Emergency Physicians' Ethical Issues with Hospital Business Models.

BACKGROUND: The changing hospital business model has raised ethical issues for emergency physicians (EPs) in a healthcare system that often prioritizes profits over patient welfare. For-profit hospitals, driven by profit motives, may prioritize treating patients with lucrative insurance plans and those who can afford expensive treatments. Private equity investors, who now own many for-profit hospitals, focus on short-term financial gains, leading to cost-cutting measures and pressure on EPs to prioritize financial goals over patient welfare. Nonprofit hospitals, mandated to provide charity care to the underserved, may fail to meet their community service obligations, resulting in disparities in healthcare access. OBJECTIVE: This review examines the ethical challenges faced by emergency physicians (EPs) in response to the evolving hospital business model, which increasingly prioritizes profits over patient welfare. DISCUSSION: Emergency physicians face ethical dilemmas in this changing environment, including conflicts between patient care and financial interests. Upholding professional ethics and the principle of beneficence is essential. Another challenge is equitable access to healthcare, with some nonprofit hospitals reducing charity care, thus exacerbating disparities. EPs must uphold the ethical principle of justice, ensuring quality care for all patients, regardless of financial means. Conflicts of interest may arise when EPs work in hospitals owned by private equity firms or with affiliations with pharmaceutical companies or medical device manufacturers, potentially compromising patient care. CONCLUSION: Emergency physicians must navigate these ethical issues while upholding professional ethics and advocating for patients' best interests. Collaboration with hospital administrators, policymakers, and stakeholders is vital to address these concerns and prioritize patient welfare in healthcare delivery.

The effects of a 6-month mandatory military police academy training on recruits' physical fitness.

BACKGROUND: Physical fitness for health and professional performance play important roles in police workforce considering that policing is a dangerous job, associated with high physical demands. OBJECTIVES: (1) To evaluate the effects of a 6-month course of police academy training on health-related physical fitness (HRPF) of military police recruits. (2) To investigate whether recruits' HRPF still met the academy entry standards after an unsupervised 7-month period prior to academy. METHODS: We conducted an observational and longitudinal study with 219 male police recruits (aged 25.5±3.6 years; BMI of 24.4±2.5 kg/m2). HRPF parameters included the Cooper 12-min running test for cardiorespiratory fitness (CRF), curl-ups, pull-ups and push-ups for muscle strength/endurance which were evaluated 3 times: 7 months prior to academy course and pre- and post-academy training period. RESULTS: Participants maintained optimal age-related HRPF during the unsupervised period prior to academy. After academy training upon graduation, all HRPF parameters further increased an average of 7.7 to 69.0% (p < 0.001; calculated Cohen's d effect size ≥0.95). CRF was the only HRPF that improved less than 10% after the academy course. CONCLUSIONS: Police recruits that had passed the application fitness standards maintained their HRPF prior to academy, and all their HRPF parameters increased after a 6-month academy training period which was not primarily focused on exercise training. Among all components of HRPF, CRF appears to be the most challenging one to improve among police recruits. Our findings suggest that regular training with minimum physical standards could be potentially beneficial to police officers' health and career longevity.

Proteolysis: a key post-translational modification regulating proteoglycans.

Proteoglycans are composite molecules comprising a protein backbone, i.e., the core protein, with covalently attached glycosaminoglycan chains of distinct chemical types. Most proteoglycans are secreted or attached to the cell membrane. Their specialized structures, binding properties, and biophysical attributes underlie diverse biological roles, which include modulation of tissue mechanics, cell adhesion, and the sequestration and regulated release of morphogens, growth factors, and cytokines. As an irreversible post-translational modification, proteolysis has a profound impact on proteoglycan function, abundance, and localization. Proteolysis is required for molecular maturation of some proteoglycans, clearance of extracellular matrix proteoglycans during tissue remodeling, generation of bioactive fragments from proteoglycans, and ectodomain shedding of cell-surface proteoglycans. Genetic evidence shows that proteoglycan core protein proteolysis is essential for diverse morphogenetic events during embryonic development. In contrast, dysregulated proteoglycan proteolysis contributes to osteoarthritis, cardiovascular disorders, cancer, and inflammation. Proteolytic fragments of perlecan, versican, aggrecan, brevican, collagen XVIII, and other proteoglycans are associated with independent biological activities as so-called matrikines. Yet, proteoglycan proteolysis has been investigated to only a limited extent to date. Here, we review the actions of proteases on proteoglycans and illustrate their functional impact with several examples. We discuss the applications and limitations of strategies used to define cleavage sites in proteoglycans and explain how proteoglycanome-wide proteolytic mapping, which is desirable to fully understand the impact of proteolysis on proteoglycans, can be facilitated by integrating classical proteoglycan isolation methods with mass spectrometry-based proteomics.

Visualizing Staphylococcus aureus pathogenic membrane modification within the host infection environment by multimodal imaging mass spectrometry.

Bacterial pathogens have evolved virulence factors to colonize, replicate, and disseminate within the vertebrate host. Although there is an expanding body of literature describing how bacterial pathogens regulate their virulence repertoire in response to environmental signals, it is challenging to directly visualize virulence response within the host tissue microenvironment. Multimodal imaging approaches enable visualization of host-pathogen molecular interactions. Here we demonstrate multimodal integration of high spatial resolution imaging mass spectrometry and microscopy to visualize Staphylococcus aureus envelope modifications within infected murine and human tissues. Data-driven image fusion of fluorescent bacterial reporters and matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance imaging mass spectrometry uncovered S. aureus lysyl-phosphatidylglycerol lipids, localizing to select bacterial communities within infected tissue. Absence of lysyl-phosphatidylglycerols is associated with decreased pathogenicity during vertebrate colonization as these lipids provide protection against the innate immune system. The presence of distinct staphylococcal lysyl-phosphatidylglycerol distributions within murine and human infections suggests a heterogeneous, spatially oriented microbial response to host defenses.

Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development.

The embryonic extracellular matrix (ECM) undergoes transition to mature ECM as development progresses, yet few mechanisms ensuring ECM proteostasis during this period are known. Fibrillin microfibrils are macromolecular ECM complexes serving structural and regulatory roles. In mice, Fbn1 and Fbn2, encoding the major microfibrillar components, are strongly expressed during embryogenesis, but fibrillin-1 is the major component observed in adult tissue microfibrils. Here, analysis of Adamts6 and Adamts10 mutant mouse embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics discovery of ADAMTS6-cleaved sites, identifies a proteostatic mechanism contributing to postnatal fibrillin-2 reduction and fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development defined by a drastic reduction of aggrecan and cartilage link protein, impaired BMP signaling in cartilage, and increased GDF5 sequestration in fibrillin-2-rich tissue. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of the defects in Adamts6-/- embryos by genetic reduction of Fbn2, but not Fbn1.

Post-translational regulation and proteolytic activity of the metalloproteinase ADAMTS8.

A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs (ADAMTS)8 is a secreted protease, which was recently implicated in pathogenesis of pulmonary arterial hypertension (PAH). However, the substrate repertoire of ADAMTS8 and regulation of its activity are incompletely understood. Although considered a proteoglycanase because of high sequence similarity and close phylogenetic relationship to the proteoglycan-degrading proteases ADAMTS1, 4, 5, and 15, as well as tight genetic linkage with ADAMTS15 on human chromosome 11, its aggrecanase activity was reportedly weak. Several post-translational factors are known to regulate ADAMTS proteases such as autolysis, inhibition by endogenous inhibitors, and receptor-mediated endocytosis, but their impacts on ADAMTS8 are unknown. Here, we show that ADAMTS8 undergoes autolysis at six different sites within its spacer domain. We also found that in contrast to ADAMTS4 and 5, ADAMTS8 levels were not regulated through low-density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytosis. Additionally, ADAMTS8 lacked significant activity against the proteoglycans aggrecan, versican, and biglycan. Instead, we found that ADAMTS8 cleaved osteopontin, a phosphoprotein whose expression is upregulated in PAH. Multiple ADAMTS8 cleavage sites were identified using liquid chromatography-tandem mass spectrometry. Osteopontin cleavage by ADAMTS8 was efficiently inhibited by TIMP-3, an endogenous inhibitor of ADAMTS1, 4, and 5, as well as by TIMP-2, which has no previously reported inhibitory activity against other ADAMTS proteases. These differences in post-translational regulation and substrate repertoire differentiate ADAMTS8 from other family members and may help to elucidate its role in PAH.

Identification of novel ADAMTS1, ADAMTS4 and ADAMTS5 cleavage sites in versican using a label-free quantitative proteomics approach.

The chondroitin sulfate proteoglycan versican is important for embryonic development and several human disorders. The versican V1 splice isoform is widely expressed and cleaved by ADAMTS proteases at a well-characterized site, Glu441-Ala442. Since ADAMTS proteases cleave the homologous proteoglycan aggrecan at multiple sites, we hypothesized that additional cleavage sites existed within versican. We report a quantitative label-free approach that ranks abundance of liquid chromatography-tandem mass spectrometry (LC-MS/MS)-identified semi-tryptic peptides after versican digestion by ADAMTS1, ADAMTS4 and ADAMTS5 to identify site-specific cleavages. Recombinant purified versican V1 constructs were digested with the recombinant full-length proteases, using catalytically inactive mutant proteases in control digests. Semi-tryptic peptide abundance ratios determined by LC-MS/MS in ADAMTS:control digests were compared to the mean of all identified peptides to obtain a z-score by which outlier peptides were ranked, using semi-tryptic peptides identifying Glu441 -Ala442 cleavage as the benchmark. Tryptic peptides with higher abundance in control digests supported cleavage site identification. We identified several novel cleavage sites supporting the ADAMTS1/4/5 cleavage site preference for a P1-Glu residue in proteoglycan substrates. Digestion of proteins in vitro and application of this z-score approach is potentially widely applicable for mapping protease cleavage sites using label-free proteomics. SIGNIFICANCE: Versican abundance and turnover are relevant to the pathogenesis of several human disorders. Versican is cleaved by A Disintegrin-like And Metalloprotease with Thrombospondin type 1 motifs (ADAMTS) family members at Glu441-Ala442, generating a bioactive proteoform called versikine, but additional cleavage sites and the site-specificity of individual ADAMTS proteases is unexplored. Here, we used a label-free proteomics strategy to identify versican cleavage sites for 3 ADAMTS proteases, applying a novel z-score-based statistical approach to compare the protease digests of versican to controls (digests with inactive protease) using the known protease cleavage site as a benchmark. We identified 21 novel cleavage sites that had a comparable z-score to the benchmark. Given the functional significance of versikine, they represent potentially significant cleavages and helped to refine a substrate site preference for each protease.The z-score approach is potentially widely applicable for discovery of site-specific cleavages within an purified protein or small ensemble of proteins using any protease.

Diversity pipelines: The rationale to recruit and support minority physicians.

Emergency physicians care for patients from all backgrounds with respect and expertise. We aspire to treat everyone equitably and make decisions at the bedside that are not based on age, race, socioeconomic status, gender, sexual orientation, religion, language, or any other category. In many settings, there is a stark contrast between the diversity of our patient populations and that of the physicians caring for them. Despite our intention to minimize the effects of implicit and explicit bias, when the physician workforce does not reflect the patient population, there may be significant assumptions, mistrust, and misunderstandings between people from different backgrounds. As medical professionals, increasing the diversity of our workforce and support for programs and policies that increase underrepresented minority (URM) physicians in emergency medicine is important. Increasing URM physicians will not only improve the quality of care for our patients, but also the quality of education and training in our profession. It is crucial that we prioritize pipeline programs that recruit and support URM physicians. This article describes the rationale to increase diversity within the profession of emergency medicine and the essential mechanisms to achieve this goal. In the same way that we hold individuals accountable to a clinical standard of care, we should hold our institutions to an organizational standard of diversity.

Assessing psychiatric safety in suicidal emergency department patients.

We provide a review of the assessment of suicidal emergency department patients and includes a legal and ethical perspective. Screening tools and psychiatric consultation are important adjuncts to the ED evaluation of potentially suicidal patients. Suicide risk should be assessed, and if positive, an appropriate and safe disposition should be arranged. The aim of this article is to review these assessment tools and consider ethical issues, such as patient autonomy, accountability of the emergency physician, and consultant to Emergency Medical Treatment and Labor Act (EMTALA) as well as confidentiality, privacy, and social issues.

Why are Vibrational Lines Narrow in Proteins?

The vibrational Stark effect in proteins yields line shifts indicative of strong internal electric fields up to a few volts per angstrom. These values are supported by numerical simulations of proteins. The simulations also show a significant breadth of field fluctuations translating to inhomogeneous broadening of vibrational lines. According to fluctuation-dissipation arguments, strong internal fields should lead to broad lines. Experimentally reported vibrational lines in proteins are, however, very narrow. This disconnect is explained here in terms of the insufficient (nonergodic) sampling of the protein's configurations on the lifetime of the vibrational probe. The slow component of the electric field fluctuations in proteins relaxes on the time scale of tens of nanoseconds and is dynamically frozen on the vibrational lifetime.

Proteomics identifies a convergent innate response to infective endocarditis and extensive proteolysis in vegetation components.

Infective endocarditis is a life-threatening infection of heart valves and adjacent structures characterized by vegetations on valves and other endocardial surfaces, with tissue destruction and risk of embolization. We used high-resolution mass spectrometry to define the proteome of staphylococcal and non-staphylococcal vegetations and Terminal Amine Isotopic Labeling of Substrates (TAILS) to define their proteolytic landscapes. These approaches identified over 2000 human proteins in staphylococcal and non-staphylococcal vegetations. Individual vegetation proteomes demonstrated comparable profiles of quantitatively major constituents that overlapped with serum, platelet, and neutrophil proteomes. Staphylococcal vegetation proteomes resembled one another more than the proteomes of non-staphylococcal vegetations. TAILS demonstrated extensive proteolysis within vegetations, with numerous previously undescribed cleavages. Several proteases and pathogen-specific proteins, including virulence factors, were identified in most vegetations. Proteolytic peptides in fibronectin and complement C3 were identified as potential infective endocarditis biomarkers. Overlap of staphylococcal and non-staphylococcal vegetation proteomes suggests a convergent thrombotic and immune response to endocardial infection by diverse pathogens. However, the differences between staphylococcal and non-staphylococcal vegetations and internal variance within the non-staphylococcal group indicate that additional pathogen- or patient-specific effects exist. Pervasive proteolysis of vegetation components may arise from vegetation-intrinsic proteases and destabilize vegetations, contributing to embolism.

Compensation models in emergency medicine: An ethical perspective.

There is considerable diversity in compensation models in the specialty of Emergency Medicine (EM). We review different compensation models and examine moral consequences possibly associated with the use of various models. The article will consider how different models may promote or undermine health care's quadruple aim of providing quality care, improving population health, reducing health care costs, and improving the work-life balance of health care professionals. It will also assess how different models may promote or undermine the basic bioethical principles of beneficence, non-maleficence, respect for autonomy, and justice.

Polarizability of the Active Site in Enzymatic Catalysis: Cytochrome c.

Anisotropic polarizability of the heme in cytochrome c is found to be a major factor in suppressing the activation barrier of protein electron transfer (catalytic effect). Polarizability couples to the electric field of protein and water to enhance fluctuations of the electron-transfer energy gap and the corresponding variance reorganization energy λvar. The reorganization energy observable by kinetic measurements λr = (λSt)2/λvar is composed of λvar and the Stokes-shift reorganization energy λSt. It is lowered compared to the usually reported λSt due to polarizability of the active site leading to λvar > λSt. The coupling of electrostatic protein-water fluctuations to the polarizable active site is accounted for here by empirical valence-bond diagonalization of the active-site Hamiltonian along the simulation trajectory. We show that recent simulations employing this technique, which failed to find the effect of polarizability on electron-transfer kinetics, were erroneous in neglecting the diagonal dipole moments in the Hamiltonian matrix and failing to rotate the electric field produced by the protein-water medium into the molecular frame of the active site. We find that anisotropy of the tensor of polarizability difference in the two oxidation states of the heme matches anisotropy of the second-rank tensor constructed from the electric field at the active site. Exposure of the heme to water from only one side carries significant catalytic function, directly leading to the field anisotropy and the corresponding depression of the activation barrier.

Applicants with Prior Training.

Emergency medicine (EM) has its challenges, downsides, advantages, and accompanying lifestyle. Additionally, graduates of EM residency programs have abundant job opportunities. Accordingly, there is an increased interest in residency training in EM, even among residents with prior training. Transitioning from another specialty to EM can be complicated yet achievable, especially if EM is the transitioning physician's passion and career goal. Therefore, in this article, we elaborate on the transition process from another discipline to EM in light of changes in residency funding. We also explore the advantages and disadvantages of transitioning to EM with previous training in another specialty. Moreover, we expand on credit equivalencies for months already completed in another training programs, as well as the difficulties to be anticipated by transitioning physicians.

Screening of Coulomb interactions in liquid dielectrics.

The interaction of charges in dielectric materials is screened by the dielectric constant of the bulk dielectric. In dielectric theories, screening is assigned to surface charges appearing from preferential orientations of dipoles along the local field in the interface. For liquid dielectrics, such interfacial orientations are affected by the interfacial structure characterized by a separate interfacial dipolar susceptibility. We argue that dielectric properties of polar liquids should be characterized by two distinct susceptibilities responsible for local response (solvation) and long-range response (dielectric screening). A microscopic model for dipolar screening in polar liquids is developed here. It shows that the standard bulk dielectric constant is responsible for screening at large distances. The potential of mean force between ions in polar liquids becomes oscillatory at short distances. Oscillations arise from the coupling of collective longitudinal excitations (dipolarons) of the polar liquid with its interfacial density profile. Interfacial electrostatics demonstrates a crossover beyond the solute radius of ∼1 nm from the scaling laws roughly consistent with continuum expectations for small solutes to new scaling trends characterizing the much softer nano-scale solute-solvent interface. This crossover also marks the transition to a continuum-type electrostatic screening between ions, when short-distance oscillation of the potential of mean force become strongly damped. Screening oscillations are enhanced for more structured interfaces.

Wetting of the Protein Active Site Leads to Non-Marcusian Reaction Kinetics.

Enzymes exist in continuously fluctuating water bath dramatically affecting their function. Water not only forms the solvation shell but also penetrates into the protein interior. Changing the wetting pattern of the protein's active site in response to altering redox state initiates a highly nonlinear structural change and non-Gaussian electrostatic fluctuations at the active site. The free-energy surfaces of electron transfer are highly nonparabolic (non-Marcusian), as shown by atomistic molecular dynamics simulations of hydrated ferredoxin protein and by an analytical model in agreement with simulations. The reorganization energy of electron transfer passes through a spike marking equal probabilities of the wet and dry states of the active site. The activation thermodynamics affected by wetting leads to a non-Arrhenius, passing through a maximum, plot for the reaction rate vs the inverse temperature.

Complex Dynamics of Water in Protein Confinement.

This paper studies single-molecule and collective dynamics of water confined in protein powders by means of molecular dynamics simulations. The single-particle dynamics show a modest retardation compared to the bulk but become highly stretched in the powder, with the stretching exponent of ≃0.2. The collective dynamics of the total water dipole are affected by intermolecular correlations inside water and by cross-correlations between the water and the protein. The dielectric spectrum of water in the powder has two nearly equal-amplitude peaks: a Debye peak with ≃16 ps relaxation time and a highly stretched peak with the relaxation time of ≃13 ns and a stretching exponent of ≃0.12. The slower relaxation component is not seen in the single-molecule correlation functions and can be assigned to elastic protein motions displacing water in the powder. The loss spectrum of the intermediate scattering function reported by neutron-scattering experiments is also highly stretched, with the high-frequency wing scaling according to a power law. Translational dynamics can become much slower in the powder than in the bulk but are overshadowed by the rotational loss in the overall loss spectrum of neutron scattering.

Terahertz absorption of lysozyme in solution.

Absorption of radiation by solution is described by its frequency-dependent dielectric function and can be viewed as a specific application of the dielectric theory of solutions. For ideal solutions, the dielectric boundary-value problem separates the polar response into the polarization of the void in the liquid, created by the solute, and the response of the solute dipole. In the case of a protein as a solute, protein nuclear dynamics do not project on significant fluctuations of the dipole moment in the terahertz domain of frequencies and the protein dipole can be viewed as dynamically frozen. Absorption of radiation then reflects the interfacial polarization. Here we apply an analytical theory and computer simulations to absorption of radiation by an ideal solution of lysozyme. Comparison with the experiment shows that Maxwell electrostatics fails to describe the polarization of the protein-water interface and the "Lorentz void," which does not anticipate polarization of the interface by the external field (no surface charges), better represents the data. An analytical theory for the slope of the solution absorption against the volume fraction of the solute is formulated in terms of the cavity field response function. It is calculated from molecular dynamics simulations in good agreement with the experiment. The protein hydration shell emerges as a separate sub-ensemble, which, collectively, is not described by the standard electrostatics of dielectrics.