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Rationale & Objective: Both hypo- and hyperkalemia can cause fatal cardiac arrhythmias. Although predialysis serum potassium level is a known modifiable risk factor for death in patients receiving hemodialysis, especially for hypokalemia, this risk may be underestimated. Therefore, we investigated the relationship between predialysis serum potassium level and death in incident hemodialysis patients and whether there is an optimum level. Study Design: Prospective multicenter cohort study. Setting & Participants: 1,117 incident hemodialysis patients (aged >18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis-2 study were included and followed from their first hemodialysis treatment until death, transplantation, switch to peritoneal dialysis, or a maximum of 10 years. Exposure: Predialysis serum potassium levels were obtained every 6 months and divided into 6 categories: ≤4.0 mmol/L, >4.0 mmol/L to ≤4.5 mmol/L, >4.5 mmol/L to ≤5.0 mmol/L, >5.0 mmol/L to ≤5.5 mmol/L (reference), >5.5 mmol/L to ≤6.0 mmol/L, and >6.0 mmol/L. Outcomes: 6-month all-cause mortality. Analytical Approach: Cox proportional hazards and restricted cubic spline analyses with time-dependent predialysis serum potassium levels were used to calculate the adjusted HRs for death. Results: At baseline, the mean age of the patients was 63 years (standard deviation, 14 years), 58% were men, 26% smoked, 24% had diabetes, 32% had cardiovascular disease, the mean serum potassium level was 5.0 mmol/L (standard deviation, 0.8 mmol/L), 7% had a low subjective global assessment score, and the median residual kidney function was 3.5 mL/min/1.73 m2 (IQR, 1.4-4.8 mL/min/1.73 m2). During the 10-year follow-up, 555 (50%) deaths were observed. Multivariable adjusted HRs for death according to the 6 potassium categories were as follows: 1.42 (95% CI, 1.01-1.99), 1.09 (95% CI, 0.82-1.45), 1.21 (95% CI, 0.94-1.56), 1 (reference), 0.95 (95% CI, 0.71-1.28), and 1.32 (95% CI, 0.97-1.81). Limitations: Shorter intervals between potassium measurements would have allowed for more precise mortality risk estimations. Conclusions: We found a U-shaped relationship between serum potassium level and death in incident hemodialysis patients. A low predialysis serum potassium level was associated with a 1.4-fold stronger risk of death than the optimal level of approximately 5.1 mmol/L. These results may imply the cautious use of potassium-lowering therapy and a potassium-restricted diet in patients receiving hemodialysis.

How teachers attend to and interpret positive relational interactions shapes how they enact instructional practices for equity. We draw on frameworks from equitable mathemat- ics instruction, relational interactions, and teacher noticing to conceptualize mathematics teachers’ relational noticing. Using noticing interview and classroom observation data from a research collaborative between secondary mathematics teachers and university-based teacher educators, we document the range and diversity of ten teachers’ relational noticing. We use this analysis to examine how teachers’ relational noticing supports enacting equi- table instructional practices. Our findings indicate five themes of teachers’ relational notic- ing that are informed by their personal histories, understanding of dominant narratives of mathematics education, and their local sociopolitical school context. Additionally, teachers enacted a range of practices for creating positive relational interactions, with attending to student thinking being the most enacted practice. Our findings suggest that mathematics teachers’ relational noticing can support the three axes of equitable instruction.

Abstract Prioritizing field practices according to their contribution to regenerative efforts, in a structured and standardized manner, can enable efficient resource allocation and higher adoption rates. However, it is remarkably hampered by the diversity of production environments and their respective best management practices. This paper proposes prioritizing regenerative practices using a multicriteria assessment method informed by expert knowledge. To develop it, we mined and synthesized knowledge from eleven experts for three diverse cropping systems, showing that the prioritization of practices varies greatly across production environments. By integrating the multicriteria approach with a multi-indicator sustainability framework, we demonstrate how practice weights can be used to monitor sustainability efforts and outcomes of thirty vineyard farms in Maharashtra, India. The suggested prioritization approach can be used to standardize the assessment of the importance of regenerative practices in different cropping systems and be adopted in sustainable sourcing schemes of the agro-food industry.

Beginning teachers are challenged to make concrete the identities they envision for themselves in their practice. We examine how a particular context, the noticing interview, supported a novice teacher's identity work through disciplined awareness to cultivate the inner witness. In a noticing interview, teachers view and discuss video segments from a classroom observation as a way to capture in-the-moment attention and sensemaking. Using the case of a beginning teacher, we found that creating accounts of instructional practice and accounts for instructional decisions helped her connect the dots between her vision of teaching, her personal and social identities, and her pedagogical commitments. These findings have implications for whether and how the noticing interview can become a generative context for teachers developing insights about themselves as noticers in practice and their emerging professional identities.

Abstract Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43 Tg -ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.

Summary: Isogenic disease models, such as genetically engineered organoids, provide insight into the impact of genetic variants on organ function. Here, we present a protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools. We describe steps for single guide RNA (sgRNA) design and cloning, electroporation, and selecting electroporated cells. We then detail procedures for clonal line generation. Next-generation CRISPR tools do not require double-stranded break (DSB) induction for their function, thus simplifying in vitro disease model generation.For complete details on the use and execution of this protocol, please refer to Geurts et al.1,2 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background A recent study found that ethnic minority General Practice (GP)-trainees receive more negative assessments than their majority peers. Previous qualitative research suggested that learning climate-related factors play a pivotal role in unequal opportunities for trainees in post-graduate medical settings, indicating that insufficient inclusivity had put minority students at risk of failure and dropout. Study objectives We aimed to develop broadly supported strategies for an inclusive learning climate in Dutch GP-specialty training. Methods We employed Participatory Action Research (PAR)-methods, incorporating Participatory Learning and Action (PLA)-techniques to ensure equal voices for all stakeholders in shaping Diversity, Equity, and Inclusion (DEI)-strategies for GP-specialty training. Our approach engaged stakeholders within two pilot GP-specialty training institutes across diverse roles, including management, support staff, in-faculty teachers, in-clinic supervisors, and trainees, representing ethnic minorities and the majority population. Purposeful convenience sampling formed stakeholder- and co-reader groups in two Dutch GP-specialty training institutes. Stakeholder discussion sessions were based on experiences and literature, including two relevant frameworks, and explored perspectives on the dynamics of potential ethnic minority trainees’ disadvantages and opportunities for inclusive strategies. A co-reader group commented on discussion outcomes. Consequently, a management group prioritized suggested strategies based on expected feasibility and compatibility. Results Input from twelve stakeholder group sessions and thirteen co-readers led to implementation guidance for seven inclusive learning environment strategies, of which the management group prioritized three: • Provide DEI-relevant training programs to all GP-specialty training stakeholders; • Appoint DEI ambassadors in all layers of GP-specialty training; • Give a significant voice to minority GP-trainees in their education. Conclusion The study’s participatory approach engaged representatives of all GP-specialty training stakeholders and identified seven inclusive learning climate strategies, of which three were prioritized for implementation in two training institutions.

Background Preclinical animal studies have suggested that myeloid cell-synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran. Methods and findings This nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period. Conclusions In this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort., Author(s): Floris Bosch 1,2,3,*, Erzsébet Horváth-Puhó 4, Suzanne C. Cannegieter 5,6, Nick van Es 2,3, Henrik T. Sørensen 4 Introduction Cancer activates the hemostatic system, thereby promoting tumor growth and [...]

Seasonal variations directly impact the biochemical and microbial properties of the soil, influence carbon and nutrient cycling within the soil system. Soils under tree plantation (TP) are rich in organic matter and microbial population, making them more susceptible to seasonal variation. We studied the effect of seasonal variations in soil chemical properties (pH, electrical conductivity (EC), total organic carbon (TOC), total nitrogen (TN), C/N ratio etc) and microclimate (moisture and temperature) on microbial respiration (SR), biomass, and carbon (C) utilization efficiency under 13 years old Kadamb (Anthocephalus cadamba Miq.), Simaraubha (Simarouba glauca DC), and Litchi (Litchi chinensis Sonn.) based TPs in middle Gangetic region. In contrast to higher SR and metabolic quotient (qCO2) in winter, the microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN) in fall > summer > spring > winter, irrespective of TPs. The positive relationship between qCO2 and C/N ratios strongly supports the dependence of microbes on soil carbon for respiration. qCO2 had a significantly positive relationship with soil moisture (MC) and Electrical conductivity (EC), but a significantly negative relationship with temperature and pH. Higher MBN/TN and MBC/TOC ratios fall under simaraubha, and litchi-based TPs indicated more nitrogen (N) and carbon accumulation into microbial biomass. The seasonal variation of MBC/MBN ratios signifies the changes in microbial communities and fungi dominate over bacteria during winter, as bacteria have a lower C/N ratio than fungi. Stepwise regression analysis suggested that soil properties and micro-climate regulated microbial biomass and SR differ with TPs. Thus, the study indicates that microbial activities and biomass production can significantly influence by soil properties and seasonal variations under TPs.

Cardiovascular diseases (CVDs) are a global burden that requires attention. For the detection and diagnosis of CVDs, the 12-lead ECG is a key tool. With technological advancements, ECG devices are becoming smaller and available for home use. Most of these devices contain a limited number of leads and are aimed to detect atrial fibrillation (AF). To investigate whether a four-electrode arrangement could provide enough information to diagnose other CVDs, further research is necessary. At the University Medical Center Utrecht in a multidisciplinary team, we developed the miniECG, a four-electrode ECG handheld system for scientific research in clinical environments (TRL6). This paper describes the process followed during the development of the miniECG. From assembling a multidisciplinary team, which includes engineers, cardiologists, and clinical physicians to the contribution of team members in the design input, design, and testing for safety and functionality of the device. Finally, we detail how the development process was composed by iterative design steps based on user input and intended use evolution. The miniECG is a device compliant for scientific research with patients within Dutch Medical Centers. We believe that hospital-based development led to a streamlined process, which could be applied for the design and development of other technologies used for scientific research in clinical environments.

Introduction: Up to 50% of pulmonary embolism (PE) patients have perfusion defects or residual vascular obstruction during follow-up despite adequate anticoagulant treatment, and a similar percentage experience chronic functional limitations and/or dyspnoea post-PE. We aimed to evaluate the association between pulmonary perfusion defects or residual vascular obstruction and functional recovery after PE. Methods: We performed a systematic review and meta-analysis including studies assessing both the presence of perfusion defects or residual vascular obstruction and functional recovery (i.e. persistent symptoms, quality of life, exercise endurance). An odds ratio was pooled for perfusion defects or residual vascular obstruction and persistent symptoms using a random-effect model. Results: 12 studies were included totalling 1888 PE patients; at a median of 6 months after PE (range 2–72 months), 34% had perfusion defects or residual vascular obstruction and 37% reported persistent symptoms. Among patients with perfusion defects or residual vascular obstruction, 48% (95% CI 37–60%, I2=82%) remained symptomatic during follow-up, compared to 34% (95% CI 20–51%, I2=96%) of patients without such defects. Presence of perfusion defects or residual vascular obstruction was associated with persistent symptoms (OR 2.15, 95% CI 1.66–2.78; I2=0%, τ=0). Notably, there was no association between these defects and quality of life or cardiopulmonary exercise test parameters. Conclusion: While the odds of having persistent symptoms was higher in patients with perfusion defects or residual vascular obstruction after acute PE, a significant proportion of these patients reported no limitations. A possible causality between perfusion defects or residual vascular obstruction and residual functional limitation therefore remains to be proven.

Abstract Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is an enveloped DNA virus of the Baculoviridae family. This baculovirus is widely exploited for the biological control of insect pest species and as an expression platform to produce recombinant proteins in insect cells. Extracellular vesicles (EVs) are secreted by all cells and are involved in key roles in many biological processes through their cargo consisting of proteins, RNA or DNA. In viral infections, EVs have been found to transfer both viral and cellular cargo that can elicit either a pro‐ or antiviral response in recipient cells. Here, small EVs (sEVs) released by Spodoptera frugiperda (Sf) insect cells were characterised for the first time. Using S. frugiperda (SfC1B5) cells stably expressing the baculovirus gp64, the viral envelope protein GP64 was shown to be incorporated into sEVs. Sf9 cells were also transfected with a bacmid AcMNPV genome lacking p6.9 (AcΔP6.9) to prevent budded virus production. The protein content of sEVs from both mock‐ and AcΔP6.9‐transfected cells were analysed by mass spectrometry. In addition to GP64, viral proteins Ac‐F, ME‐53 and viral ubiquitin were identified, as well as many host proteins including TSG101—which may be useful as a protein marker for sEVs.

BackgroundPreclinical animal studies have suggested that myeloid cell-synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran.Methods and findingsThis nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period.ConclusionsIn this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort.

Current online adaptive radiotherapy (oART) workflows require dedicated equipment. Our aim was to develop and implement an oART workflow for a C-arm linac which can be performed using standard clinically available tools. A workflow was successfully developed and implemented. Three patients receiving palliative radiotherapy for bladder cancer were treated, with 33 of 35 total fractions being delivered with the cone-beam computed tomography (CBCT)-guided oART workflow. Average oART fraction duration was 24 min from start of CBCT acquisition to end of beam on. This work shows how oART could be performed without dedicated equipment, broadening oART availability for application at existing treatment machines.

Abstract Background Focal adhesion signaling involving receptor tyrosine kinases (RTK) and integrins co-controls cancer cell survival and therapy resistance. However, co-dependencies between these receptors and therapeutically exploitable vulnerabilities remain largely elusive in HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods The cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin was determined in up to 20 3D matrix-grown HNSCC cell models followed by drug screening and patient-derived organoid validation. RNA sequencing and protein-based biochemical assays were performed for molecular characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. Results Fibroblast growth factor receptor (FGFR 1–4) targeting exhibited the strongest cytotoxic and radiosensitizing effects as monotherapy and combined with β1 integrin inhibition, exceeding the efficacy of the other RTK studied. Pharmacological pan-FGFR inhibition elicited responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence analysis revealed a mesenchymal-to-epithelial transition (MET) in sensitive cell models, whereas resistant cell models exhibited a partial epithelial-to-mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid-dependently. Transferring the EMT-associated transcriptomic profiles to HNSCC patient cohorts not only demonstrated their prognostic value but also provided a conclusive validation of the presence of EGFR-related vulnerabilities that can be strategically exploited for therapeutic interventions. Conclusions This study demonstrates that pan-FGFR inhibition elicits a beneficial radiochemosensitizing and a detrimental radioprotective potential in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically.

Because of the COVID-19 pandemic, several health care services, including cardiac rehabilitation (CR), had to transition to virtual delivery, for which formal evaluations are lacking. In this pilot study, we investigated the implementation of a virtual CR program by surveying 30 patients attending virtual CR. Virtual CR was well received, although patients provided recommendations to improve delivery such as offering individual sessions and changing how education materials were delivered. Virtual delivery of CR likely has a role in health care, either independently or as part of a hybrid model; however, further evaluation is required. Résumé: En raison de la pandémie de COVID-19, plusieurs services de santé, comme la réadaptation cardiaque (RC), ont dû faire la transition vers le mode virtuel, pour lequel il manque d’évaluations formelles. Dans cette étude pilote, nous avons examiné la mise en œuvre d’un programme de RC virtuel en interrogeant 30 patients participant à un tel programme. La RC en mode virtuel a été accueillie favorablement, même si les patients ont formulé des recommandations pour en améliorer la prestation, comme offrir des séances individuelles et changer la façon dont le matériel éducatif est présenté. La prestation de la RC en mode virtuel a probablement un rôle à jouer dans les soins de santé, soit de manière indépendante, soit dans le cadre d’un modèle hybride; cependant, une évaluation plus poussée est requise.