Physician Burnout and Ethics Committees.

This article provides a brief background of key issues in physician burnout, a significant problem in the healthcare industry. The extent and severity of burnout are not well understood; and those seeking help are often stigmatized. A number of different approaches to alleviating burnout have been suggested, but the problem lacks any single or simple solution. We posit that an ethics committee may be well positioned to help address this issue because of its unique position within an institution. An ethics committee serves the entire hospital staff regardless of department. As such it may be able to identify common elements in the development of burnout, and can serve as a conduit to administration in identifying these. An ethics committee can obtain information about the extent of burnout by conducting surveys to assess the extent and severity of burnout in aninstitution, and serve as a central resource to help address and alleviate it. Finally, an ethics committee may be able to act as an intermediary between practitioners and the administration, in advising the administration of the extent of the problem and offer suggestions for alleviating it.

Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU.

RATIONALE: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. OBJECTIVES: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. METHODS: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. MEASUREMENTS AND MAIN RESULTS: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. CONCLUSIONS: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502).

Does Parkinson Disease Increase the Risk of Perioperative Complications After Total Hip Arthroplasty? A Nationwide Database Study.

BACKGROUND: Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States, affecting over 1 million people. As part of the disease process, PD can cause poor bone quality and other musculoskeletal problems that can affect a patient's quality of life. With advances in treatment, PD patients can be more active and may be candidates for total hip arthroplasty (THA). However, there is a paucity of literature on the outcomes of THA in PD patients. Therefore, the purpose of this study was to evaluate the perioperative outcomes of PD patients who underwent THA. Specifically, we assessed: (1) perioperative surgical and medical complications; (2) lengths of stay (LOSs); and (3) total hospital charges. METHODS: Using the Nationwide Inpatient Sample, patients who had PD and underwent THA between 2002 and 2013 were identified. With the use of propensity scores, PD patients were matched in a 1:3 ratio to patients without PD by the year of surgery, age, gender, race, Charlson/Deyo score, and insurance type. This yielded a total of 10,519 PD and 31,679 non-PD THA patients. Regression analyses were used to compare the risk of perioperative complications (any, surgical, medical), the percent differences in mean LOS, and the percent differences in total hospital charges. RESULTS: Compared with the matched cohort, PD patients had a 52% higher risk for any complication (odds ratio [OR] = 1.52; 95% confidence interval [CI], 1.37-1.69), a 30% higher risk for any surgical complication (OR = 1.30; 95% CI: 0.88-1.91), and a 54% higher risk for any medical complication (OR = 1.54; 95% CI, 1.38-1.71). Specifically, PD patients were more likely to have postoperative delirium (OR = 2.61; 95% CI: 1.77-3.85), altered mental status (OR = 3.01; 95% CI: 1.35-6.71), urinary tract infection (OR = 1.34; 95% CI: 1.09-1.76), and blood transfusion (OR = 1.62; 95% CI: 1.44-1.82). Also, PD patients had a mean LOS that was 8.57% longer (P < .0001), and mean total hospital charges that were 3.85% higher (P < .0001). CONCLUSION: Orthopedic surgeons and neurologists should be involved in the preoperative counseling of PD patients regarding their potential increased risks associated with THA, which could help optimize their preoperative care. Furthermore, the risk of complications and higher costs could potentially lead to the development of different reimbursement methods in this population of patients.

Pharmacological Therapy for the Prevention and Treatment of Weakness After Critical Illness: A Systematic Review.

OBJECTIVES: ICU-acquired weakness is a common complication of critical illness and can have significant effects upon functional status and quality of life. As part of preliminary work to inform the design of a randomized trial of a complex intervention to improve recovery from critical illness, we sought to identify pharmacological interventions that may play a role in this area. DATA SOURCES: We systematically reviewed the published literature relating to pharmacological intervention for the treatment and prevention of ICU-acquired weakness. STUDY SELECTION: We searched MEDLINE, EMBASE, CINAHL+, Web of Science, and both U.S. and European trial registries up to July 2014 alongside reviews and reference lists from populations with no age or language restrictions. We included studies that reported a measure of muscle structure or physical function as an outcome measure. DATA EXTRACTION: We estimated pooled odds ratios and 95% CI using data extracted from published articles or where available, original data provided by the authors. Assessment of bias was performed using the Cochrane Collaboration's risk of bias tool. DATA SYNTHESIS: Ten studies met the inclusion criteria. The current body of evidence does not support the use of any pharmacological agent in this setting, although maintaining euglycemia may reduce the prevalence of critical illness polyneuropathy. CONCLUSIONS: At present, no pharmacological intervention can be recommended to prevent or treat ICU-acquired weakness. Further research is required into this field to include more novel agents such as myostatin inhibitors. Challenges in the conduct of research in this area are highlighted.

A workflow to practically apply true dose considerations to in vitro testing for next generation risk assessment.

With the move away from safety testing assessment based on data generated in experimental animals the concept of Next Generation Risk Assessment (NGRA) has arisen which instead uses data from in silico and in vitro models. A key uncertainty in risk assessment is the actual dose of test chemical at the target site, and therefore surrogate dose metrics, such as nominal concentration in test media are used to describe in vitro effect (or no-effect) doses. The reliability and accuracy of the risk assessment therefore depends largely on our ability to understand and characterise the relationship between the dose metrics used and the actual biologically effective dose at the target site. The objective of this publication is to use 40 case study chemicals to illustrate how in vitro dose considerations can be applied to characterise the "true dose" and build confidence in the understanding of the biologically effective dose in in vitro test systems for the determination e.g. points of departure (PoDs) for NGRA. We propose a workflow that can be applied to assess whether the nominal test concentration can be considered a conservative dose metric for use in NGRA. The workflow examines the implications of volatility, stability, hydrophobicity, binding to plastic and serum, solubility, and the potential use of in silico models for some of these parameters. For the majority of the case study chemicals we found that the use of nominal concentrations in risk assessment would result in conservative decision making. However, for serval chemicals a potential for underestimation of the risk in humans in vivo based on in vitro nominal effect concentrations was identified, and approaches for refinement by characterisation of the actual effect concentration are proposed.

EMDataBank.org: unified data resource for CryoEM.

Cryo-electron microscopy reconstruction methods are uniquely able to reveal structures of many important macromolecules and macromolecular complexes. EMDataBank.org, a joint effort of the Protein Data Bank in Europe (PDBe), the Research Collaboratory for Structural Bioinformatics (RCSB) and the National Center for Macromolecular Imaging (NCMI), is a global 'one-stop shop' resource for deposition and retrieval of cryoEM maps, models and associated metadata. The resource unifies public access to the two major archives containing EM-based structural data: EM Data Bank (EMDB) and Protein Data Bank (PDB), and facilitates use of EM structural data of macromolecules and macromolecular complexes by the wider scientific community.

Indoor Radon Levels in Homes and Schools in the Western Cape, South Africa-Results from a Schools Science Outreach Initiative and Corresponding Model Predictions.

We describe a school science outreach initiative that introduced learners to applied nuclear physics research by means of a two-day workshop that involved learners and teachers from 5 schools in the Western Cape province of South Africa. During this workshop, the participants were introduced to the naturally occurring, inert, colorless, and tasteless radioactive gas radon (222Rn). During the first day of the workshop, the participants were informed about the detrimental health impacts of inhaling radon and its daughter radionuclides and were shown how indoor radon activity concentrations can be measured using the electret ion chamber (EIC) technology. The learners were then each supplied with a short-term electret (E-PERM, Radelec, Frederick, MD, USA) and associated ion chamber to enable them to make radon measurements in their homes. The teachers in turn were supplied with EICs to enable them make radon measurements in their schools. The participants returned the EICs on the second day of the workshop, one week later. Here, the drop in the potential difference across each electret was measured in order to calculate the average indoor radon activity concentration. A total of 49 indoor radon concentrations were measured. The average indoor radon concentrations were 36 ± 26 Bqm-3 in homes and 41 ± 36 Bqm-3 in schools, while the highest concentration was found to be 144 Bqm-3. These levels were compared to predictions from a model that uses input information about the uranium content associated with the surface geology at each measurement location. The predictions compared well with the measured values.

Experimental Setups for In Vitro Studies on Radon Exposure in Mammalian Cells-A Critical Overview.

Naturally occurring radon and its short lived progeny are the second leading cause of lung cancer after smoking, and the main risk factor for non-smokers. The radon progeny, mainly Polonium-218 (218Po) and Polonium-214 (214Po), are responsible for the highest dose deposition in the bronchial epithelium via alpha-decay. These alpha-particles release a large amount of energy over a short penetration range, which results in severe and complex DNA damage. In order to unravel the underlying biological mechanisms which are triggered by this complex DNA damage and eventually give rise to carcinogenesis, in vitro radiobiology experiments on mammalian cells have been performed using radon exposure setups, or radon analogues, which mimic alpha-particle exposure. This review provides an overview of the different experimental setups, which have been developed and used over the past decades for in vitro radon experiments. In order to guarantee reliable results, the design and dosimetry of these setups require careful consideration, which will be emphasized in this work. Results of these in vitro experiments, particularly on bronchial epithelial cells, can provide valuable information on biomarkers, which can assist to identify exposures, as well as to study the effects of localized high dose depositions and the heterogeneous dose distribution of radon.

FhCaBP4: a Fasciola hepatica calcium-binding protein with EF-hand and dynein light chain domains.

In trematodes, there is a family of proteins which combine EF-hand-containing domains with dynein light chain (DLC)-like domains. A member of this family from the liver fluke, Fasciola hepatica-FhCaBP4-has been identified and characterised biochemically. FhCaBP4 has an N-terminal domain containing two imperfect EF-hand sequences and a C-terminal dynein light chain-like domain. Molecular modelling predicted that the two domains are joined by a flexible linker. Native gel electrophoresis demonstrated that FhCaBP4 binds to calcium, manganese, barium and strontium ions, but not to magnesium or zinc ions. The hydrophobic, fluorescent probe 8-anilinonaphthalene-1-sulphonate bound more tightly to FhCaBP4 in the presence of calcium ions. This suggests that the protein undergoes a conformational change on ion binding which increases the number of non-polar residues on the surface. FhCaBP4 was protected from limited proteolysis by the calmodulin antagonist W7, but not by trifluoperazine or praziquantel. Protein-protein cross-linking experiments showed that FhCaBP4 underwent calcium ion-dependent dimerisation. Since DLCs are commonly dimeric, it is likely that FhCaBP4 dimerises through this domain. The molecular model reveals that the calcium ion-binding site is located close to a key sequence in the DLC-like domain, suggesting a plausible mechanism for calcium-dependent dimerisation.

Intraductal Injections into the Mouse Mammary Gland.

The mammary intraductal xenografting technique has been established to inject cells or other substances directly into the mammary ducts of female mice. Using this refined xenografting method provides the possibility of mimicking the normal microenvironment of preinvasive breast lesions including, ductal carcinoma in situ (DCIS), to study of the progression of DCIS to invasive breast cancer in a more relevant manner than with other mammary xenografting methods. Xenografting into the mammary fat pad delivers cells directly into the stroma and bypasses the occurrence of invasive transition, during which cells invade through the basement membrane. Either breast cancer cell lines or patient-derived breast cancer cells can be injected into the mammary duct using this protocol to model breast cancer progression. This protocol will cover the procedures required to perform this technique.

Roadmap for achieving net-zero emissions in global food systems by 2050.

Food systems (FSs) emit ~ 20 GtCO2e/y (~ 35% of global greenhouse gas emissions). This level tends to raise given the expected increases in food demands, which may threaten global climate targets. Through a rapid assessment, evaluating 60+ scenarios based on existing low-emission and carbon sequestration practices, we estimate that intensifying FSs could reduce its emissions from 21.4 to - 2.0 GtCO2e/y and address increasing food demands without relying on carbon offsets (e.g., related to afforestation and reforestation programs). However, given historical trends and regional contexts, a more diverse portfolio of practices, including diet shifts and new-horizon technologies, will be needed to increase the feasibility of achieving net-zero FSs. One likely pathway consists of implementing practices that shift food production to the 30th-percentile of least emission-intensive FSs (~ 45% emissions reduction), sequester carbon at 50% of its potential (~ 5 GtCO2e/y) and adopt diet shifts and new-horizon technologies (~ 6 GtCO2e/y). For a successful transition to happen, the global FSs would, in the next decade (2020s), need to implement cost-effective mitigation practices and technologies, supported by improvements in countries' governance and technical assistance, innovative financial mechanisms and research focused on making affordable technologies in the following two decades (2030-2050). This work provides options and a vision to guide global FSs to achieving net-zero by 2050.

The Anthropogenic Impact on Indoor Radon Concentrations for Secunda, Mpumalanga Province, South Africa.

ABSTRACT: Secunda is a town built amid the coalfields of the Mpumalanga province of South Africa. Surrounding the town are 11 coal-fired plants (CFPs) contributing around 59% of the country's energy needs. It is also home to Sasol Synfuels, which produces synthetic gas through coal gasification and natural gas reforming. Coal, like most materials found in nature, contains trace elements of the naturally occurring primordial radionuclides 40K, 238U, 232Th, and their decay products. The milling and combustion of coal in a CFP increases the mass concentration of these trace elements, and the residuals end up on ash heaps as fly ash, bottom ash, and boiler slag. A small percentage of fly ash also ends up in the atmosphere. This paper sets out to determine the anthropogenic impact of the industrial activity on indoor radon in the town of Secunda in the Mpumalanga region of South Africa. Measurements were done in 37 homes during July when higher indoor radon levels are expected due to homes typically being closed due to the low temperatures. The average indoor radon concentration was found to be 76.4 Bq m-3. This indicates that the fallout from the industrial activity surrounding Secunda does not enhance the emanation of radon. This may be due to the type of activity or the climate and prevailing winds mitigating its indoor build-up. Measurements during the warmer months and in neighboring towns with different industrial activities are required to confirm the trends established by this research.

Sox11 regulates mammary tumour-initiating and metastatic capacity in Brca1-deficient mouse mammary tumour cells.

Little is known about the role of Sox11 in the regulation of mammary progenitor cells. Sox11 is expressed by mammary bud epithelial cells during embryonic mammary gland development and is not detected in mammary epithelial cells after birth. As Sox11 is an oncofetal gene, we investigated the effects of reducing Sox11 levels in embryonic mammary progenitor cells and found that Sox11 regulates proliferative state, stem cell activity and lineage marker expression. We also investigated the effect of reducing Sox11 levels in two transplantable Brca1-deficient oestrogen receptor-negative mouse mammary tumour cell lines, to assess whether Sox11 regulates similar functions in tumour progenitor cells. When Sox11 levels were reduced in one Brca1-deficient mammary tumour cell line that expressed both epithelial and mesenchymal markers, similar effects on proliferation, stem cell activity and expression of lineage markers to those seen in the embryonic mammary progenitor cells were observed. Orthotopic grafting of mammary tumour cells with reduced Sox11 levels led to alterations in tumour-initiating capacity, latency, expression of lineage markers and metastatic burden. Our results support a model in which tumours expressing higher levels of Sox11 have more stem and tumour-initiating cells, and are less proliferative, whereas tumours expressing lower levels of Sox11 become more proliferative and capable of morphogenetic/metastatic growth, similar to what occurs during embryonic mammary developmental progression.

Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance.

Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.

Remediation of the protein data bank archive.

The Worldwide Protein Data Bank (wwPDB; wwpdb.org) is the international collaboration that manages the deposition, processing and distribution of the PDB archive. The online PDB archive at ftp://ftp.wwpdb.org is the repository for the coordinates and related information for more than 47 000 structures, including proteins, nucleic acids and large macromolecular complexes that have been determined using X-ray crystallography, NMR and electron microscopy techniques. The members of the wwPDB-RCSB PDB (USA), MSD-EBI (Europe), PDBj (Japan) and BMRB (USA)-have remediated this archive to address inconsistencies that have been introduced over the years. The scope and methods used in this project are presented.

The Magnitude of the Spatial Disorientation Problem in Transport Airplanes.

INTRODUCTION: Loss-of-control (LOC) is the major cause of transport airplane mishaps. There have been many published reports and papers examining these accidents. While these studies did mention spatial disorientation (SD) as a cause or a factor, none of them analyzed it further. The present study uses transport and commuter airplane mishap data for a recent 35-yr period and examines the results of those mishaps involving spatial disorientation.METHOD: We identified LOC and SD accidents from five national aviation accident organizations and two independent groups. Only "normal" operations (air carrier, noncommercial transportation, ferry flights, and training) were considered. We reviewed transport and commuter airplane accidents using the published reports and identified 94 involving SD.RESULTS: We found the distribution of SD mishaps differs from LOC mishaps. During initial climb, there were relatively fewer SD mishaps (16%) than LOC mishaps (31%). During enroute climb SD has relatively more mishaps (18%) than LOC (11%). During go-around or missed approach phases, there were relatively more SD mishaps (21%) than LOC mishaps (4%). Perhaps the most significant observation was an increasing number of SD mishaps during the period reviewed.DISCUSSION: There are several possible reasons for the increasing numbers of SD mishaps over the study period from 1981 to 2016. Somatogravic illusion during go-around or missed approach accounts for only some of this increase. There is insufficient data to determine the reason for the remaining increase.Newman RL, Rupert AH. The magnitude of the spatial disorientation problem in transport airplanes. Aerosp Med Hum Perform. 2020; 91(2):65-70.

Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation.

Prostate cancer (PCa) is one of the most frequent tumor types in the male Western population. Early-stage PCa and late-stage PCa are dependent on androgen signaling, and inhibitors of the androgen receptor (AR) axis represent the standard therapy. Here, we studied in detail the global impact of darolutamide, a newly approved AR antagonist, on the transcriptome and AR-bound cistrome in two PCa cell models. Darolutamide strongly depleted the AR from gene regulatory regions and abolished AR-driven transcriptional signaling. Enhancer activation was blocked at the chromatin level as evaluated by H3K27 acetylation (H3K27ac), H3K4 monomethylation (H3K4me1), and FOXA1, MED1, and BRD4 binding. We identified genomic regions with high affinities for the AR in androgen-stimulated, but also in androgen-depleted conditions. A similar AR affinity pattern was observed in healthy and PCa tissue samples. High FOXA1, BRD4, H3K27ac, and H3K4me1 levels were found to mark regions showing AR binding in the hormone-depleted setting. Conversely, low FOXA1, BRD4, and H3K27ac levels were observed at regulatory sites that responded strongly to androgen stimulation, and AR interactions at these sites were blocked by darolutamide. Beside marked loss of AR occupancy, FOXA1 recruitment to chromatin was also clearly reduced after darolutamide treatment. We furthermore identified numerous androgen-regulated super-enhancers (SEs) that were associated with hallmark androgen and cell proliferation-associated gene sets. Importantly, these SEs are also active in PCa tissues and sensitive to darolutamide treatment in our models. Our findings demonstrate that darolutamide is a potent AR antagonist blocking genome-wide AR enhancer and SE activation, and downstream transcription. We also show the existence of a dynamic AR cistrome that depends on the androgen levels and on high AR affinity regions present in PCa cell lines and also in tissue samples.

SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells.

SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.

Sequential SNARE disassembly and GATE-16-GOS-28 complex assembly mediated by distinct NSF activities drives Golgi membrane fusion.

Characterization of mammalian NSF (G274E) and Drosophila NSF (comatose) mutants revealed an evolutionarily conserved NSF activity distinct from ATPase-dependent SNARE disassembly that was essential for Golgi membrane fusion. Analysis of mammalian NSF function during cell-free assembly of Golgi cisternae from mitotic Golgi fragments revealed that NSF disassembles Golgi SNAREs during mitotic Golgi fragmentation. A subsequent ATPase-independent NSF activity restricted to the reassembly phase is essential for membrane fusion. NSF/alpha-SNAP catalyze the binding of GATE-16 to GOS-28, a Golgi v-SNARE, in a manner that requires ATP but not ATP hydrolysis. GATE-16 is essential for NSF-driven Golgi reassembly and precludes GOS-28 from binding to its cognate t-SNARE, syntaxin-5. We suggest that this occurs at the inception of Golgi reassembly to protect the v-SNARE and regulate SNARE function.

VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo.

NSF and p97 are ATPases required for the heterotypic fusion of transport vesicles with their target membranes and the homotypic fusion of organelles. NSF uses ATP hydrolysis to dissociate NSF/SNAPs/SNAREs complexes, separating the v- and t-SNAREs, which are then primed for subsequent rounds of fusion. In contrast, p97 does not dissociate the p97/p47/SNARE complex even in the presence of ATP. Now we have identified a novel essential factor for p97/p47-mediated membrane fusion, named VCIP135 (valosin-containing protein [VCP][p97]/p47 complex-interacting protein, p135), and show that it binds to the p97/p47/syntaxin5 complex and dissociates it via p97 catalyzed ATP hydrolysis. In living cells, VCIP135 and p47 are shown to function in Golgi and ER assembly.