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The management of acute distal tibiofibular syndesmotic injuries has evolved over time and therefore, the aim of this study was to evaluate the use of different methods and the changes regarding management of distal tibiofibular syndesmotic injury among Dutch trauma- and orthopedic surgeons. A digital survey based on a previous survey conducted in 2012 was sent to (orthopedic) trauma surgeons from all different hospitals in the Netherlands. Sixty out of the 68 invited hospitals completed at least one survey (88.2 %). For Weber B or low Weber C fractures, there was a preference for the use of a single syndesmotic screw (SS)(73.6 %), while two screws were mainly used in Maisonneuve fractures (89.3 %). Furthermore, there was a clear preference for 3.5-mm screws, engaging three cortices, 2 to 4-cm above the tibiotalar joint. There is a significant decrease in routine removal of SSs (23.2 % compared to 87.0 % in 2012, p < 0.01). The percentage of hospitals in this survey that used the suture button (SB) was relatively low: 8.3 % for low fibular fractures and 5.0 % in high fibular fractures. In conclusion, the most striking difference compared to 2012 is the large decline in routine removal of the SS, which is in line with current literature. The SS is mainly implanted engaging three cortices, placed 2-4 cm above the tibiotalar joint and 3.5 mm in size and for the treatment of Maisonneuve fractures, two screws are preferred over a single SS. LEVEL OF EVIDENCE: Level III., Competing Interests: Declarations of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Grapevine downy mildew, caused by Plasmopara viticola, is an economically important disease in Australia and worldwide. The application of fungicides is the main tool to control this disease. Frequent fungicide applications can lead to the selection of resistant P. viticola populations, which has negative impacts on the management of the disease. Identification of resistance and its prevalence is necessary to inform resistance management strategies., Results: A total of 86 P. viticola isolates were collected between 2017 and 2022 from vineyards in 15 growing regions across Australia for four fungicide groups; phenylamide (PA, group 4), carboxylic acid amide (CAA, group 40), quinone outside inhibitor (QoI, group 11) and quinone outside inhibitor stigmatellin binding type (QoSI, group 45). Decreased phenotypic sensitivity was detected for all four groups, and resistance to metalaxyl-M (PA) and pyraclostrobin (QoI), was detected. Genetic analysis to detect the G143A (QoI) and G1105S (CAA) mutations using amplicon-based sequencing was performed for 239 and 65 isolates collected in 2014-2017 and 2017-2022, respectively. G143A was detected in 8% and 52% of isolates, respectively, with strong association to phenotypic resistance. However, G1105S was not detected in any isolates., Conclusion: Plasmopara viticola isolates in Australia with resistance to at least two fungicide groups have been detected, therefore it is necessary to adopt resistance management strategies where resistance has been detected. Vineyards should continue to be monitored to improve management strategies for downy mildew. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Over 6 years, we conducted an extensive survey of spontaneous grape fermentations, examining 3105 fungal microbiomes across 14 distinct grape-growing regions. Our investigation into the biodiversity of these fermentations revealed that a small number of highly abundant genera form the core of the initial grape juice microbiome. Consistent with previous studies, we found that the region of origin had the most significant impact on microbial diversity patterns. We also discovered that certain taxa were consistently associated with specific geographical locations and grape varieties, although these taxa represented only a minor portion of the overall diversity in our dataset. Through unsupervised clustering and dimensionality reduction analysis, we identified three unique community types, each exhibiting variations in the abundance of key genera. When we projected these genera onto global branches, it suggested that microbiomes transition between these three broad community types. We further investigated the microbial community composition throughout the fermentation process. Our observations indicated that the initial microbial community composition could predict the diversity during the early stages of fermentation. Notably, Hanseniaspora uvarum emerged as the primary non-Saccharomyces species within this large collection of samples., (© 2024 John Wiley & Sons Ltd.)

Purpose: In treating cancer, different chemotherapy regimens cause chemotherapy-induced peripheral neuropathy (CIPN). Despite recent international guidelines, a gold standard for diagnosis, treatment, and care is lacking. To identify the current clinical practice and the physicians' point of view and ideas for improvement, we evaluated CIPN care by interviewing different specialists involved., Methods: We performed semi-structured, audio-recorded, transcribed, and coded interviews with a purposive sample of oncologists, pain specialists, and neurologists involved in CIPN patients' care. Data is analyzed by a constant comparative method for content analysis, using ATLAS.ti software. Codes, categories, and themes are extracted, generating common denominators and conclusions., Results: With oncologists, pain specialists, and neurologists, nine, nine, and eight interviews were taken respectively (including three, two, and two interviews after thematic saturation occurred). While useful preventive measures and predictors are lacking, patient education (e.g., on symptoms and timely reporting) is deemed pivotal, as is low-threshold screening (e.g., anamnesis and questionnaires). Diagnosis focusses on a temporal relationship to chemotherapy, with adjuvant testing (e.g., EMG) used in severe or atypical cases. Symptomatic antineuropathic and topical medication are often prescribed, but personalized and multidimensional care based on individual symptoms and preferences is highly valued. The limited efficacy of existing treatments, and the lack of standardized protocols, interdisciplinary coordination, and awareness among healthcare providers pose significant challenges., Conclusion: Besides the obvious need for better therapeutic options, and multidisciplinary exploration of patients' perspectives, a structured and collaborative approach towards diagnosis, treatment, referral, and follow-up, nurtured by improving knowledge and use of existing CIPN guidelines, could enhance care., (© 2024. The Author(s).)

Cultural exchange of fermentation techniques has driven the spread of Saccharomyces cerevisiae across the globe, establishing natural populations in many countries. Despite this, Oceania is thought to lack native populations of S. cerevisiae, only being introduced after colonisation. Here we investigate the genomic landscape of 411 S. cerevisiae isolated from spontaneous grape fermentations in Australia across multiple locations, years, and grape cultivars. Spontaneous fermentations contained highly recombined mosaic strains that exhibited high levels of genome instability. Assigning genomic windows to putative ancestral origin revealed that few closely related starter lineages have come to dominate the genetic landscape, contributing most of the genetic variation. Fine-scale phylogenetic analysis of loci not observed in strains of commercial wine origin identified widespread admixture with European derived beer yeast along with three independent admixture events from potentially endemic Oceanic lineages that was associated with genome instability. Finally, we investigated Australian ecological niches for basal isolates, identifying phylogenetically distinct S. cerevisiae of non-European, non-domesticated origin associated with admixture loci. Our results illustrate the effect commercial use of microbes may have on local microorganism genetic diversity and demonstrates the presence of non-domesticated, potentially endemic lineages of S. cerevisiae in Australian niches that are actively admixing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ward et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Rapid exome sequencing (rES) has become the first-choice genetic test for critically ill patients, mostly neonates, young infants, or fetuses in prenatal care, in time-sensitive situations and when it is expected that the genetic test result may guide clinical decision making. The implementation of rES has revolutionized medicine by enabling timely identification of genetic causes for various rare diseases. The utilization of rES has increasingly been recognized as an essential diagnostic tool for the identification of complex and undiagnosed genetic disorders. Methods: We conducted a retrospective evaluation of our experiences with rES performed on 575 critically ill patients from various age groups (prenatal to adulthood), over a four-year period (2016-2019). These patients presented with a wide spectrum of rare diseases, including but not limited to neurological disorders, severe combined immune deficiency, and cancer. Results: During the study period, there was a significant increase in rES referrals, with a rise from a total of two referrals in Q1-2016 to 10 referrals per week in Q4-2019. The median turnaround time (TAT) decreased from 17 to 11 days in the period 2016-2019, with an overall median TAT of 11 days (IQR 8-15 days). The overall diagnostic yield for this cohort was 30.4%, and did not significantly differ between the different age groups (e.g. adults 22.2% vs children 31.0%; p -value 0.35). However, variability in yield was observed between clinical entities: craniofacial anomalies yielded 58.3%, while for three clinical entities (severe combined immune deficiency, aneurysm, and hypogonadotropic hypogonadism) no diagnoses were obtained. Discussion: Importantly, whereas clinical significance is often only attributed to a conclusive diagnosis, we also observed impact on clinical decision-making for individuals in whom no genetic diagnosis was established. Hence, our experience shows that rES has an important role for patients of all ages and across the broad spectrum of rare diseases to impact clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marouane, Neveling, Deden, van den Heuvel, Zafeiropoulou, Castelein, van de Veerdonk, Koolen, Simons, Rodenburg, Westra, Mensenkamp, de Leeuw, Ligtenberg, Matthijsse, Pfundt, Kamsteeg, Brunner, Gilissen, Feenstra, de Boode, Yntema, van Zelst-Stams, Nelen and Vissers.)

Aims: The primary aim of this study was to present the mid-term follow-up of a multicentre randomized controlled trial (RCT) which compared the functional outcome following routine removal (RR) to the outcome following on-demand removal (ODR) of the syndesmotic screw (SS)., Methods: All patients included in the 'ROutine vs on DEmand removal Of the syndesmotic screw' (RODEO) trial received the Olerud-Molander Ankle Score (OMAS), American Orthopaedic Foot and Ankle Hindfoot Score (AOFAS), Foot and Ankle Outcome Score (FAOS), and EuroQol five-dimension questionnaire (EQ-5D). Out of the 152 patients, 109 (71.7%) completed the mid-term follow-up questionnaire and were included in this study (53 treated with RR and 56 with ODR). Median follow-up was 50 months (interquartile range 43.0 to 56.0) since the initial surgical treatment of the acute syndesmotic injury. The primary outcome of this study consisted of the OMAS scores of the two groups., Results: The median OMAS score was 85.0 for patients treated with RR, and 90.0 for patients treated with ODR (p = 0.384), indicating no significant difference between ODR and RR. The secondary outcome measures included the AOFAS (88.0 in the RR group and 90.0 for ODR; p = 0.722), FAOS (87.5 in the RR group and 92.9 for ODR; p = 0.399), and EQ-5D (0.87 in the RR group and 0.96 for ODR; p = 0.092)., Conclusion: This study demonstrated no functional difference comparing ODR to RR in syndesmotic injuries at a four year follow-up period, which supports the results of the primary RODEO trial. ODR should be the standard practice after syndesmotic screw fixation., Competing Interests: As per the funding information and open access funding, the authors disclose funding for the APC from ZonMW, under project number 843002705., (© 2023 Schepers et al.)

In order to age successfully at work, people need to maintain or improve their work ability and motivation to work. This implies a process that develops over time and can differ substantially between individuals. This study investigated whether different trajectories of perceived work ability and motivation to work can be distinguished between older employees over time and to what extent job demands and job resources are predictive of these different trajectories. We applied growth mixture modelling amongst 5799 employees of 45 years and older at four time points. We found five distinct groups of older workers that differed in their trajectories of perceived work ability and four types of groups of older workers that differed in their trajectories of their motivation to work. Higher levels of physical demands, mental demands, autonomy, supervisor support, and colleague support were less common in unfavourable trajectories. This study gives Human Resource Management practitioners insight into how jobs should be designed to stimulate successful ageing at work., Competing Interests: Declaration of competing interest The authors declare that this manuscript has no conflicts of interest and is not related to any funding., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The design of the optimal preoperative evaluation is a much debated topic, with the anaesthetist-led in-person evaluation being most widely used. This approach is possibly leading to overuse of a valuable resource, especially in low-risk patients. Without compromising patient safety, we hypothesised that not all patients would require this type of elaborate evaluation., Objective: The current scoping review aims to critically appraise the range and nature of the existing literature investigating alternatives to the anaesthetist-led preoperative evaluation and their impact on outcomes, to inform future knowledge translation and ultimately improve perioperative clinical practice., Design: A scoping review of the available literature., Data Sources: Embase, Medline, Web-of-Science, Cochrane Library and Google Scholar. No date restriction was used., Eligibility Criteria: Studies in patients scheduled for elective low-risk or intermediate-risk surgery, which compared anaesthetist-led in-person preoperative evaluation with non-anaesthetist-led preoperative evaluation or no outpatient evaluation. The focus was on outcomes, including surgical cancellation, perioperative complications, patient satisfaction and costs., Results: Twenty-six studies with a total of 361 719 patients were included, reporting on various interventions: telephone evaluation, telemedicine evaluation, evaluation by questionnaire, surgeon-led evaluation, nurse-led evaluation, other types of evaluation and no evaluation up to the day of surgery. Most studies were conducted in the United States and were either pre/post or one group post-test-only studies, with only two randomised controlled trials. Studies differed largely in outcome measures and were of moderate quality overall., Conclusions: A number of alternatives to the anaesthetists-led in-person preoperative evaluation have already been researched: that is telephone evaluation, telemedicine evaluation, evaluation by questionnaire and nurse-led evaluation. However, more high-quality research is needed to assess viability in terms of intraoperative or early postoperative complications, surgical cancellation, costs, and patient satisfaction in the form of Patient-Reported Outcome Measures and Patient-Reported Experience Measures., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.)

Background: Though the incidence, characteristics, and pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) by taxane based chemotherapy were extensively studied, diagnostic guidelines extent only recently., Aim: To observationally investigate whether specific tests can be used to predict and monitor CIPN severity., Methods: Fourteen female breast cancer patients receiving paclitaxel or docetaxel were evaluated using the McGill Pain Questionnaire (MPQ), National Cancer Institute Common Toxicity Criteria (NCI-CTC) grading, clinical total neuropathy score (TNSc), quantitative sensory testing (QST) of pressure pain threshold (PPT), and numeric rating scale (NRS) scores and stocking and glove distribution testing (SGDT), at the start (T0), midst (T1), and end (T2) of their treatment and after 3 months (T3)., Results: At T3, patients scored NCI-CTC neuropathy grade 1 (14.3%), 2 (64.3%), and 3 (14.3%) respectively. Fifty percentage scored at least grade 1 at T0, with complaints not caused by CIPN. Pain, if present, was denominated "tingling" and "cold" in the MPQ. Median TNSc score increased from T0 (2.43) to T1 (4.71) to T2 (5.50) to T3 (5.57), as did pinprick and cold sensation disturbances in SGDT. PPT and associated NRS remained unchanged. TNSc and SGDT at T1 could not predict the NCI-CTC grade at T3., Conclusion: NCI-CTC, TNSc, and stocking and glove distribution testing can be used in the early diagnosis and monitoring of CIPN, with false-positive findings at baseline. Final NCI-CTC grades could not be predicted., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Approximately two third of patients with a rare genetic disease remain undiagnosed after exome sequencing (ES). As part of our post-test counseling procedures, patients without a conclusive diagnosis are advised to recontact their referring clinician to discuss new diagnostic opportunities in due time. We performed a systematic study of genetically undiagnosed patients 5 years after their initial negative ES report to determine the efficiency of diverse reanalysis strategies., Methods: We revisited a cohort of 150 pediatric neurology patients originally enrolled at Radboud University Medical Center, of whom 103 initially remained genetically undiagnosed. We monitored uptake of physician-initiated routine clinical and/or genetic re-evaluation (ad hoc re-evaluation) and performed systematic reanalysis, including ES-based resequencing, of all genetically undiagnosed patients (systematic re-evaluation)., Results: Ad hoc re-evaluation was initiated for 45 of 103 patients and yielded 18 diagnoses (including 1 non-genetic). Subsequent systematic re-evaluation identified another 14 diagnoses, increasing the diagnostic yield in our cohort from 31% (47/150) to 53% (79/150). New genetic diagnoses were established by reclassification of previously identified variants (10%, 3/31), reanalysis with enhanced bioinformatic pipelines (19%, 6/31), improved coverage after resequencing (29%, 9/31), and new disease-gene associations (42%, 13/31). Crucially, our systematic study also showed that 11 of the 14 further conclusive genetic diagnoses were made in patients without a genetic diagnosis that did not recontact their referring clinician., Conclusions: We find that upon re-evaluation of undiagnosed patients, both reanalysis of existing ES data as well as resequencing strategies are needed to identify additional genetic diagnoses. Importantly, not all patients are routinely re-evaluated in clinical care, prolonging their diagnostic trajectory, unless systematic reanalysis is facilitated. We have translated our observations into considerations for systematic and ad hoc reanalysis in routine genetic care., (© 2022. The Author(s).)

Polycomb Repressive Complex 2 (PRC2) catalyzes the mono-, di-, and trimethylation of histone protein H3 on lysine 27 (H3K27), which is strongly associated with transcriptionally silent chromatin. The functional core of PRC2 is highly conserved in animals and consists of four subunits. One of these, SUZ12, has not been identified in the genetic model Caenorhabditis elegans , whereas C. elegans PRC2 contains the clade-specific MES-3 protein. Through unbiased sensitive sequence similarity searches complemented by high-quality structure predictions of monomers and multimers, we here demonstrate that MES-3 is a highly divergent ortholog of SUZ12. MES-3 shares protein folds and conserved residues of key domains with SUZ12 and is predicted to interact with core PRC2 members similar to SUZ12 in human PRC2. Thus, in agreement with previous genetic and biochemical studies, we provide evidence that C. elegans contains a diverged yet evolutionary conserved core PRC2, like other animals., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Eutypa dieback of grapevine is an important disease caused by the generalist Ascomycete fungus Eutypa lata. Despite the relevance of this species to the global wine industry, its genomic diversity remains unknown, with only a single publicly available genome assembly. Whole-genome sequencing and comparative genomics was performed on forty Australian E. lata isolates to understand the genome evolution, adaptation, population size and structure of these isolates. Phylogenetic and linkage disequilibrium decay analyses provided evidence of extensive gene flow through sexual recombination between isolates obtained from different geographic locations and hosts. Investigation of the genetic diversity of these isolates suggested rapid population expansion, likely as a consequence of the recent growth of the Australian wine industry. Genomic regions affected by selective sweeps were shown to be enriched for genes associated with secondary metabolite clusters and included genes encoding proteins with a role in nutrient acquisition, degradation of host cell wall and metal and drug resistance, suggesting recent adaptation to both abiotic factors and potentially host genotypes. Genome synteny analysis using long-read genome assemblies showed significant intraspecific genomic plasticity with extensive chromosomal rearrangements impacting the secondary metabolite production potential of this species. Finally, k-mer based GWAS analysis identified a potential locus associated with mycelia recovery in canes of Vitis vinifera that will require further investigations., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The use of free vascularized fibula grafts (FVFG) in complex spinal deformity surgery intends to allow for life-long stability of the spine with good long-term clinical outcome. However, these long-term outcomes of this technique are still lacking. The objective of this study is to report the long-term postoperative outcomes and establish the long-term viability of this method for spinal reconstruction., Methods: A retrospective cohort study was conducted in all patients who underwent spinal reconstructive surgery utilizing a FVFG at a tertiary medical centre. Questionnaires taken from the participants were the Numeric Pain Rating Scale (NPRS), Oswestry Low Back Pain Disability (also known as Oswestry Disability Index (ODI)), Scoliosis Research Society 22r (SRS-22), the EQ-5D-5L and a self-assembled questionnaire regarding donor site comorbidities and patient satisfaction., Results: Over a period of 24 years (1995-2019), we used FVFG for spinal reconstruction in 31 patients. A total of 25 patients were included in this study, 8 patients were deceased at the time of this study, and sixteen patients responded to the questionnaires. Patient satisfaction was rated 6.8 out of 10, the average SRS-22r score was 3.6, EQ-5D-5L score was 0.725, and the ODI score showed a minimal disability (0-20%) postoperatively. Overall complication-free survival was 8.9 years. Nine patients underwent a re-operation in the spinal area; five for the removal of the spinal instrumentation., Conclusion: Patients reported satisfied and good long-term outcomes following FVFG surgical procedure for complex spinal deformities. Therefore, considering the alternatives, this procedure provides a good long-term solution for complex spinal deformity surgery., (Copyright © 2021 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The conserved adapter protein Scribble (Scrib) plays essential roles in a variety of cellular processes, including polarity establishment, proliferation, and directed cell migration. While the mechanisms through which Scrib promotes epithelial polarity are beginning to be unraveled, its roles in other cellular processes including cell migration remain enigmatic. In C. elegans, the Scrib ortholog LET-413 is essential for apical-basal polarization and junction formation in embryonic epithelia. However, whether LET-413 is required for postembryonic development or plays a role in migratory events is not known. Here, we use inducible protein degradation to investigate the functioning of LET-413 in larval epithelia. We find that LET-413 is essential in the epidermal epithelium for growth, viability, and junction maintenance. In addition, we identify a novel role for LET-413 in the polarized outgrowth of the epidermal seam cells. These stem cell-like epithelial cells extend anterior and posterior directed apical protrusions in each larval stage to reconnect to their neighbors. We show that the role of LET-413 in seam cell outgrowth is likely mediated largely by the junctional component DLG-1 discs large, which we demonstrate is also essential for directed outgrowth of the seam cells. Our data uncover multiple essential functions for LET-413 in larval development and show that the polarized outgrowth of the epithelial seam cells is controlled by LET-413 Scribble and DLG-1 Discs large., Competing Interests: The authors have declared that no competing interests exist.

The c.151C>T founder mutation in COCH is a frequent cause of late-onset, dominantly inherited hearing impairment and vestibular dysfunction (DFNA9) in the Dutch/Belgian population. The initial clinical symptoms only manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. The dominant inheritance pattern and established non-haploinsufficiency disease mechanism indicate that suppressing translation of mutant COCH transcripts has high therapeutic potential. Single-molecule real-time (SMRT) sequencing resulted in the identification of 11 variants with a low population frequency (<10%) that are specific to the c.151C>T mutant COCH allele. Proof of concept was obtained that gapmer antisense oligonucleotides (AONs), directed against the c.151C>T mutation or mutant allele-specific intronic variants, are able to induce mutant COCH transcript degradation when delivered to transgenic cells expressing COCH minigenes. The most potent AON, directed against the c.151C>T mutation, was able to induce a 60% decrease in mutant COCH transcripts without affecting wild-type COCH transcript levels. Allele specificity decreased when increasing concentrations of AON were delivered to the cells. With the proven safety of AONs in humans, and rapid advancements in inner ear drug delivery, our in vitro studies indicate that AONs offer a promising treatment modality for DFNA9., Competing Interests: A patent has been filed for the AONs described in this manuscript under number PCT/EP2020/080429. E.d.V. and E.v.W. report being employed by Radboudumc and inventor on this patent., (© 2021 The Author(s).)

Background: Estimates of the economic burden of work injuries and diseases can help policymakers prioritize occupational health and safety policies and interventions in order to best allocate scarce resources. Several attempts have been made to estimate these economic burdens at the national level, but most have not included a comprehensive list of cost components, and none have attempted to implement a standard approach across several countries. The aim of our study is to develop a framework for estimating the economic burden of work injuries and diseases and implement it for selected European Union countries., Methods: We develop an incidence cost framework using a bottom-up approach to estimate the societal burden of work injuries and diseases and implement it for five European Union countries. Three broad categories of costs are considered-direct healthcare, indirect productivity and intangible health-related quality of life costs. We begin with data on newly diagnosed work injuries and diseases from calendar year 2015. We consider lifetime costs for cases across all categories and incurred by all stakeholders. Sensitivity analysis is undertaken for key parameters., Results: Indirect costs are the largest part of the economic burden, then direct costs and intangible costs. As a percentage of GDP, the highest overall costs are for Poland (10.4%), then Italy (6.7%), The Netherlands (3.6%), Germany (3.3%) and Finland (2.7%). The Netherlands has the highest per case costs (€75,342), then Italy (€58,411), Germany (€44,919), Finland (€43,069) and Poland (€38,918). Costs per working-age population are highest for Italy (€4956), then The Netherlands (€2930), Poland (€2793), Germany (€2527) and Finland (€2331)., Conclusions: Our framework serves as a template for estimating the economic burden of work injuries and diseases across countries in the European Union and elsewhere. Results can assist policymakers with identifying health and safety priority areas based on the magnitude of components, particularly when stratified by key characteristics such as industry, injury/disease, age and sex. Case costing can serve as an input into the economic evaluation of prevention initiatives. Comparisons across countries provide insights into the relevant performance of health and safety systems.

Background: Oxaliplatin is a chemotherapeutic agent used to treat malignancies of the gastrointestinal tract. Neuropathy is a frequent dose-limiting side-effect of oxaliplatin therapy, without preventive or curative strategies. Concomitant administration of intravenous lidocaine could be a promising treatment. However, the effect of intravenous lidocaine on oxaliplatin pharmacokinetics was never studied before. We evaluated the effect of lidocaine on the area under the curve and C max of oxaliplatin as a part of a larger study addressing the prevention and treatment of oxaliplatin induced peripheral neuropathy with lidocaine., Methods: In this prospective cross-over trial, patients received an oxaliplatin cycle with and without lidocaine (bolus 1.5 mg kg -1 followed by 1.5 mg kg -1  h -1 in 3 h). Levels of oxaliplatin, measured as ultrafiltrable platinum were determined at 10 min after cessation of oxaliplatin infusion and hourly thereafter. Outcomes are the difference in area under the curve of oxaliplatin (primary) and the difference in the C max of oxaliplatin (secondary)., Results: No difference in the %Δ area under the curve of oxaliplatin (-2.40 ± 7.66, 90% CI +10.50 to -15.31) was found. However, %Δ C max of oxaliplatin (-28.72 ± 6.01, 90% CI -18.59 to -38.85) was lower to a statistically significant extent in the chemotherapy cycle with lidocaine. No (serious) adverse events were reported., Conclusions: Lidocaine does not affect the area under the curve of oxaliplatin, which is the most important parameter in drug interaction studies and for oxaliplatin treatment effect. The lower C max in the chemotherapeutic cycle with lidocaine is significant and remarkable, but with an unknown exact mechanism or clinical significance, making further research desirable.

SWI/SNF (switch/sucrose nonfermenting) complexes regulate transcription through chromatin remodeling and opposing gene silencing by Polycomb group (PcG) proteins. Genes encoding SWI/SNF components are critical for normal development and frequently mutated in human cancer. We characterized the in vivo contributions of SWI/SNF and PcG complexes to proliferation-differentiation decisions, making use of the reproducible development of the nematode Caenorhabditis elegans. RNA interference, lineage-specific gene knockout, and targeted degradation of SWI/SNF BAF components induced either overproliferation or acute proliferation arrest of precursor cells, depending on residual protein levels. Our data show that a high SWI/SNF BAF dosage is needed to arrest cell division during differentiation and to oppose PcG-mediated repression. In contrast, a low SWI/SNF protein level is necessary to sustain cell proliferation and hyperplasia, even when PcG repression is blocked. These observations show that incomplete inactivation of SWI/SNF components can eliminate a tumor-suppressor activity while maintaining an essential transcription regulatory function., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Polarity is the basis for the generation of cell diversity, as well as the organization, morphogenesis, and functioning of tissues. Studies in Caenorhabditis elegans have provided much insight into PAR-protein mediated polarity; however, the molecules and mechanisms critical for cell polarization within the plane of epithelia have been identified in other systems. Tissue polarity in C. elegans is organized by Wnt-signaling with some resemblance to the Wnt/planar cell polarity (PCP) pathway, but lacking core PCP protein functions. Nonetheless, recent studies revealed that conserved PCP proteins regulate directed cell migratory events in C. elegans, such as convergent extension movements and neurite formation and guidance. Here, we discuss the latest insights and use of C. elegans as a PCP model., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A correct balance between proliferative and asymmetric cell divisions underlies normal development, stem cell maintenance and tissue homeostasis. What determines whether cells undergo symmetric or asymmetric cell division is poorly understood. To gain insight into the mechanisms involved, we studied the stem cell-like seam cells in the Caenorhabditis elegans epidermis. Seam cells go through a reproducible pattern of asymmetric divisions, instructed by divergent canonical Wnt/β-catenin signaling, and symmetric divisions that increase the seam cell number. Using time-lapse fluorescence microscopy we observed that symmetric cell divisions maintain asymmetric localization of Wnt/β-catenin pathway components. Our observations, based on lineage-specific knockout and GFP-tagging of endogenous pop-1 , support the model that POP-1 TCF induces differentiation at a high nuclear level, whereas low nuclear POP-1 promotes seam cell self-renewal. Before symmetric division, the transcriptional regulator RNT-1 Runx and cofactor BRO-1 CBFβ temporarily bypass Wnt/β-catenin asymmetry by downregulating pop-1 expression. Thereby, RNT-1/BRO-1 appears to render POP-1 below the level required for its repressor function, which converts differentiation into self-renewal. Thus, we found that conserved Runx/CBFβ-type stem cell regulators switch asymmetric to proliferative cell division by opposing TCF-related transcriptional repression., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Objective: To develop a longlist of healthcare quality indicators for the care of hospitalised adults of all ages with (or at risk of) low physical activity during the hospital stay., Design: A modified RAND/UCLA Appropriateness Method Delphi study., Setting and Participants: Participants were physical therapists, nurses and managers working in Dutch university medical centres., Methods: The current study consisted of three phases. Phase I was a systematic literature search for quality indicators and relevant domains. Phase II was a survey among healthcare professionals to collect additional data. Phase III consisted of three consensus rounds. In round 1, experts rated the relevance of the potential indicators online (Delphi). The second round was a face-to-face expert panel meeting managed by an experienced moderator. Acceptability, feasibility and validity of the quality indicators were discussed by the panel members. In round 3, the panel members rated the relevance of the potential indicators that were still under discussion., Results: The search retrieved 1556 studies of which 53 studies were assessed full text. Data from 17 studies were included in a first draft longlist of indicators. Eighteen nurses and one physical therapist responded to the survey and added data for a second draft of the longlist. Experts constructed the final longlist of 23 indicators in three consensus rounds. Seven domains were identified: 'Policy', 'Attitude and education', 'Equipment and support', 'Evaluation', 'Information', 'Patient-tailored physical activity plan' and 'Outcome measure'., Conclusion and Implications: The healthcare quality indicators developed in this study could help to grade, monitor and improve healthcare for hospitalised adults of all ages with (or at risk of) low physical activity during the hospital stay. Future research will focus on the psychometric quality of the indicators and selection of key performance indicators., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Self-management of bipolar disorder (BD) education is a complex nursing intervention in which patients and informal caregivers are taught to be actively involved in self-monitoring and self-regulating activities. Some studies question if nurses are sufficiently equipped to deliver these educational tasks. Other studies suggest that nurses have gathered their knowledge implicitly by experience, but to date, this tacit knowledge is not described from the experiences of mental health nurses (MHNs) in ambulant BD care. Objective: To detect the tacit knowledge used by MHNs by interpreting their experiences in delivering self-management education to people with BD and their informal caregivers. Methods: A phenomenological-hermeneutical study amongst MHNs ( N  = 9) from three ambulant BD care clinics in the Netherlands. Face-to-face, open, in-depth interviews guided by a topic list, were conducted and transcribed verbatim prior to the hermeneutical analysis. Findings: We found five categories resembling the complex character of self-management interventions provided by MHNs: Building a trustful collaboration, Starting a dialogue about needs and responsibilities, Explaining BD, Utilizing mood monitoring instruments, and Conceptualizing self-management of BD. Conclusion: Eventually MHNs use tacit knowledge to cope with situations that demand an outside-the-box approach. Self-management education is partially trained and partially mastered through experience. Practice implications: In order to facilitate long-term self-management of BD, the collaboration of a supporting network is essential.

Purpose With an ageing workforce, employees are increasingly confronted with multi-morbidity. Especially physical and mental health problems often occur together. This study aims to (i) explore the effect of multi-morbidity on work ability of ageing employees, more specifically the effects of the number of health problems and the combination of physical and mental health problems, and to (ii) explore to what extent the effects of physical and mental health problems on work ability are explained by applying differing coping styles. Methods A 1 year follow up study (2012-2013) was conducted among 7175 employees aged 45-64 years. Linear regression analyses were conducted to examine longitudinal relationships between multi-morbidity, coping styles and work ability. To determine whether coping styles mediate the effects of multi-morbidity on work ability, Sobel tests were conducted. Results A higher number of health problems was related to poorer work ability, but this negative effect stabilized from three health problems onwards. The combination of physical and mental health problem(s) was more strongly related to poorer work ability than only physical health problems. The negative relation between physical health problems and work ability was partly suppressed by active coping, while the negative relation between the combination of physical and mental health problem(s) on work ability was partly explained by avoidant coping. Conclusions Ageing employees with multi-morbidity have a reduced work ability, especially when mental health problems are present. The greater negative effects of the combination of physical and mental health problems on work ability are partially due to unfavorable coping styles.

Polarity establishment is a key developmental process, but what determines its timing is poorly understood. New research in Caenorhabditis elegans demonstrates that the PAR polarity system extensively reconfigures before becoming competent to polarize. By inhibiting membrane localization of anterior PAR proteins, AIR-1 (aurora A) and PLK-1 (polo kinase) prevent premature polarization., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

During animal development, a single fertilized egg forms a complete organism with tens to trillions of cells that encompass a large variety of cell types. Cell cycle regulation is therefore at the center of development and needs to be carried out in close coordination with cell differentiation, migration, and death, as well as tissue formation, morphogenesis, and homeostasis. The timing and frequency of cell divisions are controlled by complex combinations of external and cell-intrinsic signals that vary throughout development. Insight into how such controls determine in vivo cell division patterns has come from studies in various genetic model systems. The nematode Caenorhabditis elegans has only about 1000 somatic cells and approximately twice as many germ cells in the adult hermaphrodite. Despite the relatively small number of cells, C. elegans has diverse tissues, including intestine, nerves, striated and smooth muscle, and skin. C. elegans is unique as a model organism for studies of the cell cycle because the somatic cell lineage is invariant. Somatic cells divide at set times during development to produce daughter cells that adopt reproducible developmental fates. Studies in C. elegans have allowed the identification of conserved cell cycle regulators and provided insights into how cell cycle regulation varies between tissues. In this review, we focus on the regulation of the cell cycle in the context of C. elegans development, with reference to other systems, with the goal of better understanding how cell cycle regulation is linked to animal development in general., (Copyright © 2019 by the Genetics Society of America.)

Background: The degree of informal caregiver involvement influences the self-management of individuals living with bipolar disorder (BD)., Objective: This article aims to provide a description of informal caregivers' learning experiences in self-management support of BD in order to guide professionals in tailoring future psychosocial and psychoeducational interventions., Design: In-depth open interviews with 10 informal caregivers of patients with BD who followed treatment in the context of specialized outpatient bipolar care were conducted., Results: Four learning phases emerged from the phenomenological analysis describing the informal caregivers learning process: (1) understanding BD, (2) overcoming the dilemmas in self-management support for individuals living with BD, (3) dividing tasks and responsibilities, and (4) acquiring a personal definition of self-management support for individuals living with BD., Conclusion: By grasping the concept of BD, informal caregivers gradually learn how to overcome dilemmas resulting from living with someone with BD, and how to control the expression of emotions. They learn to reflect on the nature of conflicts and how to share the responsibilities of illness management with individuals living with BD and professionals. Mastering these skills eventually allows them to define and delimit their supporting informal caregiver role in the self-management of BD., Practice Implications: Our findings provide information regarding the educational needs of informal caregivers to tailor counseling, and psychosocial and psychoeducational interventions in specialized outpatient care for individuals living with BD.

The specific organization of the neuronal microtubule cytoskeleton in axons and dendrites is an evolutionarily conserved determinant of neuronal polarity that allows for selective cargo sorting. However, how dendritic microtubules are organized and whether local differences influence cargo transport remains largely unknown. Here, we use live-cell imaging to systematically probe the microtubule organization in Caenorhabditis elegans neurons, and demonstrate the contribution of distinct mechanisms in the organization of dendritic microtubules. We found that most non-ciliated neurons depend on unc-116 (kinesin-1), unc-33 (CRMP) and unc-44 (ankyrin) for correct microtubule organization and polarized cargo transport, as previously reported. Ciliated neurons and the URX neuron, however, use an additional pathway to nucleate microtubules at the tip of the dendrite, from the base of the cilium in ciliated neurons. Since inhibition of distal microtubule nucleation affects distal dendritic transport, we propose a model in which the presence of a microtubule-organizing center at the dendrite tip ensures correct dendritic cargo transport., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

The position of the mitotic spindle determines the plane of cell cleavage, and thereby daughter cell location, size, and content. Spindle positioning is driven by dynein-mediated pulling forces exerted on astral microtubules, which requires an evolutionarily conserved complex of Gα∙GDP, GPR-1/2 Pins/LGN , and LIN-5 Mud/NuMA proteins. To examine individual functions of the complex components, we developed a genetic strategy for light-controlled localization of endogenous proteins in C. elegans embryos. By replacing Gα and GPR-1/2 with a light-inducible membrane anchor, we demonstrate that Gα∙GDP, Gα∙GTP, and GPR-1/2 are not required for pulling-force generation. In the absence of Gα and GPR-1/2, cortical recruitment of LIN-5, but not dynein itself, induced high pulling forces. The light-controlled localization of LIN-5 overruled normal cell-cycle and polarity regulation and provided experimental control over the spindle and cell-cleavage plane. Our results define Gα∙GDP-GPR-1/2 Pins/LGN as a regulatable membrane anchor, and LIN-5 Mud/NuMA as a potent activator of dynein-dependent spindle-positioning forces., Competing Interests: LF, RS, DD, BG, Sv No competing interests declared, AA Deputy editor of eLife Magazine, (© 2018, Fielmich et al.)

Competing Interests: Competing interests: None declared.

The adenomatous polyposis coli (APC) tumor suppressor has dual functions in Wnt/β-catenin signaling and accurate chromosome segregation and is frequently mutated in colorectal cancers. Although APC contributes to proper cell division, the underlying mechanisms remain poorly understood. Here we show that Caenorhabditis elegans APR-1/APC is an attenuator of the pulling forces acting on the mitotic spindle. During asymmetric cell division of the C. elegans zygote, a LIN-5/NuMA protein complex localizes dynein to the cell cortex to generate pulling forces on astral microtubules that position the mitotic spindle. We found that APR-1 localizes to the anterior cell cortex in a Par-aPKC polarity-dependent manner and suppresses anterior centrosome movements. Our combined cell biological and mathematical analyses support the conclusion that cortical APR-1 reduces force generation by stabilizing microtubule plus-ends at the cell cortex. Furthermore, APR-1 functions in coordination with LIN-5 phosphorylation to attenuate spindle-pulling forces. Our results document a physical basis for the attenuation of spindle-pulling force, which may be generally used in asymmetric cell division and, when disrupted, potentially contributes to division defects in cancer., Competing Interests: The authors declare no conflict of interest.

Background: Whether hip range of motion (ROM) is a risk factor for groin pain in athletes is not known., Objectives: To systematically review the relationship between hip ROM and groin pain in athletes in cross-sectional/case-control and prospective studies., Study Design: Systematic review, prospectively registered (PROSPERO) according to PRISMA guidelines., Methods: Pubmed, Embase, CINAHL and SPORTDiscus were systematically searched up to December 2015. Two authors performed study selection, data extraction/analysis, quality assessment (Critical Appraisal Skills Programme) and strength of evidence synthesis., Results: We identified seven prospective and four case-control studies. The total quality score ranged from 29% to 92%. Heterogeneity in groin pain classification, injury definitions and physical assessment precluded data pooling. There was strong evidence that total rotation of both hips below 85° measured at the pre-season screening was a risk factor for groin pain development. Strong evidence suggested that internal rotation, abduction and extension were not associated with the risk or presence of groin pain., Conclusion: Total hip ROM is the factor most consistently related to groin pain in athletes. Screening for hip ROM is unlikely to correctly identify an athlete at risk of developing groin pain because of the small ROM differences found and poor ROM measurement properties., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The position of the mitotic spindle is tightly controlled in animal cells as it determines the plane and orientation of cell division. Contacts between cytoplasmic dynein and astral microtubules (MTs) at the cell cortex generate pulling forces that position the spindle. An evolutionarily conserved Gα-GPR-1/2 Pins/LGN -LIN-5 Mud/NuMA cortical complex interacts with dynein and is required for pulling force generation, but the dynamics of this process remain unclear. In this study, by fluorescently labeling endogenous proteins in Caenorhabditis elegans embryos, we show that dynein exists in two distinct cortical populations. One population directly depends on LIN-5, whereas the other is concentrated at MT plus ends and depends on end-binding (EB) proteins. Knockout mutants lacking all EBs are viable and fertile and display normal pulling forces and spindle positioning. However, EB protein-dependent dynein plus end tracking was found to contribute to force generation in embryos with a partially perturbed dynein function, indicating the existence of two mechanisms that together create a highly robust force-generating system., (© 2017 Schmidt et al.)

Development, tissue homeostasis and tumor suppression depend critically on the correct regulation of cell division. Central in the cell division process is the decision whether to enter the next cell cycle and commit to going through the S and M phases, or to remain temporarily or permanently arrested. Cell cycle studies in genetic model systems could greatly benefit from visualizing cell cycle commitment in individual cells without the need of fixation. Here, we report the development and characterization of a reporter to monitor cell cycle entry in the nematode C. elegans. This reporter combines the mcm-4 promoter, to reveal Rb/E2F-mediated transcriptional control, and a live-cell sensor for CDK-activity. The CDK sensor was recently developed for use in human cells and consists of a DNA Helicase fragment fused to eGFP. Upon phosphorylation by CDKs, this fusion protein changes in localization from the nucleus to the cytoplasm. The combined regulation of transcription and subcellular localization enabled us to visualize the moment of cell cycle entry in dividing seam cells during C. elegans larval development. This reporter is the first to reflect cell cycle commitment in C. elegans and will help further genetic studies of the mechanisms that underlie cell cycle entry and exit., Competing Interests: The authors have declared that no competing interests exist.

During cell division, the mitotic spindle segregates replicated chromosomes to opposite poles of the cell, while the position of the spindle determines the plane of cleavage. Spindle positioning and chromosome segregation depend on pulling forces on microtubules extending from the centrosomes to the cell cortex. Critical in pulling force generation is the cortical anchoring of cytoplasmic dynein by a conserved ternary complex of Gα, GPR-1/2, and LIN-5 proteins in C. elegans (Gα-LGN-NuMA in mammals). Previously, we showed that the polarity kinase PKC-3 phosphorylates LIN-5 to control spindle positioning in early C. elegans embryos. Here, we investigate whether additional LIN-5 phosphorylations regulate cortical pulling forces, making use of targeted alteration of in vivo phosphorylated residues by CRISPR/Cas9-mediated genetic engineering. Four distinct in vivo phosphorylated LIN-5 residues were found to have critical functions in spindle positioning. Two of these residues form part of a 30 amino acid binding site for GPR-1, which we identified by reverse two-hybrid screening. We provide evidence for a dual-kinase mechanism, involving GSK3 phosphorylation of S659 followed by phosphorylation of S662 by casein kinase 1. These LIN-5 phosphorylations promote LIN-5-GPR-1/2 interaction and contribute to cortical pulling forces. The other two critical residues, T168 and T181, form part of a cyclin-dependent kinase consensus site and are phosphorylated by CDK1-cyclin B in vitro. We applied a novel strategy to characterize early embryonic defects in lethal T168,T181 knockin substitution mutants, and provide evidence for sequential LIN-5 N-terminal phosphorylation and dephosphorylation in dynein recruitment. Our data support that phosphorylation of multiple LIN-5 domains by different kinases contributes to a mechanism for spatiotemporal control of spindle positioning and chromosome segregation., Competing Interests: The authors have declared that no competing interests exist.

Occupational postures are considered to be an important group of risk factors for musculoskeletal pain. However, the exposure-outcome association is not clear yet. Therefore, we aimed to determine the exposure-outcome association of working postures and musculoskeletal symptoms. Also, we aimed to establish exposure limits for working postures. In a prospective cohort study among 789 workers, intensity, frequency and duration of postures were assessed at baseline using observations. Musculoskeletal pain was assessed cross-sectionally and longitudinally and associations of postures and pain were addressed using logistic regression analyses. Cut-off points were estimated based on ROC-curve analyses. Associations were found for kneeling/crouching and low-back pain, neck flexion and rotation and neck pain, trunk flexion and low-back pain, and arm elevation and neck and shoulder pain. The results provide insight into exposure-outcome relations between working postures and musculoskeletal symptoms as well as evidence-based working posture exposure limits that can be used in future guidelines and risk assessment tools. Practitioner Summary: Our study gives insight into exposure-outcome associations of working postures and musculoskeletal symptoms (kneeling/crouching and low-back pain, neck flexion/rotation and neck pain, trunk flexion and low-back pain, and arm elevation and neck and shoulder pain). Results furthermore deliver evidence-based postural exposure limits that can be used in guidelines and risk assessments.

Competing Interests: The authors have no conflicts of interest to declare.

Background: Affinity purification followed by mass spectrometry (AP/MS) is a widely used approach to identify protein interactions and complexes. In multicellular organisms, the accurate identification of protein complexes by AP/MS is complicated by the potential heterogeneity of complexes in different tissues. Here, we present an in vivo biotinylation-based approach for the tissue-specific purification of protein complexes from Caenorhabditis elegans. Tissue-specific biotinylation is achieved by the expression in select tissues of the bacterial biotin ligase BirA, which biotinylates proteins tagged with the Avi peptide., Results: We generated N- and C-terminal tags combining GFP with the Avi peptide sequence, as well as four BirA driver lines expressing BirA ubiquitously and specifically in the seam and hyp7 epidermal cells, intestine, or neurons. We validated the ability of our approach to identify bona fide protein interactions by identifying the known LGL-1 interaction partners PAR-6 and PKC-3. Purification of the Discs large protein DLG-1 identified several candidate interaction partners, including the AAA-type ATPase ATAD-3 and the uncharacterized protein MAPH-1.1. We have identified the domains that mediate the DLG-1/ATAD-3 interaction, and show that this interaction contributes to C. elegans development. MAPH-1.1 co-purified specifically with DLG-1 purified from neurons, and shared limited homology with the microtubule-associated protein MAP1A, a known neuronal interaction partner of mammalian DLG4/PSD95. A CRISPR/Cas9-engineered GFP::MAPH-1.1 fusion was broadly expressed and co-localized with microtubules., Conclusions: The method we present here is able to purify protein complexes from specific tissues. We uncovered a series of DLG-1 interactors, and conclude that ATAD-3 is a biologically relevant interaction partner of DLG-1. Finally, we conclude that MAPH-1.1 is a microtubule-associated protein of the MAP1 family and a candidate neuron-specific interaction partner of DLG-1.

The position of the mitotic spindle determines the cleavage plane in animal cells, but what controls spindle positioning? Kern et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201510117) demonstrate that the microtubule plus end-associated SKAP/Astrin complex participates in this process, possibly by affecting dynein-dependent pulling forces exerted on the tips of astral microtubules., (© 2016 Akhmanova and van den Heuvel.)

Introduction: The neuroinflammatory response plays a key role in several pain syndromes. Intravenous (iv) lidocaine is beneficial in acute and chronic pain. This review delineates the current literature concerning in vitro mechanisms and in vivo efficacy of iv lidocaine on the neuroinflammatory response in acute and chronic pain., Databases and Data Treatment: We searched PUBMED and the Cochrane Library for in vitro and in vivo studies from July 1975 to August 2014. In vitro articles providing an explanation for the mechanisms of action of lidocaine on the neuroinflammatory response in pain were included. Animal or clinical studies were included concerning iv lidocaine for acute or chronic pain or during inflammation., Results: Eighty-eight articles regarding iv lidocaine were included: 36 in vitro studies evaluating the effect on ion channels and receptors; 31 animal studies concerning acute and chronic pain and inflammatory models; 21 clinical studies concerning acute and chronic pain. Low-dose lidocaine inhibits in vitro voltage-gated sodium channels, the glycinergic system, some potassium channels and Gαq-coupled protein receptors. Higher lidocaine concentrations block potassium and calcium channels, and NMDA receptors. Animal studies demonstrate lidocaine to have analgesic effects in acute and neuropathic pain syndromes and anti-inflammatory effects early in the inflammatory response. Clinical studies demonstrate lidocaine to have advantage in abdominal surgery and in some neuropathic pain syndromes., Conclusions: Intravenous lidocaine has analgesic, anti-inflammatory and antihyperalgesic properties mediated by an inhibitory effect on ion channels and receptors. It attenuates the neuroinflammatory response in perioperative pain and chronic neuropathic pain., (© 2015 European Pain Federation - EFIC®)

The establishment of cell polarity is an essential process for the development of multicellular organisms and the functioning of cells and tissues. Here, we combine large-scale protein interaction mapping with systematic phenotypic profiling to study the network of physical interactions that underlies polarity establishment and maintenance in the nematode Caenorhabditis elegans. Using a fragment-based yeast two-hybrid strategy, we identified 439 interactions between 296 proteins, as well as the protein regions that mediate these interactions. Phenotypic profiling of the network resulted in the identification of 100 physically interacting protein pairs for which RNAi-mediated depletion caused a defect in the same polarity-related process. We demonstrate the predictive capabilities of the network by showing that the physical interaction between the RhoGAP PAC-1 and PAR-6 is required for radial polarization of the C. elegans embryo. Our network represents a valuable resource of candidate interactions that can be used to further our insight into cell polarization.

Objective: To validate Illumina's two-channel NextSeq 500 sequencing system for noninvasive prenatal testing (NIPT) of fetal whole chromosome and partial aberrations., Methods: A total of 162 plasma samples, previously sequenced for NIPT on a SOLiD 5500xl platform, were sequenced on the NextSeq 500 using 75-bp single-end sequencing, followed by analysis using the WISECONDOR algorithm., Results: For whole chromosome aneuploidy detection, all samples were classified correctly (in total 3× T13, 3× T18, 8× T21 and 145× euploid). Three partial aberrations (36-Mb terminal loss of 5p, 14-Mb gain on 18p and 33-Mb terminal loss of 13q) were also correctly identified. Fetal fractions in 34 male samples sequenced on both the SOLiD 5500xl and NextSeq 500 platform showed no significant difference. To test robustness, two sample sets, containing both euploid and aneuploid samples, were sequenced on different NextSeq 500 machines, revealing identical results. With unchanged laboratory flow, the NIPT turnaround time could be reduced from 15-16 calendar days to 7-8 calendar days, after switching from the SOLiD 5500xl to the NextSeq 500 platform., Conclusions: The NextSeq 500 platform can be used for NIPT to detect both whole and partial chromosome aberrations. It has fast turnaround times and is suitable for mid-sized laboratories., (© 2016 John Wiley & Sons, Ltd.)

Cell proliferation and differentiation show a remarkable inverse relationship. Precursor cells continue division before acquiring a fully differentiated state, while terminal differentiation usually coincides with proliferation arrest and permanent exit from the division cycle. Mechanistic insight in the temporal coordination between cell cycle exit and differentiation has come from studies of cells in culture and genetic animal models. As initially described for skeletal muscle differentiation, temporal coordination involves mutual antagonism between cyclin-dependent kinases that promote cell cycle entry and transcription factors that induce tissue-specific gene expression. Recent insights highlight the contribution of chromatin-regulating complexes that act in conjunction with the transcription factors and determine their activity. In particular SWI/SNF chromatin remodelers contribute to dual regulation of cell cycle and tissue-specific gene expression during terminal differentiation. We review the concerted regulation of the cell cycle and cell type-specific transcription, and discuss common mutations in human cancer that emphasize the clinical importance of proliferation versus differentiation control.

Accessible Summary: Existing evidence suggest that patient education in promoting self-management strategies of bipolar disorder (BD) is effective. However, results across the full range of service users with BD vary. Learning experiences of service users look to be a crucial factor to take into account when designing, delivering, and evaluating effective interventions that promote self-management in chronic illness. What learning activities service users actually undertake themselves when self-managing BD that might explain varying success rates, and guide future self-management educational programmes has not been examined. Unlike previous studies that suggest that outcomes in self-management depend on individual learning activities, the current study found that learning to self-manage BD takes place in a social network that functions as a learning environment in which it is saved for service users to make mistakes and to learn from these mistakes. Especially, coping with the dormant fear of a recurrent episode and acknowledging the limitations of an individual approach are important factors that facilitate this learning process. Practitioners who provide patient education in order to promote self-management of BD should tailor future interventions that facilitate learning by reflecting on the own experiences of service users. Community psychiatric nurses should keep an open discussion with service users and caregivers, facilitate the use of a network, and re-label problems into learning situations where both play an active role in building mutual trust, thereby enhancing self-management of BD., Abstract: Existing evidence suggest that self-management education of bipolar disorder (BD) is effective. However, why outcomes differ across the full range of service users has not been examined. This study describes learning experiences of service users in self-managing BD that provide a possible explanation for this varying effectiveness. We have conducted a phenomenological study via face-to-face, in-depth interviews, guided by a topic list, along service users with BD I or II (n = 16) in three specialised community care clinics across the Netherlands. Interviews were digitally recorded and transcribed verbatim prior to analysis in Atlas.ti 7. Unlike existing studies, which suggest that individual abilities of service users determine outcomes in self-management of BD, the current study found that self-management of BD is a learning process that takes place in a collaborative network. We identified five categories: acknowledgment of having BD, processing the information load, illness management, reflecting on living with BD, and self-management of BD. The success of self-management depends on the acknowledgment of individual limitations in learning to cope with BD and willingness to use a social network as a back-up instead. Especially, the dormant fear of a recurrent episode is a hampering factor in this learning process., (© 2015 John Wiley & Sons Ltd.)

The transition from proliferating precursor cells to post-mitotic differentiated cells is crucial for development, tissue homeostasis, and tumor suppression. To study cell-cycle exit during differentiation in vivo, we developed a conditional knockout and lineage-tracing system for Caenorhabditis elegans. Combined lineage-specific gene inactivation and genetic screening revealed extensive redundancies between previously identified cell-cycle inhibitors and the SWI/SNF chromatin-remodeling complex. Muscle precursor cells missing either SWI/SNF or G1/S inhibitor function could still arrest cell division, while simultaneous inactivation of these regulators caused continued proliferation and a C. elegans tumor phenotype. Further genetic analyses support that SWI/SNF acts in concert with hlh-1 MyoD, antagonizes Polycomb-mediated transcriptional repression, and suppresses cye-1 Cyclin E transcription to arrest cell division of muscle precursors. Thus, SWI/SNF and G1/S inhibitors provide alternative mechanisms to arrest cell-cycle progression during terminal differentiation, which offers insight into the frequent mutation of SWI/SNF genes in human cancers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cells are protected from toxic DNA double-stranded breaks (DSBs) by a number of DNA repair mechanisms, including some that are intrinsically error prone, thus resulting in mutations. To what extent these mechanisms contribute to evolutionary diversification remains unknown. Here, we demonstrate that the A-family polymerase theta (POLQ) is a major driver of inheritable genomic alterations in Caenorhabditis elegans. Unlike somatic cells, which use non-homologous end joining (NHEJ) to repair DNA transposon-induced DSBs, germ cells use polymerase theta-mediated end joining, a conceptually simple repair mechanism requiring only one nucleotide as a template for repair. Also CRISPR/Cas9-induced genomic changes are exclusively generated through polymerase theta-mediated end joining, refuting a previously assumed requirement for NHEJ in their formation. Finally, through whole-genome sequencing of propagated populations, we show that only POLQ-proficient animals accumulate genomic scars that are abundantly present in genomes of wild C. elegans, pointing towards POLQ as a major driver of genome diversification.