Durable lymph-node expansion is associated with the efficacy of therapeutic vaccination.

Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes.

Modulating Adjuvant Release Kinetics from Scaffold Vaccines to Tune Adaptive Immune Responses.

Increasing the potency, quality and durability of vaccines represents a major public health challenge. A critical parameter that shapes vaccine immunity is the spatiotemporal context in which immune cells interact with antigen and adjuvant. While various material-based strategies have demonstrated that extended antigen release enhances both cellular and humoral immunity, the effect of adjuvant kinetics on vaccine-mediated immunity remains incompletely understood. Here, we use a previously characterized mesoporous silica rod (MPS) biomaterial vaccine to develop a facile, electrostatics-driven approach to tune in vivo kinetics of the TLR9 agonist CpG. We demonstrate that rapid release of CpG from MPS vaccines, mediated by alterations in MPS chemistry that tune surface charge, generates potent cytotoxic T cell responses and robust, Th1-skewed IgG2a/c antibody titers. Immunophenotyping of lymphoid organs after MPS vaccination with slow or fast CpG release kinetics suggests that differential engagement of migratory dendritic cells and natural killer cells may contribute to the more potent responses observed with rapid adjuvant release. Taken together, these findings suggest that vaccine approaches that pair sustained release of antigen with rapid release of adjuvants with similar characteristics to CpG may drive particularly potent Th1 responses. This article is protected by copyright. All rights reserved.

A behaviorally anchored assessment tool for bedside teaching in the emergency department.

Evaluating a resident's development as a bedside educator in the emergency department (ED) is challenging. Teaching consults, where trainees are observed and assessed in their teaching skills, have been used to improve bedside teaching. Within emergency medicine, there are a few assessment tools to evaluate a clinician's bedside teaching, with the majority focusing on faculty. A user-friendly assessment tool adapted to the ED that emphasizes behaviorally anchored, milestone-based evaluations for residents has yet to be developed. We sought to develop such an assessment tool for evaluating residents' bedside teaching in the ED. Using a nominal-group consensus-building technique, we derived the bedside teaching assessment tool. The consensus-building panel was composed of clinician-educators with extensive experience in resident education. The teaching consult process consisted of the consultant, a faculty member with a focus in medical education, directly observing a resident's bedside teaching throughout their shift while filling out the evaluation form based on observed behaviors. A total of 35 consults were provided to 30 individual residents. The mean (±SD) scores for the 35 consults for the learning climate, content teaching, supervision, feedback and evaluation, and self-assessment were 3.84 (±0.75), 3.56 (±0.58), 3.70 (±0.60), 3.64 (±0.77), and 3.92 (±0.45), respectively. The median scores for the above domains were 4, 3.5, 4, 3.5, and 4, respectively. The tool has acceptable internal consistency with a Cronbach's alpha of 0.723 (95% CI 0.469-0.839). Eleven of 13 (85%) residents who provided feedback agreed or strongly agreed that the quantitative feedback provided by the assessment tool was useful. Twelve of 13 (92%) residents found the consultation process to be unobtrusive to their clinical performance. In conclusion, this novel behaviorally anchored assessment tool for bedside teaching can serve as a useful adjunct to a teaching consult and provide useful feedback for the development of residents' bedside teaching skills.

Rapid Ultratough Topological Tissue Adhesives.

Tissue adhesives capable of achieving strong and tough adhesion in permeable wet environments are useful in many biomedical applications. However, adhesion generated through covalent bond formation directly with the functional groups of tissues (i.e., COOH and NH2  groups in collagen), or using non-covalent interactions can both be limited by weak, unstable, or slow adhesion. Here, it is shown that by combining pH-responsive bridging chitosan polymer chains and a tough hydrogel dissipative matrix one can achieve unprecedented ultratough adhesion to tissues (>2000 J m-2 ) in 5-10 min without covalent bond formation. The strong non-covalent adhesion is shown to be stable under physiologically relevant conditions and strongly influenced by chitosan molecular weight, molecular weight of polymers in the matrix, and pH. The adhesion mechanism relies primarily on the topological entanglement between the chitosan chains and the permeable adherends. To further expand the applicability of the adhesives, adhesion time can be decreased by dehydrating the hydrogel matrix to facilitate rapid chitosan interpenetration and entanglement (>1000 J m-2  in ≤1 min). The unprecedented adhesive properties presented in this study open opportunities for new strategies in the development of non-covalent tissue adhesives and numerous bioapplications.

A vaccine targeting resistant tumours by dual T cell plus NK cell attack.

Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.

Biomaterial vaccines capturing pathogen-associated molecular patterns protect against bacterial infections and septic shock.

Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.

A Modular Biomaterial Scaffold-Based Vaccine Elicits Durable Adaptive Immunity to Subunit SARS-CoV-2 Antigens.

The coronavirus disease 2019 (COVID-19) pandemic demonstrates the importance of generating safe and efficacious vaccines that can be rapidly deployed against emerging pathogens. Subunit vaccines are considered among the safest, but proteins used in these typically lack strong immunogenicity, leading to poor immune responses. Here, a biomaterial COVID-19 vaccine based on a mesoporous silica rods (MSRs) platform is described. MSRs loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF), the toll-like receptor 4 (TLR-4) agonist monophosphoryl lipid A (MPLA), and SARS-CoV-2 viral protein antigens slowly release their cargo and form subcutaneous scaffolds that locally recruit and activate antigen-presenting cells (APCs) for the generation of adaptive immunity. MSR-based vaccines generate robust and durable cellular and humoral responses against SARS-CoV-2 antigens, including the poorly immunogenic receptor binding domain (RBD) of the spike (S) protein. Persistent antibodies over the course of 8 months are found in all vaccine configurations tested and robust in vitro viral neutralization is observed both in a prime-boost and a single-dose regimen. These vaccines can be fully formulated ahead of time or stored lyophilized and reconstituted with an antigen mixture moments before injection, which can facilitate its rapid deployment against emerging SARS-CoV-2 variants or new pathogens. Together, the data show a promising COVID-19 vaccine candidate and a generally adaptable vaccine platform against infectious pathogens.

The one-pot synthesis of CuNi nanoparticles with a Ni-rich surface for the electrocatalytic methanol oxidation reaction.

The use of fuel cells is one of the most promising renewable energy strategies, but they still suffer from many limitations. The high mass enthalpy of hydrogen as a fuel comes at the cost of inconveniences and risks associated with storage, transportation and utilization, while the high performance of Pt catalysts in commercial fuel cells is limited by their high cost, low earth abundance, and poor stability as a result of CO intermediate poisoning. To circumvent these dilemmas, direct methanol fuel cells (DMFCs) were developed, using methanol as a fuel and Ni as the anode catalyst. Thanks to the condensed form of the fuel, DMFCs are considered as the most promising fuel-cell solution for portable electronic devices. Usually, other elements have to be introduced into Ni-based catalysts to modify the active sites to provide better alternatives to pristine Ni metal in terms of activity and stability. In this study, we provide a mild synthetic method for the preparation of CuNi alloy nanoparticles. The proper alloying ratio leads to the suitable modification of the electronic structure of Ni, which promotes the MOR catalytic reaction on the NiCu alloy. The NiCu alloy catalyst exhibits a mass current density of 1028 mA mgmetal-1 for the MOR at 1.55 V (vs. RHE), which is among the best values obtained from similarly prepared Ni-based catalysts.

Assessing the CT findings and clinical course of ED patients with first-time versus recurrent acute pancreatitis.

STUDY OBJECTIVES: The primary objective of this study was to compare Emergency Department patients with first-time versus recurrent acute pancreatitis. METHODS: This study was a retrospective chart review of patients with a diagnosis of acute pancreatitis who presented to a single academic urban emergency department from 2012 to 2016. Criteria for inclusion were clinical symptoms of pancreatitis, age greater than or equal to 18 years, ED diagnosis of acute pancreatitis, and an abdominal CT scan within 24 h of triage. Exclusion criteria were traumatic mechanism and pregnancy. Charts were reviewed by a minimum of two trained abstractors using structured data collection sheets and discrepancies were resolved by a third abstractor. Patients with first time acute pancreatitis versus recurrent acute pancreatitis were compared to determine differences in characteristics, management and disposition. RESULTS: 250 patients were included in the study. Of these, 165 patients had first-time acute pancreatitis and 85 patients had recurrent acute pancreatitis. Demographics, vital signs and initial lab values were the same in both groups. Patients with recurrent acute pancreatitis were more likely to have significant findings on CT (Modified CT Severity Index, 2.09 versus 1.43, p < 0.05), more likely to require IV opiates (96% versus 75%, p < 0.001) and less likely to need ICU admission (8% versus 19%, p = 0.03). CONCLUSION: ED patients with recurrent acute pancreatitis demonstrated more significant findings on CT compared to patients with first-time acute pancreatitis but were less likely to require ICU admission.

PdO/SnO2 heterostructure for low-temperature detection of CO with fast response and recovery.

In this paper, we developed a simple two-step route to prepare a PdO/SnO2 heterostructure with the diameter of the SnO2 and PdO nanoparticles at about 15 nm and 3 nm, respectively. In the evaluation temperature window between 80 °C and 340 °C, PdO/SnO2 shows the best response to 100 ppm of CO at 100 °C with fast response time (14 s) and recovery time (8 s). Furthermore, the PdO/SnO2 nanoparticles exhibit a low detection limit and good selectivity to CO against interfering gases as well as rarely-seen low-temperature stability and reversibility. Such enhanced gas sensing performance could be attributed to both the ultrafine structure of PdO and the synergy between PdO and SnO2. The results clearly indicate the application of PdO/SnO2 as a pratical low-temperature sensing material for CO.

Exploring the attitudes & practices of shared decision-making for CT scan use in emergency department patients with abdominal pain.

BACKGROUND: Shared decision-making (SDM) has been studied in the emergency department (ED) in relation to hospital admissions but not for CT scan utilization. CT scans are a common imaging modality with high accuracy that emit considerable ionizing radiation. This study has three aims: to measure provider and patient preference for SDM; to evaluate patient involvement in the decision to order a CT scan; and to determine the association between patient involvement and CT utilization. METHODS: In this prospective study, stable ED patients with abdominal pain with CT imaging as a likely diagnostic tool, were screened and consented. The Control Preferences Scale assessed patient and provider baseline decision-making preference. Using the OPTION-5 tool, providers were assessed in each encounter for the extent to which they engaged patients in discussions. The association between the Control Preferences Scale, the OPTION-5 score and ultimate CT utilization was evaluated. RESULTS: Twenty-nine encounters were observed. CT was considered in 70% (n = 20) of encounters and ordered in 55% (n = 16). 62% of patients and 59% of providers reported that they prefer "shared responsibility" when making treatment decisions. In >80% of encounters, provider's showed no or minimal effort when discussing whether to perform a CT scan. Provider or patient preference was not associated with patient involvement. Patient involvement was not associated with CT utilization. CONCLUSIONS: High rates of provider and patient preference to use SDM for treatment plans were reported but providers were rarely observed engaging patients with abdominal pain in the decision to order a CT scan.

Reducing mortality in near-hanging patients with a novel early management protocol.

BACKGROUND: Hanging is one of the most common causes of suicide world-wide, more prevalent in developing countries. There are no established protocols for early management of near-hanging patients who present to the emergency department (ED). The use of early intubation, strict blood pressure control and targeted temperature management has shown promise in small studies. OBJECTIVE: To detect changes in mortality and neurological deficits in near-hanging patients before and after implementation of a novel early management protocol in a tertiary care hospital in India. METHODS: Prospective cohort study conducted at a tertiary-care hospital in Tamil Nadu, India from August 2014-July 2016. For first year of study (pre-implementation), near-hanging patients were treated without a structured protocol. For second year of study (post-implementation), near-hanging patients were treated per a protocol including early intubation, strict blood pressure control and targeted temperature management. Primary outcomes included: (1) in-hospital mortality and (2) hospital discharge without neurological deficit. RESULTS: 65 patients were included (27 in the pre-implementation phase and 38 in the post-implementation phase.) At presentation, there was no difference between the two groups in mean heart rate, mean arterial pressure, mean oxygen saturation, Glasgow coma score, or mean respiratory rate. Protocol implementation decreased mortality (10/27 (37%) versus 2/38 (5%), P < 0.05) and increased the number of patients discharged without neurological deficit (10/27 (37%) versus 35/38 (92%), P < 0.05). CONCLUSIONS: This novel early management protocol reduced mortality and increased the number discharged without neurological deficit in near-hanging patients in a single tertiary care center in India.

Nasogastric decompression not associated with a reduction in surgery or bowel ischemia for acute small bowel obstruction.

OBJECTIVES: Small bowel obstructions (SBOs) occur 300,000 times annually leading to $1.3 billion in cost. Approximately 20% of patients require a laparotomy to manage the obstruction and either prevent or treat intestinal ischemia. Early management may play a role in reducing these complications. Nasogastric decompression is commonly used for early management. Our primary objective was to determine if NGD was associated with lower rates of surgery, bowel ischemia or length of stay. METHODS: We retrospectively enrolled 181 ED patients with SBO from 9/2013 to 9/2015 in order to determine if nasogastric decompression was associated with a reduction in rates of surgery, bowel ischemia or hospital length of stay. RESULTS: Our subject population was 46% female, median age of 60.27% of patients received surgery. Nasogastric decompression was used in 51% of patients. There was no association with a reduction in rates of surgery (p=0.20) or bowel resection (p=0.41) with patients receiving Nasogastric decompression, and no difference in baseline characteristics. Nasogastric decompression was associated with a two-day increase in hospital length of stay. Factors that were significantly associated with surgical exploration of SBO were: female (OR 2.32 (95% CI: 1.01-5.31)) and "definite SBO" on CT (OR 3.29 (95% CI: 1.18-9.20)). Abnormal vital signs, obstipation, and lab values were not predictors of surgery. CONCLUSION: Nasogastric decompression is not associated with a reduction in need for surgery or bowel resection, but is associated with a 2-day increase in median LOS. Women were more likely to receive surgery than men.