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Introduction: At our department we have a dedicated 1.5 Tesla MRI/HDR brachytherapy suite, which provides the possibility of repeated MRI scanning before, during and after applicator insertion and before and/or after irradiation for patients with advanced cervical cancer. In this study we analysed the effect of this adaptive workflow. We investigated the number of interventions, their impact on organ doses (OAR) and the respective dose differences between total prescribed and total delivered doses. Materials and methods: Seventy patients with locally advanced cervical cancer FIGO2009 stages IB-IVA, treated from June 2016 till August 2020, were retrospectively analysed. The standard brachytherapy schedule consisted of two applicator insertions and delivery of three or four HDR fractions.OARs were recontoured on the repeated MRI scans. The D2cm3 dose difference between total prescribed and total delivered dose for bladder, rectum, sigmoid and bowel were calculated. Results: In total 153 interventions were performed, 3 replacements of the applicator, 23 adaptations of needle positions, bladder filling was changed 74 times and repeated rectal degassing 53 times. The impact of the rectal interventions was on average −1.2 Gy EQD23. Dose differences between total delivered and total prescribed D2cm3 for bladder, rectum, sigmoid and bowel were −0.6, 0.3, 2.2 and −0.6 Gy EQD23, respectively. Conclusions: An MRI scanner integrated into the brachytherapy suite enables multiple interventions based on the scans before treatment planning and dose delivery. This allows for customized treatment according to the changing anatomy of the individual patient and a better estimation of the delivered dose.

Background and purpose: Brachytherapy is treatment of choice for early stage nasal vestibule cancer. Over the years improvements were achieved by means of image guided target definition, interstitial implant techniques and also individual mold techniques. The aim of this study was to improve the technique of the implant so that the need for interstitial catheters can be limited by making use of patient individualized 3D-printed applicators. Materials and Methods: In 19 patients 3D-printed applicators were used to deliver pulse dose rate (PDR) brachytherapy. All patients underwent computed tomography (CT) and magnetic resonance imaging (MRI). A pre-plan with tumor delineation and manually optimized catheter positions to achieve tumor coverage was made. Based on the pre-plan a 3D-printed applicator was manufactured. Dose was evaluated by several indices: Conformity Index, Healthy Tissues Conformity Index, Dose Homogeneity Index, Dose non-uniformity ratio, Conformal index and high dose (HD) index. Results: A high target coverage was achieved, with a median V100%CTV of 99.1 % (range, 81.8–100 %) and median CI of 0.99 (range, 0.82–1.00), as well as a median V0.7GyGTV of 100 % (range, 93.0–100 %). The median HD was 0.39 (range, 0.20–0.83). Interstitial catheters were needed in 12 patients. None of the patients developed grade ≥ II toxicity within the median follow up of 18 months. Conclusions: This study shows that using 3D-printed applicators limits the need for interstitial catheters and also limits the high doses in normal tissue.

Osteochondral defect repair with a collagen/collagen-magnesium-hydroxyapatite (Col/Col-Mg-HAp) scaffold has demonstrated good clinical results. However, subchondral bone repair remained suboptimal, potentially leading to damage to the regenerated overlying neocartilage. This study aimed to improve the bone repair potential of this scaffold by incorporating newly developed strontium (Sr) ion enriched amorphous calcium phosphate (Sr-ACP) granules (100–150 μm). Sr concentration of Sr-ACP was determined with ICP-MS at 2.49 ± 0.04 wt%. Then 30 wt% ACP or Sr-ACP granules were integrated into the scaffold prototypes. The ACP or Sr-ACP granules were well embedded and distributed in the collagen matrix demonstrated by micro-CT and scanning electron microscopy/energy dispersive x-ray spectrometry. Good cytocompatibility of ACP/Sr-ACP granules and ACP/Sr-ACP enriched scaffolds was confirmed with in vitro cytotoxicity assays. An overall promising early tissue response and good biocompatibility of ACP and Sr-ACP enriched scaffolds were demonstrated in a subcutaneous mouse model. In a goat osteochondral defect model, significantly more bone was observed at 6 months with the treatment of Sr-ACP enriched scaffolds compared to scaffold-only, in particular in the weight-bearing femoral condyle subchondral bone defect. Overall, the incorporation of osteogenic Sr-ACP granules in Col/Col-Mg-HAp scaffolds showed to be a feasible and promising strategy to improve subchondral bone repair.

Background: The use of acellular hydrogels to repair osteochondral defects requires cells to first invade the biomaterial and then to deposit extracellular matrix for tissue regeneration. Due to the diverse physicochemical properties of engineered hydrogels, the specific properties that allow or even improve the behaviour of cells are not yet clear. The aim of this study was to investigate the influence of various physicochemical properties of hydrogels on cell migration and related tissue formation using in vitro, ex vivo and in vivo models. Methods: Three hydrogel platforms were used in the study: Gelatine methacryloyl (GelMA) (5% wt), norbornene hyaluronic acid (norHA) (2% wt) and tyramine functionalised hyaluronic acid (THA) (2.5% wt). GelMA was modified to vary the degree of functionalisation (DoF 50% and 80%), norHA was used with varied degradability via a matrix metalloproteinase (MMP) degradable crosslinker and THA was used with the addition of collagen fibrils. The migration of human mesenchymal stromal cells (hMSC) in hydrogels was studied in vitro using a 3D spheroid migration assay over 48h. In addition, chondrocyte migration within and around hydrogels was investigated in an ex vivo bovine cartilage ring model (three weeks). Finally, tissue repair within osteochondral defects was studied in a semi-orthotopic in vivo mouse model (six weeks). Results: A lower DoF of GelMA did not affect cell migration in vitro (p ​= ​0.390) and led to a higher migration score ex vivo (p ​

Abstract Introduction Guidelines on chronic kidney disease (CKD) recommend that nephrologists use clinical prediction models (CPMs). However, the actual use of CPMs seems limited in clinical practice. We conducted a national survey study to evaluate: 1) to what extent CPMs are used in Dutch CKD practice, 2) patients’ and nephrologists’ needs and preferences regarding predictions in CKD, and 3) determinants that may affect the adoption of CPMs in clinical practice. Methods We conducted semi-structured interviews with CKD patients to inform the development of two online surveys; one for CKD patients and one for nephrologists. Survey participants were recruited through the Dutch Kidney Patient Association and the Dutch Federation of Nephrology. Results A total of 126 patients and 50 nephrologists responded to the surveys. Most patients (89%) reported they had discussed predictions with their nephrologists. They most frequently discussed predictions regarded CKD progression: when they were expected to need kidney replacement therapy (KRT) (n = 81), and how rapidly their kidney function was expected to decline (n = 68). Half of the nephrologists (52%) reported to use CPMs in clinical practice, in particular CPMs predicting the risk of cardiovascular disease. Almost all nephrologists (98%) reported discussing expected CKD trajectories with their patients; even those that did not use CPMs (42%). The majority of patients (61%) and nephrologists (84%) chose a CPM predicting when patients would need KRT in the future as the most important prediction. However, a small portion of patients indicated they did not want to be informed on predictions regarding CKD progression at all (10–15%). Nephrologists not using CPMs (42%) reported they did not know CPMs they could use or felt that they had insufficient knowledge regarding CPMs. According to the nephrologists, the most important determinants for the adoption of CPMs in clinical practice were: 1) understandability for patients, 2) integration as standard of care, 3) the clinical relevance. Conclusion Even though the majority of patients in Dutch CKD practice reported discussing predictions with their nephrologists, CPMs are infrequently used for this purpose. Both patients and nephrologists considered a CPM predicting CKD progression most important to discuss. Increasing awareness about existing CPMs that predict CKD progression may result in increased adoption in clinical practice. When using CPMs regarding CKD progression, nephrologists should ask whether patients want to hear predictions beforehand, since individual patients’ preferences vary.

Neutrophils play a pivotal role in orchestrating the immune system response to biomaterials, the onset and resolution of chronic inflammation, and macrophage polarization. However, the neutrophil response to biomaterials and the consequent impact on tissue engineering approaches is still scarcely understood. Here, we report an in vitro culture model that comprehensively describes the most important neutrophil functions in the light of tissue repair. We isolated human primary neutrophils from peripheral blood and exposed them to a panel of hard, soft, naturally- and synthetically-derived materials. The overall trend showed increased neutrophil survival on naturally derived constructs, together with higher oxidative burst, decreased myeloperoxidase and neutrophil elastase and decreased cytokine secretion compared to neutrophils on synthetic materials. The culture model is a step to better understand the immune modulation elicited by biomaterials. Further studies are needed to correlate the neutrophil response to tissue healing and to elucidate the mechanism triggering the cell response and their consequences in determining inflammation onset and resolution.

Abstract Background Patient decision aids (PtDAs) support patients and clinicians in shared decision-making (SDM). Real-world outcome information may improve patients’ risk perception, and help patients make decisions congruent with their expectations and values. Our aim was to develop an online PtDA to support kidney failure treatment modality decision-making, that: 1) provides patients with real-world outcome information, and 2) facilitates SDM in clinical practice. Methods The International Patient Decision Aids Standards (IPDAS) development process model was complemented with a user-centred and convergent mixed-methods approach. Rapid prototyping was used to develop the PtDA with a multidisciplinary steering group in an iterative process of co-creation. The results of an exploratory evidence review and a needs-assessment among patients, caregivers, and clinicians were used to develop the PtDA. Seven Dutch teaching hospitals and two national Dutch outcome registries provided real-world data on selected outcomes for all kidney failure treatment modalities. Alpha and beta testing were performed to assess the prototype and finalise development. An implementation strategy was developed to guide implementation of the PtDA in clinical practice. Results The ‘Kidney Failure Decision Aid’ consists of three components designed to help patients and clinicians engage in SDM: 1) a paper hand-out sheet, 2) an interactive website, and 3) a personal summary sheet. A ‘patients-like-me’ infographic was developed to visualise survival probabilities for each treatment modality on the website. Other treatment outcomes were incorporated as event rates (e.g. hospitalisation rates) or explained in text (e.g. the flexibility of each treatment modality). No major revisions were needed after alpha and beta testing. During beta testing, some patients ignored the survival probabilities because they considered these too confronting. Nonetheless, patients agreed that every patient has the right to choose whether they want to view this information. Patients and clinicians believed that the PtDA would help patients make informed decisions, and that it would support values- and preferences-based decision-making. Implementation of the PtDA has started in October 2020. Conclusions The ‘Kidney Failure Decision Aid’ was designed to facilitate SDM in clinical practice and contains real-world outcome information on all kidney failure treatment modalities. It is currently being investigated for its effects on SDM in a clinical trial.

Background and study aims Pancreatoscopy-guided electrohydraulic lithotripsy (EHL) has proven to be an effective first-line therapy in symptomatic chronic pancreatitis (CP) patients with obstructing pancreatic duct (PD) stones 1. However, long-term outcomes of endoscopic EHL remain unknown. The aim of the present study was to evaluate the long-term treatment effects of EHL as first-line therapy and to compare with those obtained in a historical cohort of patients who underwent extracorporeal shockwave lithotripsy (ESWL) as primary treatment. Patients and methods An observational retrospective single-center long-term follow-up study was performed including 19 consecutive patients who previously underwent endoscopic EHL compared to 18 patients who underwent ESWL followed by endoscopic retrograde pancreatography (ERP). The primary endpoint was long-term treatment success after EHL or ESWL defined as no recurrence of symptomatic intraductal stones confirmed on imaging. Secondary endpoints for the EHL-population included long-term clinical success (i. e., a similar or lower Izbicki Pain Score or reduction in opiate usage as compared to 6-month follow-up), quality of life (QoL), pancreatic function and hospital re-admission rate. Results In the EHL group, 37 % of the patients developed recurrent symptomatic PD stones versus 61 % in the ESWL group after a median follow-up of 35.0 and 76.5 months. Of the patients with recurrence, 71 % versus 100 % underwent a reintervention. Median time to recurrence was 12.0 versus 13.0 months. Clinical success sustained in 58 % of the EHL patients. QoL was not significantly different compared with 6-month follow-up and baseline. Conclusions Also at long-term follow-up, endoscopic EHL as first-line treatment is moderately effective for symptomatic CP patients with treatment success rates that seems at least equally effective as ESWL.

Children with autistic symptoms experience challenges in school settings, yet little is known about their academic profiles and the mechanisms underlying the association between autistic symptoms and academic achievement. This study examined the association between autistic symptoms and academic achievement in a population-based sample of children with and without (sub)clinical autism spectrum disorder (ASD). We also investigated potential sex differences and assessed if the association is mediated by vocabulary skills and behavior problems. Information was available for 2038 participants (48.3% boys), and autistic symptoms were assessed using the Social Responsiveness Scale (M = 6.8 years). Diagnosis of ASD was clinically confirmed in 28 children. Academic achievement was determined by a nationwide, standardized test assessed at the end of primary school (M = 11.8 years). Children with more autistic symptoms in early childhood had lower achievement scores in language, mathematics, and world orientation by the end of primary education. There were no sex differences. Furthermore, vocabulary skills and behavior problems partly mediated the association between autistic symptoms and academic achievement. Then, by using propensity matching technique, we compared 140 matched typically developing peers with 28 children diagnosed with ASD. These results indicated no differences in academic achievement between children diagnosed with ASD and their matched typically developing peers. We conclude that autistic symptoms associate with lower academic achievement but by carefully matching on background variables and potential confounders, the academic achievement of children with clinical ASD might not differ from that of their typically developing peers.

BackgroundFifth metatarsal fractures are one of the most common foot fractures, and 11% to 25% of such fractures are Dancer’s fractures (distal spiral fractures). Conservative therapy while wearing a cast and operative treatment have been used as preferred modes of treatment in the limited literature available. However, we often see healing problems, such as delayed union and nonunion, when Dancer’s fractures are treated nonoperatively, resulting in a need for secondary intervention. In our institution, treatment has changed over the years from predominantly conservative treatment to mostly operative treatment. To investigate whether our hypothesis holds true that primary surgical treatment is beneficial, a retrospective study was designed. ObjectiveThe objective of the study is to compare differences between outcomes (delayed union and nonunion) of conservative and operative treatments for Dancer’s fractures. MethodsA retrospective comparative cohort study will be conducted in a level II trauma center (Zaandam Medical Center). Patients who experienced a Dancer’s fracture in the period of 2012 to 2021 will be included and divided into 2 cohorts—the conservative (2012-2015) and operative (2016-2021) treatment cohorts. The primary outcome will be the differences in percentages of delayed union and nonunion between the two groups. The secondary outcomes will be the percentage of primary conservative treatment failure, the need for secondary operative treatment, complications (infection and hardware failure), and functional outcomes. If 118 patients are included in each group, sufficient power is expected to be reached, depending on the age distribution of patients. The percentages of delayed union and nonunion among the two groups will be calculated and statistically compared via chi-square statistics. A logistic regression analysis will be used to investigate possible associations between patient characteristics and failed conservative treatment. A Mann-Whitney U test will be used to compare functional outcomes between groups. An independent, 2-tailed t test will be used to compare mean 12-Item Short Form Survey scores if they are normally distributed, and a Wilcoxon rank sum test will be used if they are nonnormally distributed. ResultsIn total, 2134 potentially relevant health insurance codes have been extracted from the hospital’s register. We expect to find a total of 236 Dancer’s fractures in this data set. ConclusionsOur study has limitations due to it being a single-center study and data collection being performed retrospectively. However, it covers a large time period and may provide the possibility to show treatment outcome differences (delayed union and nonunion, complications, and functional outcomes) in 2 reasonably large cohorts (conservative and operative treatment cohorts), which has not been done before in literature on Dancer’s fractures. If our hypothesis that surgery is beneficial for Dancer’s fractures is proven true by our study, we plan to further corroborate it by conducting a prospective randomized controlled trial. International Registered Report Identifier (IRRID)PRR1-10.2196/37171

Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects.

This article presents an immediate evaluation of a professional development course in community health literacy for Brazilian nurses. An evaluation based on an applied thematic analysis of the accounts of 63 attendees in three Brazilian cities (January 2020) was guided by the following themes: (a) expansion of understanding about community health literacy as a pillar for planning and providing health care; (b) encouragement of innovation in research and/or practice; and (c) plans to incorporate the information shared in the course into professional projects. The evaluation disclosed the complexity of social contexts for health literacy, which is intertwined with ethnocultural diversity and deep socioeconomic disparities, such as restricted access to essential public health services for socially deprived and vulnerable individuals. Expanded understanding about community health literacy is a pillar for care planning and delivery, as well as innovation in research and practice projects. Participants' evaluations revealed ideas to improve nurses' practice in promoting community health literacy and empowerment, as well as quality of life and social well-being. Future knowledge dissemination may impact nurses' clinical practice and management actions, bringing changes in various areas of practice to redesign more socially inclusive actions for clientele.

Safeguarding personal digital data is crucial and requires appropriate training. However, privacy remains a novel topic, leaving teachers with limited guidance. This study investigates how elementary school students perceive personal data and assesses pre-service teachers' accuracy in predicting children's responses. Employing Nissenbaum's contextual integrity framework, the outcomes of this research offer a nuanced perspective on privacy, considering different recipients and data types. The study surveyed 94 Grade 3 and Grade 5 students, asking them to indicate with which recipients (no one, parents, best friends, class, all other people) they would share specific information. In addition, 75 pre-service teachers were asked to indicate what they expected Grade 5 children would share with whom. The findings show: 1. what information Grade 3 and Grade 5 students consider to be most private, 2. which recipients they trust the most, 3. varying sharing practices between Grade 3 and 5, and 4. a tendency for pre-service teachers to underestimate children's privacy sharing behavior. In the discussion section we propose five recommendations for enhancing digital privacy education.

The fluorescent glutamate indicator iGluSnFR enables imaging of neurotransmission with genetic and molecular specificity. However, existing iGluSnFR variants exhibit low in vivo signal-to-noise ratios, saturating activation kinetics and exclusion from postsynaptic densities. Using a multiassay screen in bacteria, soluble protein and cultured neurons, we generated variants with improved signal-to-noise ratios and kinetics. We developed surface display constructs that improve iGluSnFR's nanoscopic localization to postsynapses. The resulting indicator iGluSnFR3 exhibits rapid nonsaturating activation kinetics and reports synaptic glutamate release with decreased saturation and increased specificity versus extrasynaptic signals in cultured neurons. Simultaneous imaging and electrophysiology at individual boutons in mouse visual cortex showed that iGluSnFR3 transients report single action potentials with high specificity. In vibrissal sensory cortex layer 4, we used iGluSnFR3 to characterize distinct patterns of touch-evoked feedforward input from thalamocortical boutons and both feedforward and recurrent input onto L4 cortical neuron dendritic spines.