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In previous studies, glucagon receptor knockout mice (Gcgr(-/-)) display reduced blood glucose and increased glucose tolerance, with hyperglucagonemia and increased levels of glucagon-like peptide (GLP)-1. However, the role of glucagon receptor signaling for the regulation of islet function and insulin sensitivity is unknown. We therefore explored beta-cell function and insulin sensitivity in Gcgr(-/-) and wild-type mice. The steady-state glucose infusion rate during hyperinsulinemic-euglycemic clamp was elevated in Gcgr(-/-) mice, indicating enhanced insulin sensitivity. Furthermore, the acute insulin response (AIR) to intravenous glucose was higher in Gcgr(-/-) mice. The augmented AIR to glucose was blunted by the GLP-1 receptor antagonist, exendin-3. In contrast, AIR to intravenous administration of other secretagogues was either not affected (carbachol) or significantly reduced (arginine, cholecystokinin octapeptide) in Gcgr(-/-) mice. In islets isolated from Gcgr(-/-) mice, the insulin responses to glucose and several insulin secretagogues were all significantly blunted compared with wild-type mice. Furthermore, glucose oxidation was reduced in islets from Gcgr(-/-) mice. In conclusion, the present study shows that glucagon signaling is required for normal beta-cell function and that insulin action is improved when disrupting the signal. In vivo, augmented GLP-1 levels compensate for the impaired beta-cell function in Gcgr(-/-) mice. [ABSTRACT FROM AUTHOR]

This study assesses the bird strike resistance of the satellite communication (SatCom) radome of a medium altitude, long endurance (MALE) remotely piloted aircraft system (RPAS), which is designed as a lightweight sandwich structure with thin quartz fibre composite skins and a cellular honeycomb core. In order to perform accurate, predictive numerical bird strike simulations, the building block approach was applied, involving extensive experimental characterisation and model validation of the materials and structures from simple coupon level up to full-scale radome level. Coupon tests of the quartz fibre composite skin material under high-rate dynamic loading revealed significant strain rate effects, which needed to be taken into account in the simulation model in order to predict the structural response under high-velocity bird strike loading. In summary, this work presents a systematic and detailed approach for obtaining validated modelling methods for high-velocity impact analyses, which could be used efficiently for various design and parameter studies during the development of the SatCom radome.

The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes 1,2 . Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia 3 . Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle 4 and a glucoside to insulin, thereby introducing a switch that can open and close in response to glucose and thereby equilibrate insulin between active and less-active conformations. The insulin receptor affinity for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions., (© 2024. The Author(s).)

Booming UK ownership of designer-crossbreed dogs resulting from intentional crossing of distinct purebred breeds is often motivated by perceived enhanced health, despite limited evidence supporting a strong 'hybrid vigour' effect in dogs. Improved evidence on the relative health of designer-crossbreed dogs could support prospective owners to make better acquisition decisions when choosing their new dog. This study used a cross-sectional survey of UK owners of three common designer-crossbreeds (Cavapoo, Cockapoo, and Labradoodle) and their progenitor breeds (Cavalier King Charles Spaniel, Cocker Spaniel, Labrador Retriever, and Poodle) to collect owner-reported health disorder information. The authors hypothesised that designer-crossbred breeds have lower odds of common disorders compared to their progenitor breeds. Multivariable analysis accounted for confounding between breeds: dog age, sex, neuter status, and owner age and gender. The odds for the 57 most common disorders were compared across the three designer-crossbreeds with each of their two progenitor breeds (342 comparisons). Valid responses were received for 9,402 dogs. The odds did not differ statistically significantly between the designer-crossbreeds and their relevant progenitor breeds in 86.6% (n = 296) of health comparisons. Designer-crossbreeds had higher odds for 7.0% (n = 24) of disorders studied, and lower odds for 6.4% (n = 22). These findings suggest limited differences in overall health status between the three designer-crossbreeds and their purebred progenitors, challenging widespread beliefs in positive hybrid vigour effects for health in this emerging designer-crossbreed demographic. Equally, the current study did not suggest that designer-crossbreeds have poorer health as has also been purported. Therefore, owners could more appropriately base acquisition decisions between designer-crossbreeds and their purebred progenitors on other factors important to canine welfare such as breeding conditions, temperament, conformation and health of parents., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bryson 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.)

Maintaining genome integrity is vital for organismal survival and reproduction. Essential, broadly conserved DNA repair pathways actively preserve genome integrity. However, many DNA repair proteins evolve adaptively. Ecological forces like UV exposure are classically cited drivers of DNA repair evolution. Intrinsic forces like repetitive DNA, which also imperil genome integrity, have received less attention. We recently reported that a Drosophila melanogaster-specific DNA satellite array triggered species-specific, adaptive evolution of a DNA repair protein called Spartan/MH. The Spartan family of proteases cleave hazardous, covalent crosslinks that form between DNA and proteins ("DNA-protein crosslink repair"). Appreciating that DNA satellites are both ubiquitous and universally fast-evolving, we hypothesized that satellite DNA turnover spurs adaptive evolution of DNA-protein crosslink repair beyond a single gene and beyond the D. melanogaster lineage. This hypothesis predicts pervasive Spartan gene family diversification across Drosophila species. To study the evolutionary history of the Drosophila Spartan gene family, we conducted population genetic, molecular evolution, phylogenomic, and tissue-specific expression analyses. We uncovered widespread signals of positive selection across multiple Spartan family genes and across multiple evolutionary timescales. We also detected recurrent Spartan family gene duplication, divergence, and gene loss. Finally, we found that ovary-enriched parent genes consistently birthed functionally diverged, testis-enriched daughter genes. To account for Spartan family diversification, we introduce a novel mechanistic model of antagonistic coevolution that links DNA satellite evolution and adaptive regulation of Spartan protease activity. This framework promises to accelerate our understanding of how DNA repeats drive recurrent evolutionary innovation to preserve genome integrity., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The importance of eosinophilic granulocytes in cancer has been widely discussed in recent years. The current study reviews the evidence on the role of eosinophilic granulocytes in melanoma as a prognostic marker for cancer progression and the efficacy of treatment with modern immune checkpoint inhibitors. A total of 33 human clinical studies were included in the review, with heterogeneous data due to differences in patients populations, study design and inclusion of small study groups. However, 28 of the 33 studies suggested that eosinophilic granulocytes could be used as a prognostic biomarker for outcome and/or potential response to systemic treatment and/or occurrence of adverse events in melanoma patients. Nevertheless, the exact role of eosinophils remains to be elucidated. Further prospective, larger and better controlled studies are warranted to clarify the significance of eosinophilic granulocytes in patients with melanoma, in more details., 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 Brand, Hunger and Seyed Jafari.)

Objective: The biomarker S100B is a sensitive biomarker to detect traumatic intracranial injury in patients mild traumatic brain injury (mTBI). Higher blood values of S100B, resulting in lower specificity and decreased head computed tomography (CT) reduction has been regarded as one of shortcomings in patients over 65 years of age. The purpose of this study was to assess the accuracy of plasma S100B to detect intracranial injury in elderly patients with mTBI., Methods: A posthoc analysis was performed of a larger prospective cohort study. Previous recorded patient variables and plasma values of S100B from patients with mTBI who presented to the Emergency Department (ED) within 6 h of injury, underwent a head CT and had a blood sample drawn as part of their routine clinical care, were partitioned at 65 years of age. Sensitivity, specificity, negative predictive value, and positive predictive value of plasma S100B for predicting traumatic intracranial lesions on head CT, with a cut-off set at 0.105 μg/L, were calculated. Results were compared with data from an additional systematic review on the accuracy of S100B to detect intracranial injury in elderly patients with mTBI., Results: Data of 240 patients (48.4 %) of 65 years or older were analyzed. Sensitivity and NPV of S100B were 89 % and 86 % respectively, which is lower than among younger patients (both 97 %). The specificity decreased stepwise with older age: 22 %, 18 %, and 5 % for the age groups 65-74, 75-84, and ≥ 85 years old, respectively. The meta-analysis comprised 4 studies and the current study with data from 2166 patients. Pooled data estimated the sensitivity of s100B as 97.4 % (95 % CI 83.3-100 %) and specificity as 17.3 % (95 % CI 9.5-29.3 %) to detect intracranial injury in elderly patients with mTBI., Conclusion: The biomarker S100B at the routine threshold has a limited clinical value in the management of elderly mTBI patients mainly due to a poor specificity leading to only a small decrease in head CTs. Alternate cut-off values and combining several plasma biomarkers with clinical variables may be useful strategies to increase the accuracy of S100B in (subgroups of) elderly mTBI patients., Competing Interests: Declaration of competing interest No competing financial interests exist., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Problem behaviours are a leading cause of relinquishment and euthanasia of young dogs. Previous research has identified associations between owner-reported problem behaviours and risk factors, including how dogs were acquired as puppies, early socialisation experiences, and owners' experience levels. Puppies acquired during the 2020 phase of the UK COVID-19 pandemic ("Pandemic Puppies") were more likely to be exposed to many of these risk factors compared to puppies acquired in 2019; however, consequences for their adult behaviour are, as yet, unexplored. This study aimed to investigate the impact of these early-life and provenance-based risk factors, in addition to owner management strategies (including training methods) into early adulthood, upon adult dog behaviour aged 21 months. An online longitudinal cohort study of n = 985 Pandemic Puppies was conducted, recruited from a cohort of n = 4369 puppies originally surveyed in November-December 2020, which included data on how and why they were acquired and their socialisation/habituation experiences <16 weeks of age. Nearly all owners (96.7%) reported that their dog had exhibited at least one problem behaviour up to 21 months of age (median: 5; IQR: 3-7). Almost one third of dogs (30.9%) were reported to have displayed separation-related behaviours. Multivariable linear regression modelling revealed that owners reporting more problem behaviours were more likely to use multiple aversive training techniques (e.g., physical punishment), the use of which was notably high in this population (82.3%) compared to previous studies. Attendance at online puppy classes was the sole protective factor against owner use of aversive training methods. Almost one third of owners had underestimated how hard training their dog would be; this view was more likely among first-time owners. Urgent efforts are required to support this vulnerable population of dogs, including providing owner education regarding humane training techniques, to improve canine emotional health and avoid future relinquishment and/or behavioural euthanasia.

The COVID-19 pandemic led to a surge in acquisitions of puppies in the UK, dubbed the "Pandemic Puppy" phenomenon. In addition to an increased demand for puppies, widespread changes to both why and how puppies were purchased during this period compared to pre-pandemic 2019 purchases were documented, many of which threatened canine welfare (e.g., puppies being collected away from their place of birth, without seeing their mother). This study aimed to explore which changes to the pre-purchase and purchase motivations and behaviours of UK owners who purchased a puppy aged <16 weeks in the 2020 phase of the COVID-19 pandemic had persisted into 2021 or had returned to pre-pandemic 2019 levels. An online survey was conducted during February to April 2022 from which 2080 valid responses were analysed ("2021 puppies") and compared with previously collected data from comparable cohorts in 2019 ( n = 1148, "2019 puppies") and 2020 ( n = 4369, "Pandemic Puppies"). While the majority of the peak pandemic changes documented in 2020 had returned to their 2019 pre-pandemic baseline, others persisted into 2021. Multinomial logistic regression models revealed that the shifts during 2020 towards owners viewing their puppy pre-purchase over video calls or via video recordings/photos rather than in-person and towards collecting their puppy from outside of their breeders' property rather than inside had persisted into 2021 and had not returned to pre-pandemic levels. Year-on-year significant rises in the number of puppies sold with a passport were documented between 2019 and 2021, with over 1 in 10 2021 puppies having been sold with a passport, the figure more than doubling since 2019. An increasing number of these puppies sold with a passport were under the minimum legal age for import at sale. Going forward, these concerning changes require further monitoring and human behaviour change interventions to tackle, including increased buyer awareness but also legislative approaches to prevent the greatest harm.

Background: Insulin detemir (IDet) is an insulin analog used to treat diabetes. IDet shows full efficacy but reduced potency compared to human insulin (HI) in both man and rat. In contrast, in pigs and dogs, IDet appears to have full in vivo potency. Non-receptor mediated degradation (NRMD) has previously been suggested as an explanation for the low potency of IDet, but this hypothesis has not been investigated further until now. Bacitracin is a nonspecific protease inhibitor which we hypothesized could inhibit NRMD of IDet in rats., Research Design and Methods: Healthy male rats instrumented with permanent catheters underwent euglycemic clamp during constant infusion of either HI or IDet at effect-matched doses with co-infusion of vehicle or bacitracin., Results: Plasma concentrations of IDet increased significantly ( p  < 0.005) during bacitracin compared to vehicle co-infusion and the concomitant increase in glucose infusion rate (GIR, p  < 0.001) required to maintain euglycemic clamp indicates that the IDet rescued from NRMD indeed was active. No significant differences were detected with co-infusions of HI with either bacitracin or vehicle., Conclusions: A large proportion of NRMD of IDet which can be inhibited by bacitracin may partly explain the reduced potency of IDet observed in rats and likely also in man.

Aims/hypothesis: Normalisation of blood glucose in individuals with diabetes is recommended to reduce development of diabetic complications. However, risk of severe hypoglycaemia with intensive insulin therapy is a major obstacle that prevents many individuals with diabetes from obtaining the recommended reduction in HbA 1c . Inhibition of glucagon receptor signalling and liver-preferential insulin action have been shown individually to have beneficial effects in preclinical models and individuals with diabetes (i.e. improved glycaemic control), but also have effects that are potential safety risks (i.e. alpha cell hyperplasia in response to glucagon receptor antagonists and increased levels of liver triacylglycerols and plasma alanine aminotransferase activity in response to glucagon receptor antagonists and liver-preferential insulin). We hypothesised that a combination of glucagon inhibition and liver-preferential insulin action in a dual-acting molecule would widen the therapeutic window. By correcting two pathogenic mechanisms (dysregulated glucagon signalling and non-physiological distribution of conventional insulin administered s.c.), we hypothesised that lower doses of each component would be required to obtain sufficient reduction of hyperglycaemia, and that the undesirable effects that have previously been observed for monotreatment with glucagon antagonists and liver-preferential insulin could be avoided., Methods: A dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule was designed and tested in rodent models (normal rats, rats with streptozotocin-induced hyperglycaemia, db/db mice and mice with diet-induced obesity and streptozotocin-induced hyperglycaemia), allowing detailed characterisation of the pharmacokinetic and pharmacodynamic properties of the dual-acting molecule and relevant control compounds, as well as exploration of how the dual-acting molecule influenced glucagon-induced recovery and spontaneous recovery from acute hypoglycaemia., Results: This molecule normalised blood glucose in diabetic models, and was markedly less prone to induce hypoglycaemia than conventional insulin treatment (approximately 4.6-fold less potent under hypoglycaemic conditions than under normoglycaemic conditions). However, compared to treatment with conventional long-acting insulin, this dual-acting molecule also increased triacylglycerol levels in the liver (approximately 60%), plasma alanine aminotransferase levels (approximately twofold) and alpha cell mass (approximately twofold)., Conclusions/interpretation: While the dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule showed markedly improved regulation of blood glucose, effects that are potential safety concerns persisted in the pharmacologically relevant dose range., (© 2022. The Author(s).)

Age is variably described as a minor or major risk factor for traumatic intracranial lesions after head injury. However, at present, no specific CT decision rule is available for elderly patients with minor head injury (MHI). The aims of this prospective multicenter cohort study were to assess the performance of existing CT decision rules for elderly MHI patients and to compare the clinical and CT characteristics of elderly patients with the younger MHI population. Thirty-day mortality between two age groups (cutoff ≥ 60 years), along with clinical and CT characteristics, was evaluated with four CT decision rules: the National Institute for Health and Care Excellence (NICE) guideline, the Canadian CT Head Rule (CCHR), the New Orleans Criteria (NOC), and the CT Head Injury Patients (CHIP) rule. Of the 5517 MHI patients included, 2310 were aged ≥ 60 years. Elderly patients experienced loss of consciousness (17% vs. 32%) and posttraumatic amnesia (23% vs. 31%) less often, but intracranial lesions (13% vs. 10%), neurological deterioration (1.8% vs. 0.2%), and 30-day mortality (2.0% vs. 0.1%) were more frequent than in younger patients (all p < 0.001). Elderly patients with age as their only risk factor showed intracranial lesions in 5% (NOC and CHIP) to 8% (CCHR and NICE) of cases. The sensitivity of decision rules in the elderly patients was 60% (CCHR) to 97% (NOC) when age was excluded as a risk factor. Current risk factors considered when evaluating elderly patients show lower sensitivity to identify intracranial abnormalities, despite more frequent intracranial lesions. Until age-specific CT decision rules are developed, it is advisable to scan every elderly patient with an MHI.

Objective: To update the existing CHIP (CT in Head Injury Patients) decision rule for detection of (intra)cranial findings in adult patients following minor head injury (MHI)., Methods: The study is a prospective multicenter cohort study in the Netherlands. Consecutive MHI patients of 16 years and older were included. Primary outcome was any (intra)cranial traumatic finding on computed tomography (CT). Secondary outcomes were any potential neurosurgical lesion and neurosurgical intervention. The CHIP model was validated and subsequently updated and revised. Diagnostic performance was assessed by calculating the c-statistic., Results: Among 4557 included patients 3742 received a CT (82%). In 383 patients (8.4%) a traumatic finding was present on CT. A potential neurosurgical lesion was found in 73 patients (1.6%) with 26 (0.6%) patients that actually had neurosurgery or died as a result of traumatic brain injury. The original CHIP underestimated the risk of traumatic (intra)cranial findings in low-predicted-risk groups, while in high-predicted-risk groups the risk was overestimated. The c-statistic of the original CHIP model was 0.72 (95% CI 0.69-0.74) and it would have missed two potential neurosurgical lesions and one patient that underwent neurosurgery. The updated model performed similar to the original model regarding traumatic (intra)cranial findings (c-statistic 0.77 95% CI 0.74-0.79, after crossvalidation c-statistic 0.73). The updated CHIP had the same CT rate as the original CHIP (75%) and a similar sensitivity (92 versus 93%) and specificity (both 27%) for any traumatic (intra)cranial finding. However, the updated CHIP would not have missed any (potential) neurosurgical lesions and had a higher sensitivity for (potential) neurosurgical lesions or death as a result of traumatic brain injury (100% versus 96%)., Conclusions: Use of the updated CHIP decision rule is a good alternative to current decision rules for patients with MHI. In contrast to the original CHIP the update identified all patients with (potential) neurosurgical lesions without increasing CT rate., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The Dutch Surgical Aneurysm Audit (DSAA) is a nationwide mandatory quality registry that evaluates the perioperative outcomes of abdominal aortic aneurysms (AAAs). The DSAA includes perioperative outcomes that occur up to 30 days, but various complications following AAA repair occur after this period. Administrative healthcare data yield the possibility to evaluate later occuring outcomes such as reinterventions, without increasing the registration burden. The aim of this study is to assess the feasibility and the potential benefit of administrative healthcare data to evaluate mid-term reinterventions following intact AAA repair., Method: All patients that underwent primary endovascular aneurysm repair (EVAR) or open surgical repair (OSR) for an intact infrarenal AAA between January 2017 and December 2018 were selected from the DSAA. Subsequently, these patients were identified in a database containing reimbursement data. Healthcare activity codes that refer to reinterventions following AAA repair were examined to assess reinterventions within 12 and 15 months following EVAR and OSR., Results: We selected 4043 patients from the DSAA, and 2059 (51%) patients could be identified in the administrative healthcare database. Reintervention rates of 10.4% following EVAR and 9.5% following OSR within 12 months (p = 0.719), and 11.5% following EVAR and 10.8% following OSR within 15 months (p = 0.785) were reported., Conclusion: Administrative healthcare data as an addition to the DSAA is potentially beneficial to evaluate mid-term reinterventions following intact AAA repair without increasing the registration burden for clinicians. Further validation is necessary before reliable implementation of this tool is warranted., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Satellite DNA spans megabases of eukaryotic sequence and evolves rapidly. 1-6 Paradoxically, satellite-rich genomic regions mediate strictly conserved, essential processes such as chromosome segregation and nuclear structure. 7-10 A leading resolution to this paradox posits that satellite DNA and satellite-associated chromosomal proteins coevolve to preserve these essential functions. 11 We experimentally test this model of intragenomic coevolution by conducting the first evolution-guided manipulation of both chromosomal protein and DNA satellite. The 359bp satellite spans an 11 Mb array in Drosophila melanogaster that is absent from its sister species, Drosophila simulans. 12-14 This species-specific DNA satellite colocalizes with the adaptively evolving, ovary-enriched protein, maternal haploid (MH), the Drosophila homolog of Spartan. 15 To determine if MH and 359bp coevolve, we swapped the D. simulans version of MH ("MH[sim]") into D. melanogaster. MH[sim] triggers ovarian cell death, reduced ovary size, and loss of mature eggs. Surprisingly, the D. melanogaster mh-null mutant has no such ovary phenotypes, 15 suggesting that MH[sim] is toxic in a D. melanogaster background. Using both cell biology and genetics, we discovered that MH[sim] poisons oogenesis through a DNA-damage pathway. Remarkably, deleting the D. melanogaster-specific 359bp satellite array completely restores mh[sim] germline genome integrity and fertility, consistent with a history of coevolution between these two fast-evolving loci. Germline genome integrity and fertility are also restored by overexpressing topoisomerase II (Top2), suggesting that MH[sim] interferes with Top2-mediated processing of 359bp. The observed 359bp-MH[sim] cross-species incompatibility supports a model under which seemingly inert repetitive DNA and essential chromosomal proteins must coevolve to preserve germline genome integrity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This paper examines how to reduce the number of control animals in preclinical hyperinsulemic glucose clamp studies if we make use of information on historical studies. A dataset consisting of 59 studies in rats to investigate new insulin analogues for diabetics, collected in the years 2000 to 2015, is analysed. A simulation experiment is performed based on a carefully built nonlinear mixed-effects model including historical information, comparing results (for the relative log-potency) with the standard approach ignoring previous studies. We find that by including historical information in the form of the mixed-effects model proposed, we can to remove between 23% and 51% of the control rats in the two studies looked closely upon to get the same level of precision on the relative log-potency as in the standard analysis. How to incorporate the historical information in the form of the mixed-effects model is discussed, where both a mixed-effect meta-analysis approach as well as a Bayesian approach are suggested. The conclusions are similar for the two approaches, and therefore, we conclude that the inclusion of historical information is beneficial in regard to using fewer control rats., Competing Interests: Emilie Prang Nielsen, Søren Andersen and Christian Lehn Brand are employed by Novo Nordisk and hold shares in the company. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Demand for intentional crosses of purebred dog breeds, often labelled 'designer crossbreeds' (e.g., Labrador Retriever X Poodle, the 'Labradoodle'), has recently increased in the UK. This study aimed to explore this phenomenon by comparing pre-purchase motivations, pre-purchase and purchase behaviours of UK owners of designer crossbred puppies purchased during 2019-2020 with those of owners of purebred puppies purchased during the same period., Results: Data were collected in an online cross-sectional survey between November-December 2020. Responses from n = 6293 puppies (designer crossbred puppies: n = 1575; purebred puppies: n = 4718) were analysed. Perceived hypoallergenicity was cited as a motivator for breed/crossbreed choice by almost half of designer crossbreed owners (47.1%), six times more than purebred dog owners (7.86%; odds ratio [OR]: 9.12, 95% CI: 7.70-10.8). Designer crossbred puppies were more likely to have been acquired via a general selling website (e.g., Gumtree; 13.8%) compared to purebred puppies (7.67%; OR: 2.19, 95% CI: 1.77-2.71), or an animal-specific selling websites (e.g., Pets4Homes; 55.7%) compared to purebred puppies (37.4%; OR: 1.89, 95% CI: 1.65-2.17). Designer crossbreed owners were less likely to see their puppy in person prior to purchase than purebred owners (60.4% vs. 67.0%, respectively; OR: 0.74, 95% CI: 0.64-0.85), and at purchase, designer crossbred puppies were less likely to be seen with their mother (73.1% vs. 79.8%, respectively; OR: 0.82, 95% CI: 0.70-0.95), and littermates (67.7% vs. 78.1%, respectively; OR: 0.63, 95% CI: 0.55-0.73). Designer crossbreeds had a significantly higher purchase price, with 25.7% of designer crossbreed puppies costing £2000-£2999 compared to 15.1% of purebred puppies (X 2  = 207.31, p <  0.001)., Conclusions: The recent boom in designer crossbreeds in the UK has been fuelled by a desire for perceived hypoallergenic and generally healthy dogs that fit the lifestyles of households with children and limited experience with dogs. Some sought-after traits in designer crossbreeds are misconceptions that risk canine welfare, including relinquishment risk, if owner expectations are not met. Purchasing practices fuelling this boom support irresponsible breeding and selling practices, which combined with reduced pressure for health testing from buyers, may result in a higher disease burden and poorer future welfare for this growing designer dog population., (© 2022. The Author(s).)

BACKGROUND : Nonmodifiable patient and endoscopy characteristics might influence colonoscopy performance. Differences in these so-called case-mix factors are likely to exist between endoscopy centers. This study aimed to examine the importance of case-mix adjustment when comparing performance between endoscopy centers. METHODS : Prospectively collected data recorded in the Dutch national colonoscopy registry between 2016 and 2019 were retrospectively analyzed. Cecal intubation rate (CIR) and adequate bowel preparation rate (ABPR) were analyzed. Additionally, polyp detection rate (PDR) was studied in screening colonoscopies following a positive fecal immunochemical test (FIT). Variation in case-mix factors between endoscopy centers and expected outcomes for each performance measure were calculated per endoscopy center based on case-mix factors (sex, age, American Society of Anesthesiologist [ASA] score, indication) using multivariable logistic regression. RESULTS:  363 840 colonoscopies were included from 51 endoscopy centers. Mean percentages per endoscopy center were significantly different for age > 65 years, male patients, ASA ≥ III, and diagnostic colonoscopies (all P  < 0.001). In the FIT-positive screening population, significant differences were observed between endoscopy centers for age > 65 years, male patients, and ASA ≥ III (all P  ≤ 0.001). The expected CIR, ABPR, and PDR ranged from 95.0 % to 96.9 %, from 93.6 % to 96.4 %, and from 76.2 % to 79.1 %, respectively. Age, sex, ASA classification, and indication were significant case-mix factors for CIR and ABPR. In the FIT-positive screening population, age, sex, and ASA classification were significant case-mix factors for PDR. CONCLUSION:  Our findings emphasize the importance of considering case-mix adjustment when comparing colonoscopy performance measures between endoscopy centers., Competing Interests: Evelien Dekker declares to have endoscopic equipment on loan of FujiFilm, receive a research grant from FujiFilm. She received a honorarium for consultancy from FujiFilm, Olympus, Tillots, GI Supply and CPP-FAP and a speakers' fee from Olympus, Roche, GI Supply and Norgine. Paul Fockens declares to have received a honorarium for consultancy from Olympus, Cook Endoscopy and research support from Boston Scientific. The other authors declare that no conflicts of interest exist., (Thieme. All rights reserved.)

Meiotic drive supergenes are complexes of alleles at linked loci that together subvert Mendelian segregation resulting in preferential transmission. In males, the most common mechanism of drive involves the disruption of sperm bearing one of a pair of alternative alleles. While at least two loci are important for male drive-the driver and the target-linked modifiers can enhance drive, creating selection pressure to suppress recombination. In this work, we investigate the evolution and genomic consequences of an autosomal, multilocus, male meiotic drive system, Segregation Distorter ( SD ) in the fruit fly, Drosophila melanogaster . In African populations, the predominant SD chromosome variant, SD-Mal , is characterized by two overlapping, paracentric inversions on chromosome arm 2R and nearly perfect (~100%) transmission. We study the SD-Mal system in detail, exploring its components, chromosomal structure, and evolutionary history. Our findings reveal a recent chromosome-scale selective sweep mediated by strong epistatic selection for haplotypes carrying Sd , the main driving allele, and one or more factors within the double inversion. While most SD-Mal chromosomes are homozygous lethal, SD-Mal haplotypes can recombine with other, complementing haplotypes via crossing over, and with wildtype chromosomes via gene conversion. SD-Mal chromosomes have nevertheless accumulated lethal mutations, excess non-synonymous mutations, and excess transposable element insertions. Therefore, SD-Mal haplotypes evolve as a small, semi-isolated subpopulation with a history of strong selection. These results may explain the evolutionary turnover of SD haplotypes in different populations around the world and have implications for supergene evolution broadly., Competing Interests: BN, CC, CB, CM, DP, AL No competing interests declared, (© 2022, Navarro-Dominguez et al.)

To compare hospitals' hip fracture patient mortality in a quality of care registry, correction for patient characteristics is needed. This study evaluates in 39,374 patients which characteristics are associated with 30 and 90-day mortality, and showed how using these characteristics in a case mix-model changes hospital comparisons within the Netherlands., Purpose: Mortality rates after hip fracture surgery are considerable and may be influenced by patient characteristics. This study aims to evaluate hospital variation regarding patient demographics and disease burden, to develop a case-mix adjustment model to analyse differences in hip fracture patients' mortality to calculate case-mix adjusted hospital-specific mortality rates., Methods: Data were derived from 64 hospitals participating in the Dutch Hip Fracture Audit (DHFA). Adult hip fracture patients registered in 2017-2019 were included. Variation of case-mix factors between hospitals was analysed, and the association between case-mix factors and mortality at 30 and 90 days was determined through regression models., Results: There were 39,374 patients included. Significant variation in case-mix factors amongst hospitals was found for age ≥ 80 (range 25.8-72.1% p < 0.001), male gender (12.0-52.9% p < 0.001), nursing home residents (42.0-57.9% p < 0.001), pre-fracture mobility aid use (9.9-86.7% p < 0,001), daily living dependency (27.5-96.5% p < 0,001), ASA-class ≥ 3 (25.8-83.3% p < 0.001), dementia (3.6-28.6% p < 0.001), osteoporosis (0.0-57.1% p < 0.001), risk of malnutrition (0.0-29.2% p < 0.001) and fracture types (all p < 0.001). All factors were associated with 30- and 90-day mortality. Eight hospitals showed higher and six showed lower 30-day mortality than expected based on their case-mix. Six hospitals showed higher and seven lower 90-day mortality than expected. The specific outlier hospitals changed when correcting for case-mix factors., Conclusions: Dutch hospitals show significant case-mix variation regarding hip fracture patients. Case-mix adjustment is a prerequisite when comparing hospitals' 30-day and 90-day hip fracture patients' mortality. Adjusted mortality may serve as a starting point for improving hip fracture care., (© 2022. The Author(s).)

The aim of this work was to conduct a systematic review and meta-analysis of studies reporting on the risk of traumatic intracerebral hemorrhage (tICH), the course of tICH, and its treatment and mortality rates in elderly mild traumatic brain injury (mTBI) patients using direct oral anticoagulants (DOACs). We consulted PubMed and Embase for relevant cohort and case-control studies with a control group. Two authors independently selected studies, assessed methodological quality, and extracted outcome data. Estimates were pooled with the Mantel-Haenszel random-effects method. We identified 16 articles comprising 3671 elderly mTBI patients using DOACs. Use of DOACs was associated with a reduced risk of tICH compared to the use of vitamin K antagonists (VKAs; odds ratio [OR], 0.44; 95% confidence interval [CI], 0.29-0.65; I 2  = 22%) and a similar risk compared to the use of antiplatelet therapy (APT; OR, 0.98; 95% CI, 0.39-2.44; I 2  = 0%). Reversal agent use and neurosurgical intervention rate were lower in patients using DOACs compared to patients using VKAs (OR, 0.10; 95% CI, 0.06-0.16; I 2  = 0% and OR, 0.37; 95% CI, 0.21-0.67; I 2  = 0%, respectively). There was no significant difference in neurosurgical intervention rate between patients who used DOACs versus patients who used APT (OR, 0.58; 95% CI, 0.15-2.21; I 2  = 41%) or no antithrombotic therapy (OR, 0.76; 95% CI, 0.20-2.86; I 2  = 23%). ICH progression, risk of delayed ICH, and TBI-related in-hospital mortality were comparable among treatment groups. The present study indicates that elderly patients using DOACs have a lower risk of adverse outcome compared to patients using VKAs and a similar risk compared to patients using APT after mTBI.

The UK recorded sharp rises in puppy purchasing during the 2020 phase of the COVID-19 pandemic, with many first-time dog owners purchasing puppies to improve their mental health during this challenging period. Government restrictions on movement and social interaction during the pandemic led to animal welfare concerns over puppies’ reduced time-sensitive exposures to key environmental and social stimuli during their critical developmental period. This study aimed to compare demographics, health and early-life experiences of puppies purchased and brought home < 16 weeks of age between 23 March−31 December 2020 (“Pandemic Puppies”), with dogs purchased and brought home < 16 weeks during the same date period in 2019 (“2019 puppies”). An online survey of UK-based puppy owners was conducted between 10 November and 31 December 2020 with valid responses representing 5517 puppies (Pandemic Puppies: n = 4369; 2019 puppies: n = 1148). Multivariable logistic regression modelling revealed that Pandemic Puppies were less likely to have attended puppy training classes (67.9% 2019 vs. 28.9% 2020; p < 0.001) or had visitors to their home (94.5% 2019 vs. 81.8% 2020; p < 0.001) aged < 16 weeks compared with 2019 puppies. Fewer Pandemic Puppies underwent veterinary checks prior to purchase than 2019 puppies (2019: 91.3% vs. 2020: 87.4%; p < 0.001), but more were sold with a passport (2019: 4.1% vs. 2020: 7.1%; p < 0.001). Pandemic Puppies were significantly more likely to be ‘Designer Crossbreeds’ (2019: 18.8% vs. 2020: 26.1%; p < 0.001) and less likely to be Kennel Club registered than 2019 puppies (2019: 58.2% vs. 2020: 46.2%; p < 0.001). Greater support from veterinary and animal behavioural professionals is likely needed to ameliorate the health and behavioural impacts of growing up in a pandemic upon this vulnerable population.

Repeat-enriched genomic regions evolve rapidly and yet support strictly conserved functions like faithful chromosome transmission and the preservation of genome integrity. The leading resolution to this paradox is that DNA repeat-packaging proteins evolve adaptively to mitigate deleterious changes in DNA repeat copy number, sequence, and organization. Exciting new research has tested this model of coevolution by engineering evolutionary mismatches between adaptively evolving chromatin proteins of one species and the DNA repeats of a close relative. Here, we review these innovative evolution-guided functional analyses. The studies demonstrate that vital, chromatin-mediated cellular processes, including transposon suppression, faithful chromosome transmission, and chromosome retention depend on species-specific versions of chromatin proteins that package species-specific DNA repeats. In many cases, the ever-evolving repeats are selfish genetic elements, raising the possibility that chromatin is a battleground of intragenomic conflict.

Widespread media reports suggest that unusually high numbers of the public purchased, or sought to purchase, puppies following the first 'lockdown' phase of the COVID-19 pandemic in the UK, dubbed "Pandemic Puppies". This study aimed to explore this phenomenon by comparing pre-purchase motivations and behaviours, and purchase behaviours of UK owners purchasing puppies aged < 16 weeks from 23 March 2020-31 December 2020 with those of owners who purchased puppies during the same date-period in 2019. An online survey was conducted during November-December 2020, from which 5517 valid responses were analysed (2019 puppies: n = 1148; 2020 'Pandemic Puppies': n = 4369). Over 1 in 10 Pandemic Puppy owners had not considered purchasing a puppy before the pandemic, and 2 in 5 felt their decision to purchase a puppy had been influenced by the pandemic, most commonly by having more time to care for a dog (86.7%). Multivariable logistic regression models revealed that Pandemic Puppy owners were more likely to be first-time dog owners and have children in their household, were less likely to seek out a breeder that performed health testing on their breeding dog(s) or view their puppy in-person, and were more likely to pay a deposit without seeing their puppy. At purchase, Pandemic Puppies were more likely to be younger, delivered or collected from outside their breeders' property, seen without their littermates, and cost > £2000 compared with 2019 puppies. Changes in puppy purchasing during the pandemic raise welfare concerns for this unique population, including relinquishment, behavioural problems and poor health.

When acute stroke care is organised using a "drip-and-ship" model, patients receive immediate treatment at the nearest primary stroke centre followed by transfer to a comprehensive stroke centre (CSC). When stroke care is further centralised into the "direct-to-mothership" model, patients with stroke symptoms are immediately brought to a CSC to further reduce treatment times and enhance stroke outcomes. We investigated the effects of the ongoing centralization in a Dutch urban setting on treatment times of patients with confirmed ischemic stroke in a 4-year period. Next, in a non-randomized controlled trial, we assessed treatment times of patients with suspected ischemic stroke, and treatment times of patients with neurologic disorders other than suspected ischemic stroke, before and after the intervention in the CSC and the decentralized hospitals, the intervention being the change from "drip and ship" into "direct-to-mothership". Our findings provide support for the ongoing centralization of acute stroke care in urban areas. Treatment times for patients with ischemic stroke decreased significantly, potentially improving functional outcomes. Improvements in treatment times for patients with suspected ischemic stroke were achieved without negative side effects for self-referrals with stroke symptoms and patients with other neurological disorders., Competing Interests: Declaration of Competing Interest All authors work in the study setting, except for Naomi van der Linden, who currently works at the University of Twente but was employed by AstraZeneca Netherlands, a pharmaceutical company, during this study. Crispijn van den Brand worked in the study setting and is currently employed by the Dutch Institute for Clinical Auditing.The authors declare that they have no competing interests, (Copyright © 2021. Published by Elsevier B.V.)

Background: Emergency departments (EDs) are faced with a growing number of patients with traumatic brain injury (TBI) using direct oral anticoagulants (DOACs). However, there remains uncertainty about the bleeding risk, rate of hematoma expansion, and the efficacy of reversal strategies in these patients., Objective: This study aims to identify the risk of traumatic hemorrhagic complications in patients with TBI using DOACs., Methods: In this retrospective study we included patients with TBI. All TBI patients were using DOACs, attended one of the three EDs of our hospital between January 2016 and October 2019, and received a computed tomography (CT) scan of the brain. The primary outcome was any traumatic intracranial hemorrhage on CT. Secondary outcomes were the use of reversal agents, secondary neurological deterioration, a neurosurgical intervention within 30 days after the injury, length of stay (LOS), Glasgow Outcome Scale (GOS) at discharge, and mortality., Results: Of the included patients (N = 316), 24 patients (7.6%, 95% confidence interval [CI] 4.2-9.8) presented with a traumatic intracranial hematoma (ICH). Seven patients (2.2%, 95% CI 0.6-3.8) received a reversal agent and 1 patient (0.3%, 95% CI -0.3-0.9) underwent a neurosurgical intervention. Of the 24 patients with a traumatic ICH, progression of the lesion was seen in 6 patients (1.9%, 95% CI 0.4-3.4). The mean LOS was 6.5 days (95% CI 3.0-10.1) and the mean GOS at discharge was 4 (95% CI 3.6-4.6). Death occurred in 1 patient (0.3%, 95% CI -0.3-0.9) suffering from an ICH., Conclusion: Based on the present findings it can be postulated that TBI patients using DOACs have a low risk for ICH. Hematoma progression occurred, however, in a substantial number of patients. Considering the retrospective nature of the present study, future prospective trials are needed to confirm this finding., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: A new nationwide guideline for minor head injury was introduced in the Netherlands in 2010. The effect on computed tomography (CT) ratio and hospital admission ratio after introduction of the guideline is unknown. The aim was to reduce these numbers as part of cost-effective health care. Therefore, we assessed the effect on these variables after introduction of the guideline., Methods: We used an interrupted time-series study design. Data selection was done 3 years before (2007-2009) and several years after (2012, 2014, 2015) introduction of the guideline., Results: Data collection was performed for 3880 patients. Introduction of the new guideline was associated with an increase in CT ratio from 24.6% before to 55% after introduction (P < 0.001). This increase is the result of both the new guideline and a secular trend. Besides this, hospital admissions increased from 14.7 to 23.4% (P < 0.001) during the study period. This increase was less clearly associated with the new guideline. After introduction of the guideline there was no significant difference in (intra)cranial traumatic findings (2.6% vs. 3.4%; P = 0.13) and neurosurgical interventions (0.1% vs. 0.2%; P = 0.50)., Conclusion: Between 2007 and 2015, a marked increase in CT ratio and hospital admissions has been observed. The increase in CT ratio seems to be caused both by the new guideline and by a secular trend to perform more CT scans. Adaptations to the guideline should be considered to improve patient care and cost-effectiveness in patients with minor head injury.

The aim of this study was to determine the association between bicycle helmet use in adults (16 years and older) and traumatic brain injury (TBI) in emergency departments (EDs) in the Netherlands.The conducted research was a retrospective case-control study in patients aged 16 years and older who sustained a bicycle accident and therefore visited the EDs of participating hospitals throughout 2016. Cases were patients with TBI; controls were patients without TBI but with other trauma. Exposure was defined as helmet wearing during the accident. In total, 2133 patients were included in the study, 361 case patients and 1772 controls. Within the TBI group (cases) 3.9% of patients wore a helmet compared with 7.7% of patients in the control (non-head injury) group (odds ratio [OR] 0.49, 95% confidence interval [CI]: 0.28-0.86). No difference in helmet wearing was observed in patients who sustained accidents that involved motorized vehicles (OR 0.91; 95% CI: 0.29-2.83). In conclusion, adult patients (≥16 years of age) with TBI had a significantly lower odds of wearing a bicycle helmet than adult patients with other trauma, adding more evidence that wearing a bicycle helmet effectively protects against TBI., Competing Interests: S.N. and H.V. are employed by the Consumer Safety Institute, a non-profit organization that collects and analyses the LIS data that were used for this study. For the remaining authors there are no conflicts of interests, no other financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work., (© Crispijn L. van den Brand et al., 2020; Published by Mary Ann Liebert, Inc.)

Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.

Emergency departments (EDs) are eerily quiet for illnesses apart from COVID-19. In this short communication, we assessed the effect of COVID-19 on ED attendance rates for traumatic brain injury (TBI). Data were collected from all consecutive patients with TBI attending our hospital (Haaglanden Medical Center, The Hague, The Netherlands) during the first 3 weeks of the Dutch lockdown (from March 18 to April 6) and for the same period last year. We observed a 36% decrease in ED attendance for TBI since the beginning of the SARS-CoV-2 pandemic (91 vs. 143). Patients who presented during the lockdown were significantly older compared with the patients who visited the ED in the previous year (72 vs. 57, p  = 0.01). No other significant differences were found., Competing Interests: No competing financial interests exist., (© Juliette A.L. Santing et al., 2020; Published by Mary Ann Liebert, Inc.)

Objectives: Emergency medicine (EM) in the Netherlands has developed rapidly and initially without central guidance. This has led to heterogeneity in current EM practice. Our aim was to quantify this heterogeneity by answering the following questions: (1) What is the current position of emergency physicians (EPs) within hospital organizations? (2) Which roles and responsibilities do EPs have across emergency departments (EDs)?, Methods: During 2018, we conducted a survey among all EM consultant bodies (CBs, n = 56) in the Netherlands. Data was analyzed using descriptive statistics., Results: The response rate was 91.1%. Presence of EPs has been realized 24/7 in 23.1% of EDs. EPs were the main consultants for all ED patients in 9.8% of CBs, but never had this role in 13.7% of CBs. EPs supervised EM junior doctors in 78.5% of EDs, GPs in training in 80.0% of EDs, and junior doctors of other specialties in 41.5% of EDs. Procedures such as lumbar puncture (LP), procedural sedation and analgesia (PSA), and emergency ultrasound (US) were performed by all EPs in the CB in a range between 5.9 and 78.4%. In 36.9% of EDs, EPs did not analyze patients with presumed cardiac pathology due to a separate First Heart Aid., Conclusion: We conclude that there is a high degree of heterogeneity between emergency CBs in regard to the position in the hospital and the role or responsibilities in the ED. Lack of uniformity might inhibit emancipation of the profession.

Objective: The effect of insulin on blood flow distribution within muscle microvasculature has been suggested to be important for glucose metabolism. However, the "capillary recruitment" hypothesis is still controversial and relies on studies using indirect contrast-enhanced ultrasound (CEU) methods., Methods: We studied how hyperinsulinemia effects capillary blood flow in rat extensor digitorum longus (EDL) muscle during euglycemic hyperinsulinemic clamp using intravital video microscopy (IVVM). Additionally, we modeled blood flow and microbubble distribution within the vascular tree under conditions observed during euglycemic hyperinsulinemic clamp experiments., Results: Euglycemic hyperinsulinemia caused an increase in erythrocyte (80 ± 25%, P < .01) and plasma (53 ± 12%, P < .01) flow in rat EDL microvasculature. We found no evidence of de novo capillary recruitment within, or among, capillary networks supplied by different terminal arterioles; however, erythrocyte flow became slightly more homogenous. Our computational model predicts that a decrease in asymmetry at arteriolar bifurcations causes redistribution of microbubble flow among capillaries already perfused with erythrocytes and plasma, resulting in 25% more microbubbles flowing through capillaries., Conclusions: Our model suggests increase in CEU signal during hyperinsulinemia reflects a redistribution of arteriolar flow and not de novo capillary recruitment. IVVM experiments support this prediction showing increases in erythrocyte and plasma flow and not capillary recruitment., (© 2019 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

Meiotic crossing over ensures proper segregation of homologous chromosomes and generates genotypic diversity. Despite these functions, little is known about the genetic factors and population genetic forces involved in the evolution of recombination rate differences among species. The dicistronic meiosis gene, mei-217/mei-218 , mediates most of the species differences in crossover rate and patterning during female meiosis between the closely related fruitfly species, Drosophila melanogaster and D. mauritiana The MEI-218 protein is one of several meiosis-specific mini-chromosome maintenance (mei-MCM) proteins that form a multi-protein complex essential to crossover formation, whereas the BLM helicase acts as an anti-crossover protein. Here we study the molecular evolution of five genes- mei-218 , the other three known members of the mei-MCM complex, and Blm - over the phylogenies of three Drosophila species groups- melanogaster , obscura , and virilis We then use transgenic assays in D. melanogaster to test if molecular evolution at mei-218 has functional consequences for crossing over using alleles from the distantly related species D. pseudoobscura and D. virilis Our molecular evolutionary analyses reveal recurrent positive selection at two mei-MCM genes. Our transgenic assays show that sequence divergence among mei-218 alleles from D. melanogaster , D. pseudoobscura , and D. virilis has functional consequences for crossing over. In a D. melanogaster genetic background, the D. pseudoobscura mei-218 allele nearly rescues wildtype crossover rates but alters crossover patterning, whereas the D. virilis mei-218 allele conversely rescues wildtype crossover patterning but not crossover rates. These experiments demonstrate functional divergence at mei-218 and suggest that crossover rate and patterning are separable functions., (Copyright © 2019 Brand et al.)

Background: Over the past two decades, several quality improvement projects have been implemented in emergency departments (EDs) in the Netherlands, one of these being the training and deployment of emergency physicians. In this study we aim to perform a trend analysis of ED quality of care in Dutch hospitals, as measured by the incidence of medical malpractice claims., Patients and Methods: We performed a multicentre retrospective cohort study of malpractice claims in five Dutch EDs over the period 1998-2014. Incidence risk ratios were calculated to demonstrate any relation of specific quality improvement initiatives with the primary outcome, defined as the number of claims per 10 000 ED visits per year., Results: During the study period, the cumulative number of ED visits increased significantly from 99 145 in 1998 to 162 490 in 2014 (P < 0.01). In total, 228 of 2 348 417 ED visits (0.97 per 10 000) resulted in a malpractice claim. At the same time, the yearly number of ED claims filed decreased with 0.07 (0.03-0.10) per 10 000 each year. The claim rate was higher in the period before emergency physicians were employed in the ED [1.18 (0.98-1.41) claims per 10 000 visits] compared with the period after they were employed [0.81 (0.67-0.97), incidence risk ratio 0.69 (0.53-0.89), P < 0.01]., Conclusion: Even though the number of ED visits increased significantly over the past two decades, the number of malpractice claims filed after an ED visit decreased. Various quality improvement initiatives, including the training and employment of emergency physicians, may have contributed to the observed decrease in claims.

Aims: We previously quantified the hypoglycaemia-sparing effect of portal vs peripheral human insulin delivery. The current investigation aimed to determine whether a bioequivalent peripheral vein infusion of a hepatopreferential insulin analog, insulin-406, could similarly protect against hypoglycaemia., Materials and Methods: Dogs received human insulin infusions into either the hepatic portal vein (PoHI, n = 7) or a peripheral vein (PeHI, n = 7) for 180 minutes at four-fold the basal secretion rate (6.6 pmol/kg/min) in a previous study. Insulin-406 (Pe406, n = 7) was peripherally infused at 6.0 pmol/kg/min, a rate determined to decrease plasma glucose by the same amount as with PoHI infusion during the first 60 minutes. Glucagon was fixed at basal concentrations, mimicking the diminished α-cell response seen in type 1 diabetes., Results: Glucose dropped quickly with PeHI infusion, reaching 41 ± 3 mg/dL at 60 minutes, but more slowly with PoHI and Pe406 infusion (67 ± 2 and 72 ± 4 mg/dL, respectively; P < 0.01 vs PeHI for both). The hypoglycaemic nadir (c. 40 mg/dL) occurred at 60 minutes with PeHI infusion vs 120 minutes with PoHI and Pe406 infusion. ΔAUC epinephrine during the 180-minute insulin infusion period was two-fold higher with PeHI infusion compared with PoHI and Pe406 infusion. Glucose production (mg/kg/min) was least suppressed with PeHI infusion (Δ = 0.79 ± 0.33) and equally suppressed with PoHI and Pe406 infusion (Δ = 1.16 ± 0.21 and 1.18 ± 0.17, respectively; P = NS). Peak glucose utilization (mg/kg/min) was highest with PeHI infusion (4.94 ± 0.17) and less with PoHI and Pe406 infusion (3.58 ± 0.58 and 3.26 ± 0.08, respectively; P < 0.05 vs Pe for both)., Conclusions: Peripheral infusion of hepatopreferential insulin can achieve a metabolic profile that closely mimics portal insulin delivery, which reduces the risk of hypoglycaemia compared with peripheral insulin infusion., (© 2019 John Wiley & Sons Ltd.)

Various guidelines for minor head injury focus on patients with a Glasgow Coma Scale (GCS) score of 13-15 and loss of consciousness (LOC) or post-traumatic amnesia (PTA), while clinical management for patients without LOC or PTA is often unclear. We aimed to investigate the effect of presence and absence of LOC or PTA on intracranial complications in minor head injury. A prospective multi-center cohort study of all patients with blunt head injury and GCS score of 15 was conducted at six Dutch centers between 2015 and 2017. Five centers used the national guideline and one center used a local guideline-both based on the CT in Head Injury Patients (CHIP) prediction model-to identify patients in need of a computed tomography (CT) scan. We studied the presence of traumatic findings and neurosurgical interventions in patients with and without LOC or PTA. In addition, we assessed the association of LOC and PTA with traumatic findings with logistic regression analysis and the additional predictive value of LOC and PTA compared with other risk factors in the CHIP model. Of 3914 patients, 2249 (58%) experienced neither LOC nor PTA and in 305 (8%) LOC and PTA was unknown. Traumatic findings were present in 153 of 1360 patients (11%) with LOC or PTA and in 67 of 2249 patients (3%) without LOC and PTA. Five patients without LOC and PTA had potential neurosurgical lesions and one patient underwent a neurosurgical intervention. LOC and PTA were strongly associated with traumatic findings on CT, with adjusted odds ratios of 2.9 (95% confidence interval [CI] 2.2-3.8) and 3.5 (95% CI 2.7-4.6), respectively. To conclude, patients who had minor head injury with neither LOC nor PTA are at risk of intracranial complications. Clinical guidelines should include clinical management for patients without LOC and PTA, and they should include LOC and PTA as separate risk factors rather than as diagnostic selection criteria.

Peripheral hyperinsulinemia resulting from subcutaneous insulin injection is associated with metabolic defects which include abnormal glucose metabolism. The first aim of this study was to quantify the impairments in liver and muscle glucose metabolism that occur when insulin is delivered via a peripheral vein compared to when it is given through its endogenous secretory route (the hepatic portal vein) in overnight fasted conscious dogs. The second aim was to determine if peripheral delivery of a hepato-preferential insulin analog could restore the physiologic response to insulin that occurs under meal feeding conditions. This study is the first to show that hepatic glucose uptake correlates with insulin's direct effects on the liver under hyperinsulinemic-hyperglycemic conditions. In addition, glucose uptake was equally divided between the liver and muscle when insulin was infused into the portal vein, but when it was delivered into a peripheral vein the percentage of glucose taken up by muscle was 4-times greater than that going to the liver, with liver glucose uptake being less than half of normal. These defects could not be corrected by adjusting the dose of peripheral insulin. On the other hand, hepatic and non-hepatic glucose metabolism could be fully normalized by a hepato-preferential insulin analog.

Background: Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. The effects of epidemiological changes such as ageing of the population and increased traffic safety on the incidence of TBI are unknown., Objective: The objective of this study was to evaluate trends in TBI-related emergency department (ED) visits, hospitalization and mortality in the Netherlands between 1998 and 2012., Design: This was a retrospective observational, longitudinal study., Main Outcome Measures: The main outcome measures were TBI-related ED visits, hospitalization and mortality., Results: Between 1998 and 2012, there were 500 000 TBI-related ED visits in the Netherlands. In the same period, there were 222 000 TBI-related admissions and 17 000 TBI-related deaths. During this period, there was a 75% increase in ED visits for TBI and a 95% increase for TBI-related hospitalization; overall mortality because of TBI did not change significantly. Despite the overall increase in TBI-related ED visits, this increase was not evenly distributed among age groups or trauma mechanisms. In patients younger than 65 years, a declining trend in ED visits for TBI caused by road traffic accidents was observed. Among patients 65 years or older, ED visits for TBI caused by a fall increased markedly. TBI-related mortality shifted from mainly young (67%) and middle-aged individuals (<65 years) to mainly elderly (63%) individuals (≥65 years) between 1998 and 2012. The conclusions of this study did not change when adjusting for changes in age, sex and overall population growth., Conclusion: The incidence of TBI-related ED visits and hospitalization increased markedly between 1998 and 2012 in the Netherlands. TBI-related mortality occurred at an older age. These observations are probably the result of a change in aetiology of TBI, specifically a decrease in traffic accidents and an increase in falls in the ageing population. This hypothesis is supported by our data. However, ageing of the population is not the only cause of the changes observed; the observed changes remained significant when correcting for age and sex. The higher incidence of TBI with a relatively stable mortality rate highlights the importance of clinical decision rules to identify patients with a high risk of poor outcome after TBI.

Crossing over between homologous chromosomes during meiosis repairs programmed DNA double-strand breaks, ensures proper segregation at meiosis I [1], shapes the genomic distribution of nucleotide variability in populations, and enhances the efficacy of natural selection among genetically linked sites [2]. Between closely related Drosophila species, large differences exist in the rate and chromosomal distribution of crossing over. Little, however, is known about the molecular genetic changes or population genetic forces that mediate evolved differences in recombination between species [3, 4]. Here, we show that a meiosis gene with a history of rapid evolution acts as a trans-acting modifier of species differences in crossing over. In transgenic flies, the dicistronic gene, mei-217/mei-218, recapitulates a large part of the species differences in the rate and chromosomal distribution of crossing over. These phenotypic differences appear to result from changes in protein sequence not gene expression. Our population genetics analyses show that the protein-coding sequence of mei-218, but not mei-217, has a history of recurrent positive natural selection. By modulating the intensity of centromeric and telomeric suppression of crossing over, evolution at mei-217/-218 has incidentally shaped gross differences in the chromosomal distribution of nucleotide variability between species. We speculate that recurrent bouts of adaptive evolution at mei-217/-218 might reflect a history of coevolution with selfish genetic elements., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Emergency departments (EDs) worldwide face crowding, which hampers patient flow. In this study, the impact of a dedicated neurologist present at the ED on patient flow during out-of-office hours was assessed., Methods: A cross-sectional, mixed methods study was undertaken at a Dutch ED, including a pre-post analysis of data of patients who had a primary neurological disease (n = 458) and staff surveys (n = 152). Descriptive statistics and content analysis were used for analyses., Results: Despite a 36% increase in the number of neurological patients (control period: n = 194, intervention period n = 264), a 30 min per patient decrease in ED median length of stay (LOS) was reached during the intervention period. Furthermore, the admission percentage decreased significantly (57.7% in the control period vs. 47.7% in the intervention period, p = 0.03). During half of the shifts neurologists stated that their presence had been valuable. Perceived reasons for this added value mentioned were improved quality of care, enhanced throughput of patients, and quicker consultations with other medical specialists., Conclusions: In our hypothesis-generating study, a dedicated neurologist present at the ED during out-of-office hours was associated with decreased patients' LOS and a decreased admission percentage, indicating increased decisiveness when the neurologist is present at the ED.

Objectives: Emergency medicine is a fast-growing medical profession. Nevertheless, the clinical activities emergency physicians (EPs) carry out and the responsibilities they have differ considerably between hospitals. This article addresses the question how the role of EPs is shaped and institutionalized in the everyday context of acute care in hospitals., Methods: A cross-case ethnographic study was conducted, comprising observations, document analysis, and in-depth interviews in three emergency departments in the Netherlands., Results: Drawing on the theoretical concept of institutional work, we show that managers, already established medical specialties, and EPs all conduct institutional work to enhance private interests, which both restricts and enlarges EPs' work domain. These actions are strategic and intentional, as well as unintentional and part of EPs' everyday work in acute care delivery. It is in this very process that tasks and responsibilities are redistributed and the role of the EP is shaped., Discussion: In contemporary literature it is often argued that the role and status of EPs should be enhanced by strengthening regulation and improving training programs. This article shows that attention should also be paid to the more subtle everyday processes of role development.