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The current circumstances of exploitation of natural gas fields in the Transylvanian basin under the rehabilitation concept which aims to maximize the productivity of wells and implicitly increase recovery factors, justifies the assessment of new perspectives for further exploitation of Badenian formations, in which gas accumulations are classified as being tight gas reservoirs types. The concept of stimulating productivity using high pressures in the Transylvanian basin has remained under the significance of the research, therefore it is appropriate to resume analysis of identifying new production technology by integrating new geological data acquired and other geophysical investigations. The current paper presents through a case study the process of identifying a candidate well for stimulation based on the geological-technological considerations, and then, performing a technical-economical analysis to support the proposed program.

Cantoned fluids in porous-permeable or fractured media of reservoirs have acquired during the geological time special properties. The fluids from the reservoir could be or not a mixture of reservoir water, liquid hydrocarbons and gaseous hydrocarbons. Considering if inside of a reservoir there are two types of substances like natural gas and reservoir water which may be in the form of vaporous than the condition of saturation of gases with water vaporous is fulfilled. This process is taking place due to thermodynamic equilibrium resulting the so-called gas humidity. This state corroborated with a certain chemical composition plus favourable values of pressure and temperature may be decisive in the appearance of hydrates. In this scientific paper they will be presented from a theoretical and practical point of view the favourable conditions of gas hydrates appearance and the specific ways of inhibiting the formation of this compounds. A case study in which through modelling and numerical simulation of the behaviour of a productive natural gas well will provide a series of data related to this phenomenon. The specific modelling and numerical simulation was adapted to the conditions of formation and subsequently the elimination of the appearance of hydrates.

A frequent challenge encountered in the exploitation of mature gas fields located in the Getic Depression is sand production. Causes of sand production are mainly related to degree of rock consolidation, lithology, increasing water production and production rates. The effects of sand production are multiple such us low productivity of the gas wells, accumulation into the surface equipment, erosion of downhole and surface equipment, plugging the perforation zone and casing damage. The current paper will address the sand production- challenges and new perspectives in remedial work of wells which are producing from gas reservoirs located in Getic Depression. The article presents through some case studies the research performed for the implementation of the frac-pack technology in some gas wells.

The banking sector has a special significance in each country's economy, being a constant concern for the authorities, both at national and Community level. To reduce the substantial differences between national laws on consumer credit, the European Commission issued Directive 2008/48/EC on credit agreements for consumers, transposed into Romanian legislation by the now legendary, Emergency Ordinance nr.50/2010. But what followed after the adoption of this ordinance surpassed imagination: some banks refused to make the adjustments provided by the law and they were sued in an enormous proportion by their customers, the consequence was very natural: huge losses and negative advertising. Instead, the banks which have complied with the directive came out very well from the crisis: greater number of customers, increased market share and, ultimately, an unexpected profit for this time of crisis. This article treats ,,the war between banks and their own customers" and mainly its winners and losers.

Beginning with simple delays in payments until the occurrence of bankruptcy, the notion of a firm in difficulty is extremely complex. The concept involves an economic component, but it cannot be separated from the legal component (for each country, given the legislation feature). Difficult situation of an enterprise requires the existence of vulnerable states in their activities, which upon reaching a critical threshold prevail against the forces of them, leading ultimately to the onset of insolvency process.

The exploitation of mature natural gas fields has been and will be an increasingly topic that will attract the attention of the production companies, given that most of the production, about 60-70%, comes from these reservoirs. Implementation of the project management into the exploitation of mature gas reservoirs has a notable ascension because of the fact that in the execution of the operational programs always has developed a mechanism to achieve the objectives in a sustainable manner. The project management in gas industry it is known as rehabilitation concept or integrated reservoir development, which has a major impact on increasing the recovery factor. The paper intends to present the current trends in the exploitation of mature gas fields in Romania by applying the concept of rehabilitation as well as expansion opportunities in order to drive the business performance results.

High Court of Justice recently ruled that a court has the right to change too drastic punishment inflicted on an employee by another, more appropriate in relation to the offense committed. The Supreme Court ruling clarifies such a legal provision that was applied by different courts: some substituted for disciplinary sanctions if it were disproportionate to the offense employee, while others refused to do so.

The manifestations of the difficulties for companies are represented either by the sharp deterioration ofliquidity or the reduced level of profitability of the firm or the manifestation of the two trials combined. The mostdelicate situation for business is not the losses, but the cessation of payments. This article presents comparatively theeffects of financial crisis on the evolution of key indicators of financial equilibrium of the company: working capital,normative working capital and net treasury, on the companies listed on Bucharest Stock Exchange

The insolvency of municipalities can be a real solution to their debt problem. The procedure is similar to that applied to commercial companies, but there are important differences, such as for example that public entities cannot go bankrupt. Legal regulations must take into account the specific situation of these institutions, which cannot be dissolved.

The number of bankruptcies increases by 50% in the period 2008-2011, at over 20,000 cases. Most bankruptcies are in the sector of trade and services, where falling demand and increased financial blockage cause serious financial problems. This article presents comparatively, the evolution of the number of bankruptcies, total and by main industry. Also it develops an econometric model to determine the effects of nonperforming loans in RON and foreign currency on the number of bankruptcies.

In his international novels, Henry James builds the image of England through the eyes of the American characters that travel in this country. London is the perfect setting for his international novels, as it becomes an integral part of the person or the action he is narrating.

Gas mature fields are associated with challenges to optimize the hydrocarbon flow from reservoir to the sales point in a cost effective manner due to declining well productivity. Laslau Mare field is a mature gas field in Transylvanian basin (Mures County) developed in 1970s and is producing∼99% methane with low water-gas ratio. As any brown field, the state of depleted reservoir will generate several constraints for gas flow from formation to surface facilities and further to delivery point. During the exploitation has been observed that the operation conditions are facing with unstable pressure in the system due to low demand. Therefore, the back pressure effect will affect the wells in terms of inability to unload the bottomhole accumulated liquids and the reservoir will suffer a higher pressure drawdown. The best fit-for-purpose solution to overcome the above challenges is represented by installation of group compressor. Laslau Mare field has 3 group compressors running and shows positive results, especially when external pressure fluctuates continuously. This paper explain the challenges seen in 2016 in Laslau Mare field with back pressure effects and how the compression overcome them, and also other solutions that should be considered to optimize the well production.

Background/Objectives : Cardiovascular involvement in severe cirrhosis presents diagnostic challenges and carries significant prognostic implications. This study aims to evaluate the relationship between liver disease severity and portal hypertension with the burden of diastolic dysfunction. Methods : We prospectively enrolled patients with hepatic cirrhosis, classified according to the Child-Pugh criteria. Of the 102 patients included, 65 were classified as Group A (non-severe cirrhosis: Child-Pugh Classes A and B) and 37 as Group B (severe cirrhosis: Child-Pugh Class C). Portal vein and spleen diameters were assessed using abdominal ultrasound. All patients underwent echocardiographic evaluation. LV systolic function was assessed by measuring ejection fraction, while diastolic function was evaluated using three parameters: E/Em ratio, E/Vp ratio, and indexed left atrial volume. Results : We observed a significantly greater burden of diastolic dysfunction in Group B compared to Group A. Specifically, the E/Vp ratio was 2.2 ± 0.4 in Group B versus 1.9 ± 0.3 in Group A ( p < 0.001); the indexed LA volume was 34.5 ± 3.2 mL/m 2 in Group B versus 30.1 ± 2.9 mL/m 2 in Group A ( p < 0.001); and the E/Em ratio was 17.0 ± 3.0 in Group B versus 11.5 ± 2.8 in Group A ( p < 0.001). Additionally, the mean diameters of the portal vein and spleen were larger in Group B, with measurements of 14.3 ± 2.1 mm versus 11.5 ± 1.6 mm for the portal vein and 15.0 ± 1.2 mm versus 11.7 ± 1.5 mm for the spleen ( p < 0.001), which correlated with the extent of diastolic dysfunction. Conclusions : Diastolic dysfunction was prevalent in 55% of patients with liver cirrhosis. The burden of diastolic dysfunction was higher in patients with severe hepatic cirrhosis compared to those with milder forms, and it correlated with the severity of portal hypertension, as assessed by measuring portal vein diameter and spleen diameter.

After the recent hard attempts felt on a global scale, notably in the health sector, the steady efforts of scientists have been materialized in maybe one of the most expected findings of the last decades, i.e. the launching of the COVID-19 vaccines. Although it is not our goal to plead for vaccination, as the decision in this regard is a matter of individual choice, we believe it is necessary and enlightening to analyze how one's educational status interferes with COVID-19 vaccination. There are discrepancies between world states vis-à-vis their well-being and their feedback to crises, and from the collection of features that can segregate the states in handling vaccination, in this paper, the spotlight is on education. We are referring to this topic because, generally, researches converge rather on the linkage between economic issues and COVID-19 vaccination, while education levels are less tackled in relation to this. To notice the weight of each type of education (primary, secondary, tertiary) in this process, we employ an assortment of statistical methods, for three clusters: 45 low-income countries (LICs), 72 middle-income countries (MICs) and 53 high-income countries (HICs). The estimates suggest that education counts in the COVID-19 vaccination, the tertiary one having the greatest meaning in accepting it. It is also illustrated that the imprint of education on vaccination fluctuates across the country groups scrutinized, with HICs recording the upper rates. The heterogeneity of COVID-19 vaccination-related behaviors should determine health authorities to treat this subject differently. To expand the COVID-19 vaccines uptake, they should be in an ongoing dialogue with all population categories and, remarkably, with those belonging to vulnerable communities, originated mostly in LICs. Education is imperative for vaccination, and it would ought to be on the schedule of any state, for being assimilated into health strategies and policies., Competing Interests: We, Dan Lupu and Ramona Tiganasu, authors of the article ‘Does education influence COVID-19 vaccination? A global view’ declare that- we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Global crises, regardless of the place where they started to spread or of the factors that triggered them, require a comprehensive approach, primarily based on good communication, cooperation and mutual support. No individual and no institution should remain indifferent to crises but, on the contrary, be fully aware that any involvement in curbing them matters. Although humanity can be affected by various types of crises, in this paper we refer to the one related to COVID-19 pandemic. There are certain reasons that come to justify our choice: first of all, being a shock with a strong impact on people, its analysis should be performed from several angles; this may bring to light an image with its disparate propagation and measures to counteract it both in developed countries, and especially in those with a shortage of resources. Secondly, in the context of the emergence of vaccines against COVID-19, it is helpful to have an overview of COVID-19 through the lens of the relationship between the vaccination process and the elements that characterize governance, with a differentiated dashboard by country categories worldwide: low, middle and high-income countries. Our study is far from capturing the complexity arising from such social problem, but rather aims to outline the defining role of governance when it comes to providing firm reactions to the COVID-19 crisis., Methods: Given that our sample consists of a large number of countries, namely 170, first, examined all together, and then, split into three groups (high, middle and low-income), it is challenging to address governance in association with COVID-19 vaccination, in order to see how much they interact and how each of the six aggregate governance indicators of the World Bank (Worldwide Governance Indicators) is reflected in this process. Even if they do not oscillate strongly over relatively short periods of time, reporting on health issues requires a sequential inventory, considering closer time intervals, so as to be able to act promptly. Thus, to better distinguish how the COVID-19 vaccination process evolved in low, middle and high-income countries, but also how it was imprinted by governance, we present the situation quarterly (March, June, September and December), in 2021, the year when the immunization campaigns were the most intense at the global level. Regarding the applied methods, we mention both OLS regressions with robust estimators and a panel model, used to investigate the determinants of COVID-19 vaccination, some of them describing the good governance, as well as other dimensions., Results: The findings point out that the influence of governance on COVID-19 vaccination differs depending on whether a country belongs to high, middle or low-income typology: the strongest determinism of governance on vaccination is encountered in high-income countries, and the weakest in low-income ones; in some cases, governance does not matter significantly. However, exploring the three groups of states included in the research, it is observed that the most relevant factors in this relationship are government effectiveness, regulatory quality and control of corruption., Conclusions: Besides the order of importance of governance indicators on COVID-19 vaccination, our study indicates that, overall, governance positively shapes the vaccination rate at the level of the chosen sample. In normative terms, these findings can be translated particularly by the fact that they can serve as information to raise awareness on the relevance of the existence of an institutional framework that allows the formulation of strategies according to the patterns of each country, especially since the actionable tools depend on the available resources. As a general conclusion, public policies should be designed in such a way as to strengthen trust in vaccination regulations and in governments, to reduce the multifaceted negative effects of this health crisis and to hope for its total end., (© 2023. The Author(s).)

Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the programming role of hormones during this period. A previous epidemiological study has shown association between prenatal co-exposure to 8 EDCs (Mixture N1) and language delay in children, suggesting an effect of this mixture on neurodevelopment. Furthermore, in utero exposure to Mixture N1 altered gene expression and behavior in adult mice. In this study, we investigated whether epigenetic mechanisms could underlie the long term effects of Mixture N1 on gene expression and behavior. To this end, we analyzed DNA methylation at regulatory regions of genes whose expression was affected by Mixture N1 in the hippocampus of in utero exposed mice using bisulfite-pyrosequencing. We show that Mixture N1 decreases DNA methylation in males at three genes that are part of the hypothalamus-pituitary-adrenal (HPA) axis: Nr3c1, Nr3c2, and Crhr1, coding for the glucocorticoid receptor, the mineralocorticoid receptor, and the corticotropin releasing hormone receptor 1, respectively. Furthermore, we show that the decrease in Nr3c1 methylation correlates with increased gene expression, and that Nr3c1, Nr3c2, and Crhr1 methylation correlates with hyperactivity and reduction in social behavior. These findings indicate that an EDC mixture corresponding to a human exposure scenario induces epigenetic changes, and thus programming effects, on the HPA axis that are reflected in the behavioral phenotypes of the adult male offspring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although globalization has left its mark on economic dynamism, causing conditionalities among various aspects (market openness, production networks, technological and information developments, migratory flows, international cooperation, humanitarian support, etc.), the less pleasant side of it should not be omitted, i.e. the emergence of the framework for the faster diffusion of epidemiological diseases. Thus, with the onset of the SARS-CoV-2 virus, its widespread circulation is a serious challenge for the provision of efficient solutions to combat it, especially in countries with fragile health systems, poor institutional quality and lack of resources. In this paper we aim to investigate the implications of globalization on the COVID-19 vaccination of the population. The period under analysis is January 1, 2021-January 1, 2022, using montly data, and the object of our study are 48 European states. To capture the relationship between globalization and the vaccination rate, we applied regression models, including a number of factors that may influence the progress of vaccination. In order to test the robustness of the results, the two-stage least squares (2SLS) regressions was used. The regression models developed underlined that globalization impacts the degree of vaccination. More globalized economies are more competitive in COVID-19 management, and the significance of this effect comes from better interconnection in global markets and easier access to medical discoveries. At the same time, countries with a higher vaccination rate are associated with higher levels of development. Based on the results obtained, we proposed some policy recommendations to increase the propensity to vaccinate, ensure equity in the distribution of vaccines and provide financial support to developing countries., (© 2022. The Author(s).)

Importance: Hospice is an important end-of-life service for patients with Alzheimer disease and related dementias (ADRD)., Objective: To determine whether hospice use among patients with ADRD changed in association with recent policies aimed at reducing hospice misuse and long hospice stays, an outcome that may have disproportionately affected patients with ADRD because of their lengthy end-of-life trajectories., Design Setting and Participants: This observational cross-sectional study used Medicare hospice claims data from Medicare hospice episodes of care beginning between July 2008 and December 2019 among Medicare hospice beneficiaries 65 years or older at time of enrollment. Data analysis was conducted between September 2019 and June 2021., Exposures: The 2014 Improving Medicare Post-Acute Care Transformation (IMPACT) Act, which systematized audits of hospices with a high proportion of long stays, and the 2016 2-tier payment system, which reduced daily reimbursement rates after 60 days., Main Outcomes and Measures: Monthly percentage of (1) new patient enrollees, (2) patient census, and (3) care days provided to patients with an ADRD code., Results: The sample included 11 124 992 unique hospice episodes between 2008 and 2019; mean (SD) patient enrollment age ranged from 82.0 (8.2) years to 82.8 (8.7) years; the percentage of male patients ranged from 40.5% to 42.7%, and the percentage of Black, Hispanic, and White patients ranged from 7.7% to 8.2%, 1.5% to 2.0%, and 86.2% to 88.8%, respectively, across years. The percentage of new enrollees with an ADRD code dropped significantly during the months of IMPACT passage (-1.42 percentage points; 95% CI, -2.13 to -0.71) and implementation (-1.98 percentage points; 95% CI, -2.70 to -1.26) but rose again during the following months. While no significant changes were observed at the time of 2-tier payment implementation (0.15 percentage points; 95% CI, -0.21 to 0.51), the average rate of increase during the subsequent period was slower (0.01 percentage points per month; 95% CI, 0-0.02) than in earlier periods (0.05; 95% CI, 0.04-0.06 during the baseline period). Similar patterns were observed for the percentage of patient census and care days provided to patients with an ADRD code., Conclusions and Relevance: The results of this cross-sectional study of Medicare hospice claims data suggested that recent Medicare policies were associated with immediate and lasting reductions in the share of patients receiving hospice care with an ADRD code compared with expectations from preimplementation trends. Future research should examine mechanisms through which hospices enacted change and consequences for quality of care., Competing Interests: Conflict of Interest Disclosures: Dr Gianattasio reported grants from National Institute of Aging (NIA; 5R03AG061499-02) during the conduct of the study. Dr Moghtaderi reported grants from the NIA during the conduct of the study. Dr Lupu reported grants from George Washington University during the conduct of the study and research support George Washington University outside the submitted work, as well as a patent for copyright with royalties from Oxford University Press. Dr Prather reported grants from the National Institutes of Health during the conduct of the study. Dr Power reported grants from NIA during the conduct of the study and personal fees from Biogen and grants from DC Health outside the submitted work., (Copyright 2022 Gianattasio KZ et al. JAMA Health Forum.)

Background: This study aims at analyzing the efficiency of the health systems of 31 European countries in treating COVID-19, for the period January 1, 2020 - January 1, 2021, by incorporating some factors from a multidimensional perspective., Methods: The methodology used in the research was Data Envelopment Analysis (DEA), through which efficiency scores for health systems have been calculated. The research was performed considering three stages: the first wave (January 1-June 15), the relaxation period (June 15-October 1) and the second wave (October 1-December 31). In evaluating the determinants of the efficiency of health systems, six major fields of influence were taken into account: health care, health status, population, economic, cultural/societal and governmental issues, all covering 15 indicators. After measuring the efficiency, we used the Tobit type regression to establish the influencing elements on it., Results: The results for the public health systems of European states were determined for each country and period. We evaluated the efficiency of health systems in Europe against COVID-19, starting from health inputs (COVID-19 cases, physicians, nurses, hospital beds, health expenditure) and output (COVID-19 deaths). The obtained outputs show that, especially in the first phase of the pandemic, the inefficiency of the health systems was quite high, mainly in Western countries (Italy, Belgium, Spain, UK). In the relaxation phase and in the second wave, the Western states, severely affected at the beginning of the pandemic, began to take adequate measures and improve the efficiency of their sanitary systems. Instead, Eastern European countries were hit hard by the inefficiency of health systems (Bulgaria, Greece, Hungary, Romania). After Tobit regression, results of the study show that the influencing elements are different for the three stages: concerning the first wave, comobirdities, population age, and population density are important; for relaxation period a great influence have government effectiveness and power distance; with respect to second wave, the relevant factors are education and population density., Conclusions: The results obtained could serve as starting points for health policymakers to perform comparative analyzes in terms of good practices in the health system and to develop national plans to better deal with health crises. At the same time, they can be used internationally to achieve a coherent and effective community response to the pandemic., (© 2022. The Author(s).)

Continuing the transition to competency-based education, Hospice and Palliative Medicine (HPM) fellowship programs began using context-free reporting milestones (RMs) for internal medicine subspecialties in 2014 but quickly recognized that they did not reflect the nuanced practice of the field. This article describes the development of 20 subspecialty-specific RMs through consensus group process and vetting by HPM educators. A workgroup of content experts used an iterative consensus building process between December 2017 and February 2019 to draft new RMs and create a supplemental guide that outlines the intent of each RM, examples of each developmental trajectory, assessment methods, and resources to guide educators. Program directors, program coordinators, and designated institutional officers were contacted directly to solicit feedback. Most respondents agreed or strongly agreed that each RM represented a realistic progression of knowledge, skills, and behaviors, and that the set of milestones adequately discriminated between meaningful levels of competency. Similarly, respondents felt that the supplemental guide was a useful resource. The result is a set of carefully developed and broadly vetted RMs that represent a progression of development for HPM physicians during one year of clinical fellowship training., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Ubiquitous exposure to endocrine-disrupting chemicals (EDCs) has caused serious concerns about the ability of these chemicals to affect neurodevelopment, among others. Since endocrine disruption (ED)-induced developmental neurotoxicity (DNT) is hardly covered by the chemical testing tools that are currently in regulatory use, the Horizon 2020 research and innovation action ENDpoiNTs has been launched to fill the scientific and methodological gaps related to the assessment of this type of chemical toxicity. The ENDpoiNTs project will generate new knowledge about ED-induced DNT and aims to develop and improve in vitro, in vivo, and in silico models pertaining to ED-linked DNT outcomes for chemical testing. This will be achieved by establishing correlative and causal links between known and novel neurodevelopmental endpoints and endocrine pathways through integration of molecular, cellular, and organismal data from in vitro and in vivo models. Based on this knowledge, the project aims to provide adverse outcome pathways (AOPs) for ED-induced DNT and to develop and integrate new testing tools with high relevance for human health into European and international regulatory frameworks.

Context: The need for hospice and palliative care is growing rapidly as the population increases and ages and as both hospice and palliative care become more accepted. Hospice and palliative medicine (HPM) is a relatively new physician specialty, currently training 325 new fellows annually. Given the time needed to increase the supply of specialty-trained physicians, it is important to assess future needs to guide planning for future training capacity., Objectives: We modeled the need for and supply of specialist HPM physicians through the year 2040 to determine whether training capacity should continue growing., Methods: To create a benchmark for need, we used a population-based approach to look at the current geographic distribution of the HPM physician supply. To model future supply, we calculated the annual change in current supply by adding newly trained physicians and subtracting physicians leaving the labor force., Results: The current U.S. supply of HPM specialists is 13.35 per 100,000 adults 65 and older. This ratio varies greatly across the country. Using alternate assumptions for future supply and demand, we project that need in 2040 will range from 10,640 to almost 24,000 HPM specialist physicians. Supply will range from 8100 to 19,000., Conclusion: Current training capacity is insufficient to keep up with population growth and demand for services. HPM fellowships would need to grow from the current 325 graduates annually to between 500 and 600 per year by 2030 to assure sufficient physician workforce for hospice and palliative care services given current service provision patterns., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Extensive clinical and genetic heterogeneity of inherited cancers has allowed multi-gene panel testing to become an efficient means for identification of patients with an inherited predisposition to a broad spectrum of syndromic and nonsyndromic forms of cancer. This study reports our experience with a 27-gene inherited cancer panel on a cohort of 630 consecutive individuals referred for testing at our laboratory with the following objectives: 1. Determine the rates for positive cases and those with variants of uncertain clinical significance (VUS) relative to data published in the recent literature, 2. Examine heterogeneity among the constituent genes on the panel, and 3. Review test uptake in the cohort relative to other reports describing outcomes for expanded panel testing., Methods: Clinical and genomic data were reviewed on 630 individuals tested on a panel of 27 genes selected on the basis of high (≥ 40%) or moderate to low (≤ 40%) lifetime risk of hereditary cancer. These patients were not enriched for adherence to the National Comprehensive Cancer Network (NCCN) criteria for Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) and constitute a referral laboratory cohort., Results: Sixty-five individuals with variants classified as pathogenic or likely pathogenic across 14 genes were identified for an overall positive rate of 10.3%. Although a family history of cancer constituted a major reason for referral, accounting for 84% of our cohort, excluding patients with a known familial variant did not have a significant impact on the observed positive rate (9% vs 10.3%). More than half (58%) of the pathogenic or likely pathogenic variants were observed in high or moderate to low risk genes on the panel, while only 42% occurred in classic HBOC or LS-associated genes., Conclusion: These results provide the actual percentage of family or personal history of cancer that can be attributed to pathogenic or likely pathogenic variants in one or more of the genes on our panel and corroborate the utility of multi-gene panels over sequential testing to identify individuals with an inherited predisposition to cancer., Competing Interests: For clinical diagnostic testing, it is standard for the referring physician to obtain informed consent prior to test ordering; therefore, an ethics approval was not required.Not applicableAt the time this study was conducted, all authors were employed by Integrated Genetics, Laboratory Corporation of America® Holdings and may hold stock of and/or stock options with LabCorp.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The ability to propagate mature cells and tissue from pluripotent stem cells offers enormous promise for treating many diseases, including neurodegenerative diseases. Before such cells can be used successfully in neurodegenerative diseases without causing unwanted cell growth and migration, genes regulating growth and migration of neural stem cells need to be well characterized. Estrogen receptor beta (ERβ) is essential for migration of neurons and glial cells in the developing mouse brain. To examine whether ERβ influences differentiation of mouse embryonic stem cells (mESC) into neural lineages, we compared control and ERβ knockout (BERKO) mESCs at defined stages of neural development and examined the effects of an ERβ-selective ligand (LY3201) with a combination of global and targeted gene-expression profiling and the expression of key pluripotency markers. We found that ERβ was induced in embryoid bodies (EBs) and neural precursor cells (NPCs) during development. Proliferation was higher in BERKO NPCs and was inhibited by LY3201. Neurogenesis was reduced in BERKO ES cells, and oligodendrogliogenesis was enhanced. BERKO EBs expressed higher levels of key ectodermal and neural progenitor markers and lower levels of markers for mesoderm and endoderm lineages. ERβ-regulated factors are involved in cell adhesion, axon guidance, and signaling of Notch and GABA receptor pathways, as well as factors important for the differentiation of neuronal precursors into dopaminergic neurons (Engrailed 1) and for the oligodendrocyte fate acquisition (Olig2). Our data suggest that ERβ is an important component for differentiation into midbrain neurons as well as for preventing precocious oligodendrogliogenesis., Competing Interests: The authors declare no conflict of interest.

Context: A relatively new specialty, hospice and palliative medicine (HPM), is unusual in that physicians can enter from 10 different specialties. This study sought to understand where HPM physicians were coming from, where they were going to practice, and the job market for HPM physicians., Objectives: Describe characteristics of the incoming supply of HPM physicians, their practice plans, and experience finding initial jobs., Methods: In October 2015, we conducted an online survey of physicians who completed accredited HPM fellowships the previous June. We had electronic mail addresses for 195 of the 243 graduating fellows., Results: About 112 HPM fellows responded (58% of those invited). The most common prior training was internal medicine (45%), followed by family medicine (23%), pediatrics (12%), and emergency medicine (10%). More than 40% had practiced medicine before their HPM training. After graduation, 97% were providing 20 or more hours per week of patient care, with most hours in palliative care. About 72% devoted more than 20 hours per week to palliative care, whereas only 13% worked that much in hospice care. About 81% reported no difficulty finding a satisfactory practice position. About 98% said that they would recommend HPM to others, and 63% took the time to provide written comments that were highly positive about the specialty., Conclusion: New HPM physicians are finding satisfying jobs. They are enthusiastic in recommending the specialty to others. Most are going into palliative medicine, leaving questions about how the need for hospice physicians will be filled. Although jobs appear to be numerous, there are practice areas with more limited opportunities., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed against depression during and after pregnancy. However, these compounds cross the placenta and are found in breast milk, thus reaching, and possibly affecting, the fetus and infant during critical developmental stages. Fluoxetine (FLX), a widely used SSRI, can interfere with estrogen signaling, which is important for the development of female sex organs and certain brain areas, among others. Interference with estrogen signaling can take place on different levels, e.g., by affecting receptor activity or hormone levels. FLX has previously been shown to induce estrogen receptor-dependent transcription in vitro at high concentrations. In this study we set out to assess effects of FLX on estradiol levels in vitro., Methods: FLX was tested using the OECD recommended H295R model, a human adrenocortical carcinoma cell line that is able to produce all steroid hormones found in the gonads and adrenal glands, including estradiol and testosterone. H295R cells were incubated with different doses of FLX for 48h. Subsequently, concentrations of these two steroids were measured in cell culture medium after FLX exposure, using liquid chromatography coupled with tandem mass spectrometry. Aromatase mRNA expression was assessed using qPCR., Results: Fluoxetine significantly increased estradiol secretion in H295R cells after a 48h exposure at low, submicromolar concentrations, but showed no effects on testosterone levels or aromatase mRNA expression., Conclusion: Fluoxetine has the potential to interfere with estrogenic signaling by increasing estradiol secretion at low concentrations, which are relevant for fetal and adult human exposure.

Purpose: Integrated into routine oncology care, palliative care can improve symptom burden, quality of life, and patient and caregiver satisfaction. However, not all oncology practices have access to specialist palliative medicine. This project endeavored to define what constitutes high-quality primary palliative care as delivered by medical oncology practices., Methods: An expert steering committee outlined 966 palliative care service items, in nine domains, each describing a candidate element of primary palliative care delivery for patients with advanced cancer or high symptom burden. Using modified Delphi methodology, 31 multidisciplinary panelists rated each service item on three constructs: importance, feasibility, and scope within medical oncology practice., Results: Panelists endorsed the highest proportion of palliative care service items in the domains of End-of-Life Care (81%); Communication and Shared Decision Making (79%); and Advance Care Planning (78%). The lowest proportions were in Spiritual and Cultural Assessment and Management (35%) and Psychosocial Assessment and Management (39%). In the largest domain, Symptom Assessment and Management, there was consensus that all symptoms should be assessed and managed at a basic level, with more comprehensive management for common symptoms such as nausea, vomiting, diarrhea, dyspnea, and pain. Within the Appropriate Palliative Care and Hospice Referral domain, there was consensus that oncology practices should be able to describe the difference between palliative care and hospice to patients and refer patients appropriately., Conclusion: This statement describes the elements comprising high-quality primary palliative care for patients with advanced cancer or high symptom burden, as delivered by oncology practices. Oncology providers wishing to enhance palliative care delivery may find this information useful to inform operational changes and quality improvement efforts., (Copyright © 2016 by American Society of Clinical Oncology.)