the current landscape of SARS-CoV-2 host-directed antiviral therapy and the benefits of using the most relevant cell culture models in antiviral drug discovery are discussed. Show less
This thesis focuses on child labour in producing bountiful supply of cocoa in the cocoa-producing area of Gomoa Ofaso in the Winneba District from 1874 when there was labour shortage up to 1940... Show moreThis thesis focuses on child labour in producing bountiful supply of cocoa in the cocoa-producing area of Gomoa Ofaso in the Winneba District from 1874 when there was labour shortage up to 1940 when colonial Ghana was the principal producer of cocoa globally. This thesis has been divided into six chapters. This thesis, by the use of qualitative research methodology, demonstrated that market forces after the abolition of domestic slavery in 1874 together with the introduction and export of cocoa intensified the use of child labour in this District due to the shortage of labour. The research of child labour in cocoa production in the colonial period is important because it has often been categorised as an example of the worst forms of child labour, yet it has not been adequately studied. This thesis contributes to the discourse on child labour in the colonial period and how the colonial labour problem was dealt with in cocoa production. Show less
As part of the Indo-European language family, the Indo-Iranian branch traces its origins back to the Indo-European homeland on the Pontic-Caspian steppe 5000 years ago. But how did it spread from... Show moreAs part of the Indo-European language family, the Indo-Iranian branch traces its origins back to the Indo-European homeland on the Pontic-Caspian steppe 5000 years ago. But how did it spread from there to Asia? The aim of this thesis is to uncover the early prehistory of Indo-Iranian by investigating its relationship to the Balto-Slavic languages of Eastern Europe, which have been hypothesized to form a subgroup with Indo-Iranian: Indo-Slavic. By comparing the linguistic data with evidence from archaeology and genetics, this thesis traces the migration path of prehistoric Indo-Iranian speakers from the Pontic-Caspian steppe, via the rivers and forests of Eastern Europe, across the Ural Mountains, and southwards to the steppes of Central Asia. Show less
Antimicrobial photodynamic therapy (aPDT) is an evolving treatment strategy against human pathogenic microbes such as the Candida species, including the emerging pathogen C. auris. Using a modified... Show moreAntimicrobial photodynamic therapy (aPDT) is an evolving treatment strategy against human pathogenic microbes such as the Candida species, including the emerging pathogen C. auris. Using a modified EUCAST protocol, the light-enhanced antifungal activity of the natural compound parietin was explored. The photoactivity was evaluated against three separate strains of five yeasts, and its molecular mode of action was analysed via several techniques, i.e., cellular uptake, reactive electrophilic species (RES), and singlet oxygen yield. Under experimental conditions (λ = 428 nm, H = 30 J/cm2, PI = 30 min), microbial growth was inhibited by more than 90% at parietin concentrations as low as c = 0.156 mg/L (0.55 µM) for C. tropicalis and Cryptococcus neoformans, c = 0.313 mg/L (1.10 µM) for C. auris, c = 0.625 mg/L (2.20 µM) for C. glabrata, and c = 1.250 mg/L (4.40 µM) for C. albicans. Mode-of-action analysis demonstrated fungicidal activity. Parietin targets the cell membrane and induces cell death via ROS-mediated lipid peroxidation after light irradiation. In summary, parietin exhibits light-enhanced fungicidal activity against all Candida species tested (including C. auris) and Cryptococcus neoformans, covering three of the four critical threats on the WHO's most recent fungal priority list. 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
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
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
Borgers, J.S.W.; Wesemael, T.J. van; Gelderman, K.A.; Rispens, T.; Verdegaal, E.M.E.; Moes, D.J.A.R.; ... ; Woude, D. van der 2024
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
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
