Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-α (ERα). However, ERα-expressing cells mediating these effects are not identified. We demonstrate that ...brain-specific deletion of ERα in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ERα in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ERα in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ERα from both SF1 and POMC neurons causes hypometabolism, hyperphagia, and increased visceral adiposity. Additionally, female mice lacking ERα in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ERα inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ERα neurons to regulate different aspects of energy homeostasis and reproduction.
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► ERα in the brain regulates body weight in both males and females ► ERα in female SF1 neurons regulates energy expenditure and fat distribution ► ERα in female POMC neurons regulates food intake and negative feedback
In patients with advanced-stage epithelial ovarian cancer (EOC), a diagnostic laparoscopy (DLS) to determine treatment regime prevents futile laparotomies and seems cost-neutral. The uptake of DLS in ...current practice is unknown. We evaluated the clinical application of routine DLS in treatment planning in patients with advanced-stage EOC in the Netherlands.
The implementation was evaluated over the period 2017–2019, using a health technology assessment including clinical, organizational, and economic factors. Barriers for implementation were identified and DLS use was assessed using semi-structured surveys with healthcare professionals. Data from the Dutch Gynecological Oncology Audit were used to determine (un)successful CRS rates. To assess the economic impact, we performed a budget impact analysis (BIA) of the combined interventions of DLS and primary CRS.
The DLS use to guide treatment planning increased from 16% to 20%. The majority of the centers did not support routine DLS implementation, mainly because of logistic barriers and its invasive nature. The primary CRS rate of all CRS decreased from 44% to 36%, in favor of interval CRS. The unsuccessful primary CRS rate decreased from 15% to 9% resulting in fewer patients needed a second interval CRS. Consequently, total health care costs decreased from €4.457.496 to €4.274.751.
The implementation of routine DLS for guiding treatment planning in patients with advanced-stage EOC has limited support in the Netherlands. Over the years, total health care costs decreased. For current practice, it is advised that a DLS is useful in case it is uncertain whether a successful primary CRS is feasible based on conventional work-up.
•Laparoscopy use to guide treatment regime in patients with ovarian carcinoma increased from 16% to 20% in the Netherlands.•Routine implementation of the laparoscopy to guide treatment regime was not supported by the majority of the hospitals.•Reasons for limited support were logistic barriers, its invasive nature and the availability of non-invasive diagnostics.•The slight increase in laparoscopy use did not have a large impact on Dutch national health care budget.•It is advised that the laparoscopy is useful in case it is uncertain whether a successful primary cytoreduction is feasible.
Accurate calculation of wave overtopping is important for determining the required crest height and geometry of a dike. Berms and roughness elements are widely used to reduce the average overtopping ...discharge at dikes while the reductive effects of berm and roughness are still not fully understood. Several empirical formulae are available to predict the overtopping rate at coastal structures. However, the extrapolation of these empirical formulae is not always applicable for complex structures (e.g. a dike that has a berm and/or roughness elements on the waterside slopes) or wave conditions that are outside the applicability of the empirical predictors. A 2D numerical model based on OpenFOAM® is set up in this study for predicting wave overtopping at dikes that have complex configurations with berms and roughness elements. The validation results show that this OpenFOAM® model is capable of reproducing the incident waves accurately and predicting the wave overtopping discharge with good accuracy. Subsequently, the numerical model is applied to study the reductive influence of a berm and protruding blocks on the mean overtopping discharge at dikes. The roughness of protruding blocks is incorporated by explicitly modelling the protrusions using refined mesh. The model shows reasonable behaviour of the reduction of wave overtopping influenced by a berm and roughness. This indicates the capabilities of the numerical model in the design and safety assessment of dikes.
•An OpenFOAM model has been developed to investigate the berm and roughness influence on dikes.•Average overtopping discharges were accurately predicted for dikes with simple and complex configurations.•The numerical model can deal with roughness and berm configurations that are outside the experimental ranges.•The influence of protruding roughness elements at the slope above a berm has been analysed and design guidance is provided.
Abstract Our data demonstrate that estrogens, estrogen receptor-α (ERα), and estrogen receptor-β (ERβ) regulate adipose tissue distribution, inflammation, fibrosis, and glucose homeostasis, by ...determining that αERKO mice have increased adipose tissue inflammation and fibrosis prior to obesity onset. Selective deletion of adipose tissue ERα in adult mice using a novel viral vector technology recapitulated the findings in the total body ERα null mice. Generation of a novel mouse model, lacking ERα specifically from adipocytes (AdipoERα), demonstrated increased markers of fibrosis and inflammation, especially in the males . Additionally, we found that the beneficial effects of estrogens on adipose tissue require adipocyte ERα. Lastly, we determined the role of ERβ in regulating inflammation and fibrosis, by breeding the AdipoERα into the βERKO background and found that in the absence of adipocyte ERα, ERβ has a protective role. These data suggest that adipose tissue and adipocyte ERα protects against adiposity, inflammation, and fibrosis in both males and females.
The production of dust when driving mining roadways can affect workers health. In addition, there is a decrease in productivity since Mine Safety regulations establish a reduction in the working time ...depending on the quartz content and dust concentration in the atmosphere.
One of the gate roadways of the longwall named E4-S, belonging to the underground coal mine Carbonar SA located in Northern Spain, is being driven by an AM50 roadheader machine. The mined coal has a high coal dust content.
This paper presents a study of dust behaviour in two auxiliary ventilation systems by Computational Fluid Dynamics (CFD) models, taking into account the influence of time. The accuracy of these CFD models was assessed by airflow velocity and respirable dust concentration measurements taken in six points of six roadway cross-sections of the mentioned operating coal mine.
It is concluded that these models predicted the airflow and dust behaviour at the working face, where the dust source is located, and in different roadways cross-sections behind the working face.
As a result, CFD models allow optimization of the auxiliary ventilation system used, avoiding the important deficiencies when it is calculated by conventional methods.
Initial damage, caused by previous wave loading or other events, might affect the hydraulic stability of pattern-placed revetments. Three common types of damage are considered in this study. The ...effect of this assumed initial damage on the hydraulic stability and failure probability of revetments is quantified using a FEM model. This model is developed using data from large-scale flume and field experiments. Using results from the FEM model, surrogate models are created to predict the effect of each type of initial damage on the hydraulic stability and failure probability. Through the use of these surrogate models, it is demonstrated that S-shaped deformation caused by filter migration around the wave impact zone has the largest effect on the hydraulic stability decreasing up to 30%, and failure probability per year increasing up to 10,000 times. When the granular filling between the joints of the columns is washed-out, the stability decreases up to 29% and the failure probability increases up to 700 times. A missing column has a limited effect on the hydraulic stability and failure probability when there is no other (structural) damage. However, if it originates from underlying damage, it might be an initial sign of total failure of the revetment. This study demonstrates the effectiveness of finite element modeling for studying (damaged) revetments, which can be used to complement flume experiments. The results can be used to prioritize maintenance efforts in risk-based maintenance of pattern-placed revetments.
•The effect of damage on the performance of a pattern-placed revetment is studied.•Finite element modeling is used to develop a model to study three types of damage.•Even a small deformation can cause a significant decrease in hydraulic stability.•Washed-out joint filling affects hydraulic stability in particular when most is lost.•The root cause of a missing column is vital for its effect on hydraulic stability.
A reliable estimation of average wave overtopping discharge is important for dike design and safety assessment. Berms and roughness elements are widely applied to reduce the overtopping discharge ...over dikes. In this study, the effects of a berm and roughness on the wave overtopping discharge are investigated by means of physical model tests. New empirical formulae are derived from the analysis of the experimental data in order to provide more accurate estimations of reductive influence of berms and roughness on the wave overtopping discharge. Additionally, a new formula is developed to estimate the reductive influence of varying roughness along the waterside slopes with a berm. The new equations show a significantly better performance within the tested range when compared with existing formulae for the average overtopping discharge.
•Physical model tests showed that the permeability of berms affects the berm influence factor.•New formulae are derived for the roughness influence factors and berm influence factors.•A new formula is derived for the roughness influence factor of combined multiple roughness elements along the bermed slope.•The new formulae outperform the existing formulae.
Despite more than 50 years of vaccination, pertussis is still an endemic disease, with regular epidemic outbreaks. With the exception of Poland, European countries have replaced whole-cell vaccines ...(WCVs) by acellular vaccines (ACVs) in the 1990s. Worldwide, antigenic divergence in vaccine antigens has been found between vaccine strains and circulating strains. In this work, 466
Bordetella pertussis
isolates collected in the period 1998–2012 from 13 European countries were characterised by multi-locus antigen sequence typing (MAST) of the pertussis toxin promoter (
ptxP
) and of the genes coding for proteins used in the ACVs: pertussis toxin (Ptx), pertactin (Prn), type 2 fimbriae (Fim2) and type 3 fimbriae (Fim3). Isolates were further characterised by fimbrial serotyping, multi-locus variable-number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE). The results showed a very similar
B. pertussis
population for 12 countries using ACVs, while Poland, which uses a WCV, was quite distinct, suggesting that ACVs and WCVs select for different
B. pertussis
populations. This study forms a baseline for future studies on the effect of vaccination programmes on
B. pertussis
populations.
Highlights • Nerve-sparing radical hysterectomy is safe in early-stage cervical cancer. • Survival outcomes are similar after nerve-sparing radical hysterectomy and conventional radical hysterectomy. ...• Bladder function after nerve-sparing radical hysterectomy is significantly less impaired than it is after conventional radical hysterectomy. • The next goal for nerve-sparing surgery is to preserve self-assessed function and quality of life.
The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in ...oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals.
Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard.
We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74–0.86), followed by RMI (0.71, 95%CI 0.64–0.78) and CA125 (0.69, 95%CI 0.62–0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same.
HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.
•HE4 was superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals•The addition of HE4 to RMI improved the performance of HE4 alone•Combined HE4 and RMI had a 32% higher specificity than RMI while sensitivities were similar•Clinical setting significantly influences biomarker performances in predicting malignancy in patients with an ovarian mass
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