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Brugada syndrome (BrS) is an inheritable cardiac arrhythmogenic disease, associated with an increased risk of sudden cardiac death. It is most common in males around the age of 40 and the prevalence is higher in Asia than in Europe and the United States. The pathophysiology underlying BrS is not completely understood, but several hypotheses have been proposed. So far, the best effective treatment is the implantation of an implantable cardioverter-defibrillator (ICD), but device-related complications are not uncommon. Therefore, there is an urgent need to improve diagnosis and risk stratification and to find new treatment options. To this end, research should further elucidate the genetic basis and pathophysiological mechanisms of BrS. Several experimental models are being used to gain insight into these aspects. The zebrafish (Danio rerio) is a widely used animal model for the study of cardiac arrhythmias, as its cardiac electrophysiology shows interesting similarities to humans. However, zebrafish have only been used in a limited number of studies on BrS, and the potential role of zebrafish in studying the mechanisms of BrS has not been reviewed. Therefore, the present review aims to evaluate zebrafish as an animal model for BrS. We conclude that zebrafish can be considered as a valuable experimental model for BrS research, not only for gene editing technologies, but also for screening potential BrS drugs. [ABSTRACT FROM AUTHOR]

Background: Psychotherapy is constituted through language. Due to voluntary migration or forced mobility, many people do not have access to therapy in their first language (L1). How multilingual clients manage their languages in therapy is an issue many therapists need to address in their practice. Psychotherapy is about trauma, emotions and identity, and when a multilingual client chooses a particular language, it may influence their emotional expression, cause a cultural misunderstanding, and a distorted presentation of who they are. Aims: In this study, we investigated how clients perceive psychotherapy in a foreign language (LX). We also aimed to provide psychotherapists with more insights into the effect of language choices on the course and outcome of therapy. Methods: We conducted 30 semi‐structured interviews with multilingual clients who had experience with therapy in LX. The data were analysed using thematic analysis. Findings: The data revealed that there is not one correlation between language and emotion, and that different backgrounds may lead to different preferences for the language of therapy; for some, LX may be preferred because it provides emotional distance necessary for discussing past trauma; for others, LX feels inadequate for expressing themselves fully. Conclusions: Our data suggest that there is a need for multilingual psychotherapists to learn more about their clients' linguistic and cultural profiles and how they play a role in emotion communication to facilitate a smoother therapeutic process and a more beneficial outcome. [ABSTRACT FROM AUTHOR]

A sodium current (INa) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on INa in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on INa and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak INa of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Nav1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak INa density, or the INa voltage dependence of (in)activation. Importantly, the increase in the peak INa density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases INa density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore INa and cardiac conduction. [ABSTRACT FROM AUTHOR]

Background: Clinical and experimental data on the cardiac effects of acute hypernatremia are scarce and inconsistent. We aimed to determine and understand the effects of different levels of acute hypernatremia on the human ventricular action potential. Methods: We performed computer simulations using two different, very comprehensive models of the electrical activity of a single human ventricular cardiomyocyte, i.e., the Tomek-Rodriguez model following the O'Hara-Rudy dynamic (ORd) model and the Bartolucci-Passini-Severi model as published in 2020 (known as the ToR-ORd and BPS2020 models, respectively). Mild to extreme levels of hypernatremia were introduced into each model based on experimental data on the effects of hypernatremia on cell volume and individual ion currents. Results: In both models, we observed an increase in the intracellular sodium and potassium concentrations, an increase in the peak amplitude of the intracellular calcium concentration, a hyperpolarization of the resting membrane potential, a prolongation of the action potential, an increase in the maximum upstroke velocity, and an increase in the threshold stimulus current at all levels of hypernatremia and all stimulus rates tested. The magnitude of all of these effects was relatively small in the case of mild to severe hypernatremia but substantial in the case of extreme hypernatremia. The effects on the action potential were related to an increase in the sodium-potassium pump current, an increase in the sodium-calcium exchange current, a decrease in the rapid and slow delayed rectifier potassium currents, and an increase in the fast and late sodium currents. Conclusions: The effects of mild to severe hypernatremia on the electrical activity of human ventricular cardiomyocytes are relatively small. In the case of extreme hypernatremia, the effects are more pronounced, especially regarding the increase in threshold stimulus current. [ABSTRACT FROM AUTHOR]

Background: In patients without a family history, Duchenne muscular dystrophy (DMD) is typically diagnosed at around 4–5 years of age. It is important to diagnose DMD during infancy or toddler stage in order to have timely access to treatment, opportunities for reproductive options, prevention of potential fatal reactions to inhaled anesthetics, awareness of a child's abilities needed for good parenting, and opportunities for enrolment in clinical trials. Method: We aimed to develop a short risk assessment tool based on developmental milestones that may contribute to the early detection of boys with DMD in primary care. As part of the case-control 4D-DMD study (Detection by Developmental Delay in Dutch boys with DMD), data on developmental milestones, symptoms and therapies for 76 boys with DMD and 12,414 boys from a control group were extracted from the health records of youth health care services and questionnaires. Multiple imputation, diagnostic validity and pooled backward logistic regression analyses with DMD (yes/no) as the dependent variable and attainment of 26 milestones until 36 months of age (yes/no) as the independent variable were performed. Descriptive statistics on symptoms and therapies were provided. Results: A tool with seven milestones assessed at specific ages between 12 and 36 months resulted in a sensitivity of 79% (95CI:67–88%), a specificity of 95.8% (95%CI:95.3–96.2), and a positive predictive value of 1:268 boys. Boys with DMD often had symptoms (e.g. 43% had calf muscle pseudohypertrophy) and were referred to therapy (e.g. 59% for physical therapy) before diagnosis. Discussion: This tool followed by the examination of other DMD-related symptoms could be used by youth health care professionals during day-to-day health assessments in the general population to flag children who require further action. Conclusions: The majority of boys (79%) with DMD can be identified between 12 and 36 months of age with this tool. It increases the initial a priori risk of DMD from 1 in 5,000 to approximately 1 in 268 boys. We expect that other neuromuscular disorders and disabilities can also be found with this tool. [ABSTRACT FROM AUTHOR]

Adhesive tape is a common piece of evidence that can contain a myriad of traces. Due to its adhesive properties, adhesive tape can potentially collect traces unrelated to the crime or relocate crime-relevant traces. This secondary transfer of traces can have crucial implications for the evaluation at the activity level. Therefore, this study investigated the secondary transfer of DNA between layers of adhesive tape and tape and other case- and laboratory-relevant substrates. A drop of diluted blood was deposited on different primary substrates (i.e. duct tape, metal, plastic, textile, nitrile gloves). Subsequently, the primary substrate was brought into contact with a secondary substrate, and DNA was collected from both surfaces to measure transfer rates. The highest transfer rates were detected between the adhesive side of the tape and plastic, whereas the lowest transfer rates were detected between the adhesive side and textile. It was shown that the adhesive readily collects DNA from plastic and nitrile gloves commonly used in the laboratory, which highlights the importance of working with DNA-free materials. Therefore, this study demonstrated the need for caution when interpreting traces on adhesive tapes, always taking possible situations of secondary transfer into account. [ABSTRACT FROM AUTHOR]

Despite major implications for forensic casework, limited research has been done on investigating secondary transfer of latent fingermarks. Adhesive tapes, such as duct tape, can potentially lift latent fingermarks from other surfaces due to their adhesive properties. This study aimed to investigate the possible secondary transfer between layers of adhesive tape and tape and other substrates (metal and plastic). Fingermarks were directly placed onto a primary substrate and subsequently brought into contact with a secondary substrate for varying duration. After visualization, the quality of the fingermarks was assessed to measure their loss and transfer. It was shown that fresh latent fingermarks can transfer between layers of adhesive tape, with instances of sufficient quality for comparison of the transferred fingermarks. In contrast, no transfer was detected after one week. However, a substantial loss of quality of the initially deposited fingermark was observed, suggesting an influence of time. Overall, it was shown that secondary transfer is possible and that caution has to be taken when analysing and interpreting latent fingermarks on adhesive tapes. [ABSTRACT FROM AUTHOR]

Adhesive tape is a common piece of evidence that can contain a myriad of traces. Due to its adhesive properties, adhesive tape can potentially collect traces unrelated to the crime or relocate crime-relevant traces. This secondary transfer of traces can have crucial implications for the evaluation at the activity level. Therefore, this study investigated the secondary transfer of DNA between layers of adhesive tape and tape and other case- and laboratory-relevant substrates. A drop of diluted blood was deposited on different primary substrates (i.e. duct tape, metal, plastic, textile, nitrile gloves). Subsequently, the primary substrate was brought into contact with a secondary substrate, and DNA was collected from both surfaces to measure transfer rates. The highest transfer rates were detected between the adhesive side of the tape and plastic, whereas the lowest transfer rates were detected between the adhesive side and textile. It was shown that the adhesive readily collects DNA from plastic and nitrile gloves commonly used in the laboratory, which highlights the importance of working with DNA-free materials. Therefore, this study demonstrated the need for caution when interpreting traces on adhesive tapes, always taking possible situations of secondary transfer into account. [ABSTRACT FROM AUTHOR]

Despite major implications for forensic casework, limited research has been done on investigating secondary transfer of latent fingermarks. Adhesive tapes, such as duct tape, can potentially lift latent fingermarks from other surfaces due to their adhesive properties. This study aimed to investigate the possible secondary transfer between layers of adhesive tape and tape and other substrates (metal and plastic). Fingermarks were directly placed onto a primary substrate and subsequently brought into contact with a secondary substrate for varying duration. After visualization, the quality of the fingermarks was assessed to measure their loss and transfer. It was shown that fresh latent fingermarks can transfer between layers of adhesive tape, with instances of sufficient quality for comparison of the transferred fingermarks. In contrast, no transfer was detected after one week. However, a substantial loss of quality of the initially deposited fingermark was observed, suggesting an influence of time. Overall, it was shown that secondary transfer is possible and that caution has to be taken when analysing and interpreting latent fingermarks on adhesive tapes. [ABSTRACT FROM AUTHOR]

An editorial focuses on the challenges and advancements in quantitative lexical typology, specifically examining how word meanings evolve over time using large-scale data. It explores various approaches to semantic change, including colexification patterns, partial colexifications, and semantic maps, through both conceptual analysis and empirical research.

In transitioning to a carbon‐neutral chemical industry, the intake of fossil feedstocks will have to be reduced by maximizing end‐of‐life product recycling and introducing alternative feedstocks based on renewable carbon. This perspective article analyses the potential of domestically grown and sourced woody biomass for the supply of renewable carbon for chemicals in Europe. The European chemical industry can become a major consumer of woody biomass in a context where burning wood for energy production is viewed as an unsustainable practice. [ABSTRACT FROM AUTHOR]

Climatic changes can cause unpredictability in flood regimes that traditional flood risk management (FRM) approaches may struggle with. Therefore, flood resilience is seen as a supplementation to these approaches, putting a larger emphasis on flood acceptance and minimising consequences. An (emergent) group contributing towards flood resilience is civil society. This paper examines how civil society contributions can be furthered and guided in the Netherlands as well as exploring potential limitations in doing so. To achieve this, England is used as a good practice example due to a more developed and defined role for civil society being present here. Data were collected on both actual (England and the Netherlands) and potential (The Netherlands) civil society contributions. These were compared to identify potential avenues for Dutch civil society contributions to flood resilience that can be further investigated. The research shows that the most promising avenues are improving advocacy from citizens, improving local flood awareness and developing relationships between FRM authorities and existing citizen groups that can be harnessed and mobilised to support flood resilience. Additionally, the research also provides insights into potential limitations for transferring resilience approaches from one context to another beyond the cases discussed in this publication. [ABSTRACT FROM AUTHOR]

γδ T cells are important components of the immune system due to their ability to elicit a fast and strong response against infected and transformed cells. Because they can specifically and effectively kill target cells in an MHC independent fashion, there is great interest to utilize these cells in anti-tumor therapies where antigen presentation may be hampered. Since only a small fraction of T cells in the blood or tumor tissue are γδ T cells, they require extensive expansion to allow for fundamental, preclinical and ex vivo research. Although expansion protocols can be successful, most are based on depletion of other cell types rather than γδ T cell specific isolation, resulting in unpredictable purity of the isolated fraction. Moreover, the primary focus only lies with expansion of Vd2+ T cells, while Vd1+ T cells likewise have anti-tumor potential. Here, we investigated whether γδ T cells directly isolated from blood could be efficiently expanded while maintaining function. γδ T cell subsets were isolated using MACS separation, followed by FACS sorting, yielding >99% pure γδ T cells. Isolated Vd1+ and Vd2+ T cells could effectively expand immediately after isolation or upon freeze/thawing and reached expansion ratios between 200 to 2000-fold starting from varying numbers using cytokine supported feeder stimulations. MACS/FACS isolated and PHA stimulated γδ T cells expanded as good as immobilized antibody mediated stimulated cells in PBMCs, but delivered purer cells. After expansion, potential effector functions of γδ T cells were demonstrated by IFN-g, TNF-a and granzyme B production upon PMA/ionomycin stimulation and effective killing capacity of multiple tumor cell lines was confirmed in killing assays. In conclusion, pure γδ T cells can productively be expanded while maintaining their anti-tumor effector functions against tumor cells. Moreover, γδ T cells could be expanded from low starting numbers suggesting that this protocol may even allow for expansion of cells extracted from tumor biopsies. [ABSTRACT FROM AUTHOR]

Aims Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation. Methods and results Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring an HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7 -R403Q) or cardiac troponin T (TNNT2 -R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance the relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin's effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed, electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current. Conclusion SGLT2i (canagliflozin > dapagliflozin > empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM. [ABSTRACT FROM AUTHOR]

This study provides insight into the total duration of litigation from the perspective of litigants. It examines commercial court cases with claims between 1 million and 5 million EUR in the Netherlands. It focuses on cases in which first instance judgments are appealed. In many of these cases other related procedures ensue. Using detailed data of the case administration system of the courts in the Netherlands, cases are followed as they wind their way through the court system. The results show that court statistics do not reflect the time taken for disposition from the litigant's perspective. A substantial number of high value cases are not concluded within a reasonable time and there is a wide spread of the time taken for disposition. For prospective litigants, it is not easy to predict the duration of litigation. The ensuing uncertainty makes it harder for them to assert their rights. [ABSTRACT FROM AUTHOR]

Human-induced stem cell-derived cardiomyocytes (hiPSC-CMs) are a valuable tool for studying development, pharmacology, and (inherited) arrhythmias. Unfortunately, hiPSC-CMs are depolarized and spontaneously active, even the working cardiomyocyte subtypes such as atrial- and ventricular-like hiPSC-CMs, in contrast to the situation in the atria and ventricles of adult human hearts. Great efforts have been made, using many different strategies, to generate more mature, quiescent hiPSC-CMs with more close-to-physiological resting membrane potentials, but despite promising results, it is still difficult to obtain hiPSC-CMs with such properties. The dynamic clamp technique allows to inject a current with characteristics of the inward rectifier potassium current (IK1), computed in real time according to the actual membrane potential, into patch-clamped hiPSC-CMs during action potential measurements. This results in quiescent hiPSC-CMs with a close-to-physiological resting membrane potential. As a result, action potential measurements can be performed with normal ion channel availability, which is particularly important for the physiological functioning of the cardiac SCN5A-encoded fast sodium current (INa). We performed in vitro and in silico experiments to assess the beneficial effects of the dynamic clamp technique in dissecting the functional consequences of the SCN5A-1795insD+/- mutation. In two separate sets of patch-clamp experiments on control hiPSC-CMs and on hiPSC-CMs with mutations in ACADVL and GNB5, we assessed the value of dynamic clamp in detecting delayed afterdepolarizations and in investigating factors that modulate the resting membrane potential. We conclude that the dynamic clamp technique has highly beneficial effects in all of the aforementioned settings and should be widely used in patch-clamp studies on hiPSC-CMs while waiting for the ultimate fully mature hiPSC-CMs. [ABSTRACT FROM AUTHOR]

Background: Choosing Wisely is an international movement that stimulates conversations about unnecessary care. The campaign created five recommendations including a statement that less wound care is sometimes better. Aims: The study aims to evaluate nurses' and physicians' adherence to the Choosing Wisely recommendations for acute wound care in the Netherlands and the barriers and facilitators to improve this. Design: This is a mixed methods study using a survey and interviews. Methods: The survey was completed by 171 nurses and 71 physicians from November 2017 to February 2018. A total of 17 nurses and 6 physicians were interviewed. Results: Awareness of the five recommendations ranged from 62% to 89% for nurses and 46% to 85% for physicians. However, up to 15% of the nurses and 28% of physicians were aware but did not adhere to the recommendations. Barriers to adhering were a lack of knowledge, the work environment and perceptions of patients' preferences. Repeated attention, cost‐consciousness and an open culture facilitated the implementation. Conclusion: Although most nurses and physicians were aware of the recommendations, not all adhered to them. Increasing awareness is not enough for successful implementation. A tailored approach that removes the barriers is necessary, such as increasing knowledge about wounds and changing the work environment. Summary statement: What is already known on this topic? Less wound care is sometimes better: cleaning wounds with tap water only, not bathing wounds, using simple bandages and not using bandages on wounds healing by primary intention leads to better wound care for lower costs.It is unknown to what extent this is known and practiced by nurses and physicians and what barriers and facilitators they experience in practicing this. What this paper adds? Although the majority of nurses and physicians were aware of the Choosing Wisely recommendations for acute wounds, not all adhered to them.Awareness is not always sufficient for successful implementation, which requires a broader approach that targets the barriers. The implications of this paper Implementation of these recommendations can be improved by increasing knowledge about wounds and wound care, changing the work environment, and verifying the patient's presumed preferences regarding wound care. [ABSTRACT FROM AUTHOR]

Aim: Responding to developmental delay promptly is important, as it helps children to reach their full potential. This study investigated how developmental milestones predicted primary school children with special educational needs and disabilities (SEND) at an early stage. Methods: We obtained data about 36 milestones between 12 and 45 months using the Dutch Development Instrument. Development, primary school classification and background characteristics were collected from the Dutch Preventive Child Healthcare system in Utrecht from 2008 to 2016. We investigated SEND classifications and the primary schools that the children attended at 4–12 years of age. The findings include area under the curve (AUC) data. Results: Data on 30 579 children in mainstream schools and 1055 children with SEND were available. Different milestones predicted SEND classifications. Fourteen milestones and parental education predicted attendance at special needs schools with smaller classes (AUC 0.913). Nine milestones, sex, migration background and parental education predicted attendance at schools for severe communication problems (AUC 0.963). Ten milestones and parental education predicted attendance at schools for severe learning difficulties (AUC 0.995). Milestones did not accurately predict attendance at schools for severe behavioural or psychiatric problems. Conclusion: Milestones at 12–45 months predicted most SEND classifications at primary school age, except severe behavioural or psychiatric problems. [ABSTRACT FROM AUTHOR]

Mutations in the KCNJ5 gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K+ (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K+ current (IK,ACh). hiPSC-CMs with the W101C KCNJ5 mutation (hiPSCW101C-CM) had a constitutively active IK,ACh under baseline conditions; the application of carbachol was able to increase IK,ACh, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSCW101C-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction. [ABSTRACT FROM AUTHOR]

Background: Evidence to support cryoprecipitate for reversal of alteplase-related hemorrhagic conversion of acute ischemic stroke is limited. Guidelines recommend cryoprecipitate as first line treatment, followed by aminocaproic acid as a conditional recommendation with very low-quality evidence. The purpose of this case series was to describe the use of cryoprecipitate for alteplase-related hemorrhagic conversion of acute ischemic stroke. Methods: This was an IRB-approved retrospective case series of adults who received cryoprecipitate for an alteplase-related hemorrhagic conversion of acute ischemic stroke at two comprehensive stroke centers within a large academic medical center. Thromboembolism at 14 days and hemostasis within 24 hours were collected. The outcomes of cryoprecipitate alone vs cryoprecipitate with aminocaproic acid (C + A) were also described. Results: A total of 19 patients were included. Thrombosis occurred in 1/19 (5%) and hemostasis occurred in 4/14 (29%) of evaluable patients. In-hospital mortality was seen in 9/19 (47%) patients. Seventy four percent (14/19) of patients received concomitant blood products other than cryoprecipitate and 63% received a concomitant reversal agent. Thirteen patients received cryoprecipitate alone and six received C + A. Thrombosis was seen in 1/13 (8%) vs 0/6 (0%) and hemostasis occurred in 2/11 (18%) and 2/3 (67%) evaluable cryoprecipitate vs C + A patients respectively. Conclusion: Cryoprecipitate was associated with a low rate of thrombosis and hemostasis for alteplase-associated hemorrhagic conversion of acute ischemic stroke. There was significant heterogeneity in treatment regimens, including the use of and dosing of adjunctive aminocaproic acid and monitoring of fibrinogen levels. [ABSTRACT FROM AUTHOR]

Context: Kenny--Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish. Objective: The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders. Methods: We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers. Results: Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common. Conclusion: Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features. [ABSTRACT FROM AUTHOR]

This review aimed at presenting the findings of 19 original studies that were published in the period from 2000 to 2022 in order to outline the current state of the art in the field of emotion communication (i.e., expressing and interpreting emotions) in multilingual psychotherapy. This analysis involves in particular the studies that investigate multilingual phenomena (e.g., code‐switching and language‐mixing) that occur during psychotherapeutic sessions when client and therapist can speak more than one language, as well as the articles that research emotion communication in this multilingual setting. With this in mind, the articles selected for this review are divided into two main categories: linguistic phenomena in multilingual psychotherapy and emotion communication in multilingual psychotherapy. Results of the studies in the current analysis reveal that code‐switching remains one of the main linguistic phenomena that arises in the area of multilingual psychotherapy. Switching languages in therapy tends to be considered as beneficial for both client and therapist. Besides, findings suggest a connection between speaking L1/LX and one's identity (e.g., feeling different depending on the language). Additionally, studies that investigate emotion communication in multilingual psychotherapy show that an individual's first language (L1) is predominantly viewed as more emotionally charged than their language(s) learned later in life (LX). However, some studies also demonstrate that the relationship between L1 and LX is more fluid and context‐dependent than it has traditionally been regarded. Propositions are given for future research in the field of emotion communication in multilingual psychotherapy. [ABSTRACT FROM AUTHOR]

Patients carrying the heterozygous A414G mutation in the HCN4 gene, which encodes the HCN4 protein, demonstrate moderate to severe bradycardia of the heart. Tetramers of HCN4 subunits compose the ion channels in the sinus node that carry the hyperpolarization-activated ‘funny’ current (If ), also named the ‘pacemaker current’. If plays an essential modulating role in sinus node pacemaker activity. To assess the mechanism by which the A414G mutation results in sinus bradycardia, we first performed voltage clamp measurements on wild-type (WT) and heterozygous mutant HCN4 channels expressed in Chinese hamster ovary (CHO) cells. These experiments were performed at physiological temperature using the amphotericin-perforated patch-clamp technique. Next, we applied the experimentally observed mutation-induced changes in the HCN4 current of the CHO cells to If of the single human sinus node cell model developed by Fabbri and coworkers. The half-maximal activation voltage V1/2 of the heterozygous mutant HCN4 current was 19.9 mV more negative than that of the WT HCN4 current (p < 0.001). In addition, the voltage dependence of the heterozygous mutant HCN4 current (de)activation time constant showed a −11.9 mV shift (p < 0.001) compared to the WT HCN4 current. The fully-activated current density, the slope factor of the activation curve, and the reversal potential were not significantly affected by the heterozygous A414G mutation. In the human sinus node computer model, the cycle length was substantially increased, almost entirely due to the shift in the voltage dependence of steady-state activation, and this increase was more prominent under vagal tone. The introduction of a passive atrial load into the model sinus node cell further reduced the beating rate, demonstrating that the bradycardia of the sinus node was even more pronounced by interactions between the sinus node and atria. In conclusion, the experimentally identified A414G-induced changes in If can explain the clinically observed sinus bradycardia in patients carrying the A414G HCN4 gene mutation. [ABSTRACT FROM AUTHOR]

These days, in vitro functional analysis of gene variants is becoming increasingly important for risk stratification of cardiac ion channelopathies. So far, such risk stratification has been applied to SCN5A, KCNQ1, and KCNH2 gene variants associated with Brugada syndrome and long QT syndrome types 1 and 2, respectively, but risk stratification of HCN4 gene variants related to sick sinus syndrome has not yet been performed. HCN4 is the gene responsible for the hyperpolarization-activated 'funny' current If, which is an important modulator of the spontaneous diastolic depolarization underlying the sinus node pacemaker activity. In the present study, we carried out a risk classification assay on those loss-of-function mutations in HCN4 for which in vivo as well as in vitro data have been published. We used the in vitro data to compute the charge carried by If (Qf) during the diastolic depolarization phase of a prerecorded human sinus node action potential waveform and assessed the extent to which this Qf predicts (1) the beating rate of the comprehensive Fabbri–Severi model of a human sinus node cell with mutation-induced changes in If and (2) the heart rate observed in patients carrying the associated mutation in HCN4. The beating rate of the model cell showed a very strong correlation with Qf from the simulated action potential clamp experiments (R2 = 0.95 under vagal tone). The clinically observed minimum or resting heart rates showed a strong correlation with Qf (R2 = 0.73 and R2 = 0.71, respectively). While a translational perspective remains to be seen, we conclude that action potential clamp on transfected cells, without the need for further voltage clamp experiments and data analysis to determine individual biophysical parameters of If, is a promising tool for risk stratification of sinus bradycardia due to loss-of-function mutations in HCN4. In combination with an If blocker, this tool may also prove useful when applied to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) obtained from mutation carriers and non-carriers. [ABSTRACT FROM AUTHOR]

Aims Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we aim to establish whether tramadol, fentanyl, or codeine affects Nav1.5 current. Methods and results Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. In fully available Nav1.5 channels (holding potential −120 mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33.2 µ m. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Nav1.5 channels: during partial fast inactivation (close-to-physiological holding potential −90 mV), IC50 of Nav1.5 block was 4.5 ± 1.1 μ m , while it was 16 ± 4.8 μ m during partial slow inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations. Conclusion Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current. [ABSTRACT FROM AUTHOR]

Background: Low-value care is healthcare leading to no or little clinical benefit for the patient. The best (combinations of) interventions to reduce low-value care are unclear. Purpose: To provide an overview of randomized controlled trials (RCTs) evaluating deimplementation strategies, to quantify the effectiveness and describe different combinations of strategies. Methods: Analysis of 121 RCTs (1990-2019) evaluating a strategy to reduce low-value care, identified by a systematic review. Deimplementation strategies were described and associations between strategy characteristics and effectiveness explored. Results: Of 109 trials comparing deimplementation to usual care, 75 (69%) reported a significant reduction of low-value healthcare practices. Seventy-three trials included in a quantitative analysis showed a median relative reduction of 17% (IQR 7%-42%). The effectiveness of deimplementation strategies was not associated with the number and types of interventions applied. Conclusions and Implications: Most deimplementation strategies achieved a considerable reduction of low-value care. We found no signs that a particular type or number of interventions works best for deimplementation. Future deimplementation studies should map relevant contextual factors, such as the workplace culture or economic factors. Interventions should be tailored to these factors and provide details regarding sustainability of the effect. [ABSTRACT FROM AUTHOR]

Citrus juice is widely consumed due to its high nutritional values, desirable taste, and color. The juice color is the key indicator for quality attributes affecting the consumer's attention. Conventional thermal treatment is the common method in juice processing which adversely affects its nutritional value and appearance. Measuring the color properties of the juice is an intelligent way to control the juice quality and estimating the alteration in chemicals. In this study, the effects of different treatments on the color aspects of citrus juice including L*, a* & b* values, browning index, total color difference, chroma, and hue index were reviewed. New thermal methods such as microwave, ohmic heating, and infrared radiation are used which result in the shortened process come up time (CUT). In addition, non-thermal treatments such as pulsed electric fields, high-pressure processing, high-pressure carbon dioxide, sonication, and ultraviolet are applied to process the juice, which results in better preservation of the nutritional values. These methods are less effective in the inactivation of the enzymes playing a key role in the juices stability. Therefore, a combination of thermal and non-thermal methods is suggested to increase the effectiveness of the process as well as preserving the juice quality. [ABSTRACT FROM AUTHOR]

This article argues for a gradient approach to word order, which treats word order preferences, both within and across languages, as a continuous variable. Word order variability should be regarded as a basic assumption, rather than as something exceptional. Although this approach follows naturally from the emergentist usage-based view of language, we argue that it can be beneficial for all frameworks and linguistic domains, including language acquisition, processing, typology, language contact, language evolution and change, and formal approaches. Gradient approaches have been very fruitful in some domains, such as language processing, but their potential is not fully realized yet. This may be due to practical reasons. We discuss the most pressing methodological challenges in corpus-based and experimental research of word order and propose some practical solutions. [ABSTRACT FROM AUTHOR]

New networks of public and private parties co-produce urban climate adaptation measures, for which different viewpoints and interests have to be bridged. While previous research has focused on individuals and organizations as intermediaries, little attention has been paid to boundary objects: conceptual or material objects that help to bridge competing values. This article aims to understand how local climate adaptation networks co-develop boundary objects and how they benefit the development of adaptation measures by conducting a qualitative case study comparison of two front-running Dutch networks: Amsterdam Rainproof and Water Sensitive Rotterdam. The conceptualization of a "water-sensitive city" attracted multiple stakeholders (professionals from different disciplines, communities, businesses), while material objects, such as interactive 3 D-models, addressed information needs. The objects contributed to adaptation measures by convening stakeholders, translating viewpoints and initiating collaborations. The limited diversity in the networks suggests that, rather than enabling participatory decision-making, the networks are instrumentally used by water authorities. [ABSTRACT FROM AUTHOR]

Atypical femur fractures (AFFs), considered rare associations of bisphosphonates, have also been reported in patients with monogenic bone disorders without bisphosphonate use. The exact association between AFFs and monogenic bone disorders remains unknown. Our aim was to determine the prevalence of monogenic bone disorders in a Dutch AFF cohort. AFF patients were recruited from two specialist bone centers in the Netherlands. Medical records of the AFF patients were reviewed for clinical features of monogenic bone disorders. Genetic variants identified by whole-exome sequencing in 37 candidate genes involved in monogenic bone disorders were classified based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines. Copy number variations overlapping the candidate genes were also evaluated using DNA array genotyping data. The cohort comprises 60 AFF patients (including a pair of siblings), with 95% having received bisphosphonates. Fifteen AFF patients (25%) had clinical features of monogenic bone disorders. Eight of them (54%), including the pair of siblings, had a (likely) pathogenic variant in either PLS3, COL1A2, LRP5, or ALPL. One patient carried a likely pathogenic variant in TCIRG1 among patients not suspected of monogenic bone disorders (2%). In total, nine patients in this AFF cohort (15%) had a (likely) pathogenic variant. In one patient, we identified a 12.7 Mb deletion in chromosome 6, encompassing TENT5A. The findings indicate a strong relationship between AFFs and monogenic bone disorders, particularly osteogenesis imperfecta and hypophosphatasia, but mainly in individuals with symptoms of these disorders. The high yield of (likely) pathogenic variants in AFF patients with a clinical suspicion of these disorders stresses the importance of careful clinical evaluation of AFF patients. Although the relevance of bisphosphonate use in this relationship is currently unclear, clinicians should consider these findings in medical management of these patients. [ABSTRACT FROM AUTHOR]

Aims SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such as SCN5A -1795insD, lead to an overlap syndrome, with patients exhibiting both features of BrS/CCD [decreased sodium current (I Na)] and LQT3 (increased late I Na). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late I Na and chronically increase peak I Na associated with SCN5A loss-of-function mutations. However, most studies have so far employed heterologous expression systems and high mexiletine concentrations. We here investigated the effects of a therapeutic dose of mexiletine on the mixed phenotype associated with the SCN5A -1795insD mutation in HEK293A cells and human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). Methods and results To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A -1795insD were incubated for 48 h with 10 µ m mexiletine followed by wash-out, which resulted in an increased peak I Na for both SCN5A -WT and SCN5A -1795insD and an increased late I Na for SCN5A -1795insD. Acute re-exposure of HEK293A cells to 10 µ m mexiletine did not impact on peak I Na but significantly decreased SCN5A -1795insD late I Na. Chronic incubation of SCN5A -1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak I Na, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak I Na or AP upstroke velocity, but significantly decreased AP duration. Conclusion These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome. [ABSTRACT FROM AUTHOR]

In the concluding contribution to the special issue, "Inclining Mimesis", Adriana Cavarero and Nidesh Lawtoo continue the dialogue on mimetic inclinations in view of furthering a relational, embodied, and affective conception of subjectivity that challenges homo erectus from the immanent perspective of homo mimeticus. For more information, see http://www.homomimeticus.eu and http://www.genderedmimesis.com 9 For a feminist rewriting of the stereotypical relational posture of the caring mother, see Cavarero, Inclinations, 135-168; for the centrality of maternal communication in the formation of the mimetic subject, see also Lawtoo, Homo Mimeticus, 63-4, 112-6, 10 Cavarero and Lawtoo, "Mimetic Inclinations". Referencing Cavarero's and Lawoo's dialogue around mimetic inclinations, Timár frames Cavarero's notion of relationality as an "in-betweenness" in which there is an "(at)tending to the other". To preserve a continuity in form that is adequate to the subject matter at hand, briefly in the introduction and more at length in the conclusion to this special issue, Cavarero and Lawtoo will resume the dialogue to re-set the stage for a productive encounter between mimesis and inclinations. [Extracted from the article]

This paper takes Cavarero's arguments against the Homo erectus seriously and asks: how can we model an alternative to it? It proposes that a notion of the mimetically inclined subject is required, one that thickens Cavarero's affirmative account of inclination by way of a new philosophical understanding of mimesis that includes habit and disciplinarity. Following Cavarero, the mother is positioned as a key figure to place nurturing and love at the centre of subject-making. However, they are shown to be a necessary but not sufficient step for the process of re-evaluation. An account of disciplinary mimesis which draws on a Nietzschean legacy in Michel Foucault and Judith Butler, together with Simone de Beauvoir's account of woman as a situation, demonstrate the pitfalls of idealizing the mother. I argue that to challenge the particularized universalism of the European subject with an affirmative account of mimetic inclination, other figures which embrace Cavarero's notion of relational vulnerability alongside the mother are required. The agonistic friend who practices an open, feminist curiosity is proposed as one such exemplar and, in closing remarks, I gesture to other necessary models in feminist and Indigenous thought that are key to remaking the androcentric subject of European philosophy. [ABSTRACT FROM AUTHOR]

The pacemaker activity of the sinoatrial node (SAN) has been studied extensively in animal species but is virtually unexplored in humans. Here we assess the role of the slowly activating component of the delayed rectifier K+ current (IKs) in human SAN pacemaker activity and its dependence on heart rate and β-adrenergic stimulation. HEK-293 cells were transiently transfected with wild-type KCNQ1 and KCNE1 cDNA, encoding the α- and β-subunits of the IKs channel, respectively. KCNQ1/KCNE1 currents were recorded both during a traditional voltage clamp and during an action potential (AP) clamp with human SAN-like APs. Forskolin (10 µmol/L) was used to increase the intracellular cAMP level, thus mimicking β-adrenergic stimulation. The experimentally observed effects were evaluated in the Fabbri–Severi computer model of an isolated human SAN cell. Transfected HEK-293 cells displayed large IKs-like outward currents in response to depolarizing voltage clamp steps. Forskolin significantly increased the current density and significantly shifted the half-maximal activation voltage towards more negative potentials. Furthermore, forskolin significantly accelerated activation without affecting the rate of deactivation. During an AP clamp, the KCNQ1/KCNE1 current was substantial during the AP phase, but relatively small during diastolic depolarization. In the presence of forskolin, the KCNQ1/KCNE1 current during both the AP phase and diastolic depolarization increased, resulting in a clearly active KCNQ1/KCNE1 current during diastolic depolarization, particularly at shorter cycle lengths. Computer simulations demonstrated that IKs reduces the intrinsic beating rate through its slowing effect on diastolic depolarization at all levels of autonomic tone and that gain-of-function mutations in KCNQ1 may exert a marked bradycardic effect during vagal tone. In conclusion, IKs is active during human SAN pacemaker activity and has a strong dependence on heart rate and cAMP level, with a prominent role at all levels of autonomic tone. [ABSTRACT FROM AUTHOR]

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Copyright of Huisarts En Wetenschap is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with Brugada syndrome and long QT syndrome, albeit on the basis of conflicting findings. The cardiac voltage-gated sodium channel (NaV1.5) is related to both of these syndromes, suggesting that paroxetine may have an effect on this channel. In the present study, we therefore carried out patch clamp experiments to examine the effect of paroxetine on human NaV1.5 channels stably expressed in human embryonic kidney 293 (HEK-293) cells as well as on action potentials of isolated rabbit left ventricular cardiomyocytes. Additionally, computer simulations were conducted to test the functional effects of the experimentally observed paroxetine-induced changes in the NaV1.5 current. We found that paroxetine led to a decrease in peak NaV1.5 current in a concentration-dependent manner with an IC50 of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the NaV1.5 current as well as a significant increase in its rate of inactivation. Paroxetine (3 µM) affected the action potential of the left ventricular cardiomyocytes, significantly decreasing its maximum upstroke velocity and amplitude, both of which are mainly regulated by the NaV1.5 current. Our computer simulations demonstrated that paroxetine substantially reduces the fast sodium current of human left ventricular cardiomyocytes, thereby slowing conduction and reducing excitability in strands of cells, in particular if conduction and excitability are already inhibited by a loss-of-function mutation in the NaV1.5 encoding SCN5A gene. In conclusion, paroxetine acts as an inhibitor of NaV1.5 channels, which may enhance the effects of loss-of-function mutations in SCN5A. [ABSTRACT FROM AUTHOR]

Anti-epileptic drugs (AEDs) are associated with increased risk of sudden cardiac death. To establish whether gabapentin, lamotrigine, levetiracetam, pregabalin, and valproic acid reduce the Nav1.5 current, we conducted whole-cell patch-clamp studies to study the effects of the five AEDs on currents of human cardiac Nav1.5 channels stably expressed in HEK293 cells, and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. Lamotrigine and valproic acid exhibited inhibitory effects on the Nav1.5 current in a concentration-dependent manner with an IC50 of 142 ± 36 and 2022 ± 25 µM for lamotrigine and valproic acid, respectively. In addition, these drugs caused a hyperpolarizing shift of steady-state inactivation and a delay in recovery from inactivation. The changes on the Nav1.5 properties were reflected by a reduction in AP upstroke velocity (43.0 ± 6.8% (lamotrigine) and 23.7 ± 10.6% (valproic acid) at 1 Hz) and AP amplitude; in contrast, AP duration was not changed. Gabapentin, levetiracetam, and pregabalin had no effect on the Nav1.5 current. Lamotrigine and valproic acid reduce the Nav1.5 current density and affect its gating properties, resulting in a decrease of the AP upstroke velocity. Gabapentin, levetiracetam, and pregabalin have no effects on the Nav1.5 current. [ABSTRACT FROM AUTHOR]

The Canadian Occupational Performance Measure (COPM) can be used to support children to clarify their needs themselves. However, for pediatric occupational therapists it is not sufficiently clear how to effectively use the COPM with children from 8 years of age. This study aimed to formulate specific instructions for using the COPM with children themselves, based on the experience of children, parents, and occupational therapists. In addition, professional consensus on the instructions was reached. A multi-stage approach was used to develop the instructions. Triangulation of methods was used to gather knowledge of how the COPM with children themselves is performed in daily practice: interviews with 23 children, questionnaires completed by 30 parents, interviews with 13 therapists, and 10 video recordings of COPM administration. Specific instructions were derived from this knowledge and consensus for these instructions was reached by Delphi method. The data were analyzed and resulted in 40 specific instructions. Consensus of at least 80% amongst 10 occupational therapists, who regularly use the COPM with children, was achieved on each instruction. There is consensus on 40 specific instructions for administering the COPM with children. Following these instructions might help children to formulate their own goals for intervention. [ABSTRACT FROM AUTHOR]

Aims Human-induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs) are widely used to study arrhythmia-associated mutations in ion channels. Among these, the cardiac sodium channel SCN5A undergoes foetal-to-adult isoform switching around birth. Conventional hiPSC-CM cultures, which are phenotypically foetal, have thus far been unable to capture mutations in adult gene isoforms. Here, we investigated whether tri-cellular cross-talk in a three-dimensional (3D) cardiac microtissue (MT) promoted post-natal SCN5A maturation in hiPSC-CMs. Methods and results We derived patient hiPSC-CMs carrying compound mutations in the adult SCN5A exon 6B and exon 4. Electrophysiological properties of patient hiPSC-CMs in monolayer were not altered by the exon 6B mutation compared with isogenic controls since it is not expressed; further, CRISPR/Cas9-mediated excision of the foetal exon 6A did not promote adult SCN5A expression. However, when hiPSC-CMs were matured in 3D cardiac MTs, SCN5A underwent isoform switch and the functional consequences of the mutation located in exon 6B were revealed. Up-regulation of the splicing factor muscleblind-like protein 1 (MBNL1) drove SCN5A post-natal maturation in microtissues since its overexpression in hiPSC-CMs was sufficient to promote exon 6B inclusion, whilst knocking-out MBNL1 failed to foster isoform switch. Conclusions Our study shows that (i) the tri-cellular cardiac microtissues promote post-natal SCN5A isoform switch in hiPSC-CMs, (ii) adult splicing of SCN5A is driven by MBNL1 in these tissues, and (iii) this model can be used for examining post-natal cardiac arrhythmias due to mutations in the exon 6B. Translational perspective The cardiac sodium channel is essential for conducting the electrical impulse in the heart. Postnatal alternative splicing regulation causes mutual exclusive inclusion of fetal or adult exons of the corresponding gene, SCN5A. Typically, immature hiPSCCMs fall short in studying the effect of mutations located in the adult exon. We describe here that an innovative tri-cellular three-dimensional cardiac microtissue culture promotes hiPSC-CMs maturation through upregulation of MBNL1, thus revealing the effect of a pathogenic genetic variant located in the SCN5A adult exon. These results help advancing the use of hiPSC-CMs in studying adult heart disease and for developing personalized medicine applications. [ABSTRACT FROM AUTHOR]

Background: Pelvic pain has cognitive, behavioral, sexual, and emotional consequences. Nurses involved in pelvic floor rehabilitation clinics have contacts with patients reporting chronic pain and should know the most appropriate service for patient referral, to submit the problem to professionals capable of correctly assessing and managing the condition. Furthermore, in some countries nurses can use conservative methods to treat the painful symptoms inside a multidisciplinary team such as breathing retraining, biofeedback, and noninvasive neuromodulation. This paper aims to provide an overview of the literature regarding the role of rehabilitation nurses in dealing with patients suffering from chronic urogenital pelvic pain or urogenital painful syndromes, inside a multidisciplinary team. Methods: Scoping review on Pubmed, CINAHL, Embase, Scopus, Web of Science including trials, reviews, case studies or series, and other descriptive studies regarding the role of nurses inside the multidisciplinary team in the management of males and females presenting chronic pelvic pain (CPP) or chronic pelvic pain syndrome (CPPS). Results: The 36 papers included in this review allowed answering research questions in four areas of nursing: collecting basic information, referring the person to appropriate services, evidence‐based nursing interventions for CPP and CPPS, and proper documentation. Clinical history and assessment of breathing pattern, Muscular assessment and research of trigger points are the main points of data collection. Techniques for muscular relaxation and breathing retraining are important aspects of treatment, as well as biofeedback and noninvasive neuromodulation where the law allows nurses to practice such techniques. The McGill pain questionnaire and the pain inventory of the International Pain Society allow systematic data collection and handover. Conclusion: Rehabilitation nurses work inside multidisciplinary teams when dealing with persons suffering from pelvic pain; further research is needed as our comprehension of the underlying pathophysiological mechanisms of CPP and CPPS evolve. [ABSTRACT FROM AUTHOR]