Author Correction: Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses.

In the version of this article initially published, the labels (50 Å) above the scale bars in Fig. 1b were incorrect. The correct size is 50 nm. The error has been corrected in the HTML and PDF versions of the article.

Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses.

The present vaccine against influenza virus has the inevitable risk of antigenic discordance between the vaccine and the circulating strains, which diminishes vaccine efficacy. This necessitates new approaches that provide broader protection against influenza. Here we designed a vaccine using the hypervariable receptor-binding domain (RBD) of viral hemagglutinin displayed on a nanoparticle (np) able to elicit antibody responses that neutralize H1N1 influenza viruses spanning over 90 years. Co-display of RBDs from multiple strains across time, so that the adjacent RBDs are heterotypic, provides an avidity advantage to cross-reactive B cells. Immunization with the mosaic RBD-np elicited broader antibody responses than those induced by an admixture of nanoparticles encompassing the same set of RBDs as separate homotypic arrays. Furthermore, we identified a broadly neutralizing monoclonal antibody in a mouse immunized with mosaic RBD-np. The mosaic antigen array signifies a unique approach that subverts monotypic immunodominance and allows otherwise subdominant cross-reactive B cell responses to emerge.

Co-immunization with hemagglutinin stem immunogens elicits cross-group neutralizing antibodies and broad protection against influenza A viruses.

Current influenza vaccines predominantly induce immunity to the hypervariable hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, the immunosubdominant yet conserved HA stem harbors a supersite that is targeted by broadly neutralizing antibodies (bnAbs), representing a prime target for universal vaccines. Here, we showed that the co-immunization of two HA stem immunogens derived from group 1 and 2 influenza A viruses elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum-neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and protected against diverse viruses, including H5N1 and H7N9. Genetic and structural analyses revealed strong homology between macaque and human bnAbs, illustrating common biophysical constraints for acquiring cross-group specificity. Vaccine elicitation of stem-directed cross-group-protective immunity represents a step toward the development of broadly protective influenza vaccines.

Designed nanoparticles elicit cross-reactive antibody responses to conserved influenza virus hemagglutinin stem epitopes.

Despite the availability of seasonal vaccines and antiviral medications, influenza virus continues to be a major health concern and pandemic threat due to the continually changing antigenic regions of the major surface glycoprotein, hemagglutinin (HA). One emerging strategy for the development of more efficacious seasonal and universal influenza vaccines is structure-guided design of nanoparticles that display conserved regions of HA, such as the stem. Using the H1 HA subtype to establish proof of concept, we found that tandem copies of an alpha-helical fragment from the conserved stem region (helix-A) can be displayed on the protruding spikes structures of a capsid scaffold. The stem region of HA on these designed chimeric nanoparticles is immunogenic and the nanoparticles are biochemically robust in that heat exposure did not destroy the particles and immunogenicity was retained. Furthermore, mice vaccinated with H1-nanoparticles were protected from lethal challenge with H1N1 influenza virus. By using a nanoparticle library approach with this helix-A nanoparticle design, we show that this vaccine nanoparticle construct design could be applicable to different influenza HA subtypes. Importantly, antibodies elicited by H1, H5, and H7 nanoparticles demonstrated homosubtypic and heterosubtypic cross-reactivity binding to different HA subtypes. Also, helix-A nanoparticle immunizations were used to isolate mouse monoclonal antibodies that demonstrated heterosubtypic cross-reactivity and provided protection to mice from viral challenge via passive-transfer. This tandem helix-A nanoparticle construct represents a novel design to display several hundred copies of non-trimeric conserved HA stem epitopes on vaccine nanoparticles. This design concept provides a new approach to universal influenza vaccine development strategies and opens opportunities for the development of nanoparticles with broad coverage over many antigenically diverse influenza HA subtypes.

A Critical Role for ERO1α in Arterial Thrombosis and Ischemic Stroke.

BACKGROUND: Platelet adhesion and aggregation play a crucial role in arterial thrombosis and ischemic stroke. Here, we identify platelet ERO1α (endoplasmic reticulum oxidoreductase 1α) as a novel regulator of Ca2+ signaling and a potential pharmacological target for treating thrombotic diseases. METHODS: Intravital microscopy, animal disease models, and a wide range of cell biological studies were utilized to demonstrate the pathophysiological role of ERO1α in arteriolar and arterial thrombosis and to prove the importance of platelet ERO1α in platelet activation and aggregation. Mass spectrometry, electron microscopy, and biochemical studies were used to investigate the molecular mechanism. We used novel blocking antibodies and small-molecule inhibitors to study whether ERO1α can be targeted to attenuate thrombotic conditions. RESULTS: Megakaryocyte-specific or global deletion of Ero1α in mice similarly reduced platelet thrombus formation in arteriolar and arterial thrombosis without affecting tail bleeding times and blood loss following vascular injury. We observed that platelet ERO1α localized exclusively in the dense tubular system and promoted Ca2+ mobilization, platelet activation, and aggregation. Platelet ERO1α directly interacted with STIM1 (stromal interaction molecule 1) and SERCA2 (sarco/endoplasmic reticulum Ca2+-ATPase 2) and regulated their functions. Such interactions were impaired in mutant STIM1-Cys49/56Ser and mutant SERCA2-Cys875/887Ser. We found that ERO1α modified an allosteric Cys49-Cys56 disulfide bond in STIM1 and a Cys875-Cys887 disulfide bond in SERCA2, contributing to Ca2+ store content and increasing cytosolic Ca2+ levels during platelet activation. Inhibition of Ero1α with small-molecule inhibitors but not blocking antibodies attenuated arteriolar and arterial thrombosis and reduced infarct volume following focal brain ischemia in mice. CONCLUSIONS: Our results suggest that ERO1α acts as a thiol oxidase for Ca2+ signaling molecules, STIM1 and SERCA2, and enhances cytosolic Ca2+ levels, promoting platelet activation and aggregation. Our study provides evidence that ERO1α may be a potential target to reduce thrombotic events.

Environmental health impacts and inequalities in green space and air pollution in six medium-sized European cities.

BACKGROUND: The GoGreenRoutes project aims to introduce co-created nature-based solutions (NBS) to enhance environmental quality in six medium-sized cities (Burgas, Lahti, Limerick, Tallinn, Umeå, and Versailles). We estimated the mortality and economic impacts attributed to suboptimal exposure to green space and air pollution, economic impacts, and the distribution thereof the adult population by socioeconomic status. METHODS: We retrieved data from publicly accessible databases on green space (NDVI and % Green Area), air pollution (NO2 and PM2.5) and population (≥20 years, n = 804,975) at a 250m × 250m grid-cell level, and mortality for each city for 2015. We compared baseline exposures at the grid-cell to World Health Organization's recommendations and guidelines. We applied a comparative risk assessment to estimate the mortality burden attributable to not achieving the recommendations and guidelines. We estimated attributable mortality distributions and the association with income levels. RESULTS: We found high variability in air pollution and green spaces levels. Around 60% of the population lacked green space and 90% were exposed to harmful air pollution. Overall, we estimated age-standardized mortality rates varying from 10 (Umeå) to 92 (Burgas) deaths per 100,000 persons attributable to low NDVI levels; 3 (Lahti) to 38 (Burgas) per 100,000 persons to lack of % Green Area; 1 (Umeå) to 88 (Tallinn) per 100,000 persons to exceedances of NO2 guidelines; and 1 (Umeå) to 206 (Burgas) per 100,000 persons to exceedances of PM2.5 guidelines. Lower income associated with higher or lower mortality impacts depending on whether deprived populations lived in the densely constructed, highly-trafficked city centre or greener, less polluted outskirts. CONCLUSIONS: We attributed a considerable mortality burden to lack of green spaces and higher air pollution, which was unevenly distributed across different social groups. NBS and health-promoting initiatives should consider socioeconomic aspects to regenerate urban areas while providing equally good environments.

Prehospital Hemorrhage Control and Treatment by Clinicians: A Joint Position Statement.

Exsanguination remains the leading cause of preventable death among victims of trauma. For adult and pediatric trauma patients in the prehospital phase of care, methods to control hemorrhage and hemostatic resuscitation are described in this joint consensus opinion by the American College of Surgeons Committee on Trauma, the American College of Emergency Physicians, and the National Association of EMS Physicians.

Overcoming a stubborn patent foramen ovale.

Transesophageal echocardiography (TEE) with agitated saline contrast ("bubble study") is the gold standard for detection of patent foramen ovale (PFO). Standard provocative maneuvers help facilitate right-to-left shunting necessary for diagnosing PFO but may be difficult to implement during TEE. Hypovolemia related to preprocedural fasting may challenge detection of PFO in TEE, and additional optimization measures such as fluid replenishment with passive leg raise (PLR) can enhance PFO detection. We present a 57-year-old male with history of cryptogenic stroke and stubborn PFO which during TEE bubble study responded only to ample fluid replenishment with PLR following a period of prolonged preprocedural fasting.

Plastic packaging waste in Europe: Addressing methodological challenges in recording and reporting.

A reliable comparison of European Union (EU) Member States' reporting of statistics on plastic packaging waste generation, recycling and recovery is necessary if there is to be a fair transition to a circular economy across the EU. It is a priority for there to be an improvement in the quality and validity of these statistics to assess each Member State's performance in relation to EU targets. This article explores the quality of national reporting based on the two main approaches which are used to calculate packaging waste generation, namely 'placed on the market' and 'waste analysis'. The findings outline how Member States apply a variety of approaches leading to different packaging waste statistics which makes reported data difficult to compare. Often, it is not clear what approach is applied in different counties. Factors such as freeriding, non-compliance and de minimis have represented the primary weaknesses in evaluating and reporting packaging waste statistics as producers have financial incentives for under-reporting. This article highlights the need to inform circular economy strategies by addressing the challenge of comparing data on packaging and plastic packaging waste generation across the EU.

Illicit Drug Use and Endoscopy: When Do We Say No?

BACKGROUND: Illicit drug use (IDU) is often encountered in patients undergoing elective ambulatory surgical procedures such as endoscopy. Given the variety of systemic effects of these drugs, sedation and anesthetics are believed to increase the risk of cardiopulmonary complications during procedures. Procedural cancelations are common, regardless of the drug type, recency of use, and total dosage consumed. There is a lack of institutional and society recommendations regarding the optimal approach to performing outpatient endoscopy on patients with IDU. AIM: To review the literature for current recommendations regarding the optimal management of outpatient elective endoscopic procedures in patients with IDU. Secondary aim is to provide guidance for clinicians who encounter IDU in endoscopic practice. METHODS: Systematic review of PubMed, CINAHL, Embase, and Google Scholar for articles presenting data on outcomes of elective procedures in patients using illicit drugs. RESULTS: There are no clinically relevant differences in periprocedural complications or mortality in cannabis users compared to non-users. Endoscopy in patients with remote cocaine use was also found to have similar outcomes to recent use. CONCLUSIONS: Canceling endoscopic procedures in patients with recent IDU without consideration of the type of drug, dosage, and chronicity may lead to unnecessary delays in care and increased patient morbidity. Healthcare systems would benefit from additional guidelines for evaluating the patient with recent illicit drug use for acute intoxication and consider proceeding with procedures in the non-toxic population.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Cryo-EM cools down swine fever.

African swine fever virus (ASFV) is among the most complex DNA viruses known. Outbreaks have killed millions of swine around the world, and there is currently no vaccine. Three recent papers report the cryo-EM structure of the complete ASFV virion, comprising a viral particle of multiple layers, and resolve the major outer-capsid protein p72 to higher resolution. Progress in these reports provides a further understanding of the structure-function relationships of large viruses and should aid in ASFV vaccine development.

Numerical investigation on the ingress of particulate matter from ambient air into the inlet of a building air handling unit.

The transportation of ambient particulate matter (PM) from outdoor air into the inlet of a mechanical building ventilation system is poorly understood. No studies have examined the effect commonly used commercial air handling unit (AHU) inlet designs have upon the migration of PM from the ambient environment into the building ventilation system, and implications of this on energy consumption and indoor air quality (IAQ). Through the numerical analysis of commercial AHU inlets, the differences in concentration of PM in ambient air and that within AHUs were determined, more commonly referred to as Aspiration Efficiency (AE %). A 20-50% difference in particle concentrations between ambient air and the in-AHU concentration was observed between forward and rear-facing AHUs relative to ambient wind direction and speed, and at the maximum ventilation flow rate. Furthermore, a decrease in the ventilation flow rates resulted in a significant reduction in PM concentrations entering the rear-facing AHU. Increasing the Stoke number led to lower AE as a continuous decrease was observed for both rear-facing inlets. The findings of this paper show that AHU inlet design has significant implications on IAQ and building energy consumption, and scope exists to design these inlets to impact both aspects positively.

COVID-19 Pandemic: The Role of EMS Physicians in a Community Response Effort.

The COVID-19 pandemic is a worldwide historical event that will continue to affect nearly every aspect of ordinary life, including affecting our economic, political, and healthcare eco-systems. An effective pandemic response demands a coordinated and integrated response across community healthcare stakeholders, including Public Health and Emergency Management Officials. EMS systems are in a unique position and perform an essential role on the frontlines of COVID-19, including facilitating coordination of response efforts to COVID-19 within their communities while supporting public health mitigation efforts to slow the spread of the SARS-CoV-2. EMS physicians serve their communities at a unique intersection as clinical leaders, population health experts, and advocates. This paper examines and recommends crucial roles for EMS physician leaders as communities work together in pandemic response.

Ketamine Use in Prehospital and Hospital Treatment of the Acute Trauma Patient: A Joint Position Statement.

The American College of Surgeons Committee on Trauma (ACS-COT), the American College of Emergency Physicians (ACEP), the National Association of State EMS Officials (NASEMSO), the National Association of EMS Physicians (NAEMSP) and the National Association of EMTs (NAEMT) have previously offered varied guidance on the use of ketamine in trauma patients. The following consensus statement represents the collective positions of the ACS-COT, ACEP, NASEMSO, NAEMSP and NAEMT. This updated uniform guidance is intended for use by emergency medical services (EMS) personnel, EMS medical directors, emergency physicians, trauma surgeons, nurses and pharmacists in their treatment of the trauma patient in both the prehospital and hospital setting.

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis.

Rationale: In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems.Objectives: To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection.Methods: Sphingolipids were measured using mass spectrometry in fully differentiated cultures of primary human airway epithelial cells and cocultures with Pseudomonas aeruginosa. In situ activity assays, Western blotting, and quantitative PCR were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models.Measurements and Main Results: Ceramide is increased in cystic fibrosis airway epithelium owing to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to P. aeruginosa by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in cystic fibrosis epithelia and activates NF-κB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection.Conclusions: Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration.

Vitamin D supplements: The pharmacists' perspective.

OBJECTIVE: The purpose of this narrative review was to provide guidance for pharmacists concerning vitamin D supplementation. METHODS: Relevant studies were identified in a search of MEDLINE/PubMed, EBSCOhost, and Google Scholar from January 1966 to September 2020 using the search terms vitamin D, vitamin D2, vitamin D3, calcitriol, and vitamin D deficiency. Abstracts were reviewed for relevance and, if relevant, full-text articles were retrieved and reviewed. References were checked, and citation searches using identified studies were conducted. The literature search included English-language studies involving administration of vitamin D monotherapy compared with placebo. RESULTS: Serum 25-hydroxyvitamin D levels of less than 12 ng/mL indicate a vitamin D deficiency. The Institute of Medicine recommends a daily intake of 600 IU of vitamin D in individuals aged up to 70 years and 800 IU in those aged above 70 years. Vitamin D is labeled for rickets, osetomalacia, hypophosphatemia (familial or secondary), renal osteodystrophy, and corticosteroid-induced osteoporosis. When used for these indications, vitamin D should be prescribed with appropriate monitoring by a qualified health care practitioner. There is evidence for vitamin D supplementation in individuals aged 75 years or older and in those with problems associated with mobility, gait, or balance. There is insufficient evidence to support vitamin D supplementation in the prevention of cardiovascular disease, cancer, asthma, chronic obstructive pulmonary disease exacerbations, new-onset type 2 diabetes, infectious lung diseases, cognitive dysfunction, Alzheimer disease, and depression, or in prenatal use. CONCLUSION: Pharmacists can provide evidence-based recommendations concerning the indications, dosing, monitoring, and adverse effects of vitamin D supplements.

Why are they not accessing it? User barriers to clinical information access.

The Medical Library Association's InSight Initiative provides an open and collaborative environment for library and industry partners to discuss vexing problems and find solutions to better serve their users. The initiative's fifth summit, continuing work from the previous summit, focused on understanding how users discover and access information in the clinical environment. During the summit, participants were divided into working groups and encouraged to create a tangible product as a result of their discussions. At the end of the summit, participants established a framework for understanding users' pain points, discussed possible solutions to those points, and received feedback on their work from an End User Advisory Board comprising physicians, clinical researchers, and clinical faculty in biomedicine. In addition to the pain point framework, participants are developing MLA InSight Initiative Learning content with modules to educate librarians and publishers about critical aspects of user behavior. The 2020 Insight Initiative Fall Forum will serve as a virtual home for constructive dialogue between health sciences librarians and publishers on improving discovery and access to information.

Aligning efficiency benchmarking with sustainable outcomes in the United Kingdom water sector.

The provision of fundamental services by water and sewage companies (WaSCs) requires substantial energy and material inputs. A sustainability assessment of these companies requires a holistic evaluation of both performance and efficiency. The Hicks-Moorsteen productivity index was applied to 12 WaSCs in the United Kingdom (UK) over a 6-year period to benchmark their sustainability, based on eight approaches using different input and output variables for efficiency assessment. The choice of variables had a major influence on the ranking and perceived operational efficiency among WaSCs. Capital expenditure (utilised as part of total expenditure) for example, is an important input for tracking company operations however, potential associated efficiency benefits can lag investment, leading to apparent poor short-term performance following capital expenditure. Furthermore, water supplied and wastewater treated was deemed an unconstructive output from a sustainability perspective since it contradicts efforts to improve sustainability through reduced leakage and consumption per capita. Customer satisfaction and water quality measures are potential suitable alternatives. Despite these limitations, total expenditure and water supplied and wastewater treated were used alongside customer satisfaction and self-generated renewable energy for a holistic sustainability assessment within a small sample. They indicated the UK water sector has improved in productivity by 1.8% on average for 2014-18 and still had room for improvement, as a technical decline was evident for both the best and worst performers. Collectively the sample's production frontier was unchanged but on average companies moved 2.1% closer to it, and further decomposition of productivity revealed this was due to improvements in economies of scale and scope. Careful selection of appropriate input and output variables for efficiency benchmarking across water companies is critical to align with sustainability objectives and to target future investment and regulation within the water sector.

Perceptions of legal legitimacy in veterans treatment courts: A test of a modified version of procedural justice theory.

OBJECTIVE: Perceptions of the legitimacy of a society's legal system help explain individual responses to courts and legal actors. Normative considerations such as fair and respectful treatment as well as social identification have demonstrated the ability to enhance perceived legal legitimacy and future cooperation. Veterans treatment courts (VTCs) are a rapidly disseminating and understudied intervention. Their targeting of a socially esteemed group presents an interesting venue to explore normative theories of justice. The present study tested a modified version of Tyler's theory of procedural justice in this setting. HYPOTHESES: We hypothesized that procedural justice, social bonds, and receipt of gratitude for military service would be positively associated with veteran identity and legal legitimacy. We further hypothesized that participants' identification as veterans would mediate the relationships between the three independent variables and legitimacy. METHOD: A cross-sectional survey design was used with a convenience sample (N = 191) of participants in two VTCs. Analyses controlled for race, ethnicity, recidivism risk, and combat exposure. RESULTS: Perceptions of procedural justice, social bonds, and receipt of gratitude were positively associated with veteran identity and perceptions of legal legitimacy. Further, veteran identity was found to be a significant mediator between the first three constructs and legal legitimacy. CONCLUSIONS: The results support the importance of procedural justice in explaining perceptions of legal legitimacy in a novel context that is rapidly proliferating and understudied and has unique social identity considerations. The addition of gratitude and veteran identity to Tyler's model raises implications for VTC practice and further inquiry. (PsycInfo Database Record (c) 2021 APA, all rights reserved).