Search

Abstract Background SELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG). Methods The Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient’s age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed. Discussion This study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines. Trial registration This study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee (‘METC Oost-Nederland’; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland , file number: 2023–16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15).

Abstract For many diseases, including cancer, infections, and auto-immune diseases, the immune response is a major determinant of disease progression, response to therapy, and clinical outcome. Innate and adaptive immune responses are controlled by coordinated activity of different immune cell types. The functional activity state of immune cells is determined by Signal Transduction Pathways (STPs). A recently developed technology (Simultaneous Transcriptome-based Activity Profiling of Signal Transduction Pathways, STAP-STP) enables simultaneous and quantitative activity measurement of relevant STPs in immune cells based on mRNA-analysis. STAP-STP technology was used to analyze public transcriptome data of a variety of immune cell types in resting and activated functional state. In addition, a clinical study on rheumatoid arthritis (RA) was analyzed to illustrate utility of the technology. Per sample, activity of androgen and estrogen receptor, PI3K, MAPK, TGFβ, Notch, NFκB, JAK-STAT1/2, and JAK-STAT3 STPs was calculated, generating an STP activity profile (SAP) consisting of 9 activity scores. Each analyzed immune cell type, i.e. naive/resting and immune-activated CD4 + and CD8 + T cells, T helper cells, B cells, NK cells, monocytes, macrophages, and dendritic cells, had a reproducible and characteristic SAP, reflecting both cell type and its activity state. Analysis of clinical RA samples revealed increased TGFβ STP activity in whole blood samples. In conclusion, STAP-STP technology enables quantitative measurement of the functional activity state of immune cells of the innate and adaptive immune system. Aside from diagnostic applications, utility lies in unravelling abnormal immune function in disease and immunomodulatory drug development.

Abstract Background Few animal populations have been studied under the framework of the OCBIL theory, which addresses the ecology and evolution of biodiversity on old climatically buffered infertile landscapes. Available genetic data challenge the low connectivity and high genetic differentiation predicted for isolated tepui-summit vertebrate communities, suggesting potential dispersal among summits. However, the OCBIL theory posits reduced dispersibility, enhanced resilience to habitat fragmentation and inbreeding due to small populations. We tested these hypotheses by conducting the first analytic evaluation of the spatial ecology and population biology of a tepui-summit vertebrate at multiple spatial scales. Results We used harmonic radar tracking (100 individuals/448 points of contact) and capture-mark-recapture data (596 individuals captured/52 recaptured) to reveal the temporal niche, microhabitat use, population size, and dispersal abilities of the tepui-summit endemic toad Oreophrynella quelchii on Roraima-tepui. Abundance was determined using a closed population model incorporating sources of variation in capture probability. We tested the relative influence of biotic and abiotic variables on distances moved through model selection. Our data indicate that the population size of O. quelchii is remarkably large (ca. 12 million individuals), with strong seasonal demographic fluctuations. Ecology and observed limited spatial movements challenge the likelihood of active dispersal among tepui tops in this species. Our results are counter to those predicted by the available genetic data but support two hypotheses of the OCBIL theory: reduced dispersibility and enhanced resilience. However, they do not support the expectation of a small refugial population size. Conclusion We postulate that the insular, hostile tepui-summit environment tends to produce robust demographic populations, likely to buffer stochastic adverse environmental effects, rather than diversity, as observed in much younger post-Pleistocene Neotropical landscapes. Our results draw attention to the value of faunal studies using an OCBIL framework to better understand the ecology and evolution of this unique biota worldwide.

Background: The effects of adverse childhood experiences on adult psychopathology have received ample attention in empirical studies. Despite the extensive focus on the effects of childhood adversity, research on the protective factors that might mitigate these effects remains limited. The most common measure of childhood adversity is the Adverse Childhood Experiences (ACEs) questionnaire. In 2016, a novel addition, called the ‘Protective and Compensatory Experiences’ (PACEs) questionnaire was created to be administered in tandem with the ACEs measure. Objective: Developing an understanding of PACEs can provide insight into the positive impacts of protective factors and potential ways to build resiliency among those with adversity. The aim of the present review is to provide an overview of the uses and findings of the PACEs measure and its potential contributions in the field. Methods: A literature search was used to identify peer-reviewed publications, dissertations, and conference presentations on empirical data, reporting on the administration of the PACEs measure to a clinical or community population and their findings. Results: A total of 17 studies were identified that used the PACEs. Ten empirical studies were used to explore the impact of PACEs within the realm of child development, including research on pregnant mothers, parenting, and child resilience. Six empirical studies were used to investigate the prevalence of PACEs in various at-risk populations, such as sexual minorities, racial minorities, veterans, individuals with chronic pain, and healthcare providers after the COVID-19 pandemic. One empirical study used PACEs to track attrition in longitudinal research studies. Conclusions: Overall, there appears to be little research on the PACEs, but the empirical studies that we identified suggest that PACEs may increase resiliency among various populations. Future research into positive and negative childhood experiences would benefit from the information assessed with the PACEs measure.

Severe babesiosis with 9.8% parasitemia was diagnosed in a patient in the Netherlands who had previously undergone splenectomy. We confirmed Babesia venatorum using PCR and sequencing. B. venatorum was also the most prevalent species in Ixodes ricinus ticks collected around the patient’s home. Our findings warrant awareness for severe babesiosis in similar patients.

Creativity has been conceptualized not just as a measure of artistic ability, but also as an adaptive trait of everyday innovation. We posit the relevance of "everyday creativity" to the field of psychotherapy. Although creativity has been theorized in psychotherapy models of change and the therapy process, little empirical research has examined patients' and therapists' creativity in psychotherapy treatments. Moreover, creativity research has been hampered by the vast array of definitions and operationalizations of the construct. Despite a lack of direct evidence, there appears to be substantial overlap between the empirically observed characteristics of creativity and the aims of psychotherapy treatments. First, research on characteristics of creative individuals, by way of personality, cognition, emotion, and psychopathology might overlap with what we know about individuals who benefit from psychotherapy. Second, the therapeutic process might resemble a creative process, suggesting that creativity could be a mediator of treatment outcomes. Third, creativity may be seen as a treatment outcome in that it reflects the achievement of more open-minded thinking, cognitive and emotional flexibility, as well as diminished psychopathology. We take a hypothesis-generating stance, suggesting future research that could test a potential mediating/moderating role of creativity in psychotherapy.

Abstract The emergence of antimicrobial resistance has created an urgent need for alternative treatments against bacterial pathogens. Here, we investigated kinase inhibitors as potential host-directed therapies (HDTs) against intracellular bacteria, specifically Salmonella Typhimurium (Stm) and Mycobacterium tuberculosis (Mtb). We screened 827 ATP-competitive kinase inhibitors with known target profiles from two Published Kinase Inhibitor Sets (PKIS1 and PKIS2) using intracellular infection models for Stm and Mtb, based on human cell lines and primary macrophages. Additionally, the in vivo safety and efficacy of the compounds were assessed using zebrafish embryo infection models. Our screen identified 11 hit compounds for Stm and 17 hit compounds for Mtb that were effective against intracellular bacteria and non-toxic for host cells. Further experiments were conducted to prioritize Stm hit compounds that were able to clear the intracellular infection in primary human macrophages. From these, two structurally related Stm hit compounds, GSK1379738A and GSK1379760A, exhibited significant activity against Stm in infected zebrafish embryos. In addition, we identified compounds that were active against intracellular Mtb, including morpholino-imidazo/triazolo-pyrimidinones that target PIK3CB, as well as 2-aminobenzimidazoles targeting ABL1. Overall, this study provided insights into kinase targets acting at the host–pathogen interface and identified several kinase inhibitors as potential HDTs.

In response to the growing societal awareness of the critical role of healthy soils, there has been an increasing demand for accurate and high-resolution soil information to inform national policies and support sustainable land management decisions. Despite advancements in digital soil mapping and initiatives like GlobalSoilMap, quantifying soil variability and its uncertainty across space, depth and time remains a challenge. Therefore, maps of key soil properties are often still missing on a national scale, which is also the case in the Netherlands. To meet this challenge and fill this data gap, we introduce BIS-4D, a high-resolution soil modeling and mapping platform for the Netherlands. BIS-4D delivers maps of soil texture (clay, silt and sand content), bulk density, pH, total nitrogen, oxalate-extractable phosphorus, cation exchange capacity and their uncertainties at 25 m resolution between 0 and 2 m depth in 3D space. Additionally, it provides maps of soil organic matter and its uncertainty in 3D space and time between 1953 and 2023 at the same resolution and depth range. The statistical model uses machine learning informed by soil observations amounting to between 3815 and 855 950, depending on the soil property, and 366 environmental covariates. We assess the accuracy of mean and median predictions using design-based statistical inference of a probability sample and location-grouped 10-fold cross validation (CV) and prediction uncertainty using the prediction interval coverage probability. We found that the accuracy of clay, sand and pH maps was the highest, with the model efficiency coefficient (MEC) ranging between 0.6 and 0.92 depending on depth. Silt, bulk density, soil organic matter, total nitrogen and cation exchange capacity (MEC of 0.27 to 0.78), and especially oxalate-extractable phosphorus (MEC of −0.11 to 0.38) were more difficult to predict. One of the main limitations of BIS-4D is that prediction maps cannot be used to quantify the uncertainty in spatial aggregates. We provide an example of good practice to help users decide whether BIS-4D is suitable for their intended purpose. An overview of all maps and their uncertainties can be found in the Supplement. Openly available code and input data enhance reproducibility and help with future updates. BIS-4D prediction maps can be readily downloaded at https://doi.org/10.4121/0c934ac6-2e95-4422-8360-d3a802766c71 (Helfenstein et al., 2024a). BIS-4D fills the previous data gap of the national-scale GlobalSoilMap product in the Netherlands and will hopefully facilitate the inclusion of soil spatial variability as a routine and integral part of decision support systems.

Abstract The first nationwide outbreak of COVID-19 in Vietnam started in late April 2021 and was caused almost exclusively by a single Delta lineage, AY.57. In early 2022, multiple Omicron variants co-circulated with Delta variants and quickly became dominant. The co-circulation of Delta and Omicron happened leading to possibility of co-infection and recombination events which can be revealed by viral genomic data. From January to October 2022, a total of 1028 viral RNA samples out of 4852 positive samples (Ct

Background There is strong interest in the evaluation of longer‐term outcome metrics for congenital heart diseases (CHDs); however, registries focus on postoperative metrics. Methods and Results Informed by user online discussion forums and scoping of national data, we selected sentinel CHDs and long‐term outcome metrics suitable for routine monitoring. We then developed sentinel CHD phenotypes and algorithms for identifying treatment pathway procedures using clinical codes. Finally, we calculated the metrics within a retrospective national cohort analysis. The 9 selected sentinel CHDs had a higher‐than‐average prevalence, typically involved surgery in infancy, and were associated with an increased risk of late mortality. The selected metrics of survival and reinterventions at 1, 5, and 10 years were both important and feasible. The cohort included 29 319 (41.3% of all operated CHD births) English and Welsh children born with sentinel CHDs in 2000 to 2022. Example metrics at age 10 years included: survival—hypoplastic left heart syndrome: 57.6% (95% CI, 54.9%–60.4%), functionally univentricular heart: 86.7% (95% CI, 84.6%–88.9%), transposition of the great arteries: 93.1% (95% CI, 92.2%–93.9%), pulmonary atresia: 81.0% (95% CI, 79.1%–82.9%), atrioventricular septal defect: 88.5% (95% CI, 87.5%–89.5%), tetralogy of Fallot: 95.1% (95% CI, 94.4%–95.8%), aortic stenosis: 94.4% (95% CI, 93.3%–95.6%), coarctation: 96.7% (95% CI, 96.2%–97.3%), and ventricular septal defect: 96.9% 95% CI, (96.4%–97.3%); and (2) cumulative incidence of reintervention—hypoplastic left heart syndrome : 54.5% (95% CI, 51.5%–57.3%), functionally univentricular heart: 57.3% (95% CI, 53.9%–60.5%), transposition of the great arteries: 20.9% (95% CI, 19.5%–22.3%), pulmonary atresia: 66.8% (95% CI, 64.2%–69.1%), atrioventricular septal defect: 21.6% (20.3%–23.0%), tetralogy of Fallot: 26.6% (95% CI, 25.2%–28.0%), aortic stenosis: 31.2% (95% CI, 28.8%–33.6%), coarctation: 19.8% (95% CI, 18.6%–21.1%), and ventricular septal defect: 6.1% (95% CI, 5.5%–6.8%). Conclusions It is feasible to report important long‐term outcomes of survival and reintervention for sentinel CHDs using routinely collected procedure records, adding value to national audit.

Background: Despite programmatic protocolised care and structured support, considerable variation is observed in completeness of registration and achieving targets of cardiovascular risk management (CVRM) between individual GPs in the Netherlands. Aim: To determine whether completeness of registration and achieved targets of cardiovascular risk factors improves with practice visitation. Design & setting: Observational study utilising the care group's database (2016–2019), comparing changes in registration and achieved targets in non-visited practices and visited practices. Method: We compared completeness scores of registration and scores of targets achieved before visitation and 1 year after visitation. Data were analysed on patient level and GP level. Separate analyses were performed among GPs who were ranked in the lower 25% of score distributions. Results: We observed no clinically relevant improvements in completeness of registration and targets achieved in 2017, 2018, and 2019 that could be attributed to visitations in the previous year, both on individual patient level and on aggregated level per general practice. In practices ranked in the lower 25% of the distribution, improvements over time were clinically relevant and larger than the overall changes. Yet, these findings were irrespective of the number of practice visitations. Conclusion: Practice visitations in our setting did not seem to lead to improvements in practice performance, nor in completeness of registration of risk factors or in reaching predefined target goals for cardiovascular risk factors.

The EU funded project EuroSea brought together key actors of the European ocean observing and forecasting communities with key users of the ocean observing products and services in order to better integrate existing ocean observation systems and tools, and to improve the delivery of ocean information to users. EuroSea was constructed around the ocean observing value chain that connects observations to users of ocean information, and, just as intended, the value chain concept was a useful prism to improve the system. In this article, we summarize some of the main take-home messages from EuroSea on the needs for developing the European Ocean Observing System and its links with modeling and forecasting systems. During the project, the challenges and gaps in the design and coordination of the European ocean observing and forecasting system were identified and mapped. Many gaps and challenges related to the observations of physical, chemical and biological Essential Ocean Variables were identified. Some of these gaps are related to technological developments, while others are caused by insufficient and short-term funding leading to a not sustainable system, management, and cooperation between different entities, as well as limitations in foresight activities, policies and decisions. This article represents a compilation of the broader needs for advancing the observing and forecasting system, and is meant as a guide for the community, and to funders and investors to advance ocean observing and the delivery of ocean information in Europe. To enhance the sustainability of ocean observations, which is paramount for a reliable provision of quality oceanographic data and services, several recommendations were compiled for ocean observing networks, frameworks, initiatives, as well as the ocean observing funders within the European nations, and the European Commission.

IntroductionHypodysfibrinogenemia is a rare congenital fibrinogen disorder (CFD) which may induce thrombotic and bleeding events. Therefore, patient management needs careful evaluation. Routine coagulation tests are inadequate to predict the clinical phenotype.Clinical findingsA 60-year-old woman with both bleeding and thrombotic complications and her two daughters were referred to our center for genotypic and phenotypic analysis of a CFD.DiagnosisConventional laboratory results led to the diagnosis of hypodysfibrinogenemia in all three subjects. They all carried the same heterozygous c.1124A>G mutation in FGG resulting in p.Tyr375Cys amino acid substitution, which was confirmed by protein variant analysis from plasma. In silico structure analysis predicted possible conformational and functional changes of the fibrinogen molecule. Thrombin generation indicated a hypercoagulable state confirmed by microfluidics that showed enhanced fibrin formation in both daughters, regardless of the coagulation trigger.ConclusionWe report on a family with hypodysfibrinogenemia and a novel FGG heterozygous missense mutation, possibly leading to conformational changes or covalent dimerization. Thrombin generation and particularly microfluidic measurements disclosed a hypercoagulable state, which was not detected with routine coagulation tests, justifying a different patient management.

Objectives Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination.Methods In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3–6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells.Results Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients.Conclusion Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses.Trial registration number NL8900.

Background Antimicrobial use in Laos is among the highest in Southeast Asia. The first Lao comprehensive antimicrobial prescribing guidelines have been available since 2021. This study explored the determinants of antibiotic prescribing decisions and how the new prescribing guidelines were being used. Methods In August 2022, in-depth interviews were conducted with 16 Lao prescribers from two hospitals. Participants were questioned about their prescribing behaviours, attitudes to guidelines, how they learned about the guidelines and factors influencing their uptake. The interviews were audio-recorded, transcribed, and translated into English. Thematic analysis of the transcripts was conducted. Results Lao prescribers considered multiple factors before deciding to prescribe antibiotics to their patients. The most common factor was based on the clinical judgement of the prescribers. Lack of certain antibiotics and turnaround times of laboratory results were the main challenges to prescribing antibiotics appropriately. The majority of participants were satisfied with the guidelines, regarding them as comprehensive, simple and convenient. However, most participants admitted that they did not access the guidelines very often. The main reason was that they could remember the treatment recommendations because they treat similar diseases on a daily basis. Improving antibiotic knowledge was the most common recommendation in order to improve the appropriate use of antibiotics. Raising awareness of the guidelines and promoting their use should also be considered. In addition, heads of the wards, and policy and implementation leaders, should support, monitor and feedback their use to encourage all prescribers to follow the guidelines. Conclusions Several factors contribute to enhancing appropriate antibiotic prescription. Key factors for improving antibiotic prescription include enhancing prescribers' clinical knowledge, ensuring access to essential antibiotics, and updating guidelines regularly. Health leaders must get involved to promote their use.