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Abstract Despite movements towards gender parity within academia, women faculty continue to be paid less than men. While previous research has explained the gap using academic rank/seniority and productivity, existing findings are limited by either their examination of base pay or reliance on self-reported data. Here we extend the analysis beyond base pay, link faculty salary records of one public university system in the U.S. to the OpenAlex bibliometric database, and separately analyze the gender pay gap in the base (grade) and other pay (off-grade). Using stepwise regression models, we find that faculty rank accounts for a significant gap in the base pay while performance-based variables such as H-index or specialization do not play a crucial role. For other pay, no variables stand out in explaining the substantial pay gap between women and men faculty. Our results suggest that a primary source of the remaining gender pay gap is the off-grade pay. Different policy approaches are required to reduce the gender pay gap depending on the specific type of salary being targeted.

Background: Climate change is expected to elevate exposure to several environmental health risk factors, including extreme environmental temperatures, air pollution and airborne allergenic pollen. Given their interconnected effects on respiratory and cardiovascular diseases, it is crucial to evaluate these exposures simultaneously. Yet, comprehensive efforts to do so remain limited. This research aims to develop an approach using modelled data, in conjunction with health-based threshold values, to assess whether, where and when there is simultaneous threshold exceedance of heat, air pollution and airborne allergenic pollen in Europe. Methods: Hourly exposure data for the three stressors were sourced from three models (air pollution: LOTOS-EUROS, pollen: Copernicus Atmosphere Monitoring Service, meteorological conditions: ECMWF) for 2021 and 2022. Thresholds for each stressor that indicate the boundary of acceptable limits were based on officially established tresholds or literature recommendations. The result is a 0.1°x0.1° resolution grid (approximately 10 km x 10 km) for each stressor, with each cell representing whether exposure met or exceeded the threshold. Findings: Simultaneous threshold exceedance of air pollution and heat is occurring in various degrees throughout Europe. In the summer of 2022, the exceedances ranged from below 1% in large parts of Northern Europe to as much as 25% of the time in the Mediterranean area. An assessment of monthly threshold exceedance patterns shows a dynamic and changing co-exposure pattern across the year, which differs per region. Interpretation: This work lays out a robust approach to assess simultaneous threshold exceedances of multiple environmental health risk stressors. This approach can guide policy makers in pinpointing high-risk areas particularly vulnerable to simultaneous threshold exceedances, and develop mitigation strategies for those areas. Funding: Internal funding from TNO.

Considering it contains a variety of physiologically active compounds, including flavonoids, common phenols, and essential oils (EOs), St. John’s wort (Hypericum perforatum L.) is a common plant in Bulgaria that is predominantly used in folk medicine to cure various disorders. Determining the chemical makeup of St. John’s wort inflorescences that were gathered from northern Bulgaria was the purpose of this investigation. The antioxidant activity of H. perforatum L. extracts was assessed using 1,1-diphenyl-2-picrilhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and Trolox equivalent antioxidant capacity (TEAC) tests on methanol extract. The amount of EO obtained by water distillation was 0.08%, with its main components (over 3%) being n-nonane (27.46%), β-sesquiphellandrene (11.17%), heptanal dimethyl acetal (5.94%), ethyl hexyl ketone (5.93%), undecane (3.75%), sabinene (3.3%), and tridecyl alcohol (3.1%). Methanol extracts were obtained from the inflorescences, with the total flavonoid content determined as 8.66 mg quercetin equivalents (QE)/mg and total phenolic content as 271.33 mg Gallic acid equivalent/g. The FRAP assay yielded 493.07 µmol/L of antioxidant activity, while the TEAC assay yielded 106.39 µmol/L, respectively. Our findings enable a comprehensive characterization of H. perforatum from Bulgaria and an assessment of its oil suitability for potential industrial applications. Additionally, the results could guide the selection of specimens for future targeted breeding efforts.

Background To develop and maintain suturing skills, clinical exposure is important. When clinical exposure cannot be guaranteed, an adequate training schedule for suturing skills is required. This study evaluates the effect of continuous training, ‘reflection before practice’ and self-assessment on basic open suturing skills.Methods Medical students performed four basic suturing tasks on a simulation set up before (‘pre-test’) and after their surgical rotation (‘after-test’). Participants were divided in three groups; the ‘clinical exposure group’ (n = 44) had clinical exposure during their rotation only, the ‘continuous training group’ (n = 16) completed a suturing interval training during their rotation and the ‘self-assessment group’ (n = 16) also completed a suturing interval training, but with the use of reflection before practice and self-assessment. Parameters measured by a tracking system during the suturing tasks and a calculated ‘composite score’ were compared between groups and test-moments.Results A significantly better composite score was found at the after-test compared to the pre-test for all groups for all basic suturing tasks (0.001 ≤ p ≤ 0.049). The self-assessment group scored better at the pre-test than the other two groups for all tasks, except for ‘knot tying by hand’ (0.004 ≤ p ≤ 0.063). However, this group did not score better at the after-test for all tasks, compared to the other two groups. This resulted in a smaller delta of time (‘transcutaneous suture’, p = 0.013), distance (‘Donati suture’ and ‘intracutaneous suture’, 0.005 ≤ p ≤ 0.009) or composite score (all tasks, except for knot tying by hand, 0.007 ≤ p ≤ 0.061) in the self-assessment group.Conclusion Reflection before practice and self-assessment during continuous training of basic open suturing tasks, may improve surgical skills at the start of the learning curve.

Objectives:. Sirolimus is one of the first oral drugs for safe and effective treatment of patients with vascular malformations, and may save (expensive) interventions. Therefore the objective was to investigate the cost-effectiveness of sirolimus in vascular malformations. Methods:. This cost-effectiveness analysis from a medical and societal perspective was performed alongside a clinical phase IIB effectiveness of sirolimus in patients with vascular malformations trial. Utility and quality-adjusted life years (QALY) were calculated using the short-form six-dimension in adults and pediatric quality of life inventory scores to express effectiveness in children. Total costs included medical and productivity costs. The net monetary benefit was calculated, given a range of willingness to pay (WTP) values within societies with nationalized health care. Results:. After 6 months on sirolimus, the pediatric quality of life inventory increased by a mean of 12.10 points (95% confidence interval [CI], 7.64–16.37) in children, and the QALY increased by 0.07 (95% CI, 0.03–0.11) in adults. After 6 months on sirolimus, total costs per child were numerically increased by €110.88 (95% CI, −€1786.17–€2165.95). Per adult, sirolimus resulted in a numerical decrease of mean total cost of €426.84 (95% CI, −€2831.38–€1414.60). In adults, there was a 95% chance that sirolimus treatment would be cost-effective with a WTP of €50k per QALY gained. Conclusion:. This first pharmacoeconomic analysis shows a substantial improvement in utility and health-related quality of life due to sirolimus treatment in patients with vascular malformations. It shows a high chance that sirolimus will be cost-effective in adults within the limits of acceptable WTP values within societies with nationalized health care. In children, sirolimus may become cost-effective in the future due to a possible decrease in interventions.

Background: Alcohol misuse among medical professionals poses a significant concern, and there is a lack of clarity in (inter)national guidelines regarding alcohol use during work. Moreover, there exists an insufficient body of research on the specific impact of alcohol on fine motor skills within the medical sector, specifically surgery. This study aims to investigate the impact of alcohol on fine motor skills in a minimally invasive surgical setting. Methods: A cross-sectional study was conducted at Lowland Science on August 19th, 20th, and 21st, 2022, during the Lowlands music festival in Biddinghuizen, the Netherlands. Participants were divided into five groups based on measured alcohol consumption. Exclusion criteria included drug use, prior surgical experience, being underage, and previous participation. The main outcomes were the number of correctly transferred rings during the PEG transfer task and the number of errors. Blood alcohol concentration (BAC) was measured using a breathalyser. Results: A total of 1056 participants were included in the study. The results indicated an inverse relationship between BAC levels and surgical performance, with higher alcohol levels associated with a decrease in performance (p = 0.023). However, there was no significant difference in the number of errors among the five groups (p = 0.597). The group with the highest alcohol consumption (BAC >0.08 %) exhibited significantly worse performance compared to the group with a BAC of 0.0 % (p = 0.002). Conclusion: This study uncovers a negative impact of increased alcohol intake on fine motor skills in a minimally invasive surgery simulation exercise. While there was no effect on the occurrence of errors. Professional medical organizations should reconsider and explicate their position on alcohol use in (surgical) healthcare.

The bimodal wave climate of the semi-protected shallow Gulf St Vincent in South Australia has been analyzed through a forty-year (1980-2020) wave hindcast and an investigation into the climatic drivers of wave climate anomalies is presented. The sea and swell partitions of the wave climate were modelled independently as well as using an integrated model with both partitions represented. The wave hindcast was validated against two wave buoys located off the coast of Adelaide’s metropolitan beaches and key wave parameter anomalies were calculated across the gulf. Teleconnections were investigated, and the Southern Annular Mode is found to have the strongest correlations to wave parameter anomalies while the Southern Oscillation Index and the Dipole Mode Index fluctuations are found to correlate seasonally with wave parameter anomalies. Projected future trends of these climate drivers from literature have been related to the teleconnections found in this study to inform future trends of bimodal wave conditions in the gulf. The Southern Annular Mode is projected to trend positive which will reduce wave height and the westerly component of waves in the gulf, while the Southern Oscillation Index is projected to become more variable in the future which will lead to more extreme winter and spring wave conditions. An understanding of these trends allows coastal managers to pre-emptively manage the impacts of waves on the coastline at a seasonal to annual basis and provides insight into future wave conditions beyond these time periods.

Illicit connections of wastewater to stormwater systems are the main drawback of separate sewer systems, as they lead to a direct discharge of untreated wastewater to the aquatic environment. Consequently, several inspection methods have been developed for detecting illicit connections. This study simultaneously applied several low- and high-tech methods for the detection of illicit connections in the same catchment (De Heuvel, the Netherlands). The methods included mesh wire screens for capturing coarse contamination, measurements of electroconductivity and temperature, sampling and quantification of Escherichia coli and extended-spectrum ß-lactamase-producing E. coli (ESBL-EC), DNA analysis via quantitative polymerase chain reaction for human-, dog-, and bird-specific fecal indicators, and distributed temperature sensing. Significant illicit connections could be identified using all methods. Nonetheless, hydraulic conditions and, predominantly, the sewage volume determine whether a misconnection can be detected by especially the low-tech methods. Using these results, the identified misconnections were repaired and biological and DNA analyses were repeated. Our results demonstrate that there were no changes in E. coli or ESBL-EC before and after mitigation, suggesting that these common markers of fecal contamination are not specific enough to evaluate the performance of mitigation efforts. However, a marked decrease in human wastewater markers (HF183) was observed. HIGHLIGHTS Wire screens and conductivity are not suited to detect illicit connections at outlets of storm sewers with large water volumes upstream.; Distributed temperature sensing (DTS) is capable of identifying all sorts of misconnections like household appliances.; HF183 Bacteroides are very effective in determining the presence of human fecal material in storm sewers.; Repeated sampling and quantitative polymerase chain reaction testing could be a prescreening method before labor-intensive DTS.;

A theory describing the dynamics of quantum systems interacting on a classical spacetime was recently put forward by Oppenheim et al. Quantum states may retain their coherence, at the cost of some amount of stochasticity of the spacetime metric, characterized by a spacetime diffusion parameter. Here, we report existing experimental upper bounds on such spacetime diffusion, based on a review of several types of experiments with very low force noise over a broad range of test masses from single atoms to several kilograms. We find an upper bound at least 15 orders of magnitude lower as compared to the initial bounds for explicit models presented by Oppenheim et al. The results presented here provide a path forward for future experiments that can help evaluate classical-quantum theories.

ABSTRACTIt is difficult, time consuming and expensive to assess manual skills in open surgery. The aim of this study is to investigate the construct validity of a low-cost, easily accessible tracking technique for basic open suturing tasks. Medical master students, surgical residents, and surgeons at the Radboud University Medical Center were recruited between September 2020 until September 2021. The participants were divided, according to experience, in a novice group (≤10 sutures performed) and an expert group (>50 sutures performed). For objective tracking, a tablet with SurgTrac software was used, which tracked a blue and a red tag placed on respectively their left and right index finger. The participants executed four basic tasks on a suturing model: 1) knot tying by hand, 2) transcutaneous suturing with an instrument knot, 3) ‘Donati’ (vertical mattress suture) with an instrument knot and 4) continuous intracutaneous suturing without a knot. In total 76 participants were included: 57 novices and 19 experts. All four tasks showed significant differences between the novice group and expert group for the parameters time (p

Abstract The clinical presentation of patients with slow‐flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health‐related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well‐tolerated in most patients. However, the main limitation of sirolimus is the reported high toxicity, especially when target levels of 10–15 ng/mL are being used. We report the results of a phase IIB single‐arm open‐label clinical trial consisting of 68 (67 in the challenge phase and 68 in the rechallenge phase) evaluable patients (children n = 33 and adults n = 35) demonstrating that treatment with low sirolimus target levels (4–10 ng/mL) is effective in 79.1% of the patients. When sirolimus treatment was stopped, the majority of patients experienced a recurrence of symptoms, supporting prolonged or even lifelong treatment requirement. Adults experienced a higher baseline pain score compared with children, having an estimated marginal mean of 6.2 versus 4.1, p 0.05) compared with adults. Additionally, response rates were higher in children compared with adults (93.8% vs. 65.7%, p

The densest network for measuring air pollutant concentrations in Colombia is in Medellin, where most sensors are located in the heavily polluted lower parts of the valley. Measuring stations in the higher elevations on the mountains surrounding the valley are not available, which limits our understanding of the valley’s pollutant dynamics and hinders the effectiveness of data assimilation studies using chemical transport models such as LOTOS-EUROS. To address this gap in measurements, we have designed a new network of low-cost sensors to be installed at altitudes above 2000 m.a.s.l. The network consists of custom-built, solar-powered, and remotely connected sensors. Locations were strategically selected using the LOTOS-EUROS model driven by diverse meteorology-simulated fields to explore the effects of the valley wind representation on the transport of pollutants. The sensors transmit collected data to internet gateways for posterior analysis. Various tests to verify the critical characteristics of the equipment, such as long-range transmission modeling and experiments with an R score of 0.96 for the best propagation model, energy power system autonomy, and sensor calibration procedures, besides case exposure to dust and water experiments, to ensure IP certifications. An inter-calibration procedure was performed to characterize the sensors against reference sensors and describe the observation error to provide acceptable ranges for the data assimilation algorithm (

Congenital vascular malformations (CVMs) are the result of an aberrant development during embryogenesis. Although these lesions are present at birth, they are not always visible yet. Once symptomatic, patients suffer from pain, bleeding, ulcers, infections or lymphatic leakage, depending on the subtype of vessels involved. Treatment includes conservative management, surgery, sclerotherapy, embolization and pharmacological therapy. The clinical presentation varies widely and treatment can be challenging due to the rarity of the disease and potential difficulties of treatment. This review gives an overview of the historical developments in diagnosis and classification and exposes the key elements of innovations in the past decades on the identification of genetic mutations and personalized treatment. These advances in the field and a multidisciplinary approach are highly valuable in the optimization of clinical care aimed at both curing or stabilizing the CVM and pursuing physical and psychosocial wellbeing.

β2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents. Here the authors report that two-weeks of treatment with the β2-agonist clenbuterol improves insulin-stimulated glucose disposal in healthy young men in a double-blinded, randomized cross-over trial.

Buildings in rural areas are more exposed to open weather conditions than city centres and, therefore, need to be designed to be more energy efficient. This study systematically investigates the sensitivity of critical building design parameters (building orientation, insulation thickness, glazing properties, shading, and ventilation type) on the heating and cooling energy demand of a rural building in a Mediterranean climate. This study also aims to determine optimum energy-efficient building design conditions in the Mediterranean climate. Thermal simulations were performed using the IESVE tool in a typical two-storey Mediterranean house designed in rural İzmir, Turkey. It was found that critical design parameters such as solar orientation, insulation thickness, glazing properties, shading, and ventilation type affect heating and cooling energy demand. Orientation of the building to the South, 23.5 cm insulation thickness, triple glazing windows, and shading provide maximum energy savings. In addition, South orientation or a deviation of 22.5° from the South, 15 cm insulation thickness, double-glazed windows, and shading ensure significant energy savings and acceptable energy performance in the Mediterranean climate. However, no significant difference in energy performance was found depending on ventilation type (mechanical or mixed mode (natural + mechanical)). The results of this study can promote energy-efficient building design at the local level and help architects design new energy-efficient buildings in the Mediterranean countryside. This study can also contribute to creating energy-efficient building design policies to reduce buildings’ dependence on fossil fuels.

Accurate preoperative localization is crucial for successful minimally invasive parathyroidectomy in primary hyperparathyroidism (PHPT). Preoperative localization can be challenging in patients with recurrent and/or multigland disease (MGD). This has led clinicians to investigate multiple imaging techniques, most of which are associated with radiation exposure. Magnetic resonance imaging (MRI) offers ionizing radiation-free and accurate imaging, making it an attractive alternative imaging modality. The objective of this systematic review is to provide an overview of the diagnostic performance of MRI in the localization of PHPT. PubMed and Embase libraries were searched from 1 January 2000 to 31 March 2023. Studies were included that investigated MRI techniques for the localization of PHPT. The exclusion criteria were (1) secondary/tertiary hyperparathyroidism, (2) studies that provided no diagnostic performance values, (3) studies published before 2000, and (4) studies using 0.5 Tesla MRI scanners. Twenty-four articles were included in the systematic review, with a total of 1127 patients with PHPT. In 14 studies investigating conventional MRI for PHPT localization, sensitivities varied between 39.1% and 94.3%. When employing more advanced MRI protocols like 4D MRI for PHPT localization in 11 studies, sensitivities ranged from 55.6% to 100%. The combination of MR imaging with functional techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy, with sensitivities ranging from 84.2% to 100% in five studies. Despite the limitations of the available evidence, the results of this review indicate that the combination of MR imaging with functional imaging techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy. Further research on emerging MR imaging modalities, such as 4D MRI and PET/MRI, is warranted, as MRI exposes patients to minimal or no ionizing radiation compared to other imaging modalities.

IntroductionBone metastases are frequent in patients with non-small cell lung cancer (NSCLC). The receptor activator of Nuclear Factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway is important in bone metastases development. Furthermore, epidermal growth factor receptor (EGFR) signaling promotes osteoclast formation and stimulation. The understanding of the biological mechanism of bone metastases development might have implications for treatment strategies. Therefore, we studied whether there is an association between EGFR, RANKL, RANK and OPG gene expression in the tumor and presence of bone metastases in patients with NSCLC.MethodsFrom an updated multicenter study, including patients with EGFR mutated (EGFR+), Kirsten rat sarcoma (KRAS+) and EGFR/KRAS wildtype metastatic NSCLC, all patients with available formalin-fixed paraffin-embedded (FFPE) tumor samples were selected. Ribonucleic Acid (RNA) was isolated from these samples and gene expressions of EGFR, RANKL, OPG and RANKL were determined via quantitative Polymerase Chain Reaction (qPCR). Data on demographics, histology and molecular subtyping, sample origin, presence of bone metastasis, SREs and bone progression were collected. Primary endpoint was relation between EGFR, RANK, RANKL, OPG gene expression, RANKL: OPG ratio and bone metastases.ResultsIn 73/335 (32% EGFR+, 49% KRAS+, 19% EGFR/KRAS wildtype) samples from unique patients, gene expression analysis could be performed. Of these 73 patients, 46 (63%) had bone metastases at diagnosis or developed bone metastases during the disease course. No association was found between EGFR expression and presence of bone metastases. Patients with bone metastases had a significantly higher RANKL expression and RANKL: OPG ratio compared to those without. An increased RANKL: OPG ratio resulted in a 1.65x increased risk to develop bone metastases, especially in the first 450 days after diagnosis of metastatic NSCLC.ConclusionIncreased RANKL gene expression and RANKL: OPG ratio, but not EGFR expression, was associated with presence of bone metastases. Additionally, an increased RANKL: OPG gene ratio was associated with a higher incidence of bone metastases development.

IntroductionVascular malformations are rare congenital anomalies of the vascular system, which can involve the capillaries, veins, arteries, lymphatics, or a combination of vessel types. Patients with vascular malformations experience an impaired health-related quality of life (HRQoL) because of their symptoms (e.g., pain, swelling, and bleeding) and psychosocial distress. Sirolimus is an effective drug used in the medical treatment of these patients; however, relatively little is known about the effect of sirolimus on specific changes in the HRQoL domains and its magnitude.MethodsThe magnitude of change (effect size) following intervention is more informative to clinical practitioners than statistically significant but clinically unimportant changes; therefore, this study aimed to examine the magnitude and meaningfulness of change in the HRQoL of children and adults with vascular malformations following sirolimus treatment using low target levels.ResultsIn total, 50 patients with vascular malformations (19 children, 31 adults) were included in this study. These patients experienced a lower HRQoL than the general population, with the adults reporting a significantly lower score in almost all domains. A 6-month sirolimus treatment improved the HRQoL in 29 patients, including 77.8% of the children (Pediatric Quality of Life Inventory score [PedsQL]) and 57.7% of the adults (Short Form 36 [SF-36]). The effect sizes of sirolimus for each SF-36/PedsQL domain ranged from 0.19 to 1.02. The clinically relevant moderate magnitude of changes was seen in the domains of the children's reports: “Physical functioning” and “Social functioning” and in the domains of the parent reports: “Social functioning,” “School functioning,” and “Psychosocial.” A high-magnitude change was seen in the domains “Emotional functioning” and “Psychosocial” in the children's reports and “Physical functioning” in the parent reports. In addition, the moderate magnitude of changes was also seen in the adults SF-36: in all domains except for “Role limitations—physical problems,” “Role limitations—emotional problems,” and “General health perception.”ConclusionWe believe this is the first study showing the magnitude of change in HRQoL after sirolimus treatment in patients with vascular malformations. Before treatment, these patients experienced an impaired HRQoL compared with the general Dutch population. A 6-month sirolimus treatment with low target levels led to moderate-to-high clinically relevant changes in multiple domains, which significantly improved the HRQoL.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03987152?cond=Vascular+Malformations&cntry=NL&city=Nijmegen&draw=2&rank=1, identifier: NCT03987152.

With the capacity to reduce wave energy and trap sediment, Scirpus mariqueter has become an important native species of annual grass for ecology restoration at the Yangtze Estuary in eastern China. Due to seasonal variances of biophysical characteristics, S. mariqueter usually bends and breaks in winter, resulting in flattened stems that may reduce its wave attenuation capacity. To investigate the effects of vegetation flattening on wave attenuation, a set of flume experiments were conducted for flattened and standing vegetation under different wave conditions. The model vegetation was designed to represent the wilted S. mariqueter collected in winter with dynamic similarity. Results showed that the wave damping coefficient for flattened vegetation (βF) was 33.6%-72.4% of that for standing vegetation (βS) with the same vegetation length. Both βF and βS increased with wave height but decreased with water depth. A wave attenuation indicator (WAI) was defined to generate empirical formulas for βS and βF as well as their ratio βF/βS. The empirical formulas were then applied to modify the existing standing vegetation-based wave attenuation model for flattened vegetation and performed successfully. Understanding the wave attenuation characteristics of flattened vegetation is essential for the management of ecological restoration and coastal protection.

Abstract Worldwide, communities are facing increasing flood risk, due to more frequent and intense hazards and rising exposure through more people living along coastlines and in flood plains. Nature-based Solutions (NbS), such as mangroves, and riparian forests, offer huge potential for adaptation and risk reduction. The capacity of trees and forests to attenuate waves and mitigate storm damages receives massive attention, especially after extreme storm events. However, application of forests in flood mitigation strategies remains limited to date, due to lack of real-scale measurements on the performance under extreme conditions. Experiments executed in a large-scale flume with a willow forest to dissipate waves show that trees are hardly damaged and strongly reduce wave and run-up heights, even when maximum wave heights are up to 2.5 m. It was observed for the first time that the surface area of the tree canopy is most relevant for wave attenuation and that the very flexible leaves limitedly add to effectiveness. Overall, the study shows that forests can play a significant role in reducing wave heights and run-up under extreme conditions. Currently, this potential is hardly used but may offer future benefits in achieving more adaptive levee designs.

Purpose: To assess whether contralateral parenchymal enhancement (CPE) on MRI is associated with gene expression pathways in ER+/HER2-breast cancer, and if so, whether such pathways are related to survival. Methods: Preoperative breast MRIs were analyzed of early ER+/HER2-breast cancer patients eligible for breast-conserving surgery included in a prospective observational cohort study (MARGINS). The contralateral parenchyma was segmented and CPE was calculated as the average of the top-10% delayed enhancement. Total tumor RNA sequencing was performed and gene set enrichment analysis was used to reveal gene expression pathways associated with CPE (N = 226) and related to overall survival (OS) and invasive disease-free survival (IDFS) in multivariable survival analysis. The latter was also done for the METABRIC cohort (N = 1355). Results: CPE was most strongly correlated with proteasome pathways (normalized enrichment statistic = 2.04, false discovery rate = .11). Patients with high CPE showed lower tumor proteasome gene expression. Proteasome gene expression had a hazard ratio (HR) of 1.40 (95% CI = 0.89, 2.16; P = .143) for OS in the MARGINS cohort and 1.53 (95% CI = 1.08, 2.14; P = .017) for IDFS, in METABRIC proteasome gene expression had an HR of 1.09 (95% CI = 1.01, 1.18; P = .020) for OS and 1.10 (95% CI = 1.02, 1.18; P = .012) for IDFS. Conclusion: CPE was negatively correlated with tumor proteasome gene expression in early ER+/HER2-breast cancer patients. Low tumor proteasome gene expression was associated with improved survival in the METABRIC data.

Objective: SGLT2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may be metabolic adaptations due to urinary glucose loss. Here, we investigated the cellular and molecular effects of 5 weeks of dapagliflozin treatment on skeletal muscle metabolism in type 2 diabetes patients. Methods: Twenty-six type 2 diabetes mellitus patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. Skeletal muscle acetylcarnitine levels, intramyocellular lipid (IMCL) content and phosphocreatine (PCr) recovery rate were measured by magnetic resonance spectroscopy (MRS). Ex vivo mitochondrial respiration was measured in skeletal muscle fibers using high resolution respirometry. Intramyocellular lipid droplet and mitochondrial network dynamics were investigated using confocal microscopy. Skeletal muscle levels of acylcarnitines, amino acids and TCA cycle intermediates were measured. Expression of genes involved in fatty acid metabolism were investigated. Results: Mitochondrial function, mitochondrial network integrity and citrate synthase and carnitine acetyltransferase activities in skeletal muscle were unaltered after dapagliflozin treatment. Dapagliflozin treatment increased intramyocellular lipid content (0.060 (0.011, 0.110) %, p = 0.019). Myocellular lipid droplets increased in size (0.03 μm2 (0.01–0.06), p

BackgroundIn multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the diagnostic accuracy of the currently used conventional pancreatic imaging techniques and the added value of fine needle aspirations (FNAs).MethodsPatients who had at least one imaging study were included from the population-based MEN1 database of the DutchMEN Study Group from 1990 to 2017. Magnetic resonance imaging (MRI), computed tomography (CT), endoscopic ultrasonography (EUS), FNA, and surgical resection specimens were obtained. The first MRI, CT, or EUS was considered as the index test. For a comparison of the diagnostic accuracy of MRI versus CT, patients with their index test taken between 2010 and 2017 were included. The reference standard consisted of surgical histopathology or radiological follow-up.ResultsA total of 413 patients (92.8% of the database) underwent 3,477 imaging studies. The number of imaging studies per patient increased, and a preference for MRI was observed in the last decade. Overall diagnostic accuracy was good with a positive (PPV) and negative predictive value (NPV) of 88.9% (95% confidence interval, 76.0–95.6) and 92.8% (89.4–95.1), respectively, for PanNET in the pancreatic head and 92.0% (85.3–96.0) and 85.3% (80.5–89.1), respectively, in the body/tail. For MRI, PPV and NPV for pancreatic head tumors were 100% (76.1–100) and 87.1% (76.3–93.6) and for CT, 60.0% (22.9–88.4) and 70.4% (51.3–84.3), respectively. For body/tail tumors, PPV and NPV were 91.3% (72.0–98.8) and 87.0% (75.3–93.9), respectively, for MRI and 100% (74.9–100) and 77.8% (54.3–91.5), respectively, for CT. Pathology confirmed a PanNET in 106 out of 110 (96.4%) resection specimens. FNA was performed on 34 lesions in 33 patients and was considered PanNET in 24 [all confirmed PanNET by histology (10) or follow-up (14)], normal/cyst/unrepresentative in 6 (all confirmed PanNET by follow-up), and adenocarcinoma in 4 (2 confirmed and 2 PanNET). Three patients, all older than 60 years, had a final diagnosis of pancreatic adenocarcinoma.ConclusionAs the accuracy for diagnosing MEN1-related PanNET of MRI was higher than that of CT, MRI should be the preferred (non-invasive) imaging modality for PanNET screening/surveillance. The high diagnostic accuracy of pancreatic imaging and the sporadic occurrence of pancreatic adenocarcinoma question the need for routine (EUS-guided) FNA.

Extracellular vesicles are mediators of intercellular communication with critical roles in cellular senescence and ageing. In arthritis, senescence is linked to the activation of a pro-inflammatory phenotype contributing to chronic arthritis pathogenesis. We hypothesised that senescent osteoarthritic synovial fibroblasts induce senescence and a pro-inflammatory phenotype in non-senescent osteoarthritic fibroblasts, mediated through extracellular vesicle cargo. Small RNA-sequencing and mass spectrometry proteomics were performed on extracellular vesicles isolated from the secretome of non-senescent and irradiation-induced senescent synovial fibroblasts. β-galactosidase staining confirmed senescence in SFs. RNA sequencing identified 17 differentially expressed miRNAs, 11 lncRNAs, 14 tRNAs and one snoRNA and, 21 differentially abundant proteins were identified by mass spectrometry. Bioinformatics analysis of miRNAs identified fibrosis, cell proliferation, autophagy, and cell cycle as significant pathways, tRNA analysis was enriched for signaling pathways including FGF, PI3K/AKT and MAPK, whilst protein analysis identified PAX3-FOXO1, MYC and TFGB1 as enriched upstream regulators involved in senescence and cell cycle arrest. Finally, treatment of non-senescent synovial fibroblasts with senescent extracellular vesicles confirmed the bystander effect, inducing senescence in non-senescent cells potentially through down regulation of NF-κβ and cAMP response element signaling pathways thus supporting our hypothesis. Understanding the exact composition of EV-derived small RNAs of senescent cells in this way will inform our understanding of their roles in inflammation, intercellular communication, and as active molecules in the senescence bystander effect.

Drinking water companies must limit their effects on climate change. Therefore, in this study, we conducted a hybrid life cycle assessment (LCA) for a new drinking water treatment plant (DWTP) to be built in 2025 and expected to be operational until 2075. We focused on obtaining a nearly complete carbon footprint (CF), including both construction (activities and materials) and operation phases. We compared three DWTP concepts: (i) conventional treatment followed by granular activated carbon (GAC) and ultrafiltration; (ii) conventional treatment followed by reverse osmosis; and (iii) capillary nanofiltration followed by GAC. As the DWTP is to be built in The Netherlands, we considered the current plans of the European Union for reducing CFs using two future scenarios (reductions of 80% and 100% in 2050). We found that the CF of the construction over the lifetime of the DWTP accounts for 20–70% of the total (excluding beneficial effects), depending mainly on the electricity used (Dutch mix, solar, or wind) and the future scenario. This means that the construction phase should be investigated in detail to obtain a complete and accurate estimate of the total CF of drinking water production for new DWTPs.

Cold acclimation has been shown to have beneficial metabolic effects, including improved insulin sensitivity in patients with type 2 diabetes. Here the authors show that a mild cold acclimation regiment during which overt shivering was prevented did not result in improved insulin sensitivity in a small group of patients with type 2 diabetes.

Purpose: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses. Methods and Materials: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (

The last years, capacity of vegetation to reduce wave impact is receiving considerable attention. To predict wave attenuation processes within vegetation fields reliable estimates of vegetation parameters are needed. This proves to be difficult for woody vegetation as it consists of complex branch structures, characterized by varying branch densities, diameters and angles. State of the art physical and numerical models effectively use a single value for the diameter, bv and density, N of vegetation, which is unrepresentative for complex vegetation, such as trees. Trees can be better described by the projected frontal-surface area, Av. Hence, this work compares methods to quantify the Av in space for a pollard willow forest, and determines suitability of these methods for predicting wave attenuation using a spectral wave model (SWAN). We use data from manual measurements and Terrestrial Laser Scans (TLS), to estimate the vertical distribution of Av; and data from large-scale flume experiments performed on a willow forest to verify model sensitivity to Av inferences. As a baseline for comparison, tree models that describe the structure of the trees in various degrees of complexity are compiled. The most realistic tree model is used to quantify potential errors in TLS and basic manual measurements of N and bv. An initial comparison shows that the TLS data underestimates Av, which indicates that conducting manual measurements is more suitable to quantify a homogeneous forest. We found that the TLS suffers from shadowing effects (i.e., blockage of laser beams) and we recommend to apply a correction factor to improve its measurements. Furthermore, we identified the impact that the different methods to determine Av have on the estimation of wave attenuation using SWAN; in addition we verified the model results with data from large-scale flume experiments performed on the willow forest. The modeled sensitivity tests indicate large differences in wave attenuation and, consequently, a wide range (0.94–1.70) of bulk drag coefficients, C~D, for the various methods applied. This shows the variation of outcome between measuring methods and highlights the importance of stating the selected method for reliable frontal-surface area estimations, and consequently for reliable wave attenuation predictions.

The primary means of social and intellectual reproduction in the professoriate is through mentoring doctoral students who become faculty mentors and publish research. However, opportunities to transition into such roles are not equal, and underrepresented groups face challenges building and sustaining their representation in the professoriate. What are social resources enabling them to overcome these challenges? To study this, the authors analyze nearly all PhD recipients in the United States from 1980 to 2015 (~1.03 million) and follow their careers. Women and underrepresented minorities are less likely to transition into academia than men and whites, but their chances increase when they are paired with same-attribute advisors and when they have significant group representation in their departments. In contrast, men and white scholars receive no costs or benefits from different- or same-attribute advisors. These findings warrant inspection to see how such relations can be fostered in all mentors.

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use 1H-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.

Background: A considerable proportion of acute ischemic stroke patients treated with endovascular thrombectomy (EVT) are dead or severely disabled at 3 months despite successful reperfusion. Ischemic core imaging biomarkers may help to identify patients who are more likely to have a poor outcome after endovascular thrombectomy (EVT) despite successful reperfusion. We studied the association of CT perfusion-(CTP), CT angiography-(CTA), and non-contrast CT-(NCCT) based imaging markers with poor outcome in patients who underwent EVT in daily clinical practice.Methods: We included EVT-treated patients (July 2016–November 2017) with an anterior circulation occlusion from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry with available baseline CTP, CTA, and NCCT. We used multivariable binary and ordinal logistic regression to analyze the association of CTP ischemic core volume, CTA-Collateral Score (CTA-CS), and Alberta Stroke Program Early CT Score (ASPECTS) with poor outcome (modified Rankin Scale score (mRS) 5-6) and likelihood of having a lower score on the mRS at 90 days.Results: In 201 patients, median core volume was 13 (IQR 5-41) mL. Median ASPECTS was 9 (IQR 8-10). Most patients had grade 2 (83/201; 42%) or grade 3 (28/201; 14%) collaterals. CTP ischemic core volume was associated with poor outcome [aOR per 10 mL 1.02 (95%CI 1.01–1.04)] and lower likelihood of having a lower score on the mRS at 90 days [aOR per 10 mL 0.85 (95% CI 0.78–0.93)]. In multivariable analysis, neither CTA-CS nor ASPECTS were significantly associated with poor outcome or the likelihood of having a lower mRS.Conclusion: In our population of patients treated with EVT in daily clinical practice, CTP ischemic core volume is associated with poor outcome and lower likelihood of shift toward better outcome in contrast to either CTA-CS or ASPECTS.

Background: Current guidelines aim to limit the dietary glycemic index (GI) and intake of saturated fatty acids (SFA). Several studies have shown favorable effects of low-GI or low-SFA diets on intrahepatic lipid content (IHL), but these studies were performed under overfeeding conditions or extreme differences in GI or SFA to maximize the contrast between diets. By combining changes in GI and SFA, we can mimic how people can improve their diet in a realistic setting. Objectives: We investigated the effect on liver fat content and substrate metabolism of both reducing GI and replacing SFA with polyunsaturated fat in practically realistic amounts under isocaloric conditions. Design and Methods: In a randomized crossover study, thirteen overweight participants consumed two diets, one high in GI and SFA (high GI/SFA) and one low in GI and SFA (low GI/SFA) with identical macronutrient composition, for two weeks each. Diets were equal in caloric content, consisted of habitual food items, and had a macronutrient composition that can be easily achieved in daily life. At the end of each intervention, IHL content/composition and liver glycogen were measured by magnetic resonance spectroscopy. Additionally, fasted and postprandial hepatic de novo lipogenesis and glycemic and metabolic responses were investigated. Results: IHL was significantly lower (−28%) after the two-week low-GI/SFA diet (2.4 ± 0.5% 95% CI [1.4, 3.4]) than after the two-week high-GI/SFA diet (3.3 ± 0.6% 95% CI [1.9, 4.7], p < 0.05). Although hepatic glycogen content, hepatic de novo lipogenesis, hepatic lipid composition, and substrate oxidation during the night were similar between the two diets, the glycemic response to the low-GI/SFA diet was reduced (p < 0.05). Conclusions: Changes in macronutrient quality can already have drastic effects on liver fat content and postprandial glycemia after two weeks and even when energy content and the percentage of total fat and carbohydrate remains unchanged.

After Brazil, Russia, India, and China (BRIC) started meeting in the BRIC countries format, and since 2011 with South Africa in the BRICS format, these countries’ leaders made several pledges for strengthening intra-BRICS economic cooperation. This article examines the degree this is reflected in the increase of Chinese Outward Foreign Direct Investment (COFDI) in the other four BRICS countries, the value of Chinese construction contracts, and bilateral trade between China and Brazil, India, Russia South Africa in 2009 to 2019. Focusing on these aspects contributes to the ongoing debate about the institutionalization of the BRICS political grouping. This article demonstrates that, thus far, despite the various pledges, the intensification of intra-BRICS economic cooperation is very limited. With some exemptions due to mega investment deals, COFDI in the other BRICS partners is still reasonably modest and shows no clear trend of increase over time in both absolute and relative figures. There is no significant increase in total trade, and various imbalances and asymmetries remain. Thus, the reality does not mirror the BRICS rhetoric on the intensification of economic cooperation.