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Abstract The FAIR Data Principles are being rapidly adopted by many research institutes and funders worldwide. This study aimed to assess the awareness and attitudes of clinical researchers and research support staff regarding data FAIRification. A questionnaire was distributed to researchers and support staff in six Dutch University Medical Centers and Electronic Data Capture platform users. 164 researchers and 21 support staff members completed the questionnaire. 62.8% of the researchers and 81.0% of the support staff are currently undertaking at least some effort to achieve any aspect of FAIR, 11.0% and 23.8%, respectively, address all aspects. Only 46.6% of the researchers add metadata to their datasets, 39.7% add metadata to data elements, and 35.9% deposit their data in a repository. 94.7% of the researchers are aware of the usefulness of their data being FAIR for others and 89.3% are, given the right resources and support, willing to FAIRify their data. Institutions and funders should, therefore, develop FAIRification training and tools and should (financially) support researchers and staff throughout the process.

Abstract Introduction Malalignment of the Total Ankle Replacement (TAR) has often been postulated as the main reason for the high incidence of TAR failure. As the ankle joint has a small contact area, stresses are typically high, and malalignment may lead to non-homogeneous stress distributions, including stress peaks that may initiate failure. This study aims to elucidate the effect of TAR malalignment on the contact stresses on the bone-implant interface, thereby gaining more understanding of the potential role of malalignment in TAR failure. Methods Finite Element (FE) models of the neutrally aligned as well as malaligned CCI (Ceramic Coated Implant) Evolution TAR implant (Van Straten Medical) were developed. The CCI components were virtually inserted in a generic three-dimensional (3D) reconstruction of the tibia and talus. The tibial and talar TAR components were placed in neutral alignment and in 5° and 10° varus, valgus, anterior and posterior malalignment. Loading conditions of the terminal stance phase of the gait cycle were applied. Peak contact pressure and shear stress at the bone-implant interface were simulated and stress distributions on the bone-implant interface were visualized. Results In the neutral position, a peak contact pressure and shear stress of respectively 98.4 MPa and 31.9 MPa were found on the tibial bone-implant interface. For the talar bone-implant interface, this was respectively 68.2 MPa and 39.0 MPa. TAR malalignment increases peak contact pressure and shear stress on the bone-implant interface. The highest peak contact pressure of 177 MPa was found for the 10° valgus malaligned tibial component, and the highest shear stress of 98.5 MPa was found for the 10° posterior malaligned talar model. High contact stresses were mainly located at the edges of the bone-implant interface and the fixation pegs of the talar component. Conclusions The current study demonstrates that TAR malalignment leads to increased peak stresses. High peak stresses could contribute to bone damage and subsequently reduced implant fixation, micromotion, and loosening. Further research is needed to investigate the relationship between increased contact stresses at the bone-implant interface and TAR failure.

Abstract Background Natural antibodies (NAb) are antibodies that are present in a healthy individual without requiring previous exposure to an exogenous antigen. Selection for high NAb levels might contribute to improved general disease resistance. Our aim was to analyse the genetic background of NAb based on a divergent selection experiment in poultry, and in particular the effect of a polymorphism in the TLR1A gene. Methods The study population consisted of a base population from a commercial pure-bred elite white leghorn layer line and seven generations of birds from a High and Low selection line. Birds were selected for total KLH-binding NAb titer (IgTotal). An enzyme-linked immunosorbent assay was performed to determine NAb titers in blood plasma for IgTotal and the antibody isotypes IgM and IgG. NAb titers were available for 10,878 birds. Genotypes for a polymorphism in TLR1A were determined for chickens in generations 5, 6 and 7. The data were analysed using mixed linear animal models. Results The heritability estimate for IgM was 0.30 and higher than that for IgG and IgTotal (0.12). Maternal environmental effects explained 2 to 3% of the phenotypic variation in NAb. Selection for IgTotal resulted in a genetic difference between the High and Low line of 2.4 titer points (5.1 genetic standard deviation) in generation 7. For IgM, the selection response was asymmetrical and higher in the Low than the High line. The frequency of the TLR1A C allele was 0.45 in the base population and 0.66 and 0.04 in generation 7 of the High and Low line, respectively. The TLR1A polymorphism had large and significant effects on IgTotal and IgM. Estimated genotypic effects suggest full dominance of the TLR1A C allele. Significant TLR1A by generation interactions were detected for IgM and IgTotal. Conclusions The effect of a polymorphism in the TLR1A gene on IgTotal and IgM NAb was confirmed. Furthermore, we provide experimental verification of changes in allele frequencies at a major gene with dominant gene action on a quantitative trait that is subjected to mass selection. TLR1A by generation interactions indicate sensitivity to environmental factors.

As learning societies necessitate continuous education, a growing number of part-time programs are being offered. A key challenge for part-time programs is adequately supporting students in connecting their learning within the program to their work life, which in contrast to dual education is not part of the program. To better understand such boundary-crossing support in part-time higher professional education, this explanatory sequential mixed-methods study was conducted. A large-scale study, consisting of quantitative data analysis of the Dutch National Student Survey, confirmed that part-time programs (n = 600) differ in perceived boundary crossing, with a medium effect size of [eta]2 = 0.13, and that factors postulated in the literature are related. An in-depth cross-case analysis of the boundary-crossing support provided in four purposefully selected part-time higher education programs (with high and low perceived support) indicated that brokers, boundary objects, hybrid practices, boundary interactions, degrees of freedom, degrees of clarity, and supervision are ways to support boundary crossing. These findings provide actionable strategies by which part-time higher professional education programs can support student learning across contexts.

Abstract Background Accurate proxy-report questionnaires, adapted to the child’s developmental stage, are required to monitor 24-h movement behaviors in young children, especially for large samples and low-resource settings. Objectives This review aimed to summarize available studies evaluating measurement properties of proxy-report questionnaires assessing physical activity, sedentary behavior and/or sleep in children aged 0–5 years. Methods Systematic literature searches were carried out in the PubMed, Embase and SPORTDiscus databases, up to January 2021. For physical activity and sedentary behavior questionnaires this is a review update, whereas for sleep questionnaires we included all relevant studies published up to now. Studies had to evaluate at least one of the measurement properties of a proxy-report questionnaire assessing at least duration and/or frequency of physical activity, sedentary behavior and/or sleep in 0- to 5-year-old children. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guideline was used to evaluate the quality of evidence. Results Thirty-three studies were included, examining a total of 37 questionnaires. Ten questionnaires were designed for infants, two for toddlers, 11 for preschoolers, and 14 for a broader age range targeting multiple of these age groups. Twenty questionnaires assessed constructs of sleep, four assessed constructs of physical activity, two assessed screen behavior, five assessed constructs of both physical activity and sedentary behavior, and six assessed constructs of all 24-h movement behaviors. Content validity was evaluated for six questionnaires, structural validity for two, internal consistency for three, test-retest reliability for 16, measurement error for one, criterion validity for one, and construct validity for 26 questionnaires. None of the questionnaires were considered sufficiently valid and/or reliable for assessing one or more movement behaviors in 0- to 5-year-old children, and the quality of evidence was mostly low or very low. Conclusions Valid and/or reliable questionnaires assessing 24-h movement behaviors in 0- to 5-year-olds are lacking. High-quality studies are therefore required, to develop proxy-report questionnaires and evaluate their measurement properties. PROSPERO registration number CRD42020169268.

Abstract Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to “lose” their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region.

Background: Incomplete surgical staging of patients with early-stage epithelial ovarian cancer (EOC) has been reported in up to 98% of cases, when based on the International Federation of Obstetrics and Gynecology (FIGO) staging procedure. The aim of the present retrospective study was to clarify the reasons for incomplete staging. Methods: The PRISMA (Prevention Recovery Information System for Monitoring and Analysis) technique was used to evaluate cases with FIGO I-IIa EOC based on incomplete staging from five gynecologic oncologic center hospitals in the Netherlands in the period 2010–2014. Results: Fifty cases with an incomplete surgical staging of EOC according to national guidelines were included. The most common reasons for incomplete staging were insufficient random biopsies of the peritoneum (n = 34, 68%), and less than ten lymph nodes being resected and/or found at pathology (n = 16, 32%). The most mentioned reason for not performing biopsies was, besides forgetting to do so, believing that after careful inspection and palpation, taking biopsies is irrelevant and/or already are being taken while performing a hysterectomy (peritoneum of cul-de-sac, bladder). The value of contralateral pelvic lymph node dissection in case of a unilateral ovarian malignancy was also doubted, influencing the number of lymph nodes resected. Conclusions: The most important reasons for incomplete staging in EOC are, besides omitting elements by accident, questioning the importance of obligatory elements of the staging procedure. A structured list of staging steps during surgery and more evidence-based consensus concerning these obligatory elements might increase the number of complete staging procedures in EOC.

Abstract Background Malalignment is often postulated as an important reason for the high failure rate of total ankle replacements (TARs). The correlation between TAR malalignment and clinical outcome, however, is not fully understood. Improving and expanding radiographic TAR alignment measurements in the clinic might lead to a better insight into the correlation between malalignment and the clinical outcome. This study aims to develop and validate a tool to semi‐automatic measure TAR alignment, and to improve alignment measurements on radiographs in the clinic. Methods A tool to semi‐automatically measure TAR alignment on anteroposterior and lateral radiographs was developed in MATLAB. Using the principle of edge contouring and the perpendicular relationship between the anteroposterior and lateral radiographs, the exact configuration of the TAR components can be found. Two observers validated the tool by measuring TAR alignment of ten patients using the tool. The Intraclass Coefficient (ICC) was calculated to assess the reliability of the developed method. The results obtained by the tool were compared to clinical results during radiographic follow‐up in the past, and the accuracy of both methods was calculated using three‐dimensional CT data. Results The tool showed an accuracy of 76% compared to 71% for the method used during follow‐up. ICC values were 0.94 (p

Abstract Background Total ankle arthroplasty is increasingly used as a treatment for end stage ankle arthropathy. The aim of this study was to report the mid‐term clinical function and survival results of Ceramic Coated Implant (CCI) ankle replacements and assess the association between the alignment of the CCI total ankle replacements and early functional outcome and complication incidence. Methods Data of 61 patients, who received 65 CCI implants between 2010 and 2016, were obtained from a prospectively documented database. Mean follow‐up time was 85.2 months (range 27–99 months). Clinical function was assessed with AOFAS questionnaire and passive range of motion (ROM). Survival analysis and elaborate radiographic analysis was performed. Furthermore, complications and reoperations were recorded for all patients. Results Progression in ROM was most seen in the first 10 months from 21.8 degrees of passive range of motion preoperative to 27.6 degrees postoperative (p

Digital health technologies can help tackle challenges in global public health. Digital and AI-for-Health Challenges, controlled events whose goal is to generate solutions to a given problem in a defined period of time, are one way of catalysing innovation. This article proposes an expanded investment framework for Global Health AI and digitalhealth Innovation that goes beyond traditional factors such as return on investment. Instead, we propose non monetary and non GDP metrics, such as Disability Adjusted Life Years or achievement of universal health coverage. Furthermore, we suggest a venture building approach around global health, which includes filtering of participants to reduce opportunity cost, close integration of implementation scientists and an incubator for the long-term development of ideas resulting from the challenge. Finally, we emphasize the need to strengthen human capital across a range of areas in local innovation, implementation-science, and in health services.

Here we describe a complicated case of a relapsed Leishmania infantum infection after an allogeneic stem cell transplantation (allo-SCT) for primary myelofibrosis. Three years earlier the patient had been diagnosed with a hemophagocytic lymphohistiocytosis secondary to a visceral Leishmania infantum infection, for which he was effectively treated with a cumulative dose of 40 mg/kg liposomal amphotericin B. During the first disease episode he was also diagnosed with primary myelofibrosis for which he received medical follow-up. One year later ruxolitinib was started due to progressive disease. No Leishmania relapse occurred. Nevertheless, the marrow fibrosis progressed, and an allo-SCT was performed. Two months after allo-SCT prolonged fever and a persistent pancytopenia occurred, which was due to a relapse of visceral Leishmaniasis. The infection was refractory to a prolonged treatment with liposomal amphotericin B with a cumulative dose up to 100 mg/kg. Salvage treatment with miltefosine led to reduction of fever within a few days and was followed by a slow recovery of pancytopenia over the following months. The Leishmania parasite load by PCR started to decline and after 3.5 months no Leishmania DNA could be detected anymore and follow-up until ten months afterwards did not show a relapse.

ObjectivesPatients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA.MethodsIn 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions.Results5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p

Abstract Despite the growing popularity of Instagram as a medium to portray nature and the outdoors, there remains limited research available exploring its influence on people's experiences in nature. We investigate Instagram as a three‐way negotiation between users, the platform's affordances and social norms associated with both Instagram use and outdoor experiences. Moving beyond polarized, conceptual debates situating social media affordances within dystopias and eutopias, we provide empirical insight from the lived experiences of everyday Instagram users reflecting upon their mediated outdoor activities. We found that participants shared special moments, beautiful landscapes and happy memories while they struggled with notions of authenticity associated with these experiences. They perceived certain scenes as more ‘Instagrammable’ than others, and this led to sharing homogenous stories and visual representations of the outdoors. At the same time, participants actively reflected on this standardization and aestheticization of the landscape and their experiences, and highlighted strategies to counter this, such as actively following voices normally under‐represented in media portraying outdoor activities or posting pictures that were not ‘polished’. We conclude that to understand modern‐day interactions with nature and move beyond purely theoretical discussions about the flaws or merits of social media, we need to look at users' own strategies that integrate visual social media into their outdoor activities, while taking into account how platform features and social norms contribute to the construction of these activities. A free Plain Language Summary can be found within the Supporting Information of this article.

Currently, genetically encoded calcium indicators are not suitable for direct quantification. Here the authors engineer a fluorescence lifetime imaging calcium biosensor, Turquoise Calcium Fluorescence LIfeTime Sensor (Tq-Ca-FLITS), and measure intracellular calcium concentrations in human-derived organoids.

BackgroundA spinal epidural abscess (SEA) of the cervical spine is a relatively rare disease and is generally characterized by progressive neurological deterioration due to compression of the spinal cord. Up to 40% of cervical SEAs are located ventrally of the spinal cord. Urgent surgical intervention is warranted to decompress the spinal cord and collect material for cultures to guide antibiotic treatment. However, the optimal timing of the intervention is unclear, and the associated risk of spinal instability in the presence of an extensive infection is a significant clinical dilemma.MethodsIn this paper, we present a novel surgical technique to treat a cervical SEA by anterior decompression through a linear transvertebral midline approach. This technique has the advantage of effectively draining the ventrally located SEA and obtaining material for bacteria culture while maintaining spinal stability without additional instrumentation.ResultsThis case study presents seven patients with cervical SEAs who were successfully treated with surgical decompression by this transvertebral linear midline technique and antibiotic treatment.ConclusionAnterior decompression through a linear transvertebral midline approach for a ventrally located cervical SEA is a safe and pragmatic surgical procedure to achieve spinal cord decompression and collect bacteria culture without destabilizing the cervical spine.

Adolescents with Developmental Language Disorders (DLD) have more difficulties in social emotional functioning than their typically developing peers (TD), such as shyness and anxiety in social situations, fewer peer relations, greater risk of victimization, social isolation and depression. In addition, they are more likely to report higher levels of hyperactivity and conduct problems. These problems derive from a complex interplay between difficulties in language, social communication, underlying cognitive deficits in Theory of Mind (ToM), Executive Functioning (EF) and self-directed speech (SDS). The aim of this mini review is to provide an overview of studies examining the effectiveness of interventions targeting the factors underlying social emotional functioning of school-aged children and adolescents with DLD. We found that studies dedicated to social emotional functioning in school-aged children and adolescents with DLD were relatively scarce. Based on this overview, we give suggestions to improve social emotional functioning in adolescents with DLD. We propose that intervention programs should target the social, linguistic and cognitive functions underlying social emotional functioning and create opportunities to practice these skills in daily, real-life situations with peers.

The aim of this work is to identify the molecular cause of autosomal recessive early onset retinal degeneration in a consanguineous pedigree. Seventeen members of a four-generation Pakistani family were recruited and underwent a detailed ophthalmic examination. Exomes of four affected and two unaffected individuals were sequenced. Variants were filtered using exomeSuite to identify rare potentially pathogenic variants in genes expressed in the retina and/or brain and consistent with the pattern of inheritance. Effect of the variant observed in the gene Intraflagellar Transport Protein 43 (IFT43) was studied by heterologous expression in mIMCD3 and MDCK cells. Expression and sub-cellular localization of IFT43 in the retina and transiently transfected cells was examined by RT-PCR, western blot analysis, and immunohistochemistry. Affected members were diagnosed with early onset non-syndromic progressive retinal degeneration and the presence of bone spicules distributed throughout the retina at younger ages while the older affected members showed severe central choroidal atrophy. Whole-exome sequencing analysis identified a novel homozygous c.100 G > A change in IFT43 segregating with retinal degeneration and not present in ethnicity-matched controls. Immunostaining showed IFT43 localized in the photoreceptors, and to the tip of the cilia in transfected mIMCD3 and MDCK cells. The cilia in mIMCD3 and MDCK cells expressing mutant IFT43 were found to be significantly shorter (P

Introduction: Chronic osteomyelitis is a challenging condition in the orthopedic practice and traditionally treated using local and systemic antibiotics in a two-stage surgical procedure. With the introduction of the antimicrobial biomaterial S53P4 bioactive glass (Bonalive®), chronic osteomyelitis can be treated in a one-stage procedure. This study evaluated the mid-term clinical results of patients treated with S53P4 bioactive glass for long bone chronic osteomyelitis. Methods: In this prospective multi-center study, patients from two different university medical centers in the Netherlands were included. One-stage treatment consisted of debridement surgery, implantation of S53P4 bioactive glass, and treatment with culture-based systemic antibiotics. If required, wound closure by a plastic surgeon was performed. The primary outcome was the eradication of infection, and a secondary statistical analysis was performed on probable risk factors for treatment failure. Results: In total, 78 patients with chronic cavitary long bone osteomyelitis were included. Follow-up was at least 12 months (mean 46; standard deviation, SD, 20), and 69 patients were treated in a one-stage procedure. Overall infection eradication was 85 %, and 1-year infection-free survival was 89 %. Primary closure versus local/muscular flap coverage is the only risk factor for treatment failure. Conclusion: With 85 % eradication of infection, S53P4 bioactive glass is an effective biomaterial in the treatment of chronic osteomyelitis in a one-stage procedure. A major risk factor for treatment failure is the necessity for local/free muscle flap coverage. These results confirm earlier published data, and together with the fundamentally different antimicrobial pathways without antibiotic resistance, S53P4 bioactive glass is a recommendable biomaterial for chronic osteomyelitis treatment and might be beneficial over other biomaterials.

Mutations in genes critical for proper intra-Golgi transport can cause human syndromes due to defects in glycosylation of proteins. Here, the authors identify a human variant of Syntaxin-5 that causes fatal multisystem disease and mislocalization of glycosyltransferases due to altered Golgi transport.

Abstract Background Patient data registries that are FAIR—Findable, Accessible, Interoperable, and Reusable for humans and computers—facilitate research across multiple resources. This is particularly relevant to rare diseases, where data often are scarce and scattered. Specific research questions can be asked across FAIR rare disease registries and other FAIR resources without physically combining the data. Further, FAIR implies well-defined, transparent access conditions, which supports making sensitive data as open as possible and as closed as necessary. Results We successfully developed and implemented a process of making a rare disease registry for vascular anomalies FAIR from its conception—de novo. Here, we describe the five phases of this process in detail: (i) pre-FAIRification, (ii) facilitating FAIRification, (iii) data collection, (iv) generating FAIR data in real-time, and (v) using FAIR data. This includes the creation of an electronic case report form and a semantic data model of the elements to be collected (in this case: the “Set of Common Data Elements for Rare Disease Registration” released by the European Commission), and the technical implementation of automatic, real-time data FAIRification in an Electronic Data Capture system. Further, we describe how we contribute to the four facets of FAIR, and how our FAIRification process can be reused by other registries. Conclusions In conclusion, a detailed de novo FAIRification process of a registry for vascular anomalies is described. To a large extent, the process may be reused by other rare disease registries, and we envision this work to be a substantial contribution to an ecosystem of FAIR rare disease resources.

Abstract Background Evidence from previous studies comparing lung ultrasound to thoracic computed tomography (CT) in intensive care unit (ICU) patients is limited due to multiple methodologic weaknesses. While addressing methodologic weaknesses of previous studies, the primary aim of this study is to investigate the diagnostic accuracy of lung ultrasound in a tertiary ICU population. Methods This is a single-center, prospective diagnostic accuracy study conducted at a tertiary ICU in the Netherlands. Critically ill patients undergoing thoracic CT for any clinical indication were included. Patients were excluded if time between the index and reference test was over eight hours. Index test and reference test consisted of 6-zone lung ultrasound and thoracic CT, respectively. Hemithoraces were classified by the index and reference test as follows: consolidation, interstitial syndrome, pneumothorax and pleural effusion. Sensitivity, specificity, positive and negative likelihood ratio were estimated. Results In total, 87 patients were included of which eight exceeded the time limit and were subsequently excluded. In total, there were 147 respiratory conditions in 79 patients. The estimated sensitivity and specificity to detect consolidation were 0.76 (95%CI: 0.68 to 0.82) and 0.92 (0.87 to 0.96), respectively. For interstitial syndrome they were 0.60 (95%CI: 0.48 to 0.71) and 0.69 (95%CI: 0.58 to 0.79). For pneumothorax they were 0.59 (95%CI: 0.33 to 0.82) and 0.97 (95%CI: 0.93 to 0.99). For pleural effusion they were 0.85 (95%CI: 0.77 to 0.91) and 0.77 (95%CI: 0.62 to 0.88). Conclusions In conclusion, lung ultrasound is an adequate diagnostic modality in a tertiary ICU population to detect consolidations, interstitial syndrome, pneumothorax and pleural effusion. Moreover, one should be careful not to interpret lung ultrasound results in deterministic fashion as multiple respiratory conditions can be present in one patient. Trial registration This study was retrospectively registered at Netherlands Trial Register on March 17, 2021, with registration number NL9344.