ABSTRACT
The cell-cell adhesion cadherin-catenin complexes recruit vinculin to the adherens junction (AJ) to modulate the mechanical couplings between neighboring cells. However, it is unclear how vinculin influences the AJ structure and function. Here, we identified two patches of salt bridges that lock vinculin in the head-tail autoinhibited conformation and reconstituted the full-length vinculin activation mimetics bound to the cadherin-catenin complex. The cadherin-catenin-vinculin complex contains multiple disordered linkers and is highly dynamic, which poses a challenge for structural studies. We determined the ensemble conformation of this complex using small-angle x-ray and selective deuteration/contrast variation small-angle neutron scattering. In the complex, both α-catenin and vinculin adopt an ensemble of flexible conformations, but vinculin has fully open conformations with the vinculin head and actin-binding tail domains well separated from each other. F-actin binding experiments show that the cadherin-catenin-vinculin complex binds and bundles F-actin. However, when the vinculin actin-binding domain is removed from the complex, only a minor fraction of the complex binds to F-actin. The results show that the dynamic cadherin-catenin-vinculin complex employs vinculin as the primary F-actin binding mode to strengthen AJ-cytoskeleton interactions.
Subject(s)
Actins , Cadherins , Cadherins/metabolism , Actins/metabolism , Vinculin/metabolism , alpha Catenin/chemistry , Protein Binding , Actin Cytoskeleton/metabolism , Cell AdhesionABSTRACT
OBJECTIVES: The COVID-19 pandemic has required significant modifications of hospital care. The objective of this study was to examine the operational approaches taken by US hospitals over time in response to the COVID-19 pandemic. DESIGN, SETTING AND PARTICIPANTS: This was a prospective observational study of 17 geographically diverse US hospitals from February 2020 to February 2021. OUTCOMES AND ANALYSIS: We identified 42 potential pandemic-related strategies and obtained week-to-week data about their use. We calculated descriptive statistics for use of each strategy and plotted percent uptake and weeks used. We assessed the relationship between strategy use and hospital type, geographic region and phase of the pandemic using generalised estimating equations (GEEs), adjusting for weekly county case counts. RESULTS: We found heterogeneity in strategy uptake over time, some of which was associated with geographic region and phase of pandemic. We identified a body of strategies that were both commonly used and sustained over time, for example, limiting staff in COVID-19 rooms and increasing telehealth capacity, as well as those that were rarely used and/or not sustained, for example, increasing hospital bed capacity. CONCLUSIONS: Hospital strategies during the COVID-19 pandemic varied in resource intensity, uptake and duration of use. Such information may be valuable to health systems during the ongoing pandemic and future ones.
Subject(s)
COVID-19 , Telemedicine , Humans , COVID-19/epidemiology , Pandemics , SARS-CoV-2 , HospitalsABSTRACT
Noninvasive positive-pressure ventilation (NPPV) is a form of ventilatory support that does not require the placement of an advanced airway. The authors discuss the use of NPPV on patients who will likely benefit. The use of NPPV has reduced the need for patients to require intubation and/or mechanical ventilation in some cases, as well as benefits.
Subject(s)
Positive-Pressure Respiration , Respiration, Artificial , HumansABSTRACT
Law enforcement (LE) use of force (UOF) is a complex social, medical, and legal issue. In recent years, highly visible and publicized UOF incidents have sparked public outrage about racial inequity and motivated broad institutional reflection on sanctioning violence in the name of protecting communities. A public health approach to violence and to LE-UOF is required to develop 21st-century policing recommendations. Tactical emergency medical services physicians are uniquely positioned to convene and to serve as advisors, educators, and advocates to LE departments, community leaders, and public policy developers in order to improve UOF policies.
El uso de la fuerza (UOF, por sus siglas en inglés) por parte de las fuerzas de orden público (LE, por sus siglas en inglés) es un tema complejo a nivel social, médico y legal. En los últimos años, ha habido incidentes de UOF muy visibles y publicitados que han enfurecido a la sociedad respecto de la inequidad racial y han motivado una reflexión institucional amplia sobre la autorización de la violencia en pos de proteger a las comunidades. Se requiere un enfoque desde la salud pública a la violencia y al UOF de las LE a fin de desarrollar recomendaciones para la policía del siglo XXI. Los médicos de los servicios de emergencia táctica cuentan con una posición única para mediar y dar servicio en calidad de asesores, educadores y defensores de departamentos, líderes de la comunidad y creadores de políticas públicas de las LE a fin de mejorar las políticas del UOF.
Subject(s)
Emergency Medical Services , Law Enforcement , Humans , Police , Public Policy , Violence/prevention & controlABSTRACT
OBJECTIVE: In this manuscript, we discuss the implementation and deployment of mobile integrated health and community paramedicine (MIH/CP) testing sites to provide screening, testing, and community outreach during the first months of the 2019 coronavirus disease (COVID-19) pandemic in the metropolitan region of Charlotte, North Carolina. This program addresses the need for an agile testing strategy during the current pandemic. We disclose the number of patients evaluated as "persons under investigation" and the proportion with positive severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) results from these sites. We describe how the programs were applied to patient care and include considerations on how additional staffing, scalability, and flexibility of these services may be applied to future patient and health care crises. METHODS: This is a descriptive report of the implementation of MIH/CP test sites in our health care system's early response to the COVID-19 pandemic in March 2020. Retrospective data on the number of patients and their associated demographics are reported here as raw data. No statistical analysis was performed. RESULTS: Between March 15, 2020, and April 15, 2020, our 6 MIH/CP test sites evaluated 4342 patients. Of these, 401 patients (9.2%) had positive test results, 62.8% of whom were women. The estimated duration of each patient encounter under investigation was 3 to 5 minutes. The paramedics were able to perform a brief history, specific physical examination, and screening for signs of hypoxemic respiratory failure. There were no cases of accidental exposure or failure of personal protective equipment for the MIH/CP paramedics. CONCLUSIONS: In our health care system, we pivoted the traditional MIH/CP model to rapidly initiate remote drive-through testing for COVID-19 in pre-screened individuals. This model allowed us to test patients with suspected COVID-19 patients away from traditional health care sites and mitigate exposure to health care workers and other patients.
Subject(s)
COVID-19 , Pandemics , Humans , Female , Male , COVID-19 Testing , COVID-19/diagnosis , COVID-19/epidemiology , Retrospective Studies , SARS-CoV-2 , Allied Health PersonnelABSTRACT
The United States Centers for Disease Control and Prevention and the World Health Organization broadly categorize mass gathering events as high risk for amplification of coronavirus disease 2019 (COVID-19) spread in a community due to the nature of respiratory diseases and the transmission dynamics. However, various measures and modifications can be put in place to limit or reduce the risk of further spread of COVID-19 for the mass gathering. During this pandemic, the Johns Hopkins University Center for Health Security produced a risk assessment and mitigation tool for decision-makers to assess SARS-CoV-2 transmission risks that may arise as organizations and businesses hold mass gatherings or increase business operations: The JHU Operational Toolkit for Businesses Considering Reopening or Expanding Operations in COVID-19 (Toolkit). This article describes the deployment of a data-informed, risk-reduction strategy that protects local communities, preserves local health-care capacity, and supports democratic processes through the safe execution of the Republican National Convention in Charlotte, North Carolina. The successful use of the Toolkit and the lessons learned from this experience are applicable in a wide range of public health settings, including school reopening, expansion of public services, and even resumption of health-care delivery.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2 , Pandemics/prevention & control , Risk Assessment , Delivery of Health CareABSTRACT
Mass vaccination campaigns have been used effectively to limit the impact of communicable disease on public health. However, the scale of the coronavirus disease (COVID-19) vaccination campaign is unprecedented. Mass vaccination sites consolidate resources and experience into a single entity and are essential to achieving community ("herd") immunity rapidly, efficiently, and equitably. Health care systems, local and regional public health entities, emergency medical services, and private organizations can rapidly come together to solve problems and achieve success. As medical directors at several mass vaccination sites across the United States, we describe key mass vaccination site concepts, including site selection, operational models, patient flow, inventory management, staffing, technology, reporting, medical oversight, communication, and equity. Lessons learned from experience operating a diverse group of mass vaccination sites will help inform not only sites operating during the current pandemic, but also may serve as a blueprint for future outbreaks of highly infectious communicable disease.
Subject(s)
COVID-19 , Communicable Diseases , Humans , United States/epidemiology , Mass Vaccination , COVID-19/epidemiology , COVID-19/prevention & control , Public Health , Disease Outbreaks , VaccinationABSTRACT
As the core component of the adherens junction in cell-cell adhesion, the cadherin-catenin complex transduces mechanical tension between neighboring cells. Structural studies have shown that the cadherin-catenin complex exists as an ensemble of flexible conformations, with the actin-binding domain (ABD) of α-catenin adopting a variety of configurations. Here, we have determined the nanoscale protein domain dynamics of the cadherin-catenin complex using neutron spin echo spectroscopy (NSE), selective deuteration, and theoretical physics analyses. NSE reveals that, in the cadherin-catenin complex, the motion of the entire ABD becomes activated on nanosecond to submicrosecond timescales. By contrast, in the α-catenin homodimer, only the smaller disordered C-terminal tail of ABD is moving. Molecular dynamics (MD) simulations also show increased mobility of ABD in the cadherin-catenin complex, compared to the α-catenin homodimer. Biased MD simulations further reveal that the applied external forces promote the transition of ABD in the cadherin-catenin complex from an ensemble of diverse conformational states to specific states that resemble the actin-bound structure. The activated motion and an ensemble of flexible configurations of the mechanosensory ABD suggest the formation of an entropic trap in the cadherin-catenin complex, serving as negative allosteric regulation that impedes the complex from binding to actin under zero force. Mechanical tension facilitates the reduction in dynamics and narrows the conformational ensemble of ABD to specific configurations that are well suited to bind F-actin. Our results provide a protein dynamics and entropic explanation for the observed force-sensitive binding behavior of a mechanosensitive protein complex.
Subject(s)
Cadherins/chemistry , Catenins/chemistry , Binding Sites , Humans , Magnetic Resonance Spectroscopy , Molecular Dynamics Simulation , Motion , Neutrons , Protein DomainsABSTRACT
BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, healthcare systems in many regions of the country were being overwhelmed by large numbers of patients needing care. In this paper, we discuss use of an external emergency department (ED) site by a hospital system based in Charlotte, North Carolina to address concerns of a local surge similar to those seen around the country. OBJECTIVE: Demonstrate how expansion of ED facilities can increase efficiency of care for patients while also improving safety for clinicians, staff, and non-infected patients. METHODS: We describe development and implementation of our external ED drive-through testing sites during the COVID-19 pandemic. We collected data from three external ED sites in the Atrium Health system between March 15th and April 15th, 2020. Patients were included if they were seen at one of the sites and tested for COVID-19. There were no exclusion criteria. We analyzed the data to identify any differences in patient demographics between sites. RESULTS: We saw 580 patients across the three sites, 302 of whom met criteria for COVID-19 testing. The majority of patients tested were Caucasian females. The majority who tested positive, however, were males. Thirteen patients were redirected into the hospital ED for further medical evaluation. CONCLUSIONS: External expansion of the ED is an important strategy that can allow hospitals to accommodate potentially infectious patients while maintaining appropriate isolation and rapid throughput. Proper implementation of the right system to meet hospital-specific needs can prove effective for the healthcare system.
Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , Clinical Laboratory Techniques/methods , Emergency Service, Hospital/trends , Triage/methods , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19 Testing/trends , Clinical Laboratory Techniques/trends , Emergency Service, Hospital/organization & administration , Female , Humans , Male , Middle Aged , North Carolina/epidemiology , Pandemics , Triage/standards , Triage/trendsABSTRACT
Importance: Trauma is the leading cause of death for US individuals younger than 45 years, and uncontrolled hemorrhage is a major cause of trauma mortality. The US military's medical advancements in the field of prehospital hemorrhage control have reduced battlefield mortality by 44%. However, despite support from many national health care organizations, no integrated approach to research has been made regarding implementation, epidemiology, education, and logistics of prehospital hemorrhage control by layperson immediate responders in the civilian sector. Objective: To create a national research agenda to help guide future work for prehospital hemorrhage control by laypersons. Evidence Review: The 2-day, in-person, National Stop the Bleed (STB) Research Consensus Conference was conducted on February 27 to 28, 2019, to identify and achieve consensus on research gaps. Participants included (1) subject matter experts, (2) professional society-designated leaders, (3) representatives from the federal government, and (4) representatives from private foundations. Before the conference, participants were provided a scoping review on layperson prehospital hemorrhage control. A 3-round modified Delphi consensus process was conducted to determine high-priority research questions. The top items, with median rating of 8 or more on a Likert scale of 1 to 9 points, were identified and became part of the national STB research agenda. Findings: Forty-five participants attended the conference. In round 1, participants submitted 487 research questions. After deduplication and sorting, 162 questions remained across 5 a priori-defined themes. Two subsequent rounds of rating generated consensus on 113 high-priority, 27 uncertain-priority, and 22 low-priority questions. The final prioritized research agenda included the top 24 questions, including 8 for epidemiology and effectiveness, 4 for materials, 9 for education, 2 for global health, and 1 for health policy. Conclusions and Relevance: The National STB Research Consensus Conference identified and prioritized a national research agenda to support laypersons in reducing preventable deaths due to life-threatening hemorrhage. Investigators and funding agencies can use this agenda to guide their future work and funding priorities.
Subject(s)
Emergency Medical Services , Hemorrhage , Research Design , Wounds and Injuries , Biomedical Research/methods , Consensus , Delphi Technique , Emergency Medical Services/methods , Emergency Medical Services/organization & administration , Hemorrhage/etiology , Hemorrhage/mortality , Hemorrhage/therapy , Humans , Surveys and Questionnaires , Wounds and Injuries/complications , Wounds and Injuries/mortalityABSTRACT
On September 1, 2019, Hurricane Dorian made landfall as a category 5 hurricane on Great Abaco Island, Bahamas. Hurricane Dorian matched the "Labor Day" hurricane of 1935 as the strongest recorded Atlantic hurricane to make landfall with maximum sustained winds of 185 miles/h.1 At the request of the Government of the Bahamas, Team Rubicon activated a World Health Organization Type 1 Mobile Emergency Medical Team and responded to Great Abaco Island. The team provided medical care and reconnaissance of medical clinics on the island and surrounding cays .
Subject(s)
Cyclonic Storms/statistics & numerical data , Disaster Medicine/methods , Bahamas , Disaster Medicine/trends , Emergency Medical Services/methods , Humans , Organizations/organization & administration , Organizations/trendsABSTRACT
The cadherin-catenin adhesion complex is the central component of the cell-cell adhesion adherens junctions that transmit mechanical stress from cell to cell. We have determined the nanoscale structure of the adherens junction complex formed by the α-cateninâ¢ß-cateninâ¢epithelial cadherin cytoplasmic domain (ABE) using negative stain electron microscopy, small-angle X-ray scattering, and selective deuteration/small-angle neutron scattering. The ABE complex is highly pliable and displays a wide spectrum of flexible structures that are facilitated by protein-domain motions in α- and ß-catenin. Moreover, the 107-residue intrinsically disordered N-terminal segment of ß-catenin forms a flexible "tongue" that is inserted into α-catenin and participates in the assembly of the ABE complex. The unanticipated ensemble of flexible conformations of the ABE complex suggests a dynamic mechanism for sensitivity and reversibility when transducing mechanical signals, in addition to the catch/slip bond behavior displayed by the ABE complex under mechanical tension. Our results provide mechanistic insight into the structural dynamics for the cadherin-catenin adhesion complex in mechanotransduction.
Subject(s)
Cadherins/chemistry , Cadherins/metabolism , Mechanotransduction, Cellular , alpha Catenin/chemistry , alpha Catenin/metabolism , beta Catenin/chemistry , beta Catenin/metabolism , Adherens Junctions/chemistry , Adherens Junctions/genetics , Adherens Junctions/metabolism , Amino Acid Motifs , Cadherins/genetics , Humans , Molecular Conformation , Protein Binding , Protein Domains , Scattering, Small Angle , alpha Catenin/genetics , beta Catenin/geneticsABSTRACT
This case report describes the technical aspects in first use of a novel field improvised autologous transfusion (FIAT) system. It highlights a potential solution for specific trauma patients during advanced resuscitative care (ARC) and prolonged field care (PFC) scenarios where other blood products are not available.
Subject(s)
Blood Transfusion, Autologous/methods , Military Medicine , Resuscitation , War-Related Injuries/therapy , HumansABSTRACT
OBJECTIVE: Disability-related education is essential for disaster responders and critical care transporters to ensure positive patient outcomes. This pilot study evaluated the effect of an online educational intervention on disaster responders and critical care transporters' knowledge of and feelings of self-efficacy about caring for individuals with developmental disabilities. METHODS: A 1-group, pretest-posttest, quasi-experimental design was used. A convenience sample of 33 disaster responders and critical care transporters participated. RESULTS: Of the 33 participants, only 24% had received prior education on this topic, and 88% stated that such education would be beneficial to their care of patients. Nineteen participants completed both the pretest and posttest, and overall performance on knowledge items improved from 66% correct to 81% correct. Self-efficacy for caring for developmentally disabled individuals improved, with all 10 items showing a statistically significant improvement. CONCLUSION: Online education is recommended to improve the knowledge and self-efficacy of disaster responders and critical care transporters who care for this vulnerable population after disasters and emergencies. (Disaster Med Public Health Preparedness. 2019;13:677-681).
Subject(s)
Developmental Disabilities/therapy , Emergency Medical Services/methods , Emergency Responders/education , Self Efficacy , Clinical Competence/standards , Developmental Disabilities/psychology , Emergency Medical Services/statistics & numerical data , Emergency Responders/psychology , Emergency Responders/statistics & numerical data , Humans , New Jersey , Pilot Projects , Vulnerable PopulationsSubject(s)
Antifibrinolytic Agents/therapeutic use , Blood Transfusion , Hemorrhage/therapy , Resuscitation/standards , Tranexamic Acid/therapeutic use , Balloon Occlusion , Humans , Monitoring, Physiologic , Practice Guidelines as Topic , Resuscitation/methods , Terminal Care , Time Factors , TourniquetsABSTRACT
As a core component of the adherens junction, α-catenin stabilizes the cadherin/catenin complexes to the actin cytoskeleton for the mechanical coupling of cell-cell adhesion. α-catenin also modulates actin dynamics, cell polarity, and cell-migration functions that are independent of the adherens junction. We have determined the solution structures of the α-catenin monomer and dimer using in-line size-exclusion chromatography small-angle X-ray scattering, as well as the structure of α-catenin dimer in complex to F-actin filament using selective deuteration and contrast-matching small angle neutron scattering. We further present the first observation, to our knowledge, of the nanoscale dynamics of α-catenin by neutron spin-echo spectroscopy, which explicitly reveals the mobile regions of α-catenin that are crucial for binding to F-actin. In solution, the α-catenin monomer is more expanded than either protomer shown in the crystal structure dimer, with the vinculin-binding M fragment and the actin-binding domain being able to adopt different configurations. The α-catenin dimer in solution is also significantly more expanded than the dimer crystal structure, with fewer interdomain and intersubunit contacts than the crystal structure. When in complex to F-actin, the α-catenin dimer has an even more open and extended conformation than in solution, with the actin-binding domain further separated from the main body of the dimer. The α-catenin-assembled F-actin bundle develops into an ordered filament packing arrangement at increasing α-catenin/F-actin molar ratios. Together, the structural and dynamic studies reveal that α-catenin possesses dynamic molecular conformations that prime this protein to function as a mechanosensor protein.
Subject(s)
Actins/metabolism , Nanotechnology , alpha Catenin/chemistry , alpha Catenin/metabolism , Humans , Molecular Dynamics Simulation , Protein Binding , Protein Multimerization , Protein Structure, Quaternary , SolutionsABSTRACT
BACKGROUND: Uncontrolled hemorrhage remains a leading cause of preventable death in tactical and combat settings. Alternate routes of delivery of tranexamic acid (TXA), an adjunct in the management of hemorrhagic shock, are being studied. A working group for the Committee for Tactical Emergency Casualty Care reviewed the available evidence on the potential role for intramuscular (IM) administration of TXA in nonhospital settings as soon as possible from the point of injury. METHODS: EMBASE and MEDLINE/PubMed databases were sequentially searched by medical librarians for evidence of TXA use in the following contexts and/or using the following keywords: prehospital, trauma, hemorrhagic shock, optimal timing, optimal dose, safe volume, incidence of venous thromboembolism (VTE), IM bioavailability. RESULTS: A total of 183 studies were reviewed. The strength of the available data was variable, generally weak in quality, and included laboratory research, case reports, retrospective observational reviews, and few prospective studies. Current volume and concentrations of available formulations of TXA make it, in theory, amenable to IM injection. Current bestpractice guidelines for large-volume injection (i.e., 5mL) support IM administration in four locations in the adult human body. One case series suggests complete bioavailability of IM TXA in healthy patients. Data are lacking on the efficacy and safety of IM TXA in hemorrhagic shock. CONCLUSION: There is currently insufficient evidence to support a strong recommendation for or against IM administration of TXA in the combat setting; however, there is an abundance of literature demonstrating efficacy and safety of TXA use in a broad range of patient populations. Balancing the available data and risk- benefit ratio, IM TXA should be considered a viable treatment option for tactical and combat applications. Additional studies should focus on the optimal dose and bioavailability of IM dosing of patients in hemorrhagic shock, with assessment of potential downstream sequelae.