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Abstract Background Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia. Methods Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n = 10 without cachexia, n = 20 cachectic without inflammation (CRP

Abstract Palaeocurrent analysis is vital for basin analysis and helps in the interpretation of depositional environments (along‐slope or downslope). For that, it is crucial to have multiple measuring methods at hand to apply palaeocurrent analysis with a wide range of different datasets (outcrops, cores and photographs). Here, two relatively underexploited palaeocurrent measurement techniques are assessed when applied to trough cross‐stratification observed in the Arenazzolo Formation at Eraclea Minoa (Sicily). The first technique is a novel design of a qualitative approach to infer palaeocurrent directions from photographs of two‐dimensional sedimentary structures. The second technique involves measurements of the anisotropy of magnetic susceptibility from drilled samples. A broad agreement, with overlapping uncertainty boundaries, is observed between results from both techniques. This agreement validates the use of trough cross‐strata to infer palaeocurrent directions. Moreover, the addition of photographs improves reproducibility and prevents a bias towards the best‐exposed troughs. The application of both techniques to outcrops and sedimentary cores provides new opportunities for palaeocurrent analysis in any type of sedimentary environment.

Abstract Objective Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro‐diffusely abnormal white matter, mDAWM). Methods We used an in‐depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. Results mDAWM‐defined areas exhibit ill‐defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. Interpretation We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo‐myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.

Abstract Reactivation of fetal hemoglobin expression alleviates the symptoms associated with β‐globinopathies, severe hereditary diseases with significant global health implications due to their high morbidity and mortality rates. The symptoms emerge following the postnatal transition from fetal‐to‐adult hemoglobin expression. Extensive research has focused on inducing the expression of the fetal γ‐globin subunit to reverse this switch and ameliorate these symptoms. Despite decades of research, only one compound, hydroxyurea, found its way to the clinic as an inducer of fetal hemoglobin. Unfortunately, its efficacy varies among patients, highlighting the need for more effective treatments. Erythroid cell lines have been instrumental in the pursuit of both pharmacological and genetic ways to reverse the postnatal hemoglobin switch. Here, we describe the first endogenously tagged fetal hemoglobin reporter cell line based on the adult erythroid progenitor cell line HUDEP2. Utilizing CRISPR‐Cas9‐mediated knock‐in, a bioluminescent tag was integrated at the HBG1 gene. Subsequent extensive characterization confirmed that the resulting reporter cell line closely mirrors the HUDEP2 characteristics and that the cells report fetal hemoglobin induction with high sensitivity and specificity. This novel reporter cell line is therefore highly suitable for evaluating genetic and pharmacologic strategies to induce fetal hemoglobin. Furthermore, it provides an assay compatible with high‐throughput drug screening, exemplified by the identification of a cluster of known fetal hemoglobin inducers in a pilot study. This new tool is made available to the research community, with the aspiration that it will accelerate the search for safer and more effective strategies to reverse the hemoglobin switch.

Abstract Bullous cutaneous reactions can be caused by many factors, including vaccines.1 However, among all cutaneous reactions following coronavirus disease 2019 (COVID‐19) mRNA vaccines, bullous reactions are rare. Here, we describe two patients with delayed generalised bullous cutaneous reactions 7 days after receiving Moderna (Spikevax®) and Pfizer–BioNTech (Comirnaty®) COVID‐19 vaccination, respectively.

Abstract The most common forms of sickle cell disease (SCD) are sickle cell anemia (SCA; HbSS) and HbSC disease. In both, especially the more dense, dehydrated and adherent red blood cells (RBCs) with reduced deformability are prone to hemolysis and sickling, and thereby vaso‐occlusion. Based on plasma amino acid profiling in SCD, a composition of 10 amino acids and derivatives (RCitNacQCarLKHVS; Axcella Therapeutics, USA), referred to as endogenous metabolic modulators (EMMs), was designed to target RBC metabolism. The effects of ex vivo treatment with the EMM composition on different RBC properties were studied in SCD (n = 9 SCA, n = 5 HbSC disease). Dose‐dependent improvements were observed in RBC hydration assessed by hemocytometry (MCV, MCHC, dense RBCs) and osmotic gradient ektacytometry (Ohyper). Median (interquartile range [IQR]) increase in Ohyper compared to vehicle was 4.9% (4.0%–5.5%), 7.5% (6.9%–9.4%), and 12.8% (11.5%–14.0%) with increasing 20×, 40×, and 80X concentrations, respectively (all p

Abstract Mitapivat is an investigational, oral, small‐molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3‐DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3‐DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator‐initiated, open‐label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019‐003438‐18), untargeted metabolomics was used to explore the overall metabolic effects of 8‐week treatment with mitapivat in the dose‐finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate‐adjusted p

Abstract Background The tissue response viewer (TRV) is a novel marker for ablation lesion quality that aims to classify lesions into transmural or nontransmural lesions (high or low dielectric response, HDR or LDR) using dielectric‐based tissue assessment. The objective of this study was to gain insight in the TRV by relating its outcomes to conventional ablation parameters. Methods Patients that had repeat ablation for atrial fibrillation with a dielectric imaging‐based mapping system were enrolled. All ablation data were downloaded from the mapping system and analyzed to explore associations between TRV outcomes and other ablation parameters. Results The cohort included 24 patients, in which 58 pulmonary veins and 8 superior vena cavas were targeted. A total of 388 energy applications were applied, resulting in 639 ablation points. The system classified 36% of ablation points as HDR and 44% as LDR. The system did not provide a dielectric response in 20%. The system's ability to provide a dielectric response was related to longer ablation duration and absence of dragging ablation. HDR (versus LDR) was multivariably associated with longer energy applications, higher mean ablation power, and lower wall thickness. Greater impedance drop was univariably associated with HDR. Conclusion Outcomes of the TRV are associated with conventional ablation parameters (e.g., duration and power) but also local wall thickness. Catheter stability seems important for successful lesion assessment with the TRV. Further reduction of missing outcomes and validation of the tool are warranted before widespread use.

Abstract Although nesting in colonies can offer substantial reproductive benefits for many seabird species, increased visibility to predators remains a significant disadvantage for most colony‐breeders. To counteract this, some seabird species have evolved aggressive nest defense strategies to protect vulnerable eggs and chicks. Here, we used an experimental approach to test whether colony inhabitance by breeding gulls Larus spp. in western Norway impacts visitation rates of a native, mammalian predator, the Eurasian otter Lutra lutra during the breeding season. Camera traps were placed inside of and on the periphery of seabird colonies prior to the breeding season and left to run for one continuous year. Sighting frequency of otters on these cameras was compared to a control region free of gull nesting. We found that otter activity was significantly reduced in the colonies when gulls were incubating and rearing chicks, compared to time periods when gulls were building nests and absent from the colonies. Rhythmic activity patterns did not seem to be significantly impacted by the presence of gulls. This study provides clear evidence that certain colony‐nesting species can have a direct, negative impact on visitation rates of a native carnivore. Seasonal carnivore activity patterns are likely to be highly dependent on differing nesting strategies and level of nest defense by seabirds.

Abstract Overharvesting is a serious threat to many fish populations. High mortality and directional selection on body size can cause evolutionary change in exploited populations via selection for a specific phenotype and a potential reduction in phenotypic diversity. Whether the loss of phenotypic diversity that accompanies directional selection impairs response to environmental stress is not known. To address this question, we exposed three zebrafish selection lines to thermal stress. Two lines had experienced directional selection for (1) large and (2) small body size, and one was (3) subject to random removal of individuals with respect to body size (i.e. line with no directional selection). Selection lines were exposed to three temperatures (elevated, 34°C; ambient, 28°C; low, 22°C) to determine the response to an environmental stressor (thermal stress). We assessed differences among selection lines in their life history (growth and reproduction), physiological traits (metabolic rate and critical thermal max) and behaviour (activity and feeding behaviour) when reared at different temperatures. Lines experiencing directional selection (i.e. size selected) showed reduced growth rate and a shift in average phenotype in response to lower or elevated thermal stress compared with fish from the random‐selected line. Our data indicate that populations exposed to directional selection can have a more limited capacity to respond to thermal stress compared with fish that experience a comparable reduction in population size (but without directional selection). Future studies should aim to understand the impacts of environmental stressors on natural fish stocks.

This paper presents a simple design, low-cost, electromechanical overloading system, which is easy to use and install and suitable for all types of truck chassis and suspension. This design can detect an overload, signal the driver, and also interrupt ignition when the truck is overloaded. The system was modelled using CAD software, and FEA was performed on the spring component to verify analytical solutions. Components of the overload detection system include a load carrying springs, an electrical relay, ignition system, an LED for signaling overload, and an electrical circuit. Results showed that, for a 3-axle trucks, the allowable pay load was 15.125 tonnes, and each spring in the design supports a minimum weight of 74.183 kN. A spring index of 4.009 was achieved in line with safe design conforming to 4 ≤ C ≤ 12 with a spring rate of 1464305.5 N/m. The spring displacement needed to actuate the overloading system was 51 mm. FEA which was performed validated analytical solutions in that the induced von Mises stress which was 69.92 MPa was below the yield strength of the material (200 MPa) and the factor of safety obtained was 1.24 signifying safe design. The designed electromechanical system is capable of detecting an overloadand also interrupting the truck ignition. Installation can be installed on new trucks or by retrofitting onto old trucks.

Abstract Background Implementation of an LHS in cardiology departments presents itself with ethical challenges, including ethical review and informed consent. In this qualitative study, we investigated stakeholders' attitudes toward ethical issues regarding the implementation of an LHS in the cardiology department. Methods We conducted a qualitative study using 35 semi‐structured interviews and 5 focus group interviews with 34 individuals. We interviewed cardiologists, research nurses, cardiovascular patients, ethicists, health lawyers, epidemiologists/statisticians and insurance spokespersons. Results Respondents identified different ethical obstacles for the implementation of an LHS within the cardiology department. These obstacles were mainly on ethical oversight in LHSs; in particular, informed con sent and data ownership were discussed. In addition, respondents reported on the role of patients in LHS. Respondents described the LHS as a possibility for patients to engage in both research and care. While the LHS can promote patient engagement, patients might also be reduced to their data and are therefore at risk, according to respondents. Conclusions Views on the ethical dilemmas of a LHSs within cardiology are diverse. Similar to the literary debate on oversight, there are different views on how ethical oversight should be regulated. This study adds to the literary debate on oversight by highlighting that patients wish to be informed about the learning activities within the LHS they participate in, and that they wish to actively contribute by sharing their data and identifying learning goals, provided that informed consent is obtained.

Abstract Mud plays a pivotal role in estuarine ecology and morphology. However, field data on the lateral and vertical depositional record of mud are rare. Furthermore, numerical morphodynamic models often ignore mud due to long computational times and simplifications of mixed depositional processes. This study aims to understand the spatial distribution, formative conditions and preservation of mud deposits in the intertidal zone of bars in high‐energy sand‐dominated estuaries, and to elucidate the effects of mud on morphology, ecology and stratigraphic architecture. To meet these objectives, field data (historic bathymetry, bio‐morphological maps and sediment cores of the shoal of Walsoorden, Western Scheldt estuary, the Netherlands) were combined with complementary hydro‐morphodynamic numerical modelling (Delft3D). Based on the field observations, two types of mud deposits were distinguished: (1) mudflat deposits, which are thick (>10 cm) mud beds at the surface associated with high elevations and low accumulation rates; and (2) mud drapes, which are thin (millimetre to centimetre) buried laminae that form and preserve at a wide range of elevations and energy conditions. Model results show that deposition on mudflats occurs just after high‐tide slack water in areas shielded from high flood velocities, suggesting that mud accumulation is mostly controlled by elevation, flow velocity and flow direction. Mud accumulation increases shoal elevation, sometimes to supratidal levels. This reduces flow over the shoal, which in turn reduces chute channel formation, stabilises bar morphology and decreases local tidal prism. These effects further promote mud deposition and vegetation settling. Although observations show that mud cover at the surface is relatively high (20%–40% of the intertidal area), mud constitutes only a small percentage of the total estuary volume (ca 5%) revealing that only a small fraction is preserved in the stratigraphy. Due to this mismatch between surface and subsurface expression of mud, interpretations of estuarine stratigraphy risk underestimating the influence of mud at the surface on morphodynamics and habitats.

Abstract Aim The aim of this study was to understand the provision and need, quality of and trust in COVID‐19 vaccines information from the perspectives of people who have had COVID‐19 infection. Method People who have had a COVID‐19 infection were approached via their general practice and invited to participate in the Nivel Corona Cohort. They completed questionnaires at baseline (Q1), and at three months (Q2). Outcome measures were based on health information‐seeking behaviour, as used in the Comprehensive Model of Information Seeking. Antecedents (i.e., gender, age, education level, health literacy) were used from Q1, and one's beliefs and experiences (i.e., trust in the information and healthcare system, how applicable the information is), information carrier factors (i.e., information quality perceptions and via which sources), health‐information seeking actions (i.e., decision to vaccinate and information sufficiency) and vaccination status from Q2. Data were analysed using descriptive analyses, analysis of variance tests (F‐tests) and χ2 tests with the statistical software STATA. Results Of the respondents (N = 314), 96% were vaccinated at least once, mostly after having had the virus. Most retrieved information about COVID‐19 vaccines on the website of the National Institute for Public Health and the Environment (79%), broader via the internet (56%), or from family and friends (35%). Almost all had trust in the information (89%) and healthcare system (94%). Most found the information applicable to their situation (67%). Moreover, most perceived the information as correct (71%) and did not perceive the information to be misleading (85%), while fewer people found the information reliable (59%) and clear (58%). Overall, the majority indicated that the information met their expectations to make a well‐informed decision to vaccinate (89%). Conclusion Different characteristics of people who had COVID‐19 and sought information were identified, which is important to offer tailored information. People who had COVID‐19 in this study, mainly middle‐aged, vaccinated and highly educated, were generally positive about the vaccines information, but overall the reliability and clarity could be improved. This is important for a high vaccination uptake, booster programs and coming pandemics. Patient or Public Contribution The questionnaire was reviewed by patients who had COVID‐19, one of whom is a health services researcher.

ABSTRACT In hypoparathyroidism, lack of parathyroid hormone (PTH) leads to low calcium levels and decreased bone remodeling. Treatment with recombinant human PTH (rhPTH) may normalize bone turnover. This study aimed to investigate whether rhPTH(1–84) continued to activate intracortical bone remodeling after 30 months and promoted the transition from erosion to formation and whether this effect was transitory when rhPTH(1–84) was discontinued. Cortical histomorphometry was performed on 60 bone biopsies from patients (aged 31 to 78 years) with chronic hypoparathyroidism randomized to either 100 μg rhPTH(1–84) a day (n = 21) (PTH) or similar placebo (n = 21) (PLB) for 6 months as add‐on to conventional therapy. This was followed by an open‐label extension, where patients extended their rhPTH(1–84) (PTH) (n = 5), continued conventional treatment (CON) (n = 5), or withdrew from rhPTH(1–84) and resumed conventional therapy (PTHw) for an additional 24 months (n = 8). Bone biopsies were collected at months 6 (n = 42) and 30 (n = 18). After 6 and 30 months, the overall cortical microarchitecture (cortical porosity, thickness, pore density, and mean pore diameter) in the PTH group did not differ from that of the PLB/CON and PTHw groups. Still, the PTH group had a significantly and persistently higher percentage of pores undergoing remodeling than the PLB/CON groups. A significantly higher percentage of these pores was undergoing bone formation in the PTH compared with the PLB/CON groups, whereas the percentage of pores with erosion only was not different. This resulted in a shift in the ratio between formative and eroded pores, reflecting a faster transition from erosion to formation in the PTH‐treated patients. In the rhPTH(1–84) withdrawal group PTHw, the latter effects of PTH were completely reversed in comparison to those of the PLB/CON groups. In conclusion, rhPTH(1–84) replacement therapy in hypoparathyroidism patients promotes intracortical remodeling and its transition from erosion to formation without affecting the overall cortical microstructure. The effect persists for at least 30 months and is reversible when treatment is withdrawn. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abstract Beta‐blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age‐related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta‐blockers are associated with an increased risk of falls in older beta‐blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta‐blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B‐PROOF cohort. The associations between the beta‐blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11–2.16], p = .01). No association was found for nonselective beta‐blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta‐blockers users. This might be caused by a decreased β1‐selectivity in high plasma concentrations. In the future, beta‐blocker concentrations could potentially help clinicians estimate fall risk in older beta‐blockers users and personalize treatment.

Abstract Using digital twins for decision making is a very promising concept which combines simulation models with corresponding experimental sensor data in order to support maintenance decisions or to investigate the reliability. The quality of the prognosis strongly depends on both the data quality and the quality of the digital twin. The latter comprises both the modeling assumptions as well as the correct parameters of these models. This article discusses the challenges when applying this concept to real measurement data for a demonstrator bridge in the lab, including the data management, the iterative development of the simulation model as well as the identification/updating procedure using Bayesian inference with a potentially large number of parameters. The investigated scenarios include both the iterative identification of the structural model parameters as well as scenarios related to a damage identification. In addition, the article aims at providing all models and data in a reproducible way such that other researcher can use this setup to validate their methodologies.

Abstract Aims/Hypothesis Optimal diabetes care and risk factor management are important to delay micro‐ and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets. Methods Cross‐sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c)

Abstract Background A primary goal in transoral robotic surgery (TORS) for oropharyngeal squamous cell cancer (OPSCC) survivors is to optimize swallowing function. However, the uncertainty in the outcomes of TORS including postoperative residual positive margin (PM) and extranodal extension (ENE), may necessitate adjuvant therapy, which may cause significant swallowing toxicity to survivors. Methods A secondary analysis was performed on a prospective registry data with low‐ to intermediate‐risk human papillomavirus–related OPSCC possibly resectable by TORS. Decision trees were developed to model the uncertainties in TORS compared with definitive radiation therapy (RT) and chemoradiation therapy (CRT). Swallowing toxicities were measured by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST), MD Anderson Dysphagia Inventory (MDADI), and the MD Anderson Symptom Inventory–Head and Neck (MDASI‐HN) instruments. The likelihoods of PM/ENE were varied to determine the thresholds within which each therapy remains optimal. Results Compared with RT, TORS resulted in inferior swallowing function for moderate likelihoods of PM/ENE (>60% in short term for all instruments, >75% in long term for DIGEST and MDASI) leaving RT as the optimal treatment. Compared with CRT, TORS remained the optimal therapy based on MDADI and MDASI but showed inferior swallowing outcomes based on DIGEST for moderate‐to‐high likelihoods of PM/ENE (>75% for short‐term and >40% for long‐term outcomes). Conclusion In the absence of reliable estimation of postoperative PM/ENE concurrent with significant postoperative PM, the overall toxicity level in OPSCC patients undergoing TORS with adjuvant therapy may become more severe compared with patients receiving nonsurgical treatments thus advocating definitive (C)RT protocols.

Abstract Introduction In 24/7 disability care facilities, patient‐reported experience measures (PREMs) are important to help healthcare professionals understand what matters to care users and to improve the quality of care. However, the successful implementation of a PREM is complex. In a Dutch disability care organization, stakeholders cocreated tailored implementation strategies aimed at improving the use and integration of a qualitative PREM. This study gives insights into the uptake and experiences with these cocreated implementation strategies and the perceived impact of the set of strategies. Methods We performed a prospective process evaluation between February 2020 and February 2021. We collected data in three disability care facilities from 35 care users, 11 professionals, 3 facility managers and 4 organization representatives. Data collection included observations during kick‐offs and learning goal meetings and several attendance checklists. We collected 133 questionnaires (Time 0 and Time 1). We conducted 35 individual semistructured interviews and an online focus group interview. Quantitative data were analysed using descriptive statistics and qualitative data using directed content analysis. Results The exposure to and adoption of strategies was between 76% and 100%. Participants were positive about tailoring the strategies to each facility. Implementation was hindered by challenges in care users' communication and COVID‐19. The perceived impact referred to an improved understanding of the goal and added value of the PREM and better preparation and execution of the PREM. The impact of the set of strategies was mainly experienced on the micro level. Conclusion The uptake of the cocreated implementation strategies was acceptable. The participants valued the tailored approach, which enabled them to focus on facility‐specific learning goals. Stakeholder engagement and co‐created strategies may have strengthened the adoption of and experiences with the implementation. Patient or Public Contribution In this article, we present the process evaluation of implementation strategies for the integrated use of a PREM in disability care. A development group consisting of communication vulnerable care users, trainers and professionals developed the implementation strategies. The disability care organization was responsible for the planning and organization of the implementation process. During the process evaluation the end users, trainers, professionals and managers tailored the implementation strategies to their own settings and needs. Researchers observed this implementation process and interviewed the stakeholders about their experiences and the perceived impact.

Abstract Evolution has traditionally been a historical and descriptive science, and predicting future evolutionary processes has long been considered impossible. However, evolutionary predictions are increasingly being developed and used in medicine, agriculture, biotechnology and conservation biology. Evolutionary predictions may be used for different purposes, such as to prepare for the future, to try and change the course of evolution or to determine how well we understand evolutionary processes. Similarly, the exact aspect of the evolved population that we want to predict may also differ. For example, we could try to predict which genotype will dominate, the fitness of the population or the extinction probability of a population. In addition, there are many uses of evolutionary predictions that may not always be recognized as such. The main goal of this review is to increase awareness of methods and data in different research fields by showing the breadth of situations in which evolutionary predictions are made. We describe how diverse evolutionary predictions share a common structure described by the predictive scope, time scale and precision. Then, by using examples ranging from SARS‐CoV2 and influenza to CRISPR‐based gene drives and sustainable product formation in biotechnology, we discuss the methods for predicting evolution, the factors that affect predictability and how predictions can be used to prevent evolution in undesirable directions or to promote beneficial evolution (i.e. evolutionary control). We hope that this review will stimulate collaboration between fields by establishing a common language for evolutionary predictions.

Abstract Understanding patterns of gene flow and processes driving genetic differentiation is important for a broad range of conservation practices. In marine organisms, genetic differentiation among populations is influenced by a range of spatial, oceanographic, and environmental factors that are attributed to the seascape. The relative influences of these factors may vary in different locations and can be measured using seascape genetic approaches. Here, we applied a seascape genetic approach to populations of the seagrass, Thalassia hemprichii, at a fine spatial scale (~80 km) in the Kimberley coast, western Australia, a complex seascape with strong, multidirectional currents greatly influenced by extreme tidal ranges (up to 11 m, the world's largest tropical tides). We incorporated genetic data from a panel of 16 microsatellite markers, overwater distance, oceanographic data derived from predicted passive dispersal on a 2 km‐resolution hydrodynamic model, and habitat characteristics from each meadow sampled. We detected significant spatial genetic structure and asymmetric gene flow, in which meadows 12–14 km apart were less connected than ones 30–50 km apart. This pattern was explained by oceanographic connectivity and differences in habitat characteristics, suggesting a combined scenario of dispersal limitation and facilitation by ocean current with local adaptation. Our findings add to the growing evidence for the key role of seascape attributes in driving spatial patterns of gene flow. Despite the potential for long‐distance dispersal, there was significant genetic structuring over small spatial scales implicating dispersal and recruitment bottlenecks and highlighting the importance of implementing local‐scale conservation and management measures.

Abstract Children treated in a pediatric intensive care unit (PICU) are at risk of distress and pain. This study investigated if aromatherapy massage can reduce children's distress and improve comfort. This observational before‐after study was performed in a 22‐bed PICU in Cape Town, South Africa. The aromatherapy massage consisted of soft massaging using the “M‐technique” and a 1% blend of essential oils of Lavender (Lavandula angustifolia), German Chamomile (Matricatia recutita) and Neroli (Citrus aurantium) mixed with a grapeseed carrier oil. All present children were eligible, except those who had recently returned, were asleep or deemed unstable. The primary outcome was distress measured with the COMFORT‐Behavior scale (COMFORT‐B). Secondary outcomes were heart rate, oxygen saturation (SatO2), the Numeric Rating Scale (NRS)‐Anxiety and pain assessed by the NRS‐Pain scale. Outcomes variables were evaluated with Wilcoxon signed‐rank test and multiple regression analysis. The intervention was applied to 111 children, fifty‐one of whom (45.9%) were younger than three years old. The group median COMFORT‐B score before intervention was 15 (IQR 12–19), versus 10 (IQR 6–14) after intervention. Heart rate and NRS‐Anxiety were significantly lower after the intervention (P

Abstract Background Most patients with pancreatic cancer develop cachexia, which is characterized by progressive muscle loss. The mechanisms underlying muscle loss in cancer cachexia remain elusive. Pancreatic tumour organoids are 3D cell culture models that retain key characteristics of the parent tumour. We aimed to investigate the effect of pancreatic tumour organoid‐derived factors on processes that determine skeletal muscle mass, including the regulation of muscle protein turnover and myogenesis. Methods Conditioned medium (CM) was collected from human pancreatic cancer cell lines (PK‐45H, PANC‐1, PK‐1, and KLM‐1), pancreatic tumour organoid cultures from a severely cachectic (PANCO‐9a) and a non‐cachectic patient (PANCO‐12a), and a normal pancreas organoid culture. Differentiating C2C12 myoblasts and mature C2C12 myotubes were exposed to CM for 24 h or maintained in control medium. In myotubes, NF‐kB activation was monitored using a NF‐κB luciferase reporter construct, and mRNA expression of E3‐ubiquitin ligases and REDD1 was analysed by RT‐qPCR. C2C12 myoblast proliferation and differentiation were monitored by live cell imaging and myogenic markers and myosin heavy chain (MyHC) isoforms were assessed by RT‐qPCR. Results Whereas CM from PK‐1 and KLM‐1 cells significantly induced NF‐κB activation in C2C12 myotubes (PK‐1: 3.1‐fold, P

Abstract Background Physical activity is associated with a lower risk of colorectal cancer (CRC) and CRC‐specific mortality. However, evidence for a causal relationship between physical activity and disease progression is lacking. Here, we have used CRC organoids to create a novel mouse model for spontaneous metastasis formation to multiple organs. We have used this model to assess the influence of voluntary exercise on disease progression. Methods Collagen‐embedded murine colorectal tumour organoids were transplanted into the livers of immunocompetent C57Bl/6 mice using microsurgery. Voluntary exercise in tumour‐bearing mice was modelled by offering running wheels continuously (n = 12) or 3 h/day (n = 12) versus no wheel access (n = 12). Running wheel revolutions were cumulatively measured every 30 min and physical activity was continuously monitored by infrared cameras. Food intake was monitored throughout the experiment and body composition was assessed with echoMRI. Animals were sacrificed 14 weeks after tumour initiation. Tumour load was quantified by EpCAM immunohistochemistry staining. Systemic inflammation parameters were assessed in blood plasma by a multiplex immunoassay. Results Tumour growth was initiated by implantation of CRC organoids into the livers of immunocompetent mice. The resulting tumours spontaneously formed distant metastases to non‐implanted liver lobes and to the lungs. Mice with access to the running wheels for 3 h/day ran relatively short distances (2.3 ± 0.3 km/night; 221 ± 29 km total distance) with relatively high intensity (wheel revolutions/h). Mice with continuous access to the running wheels ran significantly longer distances (6.6 ± 3.0 km/night; 600 ± 290 km total distance) with a significantly lower intensity. Both exercise groups showed increased lean body mass, and decreased fat mass and body weight compared with tumour‐bearing control mice. Food intake was unaffected by exercise or tumour growth. Primary tumour growth was not significantly affected by exercise. However, mice with continuous wheel access (long distance‐lower intensity group) displayed increased lung metastasis and decreased liver metastasis formation, when compared with the sedentary control group. Short distance‐higher intensity exercise did not affect metastasis formation. Analysis of blood cytokine levels revealed that mice with continuous wheel access displayed signs of systemic inflammation. Conclusions These results suggest that exercise has the potential to influence the patterns and extent of metastasis in CRC, and that the degree and intensity of exercise are likely to be important variables. Confirmation of these results in additional preclinical models with or without systemic treatment is warranted.

Abstract Purpose Various sustained‐release formulations incorporate high bupivacaine concentrations but data on local toxicity is lacking. This study explores local toxic effects of highly concentrated (5%) bupivacaine compared to clinically used concentrations in vivo following skeletal surgery, to assess the safety of sustained‐release formulations with high bupivacaine concentrations. Methods Sixteen rats underwent surgery, in which screws with catheters affixed were implanted in the spine or femur in a factorial experimental design, allowing single‐shot or continuous 72 h local administration of 0.5%, 2.5% or 5.0% bupivacaine hydrochloride. During the 30‐day follow‐up, animal weight was recorded and blood samples were obtained. Implantation sites underwent histopathological scoring for muscle damage, inflammation, necrosis, periosteal reaction/thickening and osteoblast activity. Effects of bupivacaine concentration, administration mode and implantation site on local toxicity scores were analyzed. Results Chi‐squared tests for score frequencies revealed a concentration‐dependent decrease in osteoblast count. Moreover, spinal screw implantation led to significantly more muscle fibrosis but less bone damage than femoral screw implantation, reflecting the more invasive muscle dissection and shorter drilling times related to the spinal procedure. No differences between bupivacaine administration modes regarding histological scoring or body weight changes were observed. Weight increased, while CK levels and leukocyte counts decreased significantly during follow‐up, reflecting postoperative recovery. No significant differences in weight, leukocyte count and CK were found between interventional groups. Conclusion This pilot study found limited concentration‐dependent local tissue effects of bupivacaine solutions concentrated up to 5.0% following musculoskeletal surgery in the rat study population.

Abstract Background Cancer cachexia is characterized by a negative energy balance, muscle and adipose tissue wasting, insulin resistance, and systemic inflammation. Because of its strong negative impact on prognosis and its multifactorial nature that is still not fully understood, cachexia remains an important challenge in the field of cancer treatment. Recent animal studies indicate that the gut microbiota is involved in the pathogenesis and manifestation of cancer cachexia, but human data are lacking. The present study investigates gut microbiota composition, short‐chain fatty acids (SCFA), and inflammatory parameters in human cancer cachexia. Methods Faecal samples were prospectively collected in patients (N = 107) with pancreatic cancer, lung cancer, breast cancer, or ovarian cancer. Household partners (N = 76) of the patients were included as healthy controls with similar diet and environmental conditions. Patients were classified as cachectic if they lost >5% body weight in the last 6 months. Gut microbiota composition was analysed by sequencing of the 16S rRNA V4 gene region. Faecal SCFA levels were quantified by gas chromatography. Faecal calprotectin was assessed with enzyme‐linked immunosorbent assay. Serum C‐reactive protein and leucocyte counts were retrieved from medical records. Results Cachexia prevalence was highest in pancreatic cancer (66.7%), followed by ovarian cancer (25%), lung cancer (20.8%), and breast cancer (17.3%). Microbial α‐diversity was not significantly different between cachectic cancer patients (N = 33), non‐cachectic cancer patients (N = 74), or healthy controls (N = 76) (species richness P = 0.31; Shannon effective index P = 0.46). Community structure (β‐diversity) tended to differ between these groups (P = 0.053), although overall differences were subtle and no clear clustering of samples was observed. Proteobacteria (P

Abstract As electric vehicles become more widely used, there is a higher demand for lithium‐ion batteries (LIBs) and hence a greater incentive to find better ways to recycle these at their end‐of‐life (EOL). This work focuses on the process of reclamation and re‐use of cathode material from LIBs. Black mass containing mixed LiMn2O4 and Ni0.8Co0.15Al0.05O2 from a Nissan Leaf pouch cell are recovered via two different recycling routes, shredding or disassembly. The waste material stream purity is compared for both processes, less aluminium and copper impurities are present in the disassembled waste stream. The reclaimed black mass is further treated to reclaim the transition metals in a salt solution, Ni, Mn, Co ratios are adjusted in order to synthesize an upcycled cathode, LiNi0.6Mn0.2Co0.2O2 via a co‐precipitation method. The two reclamation processes (disassembly and shredding) are evaluated based on the purity of the reclaimed material, the performance of the remanufactured cell, and the energy required for the complete process. The electrochemical performance of recycled material is comparable to that of as‐manufactured cathode material, indicating no detrimental effect of purified recycled transition metal content. This research represents an important step toward scalable approaches to the recycling of EOL cathode material in LIBs.

Abstract Background Myosteatosis has been associated with shorter overall survival in cancer patients. The increase in ectopic fat might not be limited to skeletal muscle only and might also extend to other sites such as the liver, resulting in non‐alcoholic fatty liver disease (NAFLD). In this study, we assessed the relationship between myosteatosis and NAFLD and their association with overall survival in patients with colorectal liver metastases undergoing partial hepatectomy. Methods Patients were selected from a prospective cohort of 289 consecutive patients with colorectal liver metastases. All patients with a preoperative computed tomography (CT)‐scan and liver biopsy obtained during surgery were included. If available a second pre‐operative CT scan was used to calculate changes in body composition over time. Muscle radiation attenuation was defined as the average Hounsfield units on CT of all muscle tissue at the L3 level. Liver biopsies were graded by a liver pathologist using the steatosis, activity, and fibrosis scoring system for NAFLD. Results Two‐hundred and eighteen patients had an available liver biopsy of which 131 patients had two available pre‐operative CT scans with an average time interval of 3.2 months. One‐hundred and thirty‐five (62%) biopsies were classified as NAFLD. In multivariable Cox‐regression analysis, NAFLD [hazard ratio (HR): 1.8, 95%‐confidence interval (CI) 1.0–3.0, P = 0.037], increase in myosteatosis (HR 1.8, 95%‐CI 1.1–2.9, P = 0.018), and skeletal muscle loss (HR 1.7, 95%‐CI 1.0–2.9, P = 0.035) were independently associated with shorter overall survival while high visceral adipose tissue fat content was associated with longer overall survival (HR: 0.7, 95%‐CI 0.5–0.9, P = 0.014). Conclusions Ectopic fat content of liver as well as skeletal muscle tissue is independently associated with shorter overall survival in patients with colorectal liver metastases, while increased visceral adipose tissue fat content is associated with longer overall survival.

Abstract Objective To define and evaluate hemodynamic criteria to distinguish between classical orthostatic hypotension (cOH) and vasovagal syncope (VVS) in tilt table testing (TTT). Methods Inclusion criteria for VVS were a history of VVS and tilt‐induced syncope defined as a blood pressure (BP) decrease and electroencephalographic changes during syncope with complaint recognition. Criteria for cOH were a history of cOH and a BP decrease meeting published criteria. Clinical diagnoses were established prior to TTT. We assessed (1) whether the decrease of systolic BP accelerated, “convex,” or decelerated, “concave”; (2) the time from head‐up tilt to when BP reached one‐half its maximal decrease; (3) the difference between baseline heart rate (HR) and HR at BP nadir. We calculated the diagnostic yield of optimized thresholds of these features and their combinations. Results We included 82 VVS cases (40% men, median age 44 years) and 65 cOH cases (66% men, median age 70 years). BP decrease was concave in cOH in 79% and convex in VVS in 94% (p

Abstract Background Cancer cachexia is characterized by impaired function of skeletal and cardiac muscle. Smooth muscle is abundantly present in the body and critical for the function of the gastrointestinal tract. Given the frequently reported gastrointestinal symptoms in cancer patients, we hypothesized that the smooth musculature could be compromised in cancer patients with sarcopenia. Methods Full‐thickness jejunal tissue sections from 57 pancreatic cancer patients were analysed by picrosirius red stains and immunohistochemistry for α‐smooth muscle actin (α‐SMA), smoothelin, and CD117 (c‐kit). Muscle wall thickness, contractile marker expression, and collagen deposition were quantified. Patients were assigned to a sarcopenia or non‐sarcopenia group based on their skeletal muscle index. Results Intestinal smooth muscle wall thickness did not differ between the sarcopenia and non‐sarcopenia group (1,661 ± 125.0 vs. 1,439 ± 93.5 μm, P = 0.41). Whereas α‐SMA staining intensity was similar in both groups, staining intensity of smoothelin, a key marker of the contractile smooth muscle cell phenotype, was reduced (143.0 ± 22.6 vs. 125.4 ± 29.3 arbitrary units, P = 0.02) in sarcopenic patients. The distribution of CD117+ interstitial cells of Cajal was similar in both groups, but pronounced collagen deposition around the myenteric plexus was more often observed in patients with sarcopenia (P = 0.04). Conclusions These data suggest that cancer cachexia is not only associated with skeletal and cardiac muscle wasting, but also affects the intestinal smooth musculature. Reduced contractile smooth muscle marker expression and fibrosis around the myenteric plexus suggest that both contractile function of smooth muscle cells and regulation of their contractile functionality could be compromised.

Abstract Background Skeletal muscle wasting and fatigue are commonly observed in cancer patients receiving chemotherapy and associated with reduced treatment outcome and quality of life. Nutritional support may mitigate these side effects, but potential interference with chemotherapy efficacy could be of concern. Here, we investigated the effects of an ω‐3 polyunsaturated fatty acid (eicosapentaenoic acid and docosahexaenoic acid), leucine‐enriched, high‐protein (100% whey), additional vitamin D, and prebiotic fibres ‘specific nutritional composition’ (SNC) and chemotherapy on state‐of‐the‐art tumour organoids and muscle cells and studied muscle function, physical activity, systemic inflammation, and chemotherapy efficacy in a mouse model of aggressive colorectal cancer (CRC). Methods Tumour‐bearing mice received a diet with or without SNC. Chemotherapy treatment consisted of oxaliplatin and 5‐fluorouracil. Tumour formation was monitored by calliper measurements. Physical activity was continuously monitored by infrared imaging. Ex vivo muscle performance was determined by myography, muscle fatty acid composition by gas chromatography, and plasma cytokine levels by Luminex xMAP technology. Patient‐derived CRC organoids and C2C12 myotubes were used to determine whether SNC affects chemotherapy sensitivity in vitro. Results Specific nutritional composition increased muscle contraction capacity of chemotherapy‐treated tumour‐bearing mice (P

Abstract Background In vivo muscle protein synthesis rates are typically assessed by measuring the incorporation rate of stable isotope labelled amino acids in skeletal muscle tissue collected from vastus lateralis muscle. It remains to be established whether muscle protein synthesis rates in the vastus lateralis are representative of muscle protein synthesis rates of other muscle groups. We hypothesized that post‐absorptive muscle protein synthesis rates differ between vastus lateralis and rectus abdominis, pectoralis major, or temporalis muscle in vivo in humans. Methods Twenty‐four patients (62 ± 3 years, 42% female), scheduled to undergo surgery, participated in this study and underwent primed continuous intravenous infusions with l‐[ring‐13C6]‐phenylalanine. During the surgical procedures, serum samples were collected, and muscle tissue was obtained from the vastus lateralis as well as from the rectus abdominis, pectoralis major, or temporalis muscle. Fractional mixed muscle protein synthesis rates (%/h) were assessed by measuring the incorporation of l‐[ring‐13C6]‐phenylalanine into muscle tissue protein. Results Serum l‐[ring‐13C6]‐phenylalanine enrichments did not change throughout the infusion period. Post‐absorptive muscle protein synthesis rates calculated based upon serum l‐[ring‐13C6]‐phenylalanine enrichments did not differ between vastus lateralis and rectus abdominis (0.032 ± 0.004 vs. 0.038 ± 0.003%/h), vastus lateralis and pectoralis major, (0.025 ± 0.003 vs. 0.022 ± 0.005%/h) or vastus lateralis and temporalis (0.047 ± 0.005 vs. 0.043 ± 0.005%/h) muscle, respectively (P > 0.05). When fractional muscle protein synthesis rates were calculated based upon tissue‐free l‐[ring‐13C6]‐phenylalanine enrichments as the preferred precursor pool, muscle protein synthesis rates were significantly higher in rectus abdominis (0.089 ± 0.008%/h) compared with vastus lateralis (0.054 ± 0.005%/h) muscle (P

Abstract Metabarcoding has improved the way we understand plants within our environment, from their ecology and conservation to invasive species management. The notion of identifying plant taxa within environmental samples relies on the ability to match unknown sequences to known reference libraries. Without comprehensive reference databases, species can go undetected or be incorrectly assigned, leading to false‐positive and false‐negative detections. To improve our ability to generate reference sequence databases, we developed a targeted capture approach using the OZBaits_CP V1.0 set, designed to capture chloroplast gene regions across the entirety of flowering plant diversity. We focused on generating a reference database for coastal temperate plant species given the lack of reference sequences for these taxa. Our approach was successful across all specimens with a target gene recovery rate of 92%, which was achieved in a single assay (i.e., samples were pooled), thus making this approach much faster and more efficient than standard barcoding. Further testing of this database highlighted 80% of all samples could be discriminated to family level across all gene regions with some genes achieving greater resolution than others—which was also dependent on the taxon of interest. Thus, we demonstrate the importance of generating reference sequences across multiple chloroplast gene regions as no single loci are sufficient to discriminate across all plant groups. The targeted capture approach outlined in this study provides a way forward to achieve this.

Abstract A debate has called into question as to which fluvial channel patterns are most widely represented in the stratigraphic record, with some advocating that distributive fluvial systems (DFS) predominate and others that a broad diversity of fluvial styles may become preserved. Critical to both sides is the adequate recognition of original channel planform from geological outcrops separated from their formative processes by millions or even billions of years. In this study the river and rock record are linked through experimentally created DFSs with both aggrading channel beds and floodplains. This approach allows depositing processes and deposited strata to be studied in tandem. Proximal areas comprise coarse, amalgamated channel‐fills with scarce fine‐grained floodplain material. The overall spread of sandbody dimensions become far more varied in medial stretches, with an overall reduction in mean width and depth. In these areas channel‐fills may be sand‐rich or mud‐rich and, following avulsion, all channels are covered by floodplain sediment. Channels, levees and splays form discrete depositional bodies each with varying aspect ratios; a novel breadth of deposits and morphologies in aggrading experiments largely concurrent with proposed trends indicative of DFSs. The proportion of floodplain material increases distally, resulting in decreased interconnectedness of distal channel‐fills. Muddy floodplain sediments significantly change DFSs behaviour and subsequent stratigraphic architecture by enhancing bank stability and reducing avulsion through the filling of floodbasins. The laboratory methods utilised here open up the possibility of controlled experimentation on the effects and mechanisms of DFSs sedimentation, which is important since the modelled stratigraphic trends are rarely so tractable in ancient geological outcrop belts.

Abstract Background The SARS‐CoV‐2 (COVID‐19) virus has wide community spread. The aim of this study was to describe patient characteristics and to identify factors associated with COVID‐19 among emergency department (ED) patients under investigation for COVID‐19 who were admitted to the hospital. Methods This was a retrospective observational study from 8 EDs within a 9‐hospital health system. Patients with COVID‐19 testing around the time of hospital admission were included. The primary outcome measure was COVID‐19 test result. Patient characteristics were described and a multivariable logistic regression model was used to identify factors associated with a positive COVID‐19 test. Results During the study period from March 1, 2020 to April 8, 2020, 2182 admitted patients had a test resulted for COVID‐19. Of these patients, 786 (36%) had a positive test result. For COVID‐19‐positive patients, 63 (8.1%) died during hospitalization. COVID‐19‐positive patients had lower pulse oximetry (0.91 [95% confidence interval, CI], [0.88–0.94]), higher temperatures (1.36 [1.26–1.47]), and lower leukocyte counts than negative patients (0.78 [0.75–0.82]). Chronic lung disease (odds ratio [OR] 0.68, [0.52–0.90]) and histories of alcohol (0.64 [0.42—0.99]) or substance abuse (0.39 [0.25—0.62]) were less likely to be associated with a positive COVID‐19 result. Conclusion We observed a high percentage of positive results among an admitted ED cohort under investigation for COVID‐19. Patient factors may be useful in early differentiation of patients with COVID‐19 from similarly presenting respiratory illnesses although no single factor will serve this purpose.

Abstract Minimally‐invasive tools to assess tumour presence and burden may improve clinical management. FDG‐PET (metabolic) imaging is the current gold standard for interim response assessment in patients with classical Hodgkin Lymphoma (cHL), but this technique cannot be repeated frequently. Here we show that microRNAs (miRNA) associated with tumour‐secreted extracellular vesicles (EVs) in the circulation of cHL patients may improve response assessment. Small RNA sequencing and qRT‐PCR reveal that the relative abundance of cHL‐expressed miRNAs, miR‐127‐3p, miR‐155‐5p, miR‐21‐5p, miR‐24‐3p and let‐7a‐5p is up to hundred‐fold increased in plasma EVs of cHL patients pre‐treatment when compared to complete metabolic responders (CMR). Notably, in partial responders (PR) or treatment‐refractory cases (n = 10) the EV‐miRNA levels remain elevated. In comparison, tumour specific copy number variations (CNV) were detected in cell‐free DNA of 8 out of 10 newly diagnosed cHL patients but not in patients with PR. Combining EV‐miR‐127‐3p and/or EV‐let‐7a‐5p levels, with serum TARC (a validated protein cHL biomarker), increases the accuracy for predicting PET‐status (n = 129) to an area under the curve of 0.93 (CI: 0.87‐0.99), 93.5% sensitivity, 83.8/85.0% specificity and a negative predictive value of 96%. Thus the level of tumour‐associated miRNAs in plasma EVs is predictive of metabolic tumour activity in cHL patients. Our findings suggest that plasma EV‐miRNA are useful for detection of small residual lesions and may be applied as serial response prediction tool.

Abstract Background Body composition assessment, measured using single‐slice computed tomography (CT) image at L3 level, and aerobic physical fitness, objectively measured using cardiopulmonary exercise testing (CPET), are each independently used for perioperative risk assessment. Sarcopenia (i.e. low skeletal muscle mass), myosteatosis [i.e. low skeletal muscle radiation attenuation (SM‐RA)], and impaired objectively measured aerobic fitness (reduced oxygen uptake) have been associated with poor post‐operative outcomes and survival in various cancer types. However, the association between CT body composition and physical fitness has not been explored. In this study, we assessed the association of CT body composition with selected CPET variables in patients undergoing hepatobiliary and pancreatic surgery. Methods A pragmatic prospective cohort of 123 patients undergoing hepatobiliary and pancreatic surgery were recruited. All patients underwent preoperative CPET. Preoperative CT scans were analysed using a single‐slice CT image at L3 level to assess skeletal muscle mass, adipose tissue mass, and muscle radiation attenuation. Multivariate linear regression was used to test the association between CPET variables and body composition. Main outcomes were oxygen uptake at anaerobic threshold ( V̇O2 at AT), oxygen uptake at peak exercise ( V̇O2 peak), skeletal muscle mass, and SM‐RA. Results Of 123 patients recruited [77 men (63%), median age 66.9 ± 11.7, median body mass index 27.3 ± 5.2], 113 patients had good‐quality abdominal CT scans available and were included. Of the CT body composition variables, SM‐RA had the strongest correlation with V̇O2 peak (r = 0.57, P

Abstract Background Living tissues maintain a fine balance between protein synthesis and protein breakdown rates. Animal studies indicate that protein synthesis rates are higher in organs when compared with skeletal muscle tissue. As such, organ and tumour protein synthesis could have major effects on whole‐body protein metabolism in wasting disorders such as cancer cachexia. We aimed to assess protein synthesis rates in pancreatic tumour tissue and healthy pancreas, liver, and skeletal muscle tissue in vivo in humans. Methods In eight patients with pancreatic cancer undergoing pancreaticoduodenectomy, primed continuous infusions with L‐[ring‐13C6]phenylalanine and L‐[3,5‐2H2]tyrosine were started prior to surgery and continued throughout the surgical procedures. During surgery, plasma samples and biopsies from the pancreas, pancreatic tumour, liver, and vastus lateralis muscle were taken. Post‐absorptive fractional protein synthesis rates were determined by measuring incorporation of labelled L‐[ring‐13C6]phenylalanine in tissue protein using the weighed plasma L‐[ring‐13C6]phenylalanine enrichments as the precursor pool. Results Five male patients and three female patients with a mean age of 67 ± 2 years were included into this study. Plasma L‐[ring‐13C6]phenylalanine enrichments (6–9 mole per cent excess) did not change during surgery (P = 0.60). Pancreatic tumour protein synthesis rates were 2.6‐fold lower than surrounding pancreatic tissue protein synthesis rates (0.268 ± 0.053 vs. 0.694 ± 0.228%/h, respectively; P = 0.028) and 1.7‐fold lower than liver protein synthesis rates (0.268 ± 0.053 vs. 0.448 ± 0.043%/h, respectively; P = 0.046). Among healthy organ samples, protein synthesis rates were 20‐fold and 13‐fold higher in pancreas and liver, respectively, compared with skeletal muscle tissue (0.694 ± 0.228 and 0.448 ± 0.043 vs. 0.035 ± 0.005%/h, respectively; P

Abstract Background Most prognostic scoring systems for colorectal liver metastases (CRLMs) account for factors related to tumour biology. Little is known about the effects of the host phenotype to the tumour. Our objective was to delineate the relationship of systemic inflammation and body composition features [i.e. low skeletal muscle mass (sarcopenia) and low visceral adipose tissue (VAT)], two well‐described host phenotypes in cancer. Methods Clinical data and pre‐operative blood samples were collected from 99 patients who underwent resection of CRLM. Pre‐operative computed tomography scans were available for 97 patients; body composition was analysed at the L3 level, stratified for sex and age. Clinicopathological variables, serum C‐reactive protein (CRP), and various body composition variables were evaluated. Overall survival was evaluated as a function of these same variables in multivariate Cox regression analysis. Results Skeletal muscle was significantly correlated with VAT (r = 0.46, P

Abstract To evaluate the clinical benefit of new medicines for type 2 diabetes mellitus (T2DM), the Dutch guideline committee T2DM in primary care established the importance of outcomes and minimal clinically important differences (MCIDs). The present study used an online questionnaire to investigate healthcare professionals’ opinions about the importance of outcomes and preferences for MCIDs. A total of 211 physicians, pharmacists, practice nurses, diabetes nurses, nurse practitioners and physician assistants evaluated the importance of mortality, macro‐ and microvascular morbidity, HbA1c, body weight, quality of life, (overall) hospital admissions and severe and other hypoglycemia on a 9‐point scale. All outcomes were considered critical (mean scores 7–9), except for body weight and other hypoglycemia (mean scores 4–6). Only HbA1c and hospital admissions were valued differently by the guideline committee (not critical). Other relevant outcomes according to the respondents were adverse events, ease of use and costs. Median MCIDs were 4 mmol/mol for HbA1c (guideline: 5 mmol/mol) and 3 kg for body weight (guideline: 5 kg weight gain and 2,5 kg weight loss). Healthcare professionals preferred relative risk reductions of 20% for mortality (guideline: 10%) and macrovascular morbidity (guideline: 25%) and 50% for other hypoglycaemia (guideline: 25%). The MCID of 25% for microvascular morbidity, hospital admissions and severe hypoglycaemia corresponded to the guideline‐MCID. Healthcare professionals’ preferences were thus comparable to the views of the guideline committee. However, healthcare professionals had a stricter view on the importance of HbA1c and hospital admissions and the MCIDs for mortality and other hypoglycemia.

This paper explores the work the Student Transitions and Family Engagement (STFE) team did to convert dynamic in-person experiences into virtual programs, advising, and courses. These opportunities were framed through the lenses of Academic and Social Integration (Tinto, 1975; Braxton et al., 2004), Belonging (Strayhorn, 2019), and Transition Theory (Schlossberg, 1981). The COVID-19 pandemic caused disruptions in every sector of business and higher education and student affairs was not immune to these effects. The unprecedented disturbances to business-as-normal forced student affairs professionals to find innovative ways to welcome new students into their universities. This article details the monumental programmatic changes employed, as well as the challenges faced and lessons learned by the New Student Orientation and First-Year Experiences teams at the University of Colorado Denver. While catalyzed by unfortunate circumstances and necessity, many of the new ideas and methods developed during 2020 will be adopted as mainstays in STFE’s suite of operations and programmatic offerings.

Abstract Aims The aim of this study was to explore the effect of insulin treatment initiation on weight by taking weight change prior to initiation into account. Materials and methods We performed an observational retrospective inception cohort study, concerning Dutch primary care. We identified all patients that initiated insulin treatment (n = 7967) and individually matched patients with a reference patient (n = 5213 pairs). We obtained estimated mean weight changes in the five years prior to five years post insulin therapy. We applied linear regression analysis on weight change in the first year after insulin therapy (T0 to T+1), with matched group as primary determinant adjusted for pre‐insulin weight change and additional covariates. Results Estimated mean weight increased in the five consecutive years prior to insulin therapy (−0.23 kg in year T‐5 to T‐4, 0.01 kg in year T‐4 to T‐3, 0.07 kg in year T‐3 to T‐2, 0.24 kg in year T‐2 to T‐1, and 0.46 kg in year T‐1 to T0) and continued to increase in the first year after, that is T0 to T+1, at a slightly lower rate (0.31 ± 3.9 kg). Pre‐insulin weight change had the highest explained variance and was inversely and independently associated with weight change (p

Abstract Background Patients often perceive a lumbar puncture (LP) as an invasive procedure. We aimed to evaluate the impact of a 3‐minute educational animation‐video explaining the LP procedure, on patients’ knowledge, uncertainty, anxiety, and post‐LP complications. Methods We included 203 newly referred memory clinic patients, who were randomly assigned to one of three conditions: (1) home viewing of the video, (2) clinic viewing of the video, or (3) control condition (care as usual). Participants completed questionnaires measuring knowledge as information recall, uncertainty, anxiety, and post‐LP complications, the latter when patients underwent an LP procedure (n = 145). Results Viewing the video increased information recall for both home (P

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

Abstract Despite an explosive growth of next‐generation sequencing data, genome diagnostics only provides a molecular diagnosis to a minority of patients. Software tools that prioritize genes based on patient symptoms using known gene‐disease associations may complement variant filtering and interpretation to increase chances of success. However, many of these tools cannot be used in practice because they are embedded within variant prioritization algorithms, or exist as remote services that cannot be relied upon or are unacceptable because of legal/ethical barriers. In addition, many tools are not designed for command‐line usage, closed‐source, abandoned, or unavailable. We present Variant Interpretation using Biomedical literature Evidence (VIBE), a tool to prioritize disease genes based on Human Phenotype Ontology codes. VIBE is a locally installed executable that ensures operational availability and is built upon DisGeNET‐RDF, a comprehensive knowledge platform containing gene‐disease associations mostly from literature and variant‐disease associations mostly from curated source databases. VIBE's command‐line interface and output are designed for easy incorporation into bioinformatic pipelines that annotate and prioritize variants for further clinical interpretation. We evaluate VIBE in a benchmark based on 305 patient cases alongside seven other tools. Our results demonstrate that VIBE offers consistent performance with few cases missed, but we also find high complementarity among all tested tools. VIBE is a powerful, free, open source and locally installable solution for prioritizing genes based on patient symptoms. Project source code, documentation, benchmark and executables are available at https://github.com/molgenis/vibe.

Abstract Background Inadequate intake of micronutrients with antioxidant properties is common among older adults and has been associated with higher risk of frailty, adverse functional outcome, and impaired muscle health. However, a causal relationship is less well known. The aim was to determine in old mice the impact of reduced dietary intake of vitamins A/E/B6/B12/folate, selenium, and zinc on muscle mass, oxidative capacity, strength, and physical activity (PA) over time. Methods Twenty‐one‐month‐old male mice were fed either AIN‐93‐M (control) or a diet low in micronutrients with antioxidant properties (=LOWOX‐B: 50% of mouse recommended daily intake of vitamins A, E, B6, and B12, folate, selenium, and zinc) for 4 months. Muscle mass, grip strength, physical activity (PA), and general oxidative status were assessed. Moreover, muscle fatigue was measured of m. extensor digitorum longus (EDL) during an ex vivo moderate exercise protocol. Effects on oxidative capacity [succinate dehydrogenase (SDH) activity], muscle fibre type, number, and fibre cross‐sectional area (fCSA) were assessed on m. plantaris (PL) using histochemistry. Results After 2 months on the diet, bodyweight of LOWOX‐B mice was lower compared with control (P

Abstract Aims Intraperitoneal (IP) insulin administration is a last‐resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As the IP route of insulin administration mimics the physiology more closely than the subcutaneous (SC) route, we hypothesized that IP insulin would result in less oxidative stress (expressed as systemic level of free sulphydryl (R‐SH) content) compared to SC insulin in subjects with T1DM. Materials and methods Prospective, observational case‐control study. Serum thiol measurements were performed at baseline and at 26 weeks in age‐ and gender‐matched patients with T1DM. Serum‐free thiols, compounds with a R‐SH group that are readily oxidized by reactive oxygen species, are considered to be a marker of systemic redox status. Results A total of 176 patients, 39 of which used IP and 141 SC insulin therapy were analysed. Mean baseline R‐SH concentration was 248 (31) μmol/L. In multivariable analysis, the route of insulin therapy had no impact on baseline R‐SH levels. The estimated geometric mean concentrations of R‐SH did not differ significantly between both groups: 264 (95% CI 257, 270) for the IP group and 258 (95% CI 254, 261) for the SC group with a difference of 6 (95% CI −2, 14) μmol/L. Conclusions Based on R‐SH as a marker of systemic oxidative stress, these findings demonstrate that the route of insulin administration, IP or SC, does not influence systemic redox status in patients with T1DM.