BackgroundThe 2022 consensus statement of the European Atherosclerosis Society (EAS) on lipoprotein(a) (Lp(a)) recognizes the role of Lp(a) as a relevant genetically determined risk factor and... Show moreBackgroundThe 2022 consensus statement of the European Atherosclerosis Society (EAS) on lipoprotein(a) (Lp(a)) recognizes the role of Lp(a) as a relevant genetically determined risk factor and recommends its measurement at least once in an individual's lifetime. It also strongly urges that Lp(a) test results are expressed as apolipoprotein (a) (apo(a)) amount of substance in molar units and no longer in confounded Lp(a) mass units (mg/dL or mg/L). Therefore, IVD manufacturers should transition to molar units. A prerequisite for this transition is the availability of an Lp(a) Reference Measurement Procedure (RMP) that allows unequivocal molecular detection and quantification of apo(a) in Lp(a). To that end an ISO 17511:2020 compliant LC-MS based and IFCC-endorsed RMP has been established that targets proteotypic peptides of apolipoprotein(a) (apo(a)) in Lp(a). The RMP is laborious and requires highly skilled operators. To guide IVD-manufacturers of immunoassay-based Lp(a) test kits in the transition from mass to molar units, a Designated Comparison Method (DCM) has been developed and evaluated.MethodsTo assess whether the DCM provides equivalent results compared to the RMP, the procedural designs were compared and the analytical performance of DCM and RMP were first evaluated in a head-to-head comparison. Subsequently, apo(a) was quantified in 153 human clinical serum samples. Both DCM and RMP were calibrated using external native calibrators that produce results traceable to SRM2B. Measurement uncertainty (MU) was checked against predefined allowable MU.ResultsThe major difference in the design of the DCM for apo(a) is the use of only one enzymatic digestion step. The analytical performance of the DCM and RMP for apo(a) is highly similar. In a direct method comparison, equivalent results were obtained with a median regression slope 0.997 of and a median bias of - 0.2 nmol/L (- 0.2%); the intermediate imprecision of the test results was within total allowable error (TEa) (CVa of 10.2% at 90 nmol/L).ConclusionsThe semi-automated, higher throughput, LC-MS-based method for Lp(a) meets the predefined analytical performance specifications and allowable MU and is hence applicable as a higher order Designated Comparison Method, which is ideally suited to guide IVD manufacturers in the transition from Lp(a) mass to molar units. Show less
Senjor, E.; Pirro, M.; Svajger, U.; Prunk, M.; Sabotic, J.; Jewett, A.; ... ; Kos, J. 2024
Cystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell... Show moreCystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell stage, called split-anergy. We show that N-glycosylation determines the localization and cellular function of cystatin F. Cystatin F mostly exhibited high-mannose glycosylation in U-937 cells, both high-mannose and complex glycosylation in NK-92 and primary NKs, and predominantly complex glycosylation in super-charged NKs. Manipulating N-glycosylation with kifunensine increased high-mannose glycosylation of cystatin F and lysosome localisation, which decreased cathepsin C activity and reduced NK cytotoxicity. Mannose-6-phosphate could significantly reduce the internalization of extracellular cystatin F. By comparing NK cells with different cytotoxic potentials, we found that high-mannose cystatin F was strongly associated with lysosomes and cathepsin C in NK-92 cell line. In contrast, in highly cytotoxic super-charged NKs, cystatin F with complex glycosylation was associated with the secretory pathway and less prone to inhibit cathepsin C. Modulating glycosylation to alter cystatin F localisation could increase the cytotoxicity of NK cells, thereby enhancing their therapeutic potential for treating cancer patients. Show less
Background: Measures against COVID-19 in nursing homes affected not only clients but also staff. However, staff perspectives on the importance of these measures remain underexplored. Objective: To... Show moreBackground: Measures against COVID-19 in nursing homes affected not only clients but also staff. However, staff perspectives on the importance of these measures remain underexplored. Objective: To investigate measures related to staff during the COVID-19 pandemic, staff perspectives of important measures and the involvement of staff in deciding on these measures. Design: A qualitative study. Setting(s): We analysed minutes of nursing home outbreak teams in the Netherlands and conducted group meetings with Dutch nursing home staff in different positions, prioritizing measures and discussing staff' involvement in deciding on the measures. Participants were recruited purposefully. Participants: The minutes of 41 nursing home organizations were collected during March-November, 2020. Four group meetings were organized in the same period, each with 5 to 7 participants, resulting in 23 participants. Methods: The meeting minutes were analysed using qualitative content analysis, whereas reflexive thematic analysis was used for the group meeting data. The group meetings were conducted online and structured by the Nominal Group Technique to discuss the importance of measures for staff. Results: Measures implemented for staff focused on prevention of COVID-19 transmission, (suspension of) educational activities, testing, additional tasks and staffing capacity, promoting wellbeing, and other means of support. The implemented measures overlapped with the measures considered important by staff. In addition, staff considered measures on decision-making support and communication to be important. Staff prioritized the measures in the group meetings because they affected their well-being, workforce scheduling, decision-making, or infection prevention. Furthermore, the group meetings revealed that decision-making shifted from mainly implementing national measures to more context-adjusted decision-making in the staff's or clients' situations. Conclusions: We showed that although nursing home staff were not always involved in decisionmaking during the first COVID-19 wave, there was overlap between the measures implemented by the organizations and measures considered important by staff. We suggest that organizations Show less
Predicting the development of rheumatoid arthritis (RA) in an early stage through magnetic resonance imaging (MRI) can initiate timely treatment and improve long-term patient outcomes. Although... Show morePredicting the development of rheumatoid arthritis (RA) in an early stage through magnetic resonance imaging (MRI) can initiate timely treatment and improve long-term patient outcomes. Although manual prediction is time-consuming and requires expert knowledge, automatic RA prediction has not been fully investigated. While standard models fail to achieve acceptable performance, we present a consistency-based deep learning framework to classify and predict RA automatically and precisely, including an output-standardized model, customized self-supervised pretraining and a loss function that is based on label consistency between original and augmented inputs. For training and evaluation, we used a database, containing 5945 MRI scans of carpal, metacarpophalangeal (MCP), and metatarsophalangeal (MTP) joints, from 2151 subjects obtained over a period of ten years. Four (three classification- and one prediction-) tasks were defined to distinguish two patient groups (with recent-onset arthritis and clinically suspect arthralgia) from healthy controls and RA from other arthritis patients within the recent-onset arthritis group, and predict RA development in a period of two years within the clinically suspect arthralgia group. The proposed method was evaluated with the area under the receiver operating curve (AUROC) on a separate test set, achieving mean AUROCs of 83.6%, 83.3%, and 69.7% in the three classification tasks, and 67.8% in the prediction task. This proves the existence of early signs of RA in MRI and the potential of a consistency-based deep learning model to detect these early signs and predict RA Show less
AimsCustom triflange acetabular components (CTACs) play an important role in reconstructive orthopaedic surgery, particularly in revision total hip arthroplasty (rTHA) and pelvic tumour resection... Show moreAimsCustom triflange acetabular components (CTACs) play an important role in reconstructive orthopaedic surgery, particularly in revision total hip arthroplasty (rTHA) and pelvic tumour resection procedures. Accurate CTAC positioning is essential to successful surgical outcomes. While prior studies have explored CTAC positioning in rTHA, research focusing on tumour cases and implant flange positioning precision remains limited. Additionally, the impact of intraoperative navigation on positioning accuracy warrants further investigation. This study assesses CTAC positioning accuracy in tumour resection and rTHA cases, focusing on the differences between preoperative planning and postoperative implant positions.MethodsA multicentre observational cohort study in Australia between February 2017 and March 2021 included consecutive patients undergoing acetabular reconstruction with CTACs in rTHA (Paprosky 3A/3B defects) or tumour resection (including Enneking P2 peri-acetabular area). Of 103 eligible patients (104 hips), 34 patients (35 hips) were analyzed.ResultsCTAC positioning was generally accurate, with minor deviations in cup inclination (mean 2.7°; SD 2.84°), anteversion (mean 3.6°; SD 5.04°), and rotation (mean 2.1°; SD 2.47°). Deviation of the hip centre of rotation (COR) showed a mean vector length of 5.9 mm (SD 7.24). Flange positions showed small deviations, with the ischial flange exhibiting the largest deviation (mean vector length of 7.0 mm; SD 8.65). Overall, 83% of the implants were accurately positioned, with 17% exceeding malpositioning thresholds. CTACs used in tumour resections exhibited higher positioning accuracy than rTHA cases, with significant differences in inclination (1.5° for tumour vs 3.4° for rTHA) and rotation (1.3° for tumour vs 2.4° for rTHA). The use of intraoperative navigation appeared to enhance positioning accuracy, but this did not reach statistical significance.ConclusionThis study demonstrates favourable CTAC positioning accuracy, with potential for improved accuracy through intraoperative navigation. Further research is needed to understand the implications of positioning accuracy on implant performance and long-term survival. Show less
Objectives To compare the effectiveness of longstanding (>52 weeks), supervised exercise therapy with usual care in adults with rheumatoid arthritis (RA) and severe functional limitations.Methods P... Show moreObjectives To compare the effectiveness of longstanding (>52 weeks), supervised exercise therapy with usual care in adults with rheumatoid arthritis (RA) and severe functional limitations.Methods Participants were randomised 1:1 to the intervention (individualised goal-setting, active exercises, education and self-management regarding physical activity) or usual care. Primary endpoint was the change in the Patient-Specific Complaints activity ranked 1 (PSC1, 0–10) at 52 weeks. Secondary endpoints included the PSC activities ranked 2 and 3 (PSC2, PSC3), Health Assessment Questionnaire-Disability Index (HAQ-DI), Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL), 6-minute walk test (6MWT), Patient Reported Outcome Measurement Information System Physical Function-10 (PROMIS PF-10) and the Short Form-36 Physical and Mental Component Summary Scales (SF-36 PCS and MCS). (Serious) Adverse events (AEs) were recorded. Measurements were done by blinded assessors. Analyses at 52 weeks were based on the intention-to-treat principle.Results In total, 217 people (90% female, age 58.8 (SD 12.9) years) were randomised (n=104 intervention, n=98 usual care available for analyses). At 52 weeks, the improvement of the PSC1 was significantly larger in the intervention group (mean difference (95% CI) −1.7 (−2.4, –1.0)). Except for the SF-36 MCS, all secondary outcomes showed significantly greater improvements favouring the intervention (PSC2 −1.8 (−2.4, –1.1), PSC3 −1.7 (−2.4, −1.0), PROMIS PF-10 +3.09 (1.80, 4.38), HAQ-DI −0.17 (−0.29, –0.06), RAQoL −2.03 (−3.39, –0.69), SF-36 PCS +3.83 (1.49, 6.17) and 6MWT +56 (38, 75) m). One mild, transient AE occurred in the intervention group.Conclusion Longstanding, supervised exercise therapy was more effective than usual care in people with RA and severe functional limitations. Show less
Dijk, B.T. van; Boeren, A.M.P.; Khidir, S.J.H.; Hollander, N.K. den; Helm-van Mil, A.H.M. van der 2024
Objectives Rheumatoid arthritis (RA) mainly affects small joints. Despite the mechanical function of joints, the role of mechanical stress in the development of arthritis is insufficiently... Show moreObjectives Rheumatoid arthritis (RA) mainly affects small joints. Despite the mechanical function of joints, the role of mechanical stress in the development of arthritis is insufficiently understood. We hypothesised that mechanical stress/physical strain is a risk factor for joint inflammation in RA. Therefore, we studied work-related physical strain in subjects with clinically suspected arthralgia (CSA) as a risk factor for the presence of imaging-detected subclinical joint inflammation and the development of clinical arthritis/RA. Methods In 501 CSA patients and 155 symptom-free persons’ occupation-related physical strain was quantified using the International Standard Classification of Occupations. Contrastenhanced hand-MRIs were made and evaluated for joint inflammation (sum of synovitis/tenosynovitis/osteitis). CSA patients were followed on RA development. Age relationship was studied using an interaction term of physical strain with age. Results The degree of physical strain in CSA is associated with the severity of joint inflammation, independent of educational-level/BMI/smoking (interaction physical strain-age p=0.007; indicating a stronger association with increasing age). Physical strain is associated with higher tenosynovitis scores, in particular. In symptom-free persons, physical strain was not associated with imaging-detected joint inflammation. Higher degrees of physical strain also associated with higher risks for RA development in an age-dependent manner (HR=1.20 (1.06–1.37)/10-year increase in age), independent of educational-level/BMI/smoking. This association was partly mediated by an effect via subclinical joint inflammation. Conclusions Work-related physical strain increases the risk of subclinical joint inflammation and of developing RA. The age relationship suggests an effect of long-term stress or that tenosynovium is more sensitive to stress at older age. Together, the data indicate that mechanical stress contributes to the development of arthritis in RA. Show less
By the early eighteenth century Edo (present-day Tokyo) was one of the largest cities in the world. Sex and erotic allure could be found in many guises in this commercialized urban setting, both in... Show moreBy the early eighteenth century Edo (present-day Tokyo) was one of the largest cities in the world. Sex and erotic allure could be found in many guises in this commercialized urban setting, both in the city’s streets and in print. This chapter sets out to argue that sex assumed a multiplicity of meanings in this context that ranged from pleasure and procreation to potential pathology. To this purpose, it begins by tracing various discourses surrounding the three phenomena that have arguably received the most sustained attention in research to date, namely the sex trade, male same-sex desire, and the erotically explicit materials known as ‘spring pictures’ (Japanese shunga 春画/ shunpon 春本). The final sections aim to move beyond the standard narrative of the Edo period’s flourishing erotic culture by focusing on the female reproductive body, as well as medical and health discourses, thus aspiring to unsettle the paradigmatic character of this (male) pleasure-centred mode of sex and repudiate the monolithic view of early modern Japanese sexuality as unregulated. Show less
Antibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses... Show moreAntibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses and disease state is not well explored. Here we profiled Mycobacterium tuberculosis-specific antibody responses in 140 TB-exposed South African individuals from the Adolescent Cohort Study. We identified distinct response features in individuals progressing to active TB from non-progressing, matched controls. A multivariate antibody score differentially associated with progression (SeroScore) identified progressors up to 2 years before TB diagnosis, earlier than that achieved with the RISK6 transcriptional signature of progression. We validated these antibody response features in the Grand Challenges 6–74 cohort. Both the SeroScore and RISK6 correlated better with risk of TB progression in adolescents compared with adults, and in males compared with females. This suggests that age and sex are important, underappreciated modifiers of antibody responses associated with TB progression. Show less
Background: Knowledge of the psychosocial impact of facial skin surgery on patients can help improve counselling strategies.Objectives: The objective was to measure the psychological impact... Show moreBackground: Knowledge of the psychosocial impact of facial skin surgery on patients can help improve counselling strategies.Objectives: The objective was to measure the psychological impact of facial skin cancer surgery on patients over a 1-year period. Secondary objective was to meas-ure the difference between Mohs micrographic surgery (MMS) and conventional excision (CE) on these parameters.Methods: This observational survey study was conducted between March 2019 and July 2020. Patients who had facial skin surgery using MMS or CE were selected. Five surveys were conducted on four timepoints (preoperative, 1 week, 3 months and 1 year post-operative) measuring the quality of life, perceived stigmatization, body image, satisfaction with facial appearance and psychosocial distress.Results: A total of 228 patients (MMS 154 patients, CE 74 patients) were included for the analysis. Scores for quality of life did not significantly change, in the year after surgery (PCS-12 mean 50.5, SD 9.3 and MCS-12 50.6, SD 9.4); however, stigmatiza-tion (F (3, 235,39) 7,26, p < 0.01, d = −0.07), body image concerns (F (3, 198,28) = 3.75, p < 0.01, d = −0.14), satisfaction with facial appearance (F (3, 205,18) = 10.74, p < 0.01, d = 0.43) and psychosocial distress (F (3, 208,69) = 9.26, p < 0.01, d = −0.15) did change over time. The use of MMS or CE did not significantly affect outcome scores after 1 year.Conclusion: Patients receiving facial skin cancer surgery exhibited low scores for perceived stigmatization and body image concerns. Their quality of life was not statistically inf luenced by facial surgery, and their satisfaction with their facial appearance and psychosocial distress even improved after 1 year. The results suggest that the surgical treatment type (MMS or CE) does not inf luence the outcome. The overall results can help in counselling strategies to improve expectations for patients receiving facial surgery. Show less
Rakers, M.; Hattem, N. van; Simic, I.; Chavannes, N.; Peet, P. van; Bonten, T.; ... ; Os, H. van 2024
Background While remote patient management (RPM) has the potential to assist in achieving treatment targets for cardiovascular risk factors in primary care, its effectiveness may vary among... Show moreBackground While remote patient management (RPM) has the potential to assist in achieving treatment targets for cardiovascular risk factors in primary care, its effectiveness may vary among different patient subgroups. Panel management, which involves proactive care for specific patient risk groups, could offer a promising approach to tailor RPM to these groups. This study aims to (i) assess the perception of healthcare professionals and other stakeholders regarding the adoption and (ii) identify the barriers and facilitators for successfully implementing such a panel management approach. Methods In total, nineteen semi-structured interviews and two focus groups were conducted in the Netherlands. Three authors reviewed the audited transcripts. The Consolidated Framework for Implementation Strategies (CFIR) domains were used for the thematic analysis. Results A total of 24 participants (GPs, nurses, health insurers, project managers, and IT consultants) participated. Overall, a panel management approach to RPM in primary care was considered valuable by various stakeholders. Implementation barriers encompassed concerns about missing necessary risk factors for patient stratification, additional clinical and technical tasks for nurses, and reimbursement agreements. Facilitators included tailoring consultation frequency and early detection of at-risk patients, an implementation manager accountable for supervising project procedures and establishing agreements on assessing implementation metrics, and ambassador roles. Conclusion Panel management could enhance proactive care and accurately identify which patients could benefit most from RPM to mitigate CVD risk. For successful implementation, we recommend having clear agreements on technical support, financial infrastructure and the criteria for measuring evaluation outcomes. Show less
Chemokine receptors are relevant targets for a multitude of immunological diseases, but drug attrition for these receptors is remarkably high. While many drug discovery programs have been pursued,... Show moreChemokine receptors are relevant targets for a multitude of immunological diseases, but drug attrition for these receptors is remarkably high. While many drug discovery programs have been pursued, most prospective drugs failed in the follow-up studies due to clinical inefficacy, and hence there is a clear need for alternative approaches. Allosteric modulators of receptor function represent an excellent opportunity for novel drugs, as they modulate receptor activation in a controlled manner and display increased selectivity, and their pharmacological profile can be insurmountable. Here, we discuss allosteric ligands and their pharmacological characterization for modulation of chemokine receptors. Ligands are included if (1) they show clear signs of allosteric modulation in vitro and (2) display evidence of binding in a topologically distinct manner compared to endogenous chemokines. We discuss how allosteric ligands affect binding of orthosteric (endogenous) ligands in terms of affinity as well as binding kinetics in radioligand binding assays. Moreover, their effects on signaling events in functional assays and how their binding site can be elucidated are specified. We substantiate this with examples of published allosteric ligands targeting chemokine receptors and hypothetical graphs of pharmacological behavior. This review should serve as an effective starting point for setting up assays for characterizing allosteric ligands to develop safer and more efficacious drugs for chemokine receptors and, ultimately, other G protein-coupled receptors. Show less
Masquerades form an important part of indigenous African religions, and headpieces of masks are found all over the world as an iconic African art form. Contrary to expectation, however, the... Show moreMasquerades form an important part of indigenous African religions, and headpieces of masks are found all over the world as an iconic African art form. Contrary to expectation, however, the geographical distribution of masking is very restricted, occurring only in three areas of the continent, mainly situated in the forested zones. I explain this peculiar distribution by tracing the ecological and historical parameters of the societies that harbor mask rituals. The main ecological factors are the absence of cattle and the type of horticulture, while a crucial historical element is the long history of slave raiding and trading to which the continent has been subjected. These factors have led to societies in which both gender and local power arrangements show a marked indeterminacy, operating as internal arenas between men and women, and between different groups of men. Crucial in the explanation of masquerades is the fact that masking is completely absent from societies that practice cattle husbandry with the Bos indicus species (zebu). Since sleeping sickness prohibits cattle husbandry, wherever the tsetse fly thrives, masks appear. Show less
Aging is a multifaceted and intricate physiological process characterized by a gradual decline in functional capacity, leading to increased susceptibility to diseases and mortality. While... Show moreAging is a multifaceted and intricate physiological process characterized by a gradual decline in functional capacity, leading to increased susceptibility to diseases and mortality. While chronological age serves as a strong risk factor for age-related health conditions, considerable heterogeneity exists in the aging trajectories of individuals, suggesting that biological age may provide a more nuanced understanding of the aging process. However, the concept of biological age lacks a clear operationalization, leading to the development of various biological age predictors without a solid statistical foundation. This paper addresses these limitations by proposing a comprehensive operationalization of biological age, introducing the “AccelerAge” framework for predicting biological age, and introducing previously underutilized evaluation measures for assessing the performance of biological age predictors. The AccelerAge framework, based on Accelerated Failure Time (AFT) models, directly models the effect of candidate predictors of aging on an individual’s survival time, aligning with the prevalent metaphor of aging as a clock. We compare predictors based on the AccelerAge framework to a predictor based on the GrimAge predictor, which is considered one of the best-performing biological age predictors, using simulated data as well as data from the UK Biobank and the Leiden Longevity Study. Our approach seeks to establish a robust statistical foundation for biological age clocks, enabling a more accurate and interpretable assessment of an individual’s aging status. Show less
Rede uitgesproken door prof. dr. Albert M. van Hemert ter gelegenheid van zijn afscheid als hoogleraar Psychiatrie aan de Universiteit Leiden op donderdag 4 april 2024
The Late Pleistocene archeological record shows emerging patterns of population turnover frequently associated with technological change between c. 50–40 thousand years ago. In Europe, this is... Show moreThe Late Pleistocene archeological record shows emerging patterns of population turnover frequently associated with technological change between c. 50–40 thousand years ago. In Europe, this is thought to be related to indigenous population admixture and/or the diffusion of developing technologies by Homo sapiens resulting in a widely distributed spatiotemporal patchwork of industries with combinations of Middle and Upper Paleolithic traits. The Late Pleistocene record of Romania forms an anomaly in these scenarios. On the one hand, the country has important Pleistocene archives that preserve direct evidence of early modern humans with Neandertal genetic introgression. On the other hand, Romania shows no evidence of novel technology during the Middle to Upper Paleolithic transition. Here, we review the Late Middle and Early Upper Paleolithic archeological record of Romania supplemented with new radiocarbon ages and excavation data to clarify the validity of this current archeological interpretation. We conclude that while Neandertals and modern humans were in regional contact, raw materials eccentricities and incomplete empirical knowledge of past intergroup cultural transmission have obscured our ability to identify indicative material cultural signals indicating that current methods of understanding hybridized material culture are incomplete. Show less
