Broad Epitope Coverage of Therapeutic Multi-Antibody Combinations Targeting SARS-CoV-2 Boosts In Vivo Protection and Neutralization Potency to Corner an Immune-Evading Virus.

Therapeutic antibodies (Abs) which act on a broader range of epitopes may provide more durable protection against the genetic drift of a target, typical of viruses or tumors. When these Abs exist concurrently on the targeted antigen, several mechanisms of action (MoAs) can be engaged, boosting therapeutic potency. This study selected combinations of four and five Abs with non- or partially overlapping epitopes to the SARS-CoV-2 spike glycoprotein, on or outside the crucial receptor binding domain (RBD), to offer resilience to emerging variants and trigger multiple MoAs. The combinations were derived from a pool of unique-sequence scFv Ab fragments retrieved from two SARS-CoV-2-naïve human phage display libraries. Following recombinant expression to full-length human IgG1 candidates, a biolayer interferometric analysis mapped epitopes to bins and confirmed that up to four Abs from across the bins can exist simultaneously on the spike glycoprotein trimer. Not all the bins of Abs interfered with the spike protein binding to angiotensin converting enzyme 2 (ACE2) in competitive binding assays, nor neutralized the pseudovirus or authentic virus in vitro, but when combined in vivo, their inclusion resulted in a much stronger viral clearance in the lungs of intranasally challenged hamsters, compared to that of those treated with mono ACE2 blockers. In addition, the Ab mixtures activated in vitro reporter cells expressing Fc-gamma receptors (FcγRs) involved in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). The best four-Ab combination neutralized seventeen variants of concern from Wuhan-Hu1 to Omicron BA.4/BA.5 in vitro.

Impact of Standardized Multidisciplinary Critical Care Training on Confidence with Critical Illness and Attitudes Towards Interprofessional Education and Multidisciplinary Care.

INTRODUCTION: The Fundamental Critical Care Support Course (FCCS) is a standardized multidisciplinary program designed to educate participants on the basics of identification and management of patients with critical illness. Our objective was to evaluate the effect of FCCS participation on confidence in the assessment and management of critically ill patients and attitudes towards multidisciplinary education and interprofessional care in a multidisciplinary group of participants. METHODS: Participants enrolled in the FCCS course from May 2018 to November 2019 were solicited to participate in a series of surveys evaluating their course experience and confidence in critical care. Attitudes towards multidisciplinary education and interprofessional care were evaluated using the Student Perceptions of Interprofessional Clinical Education-Revised Instrument version 2 (SPICE-R2) tool. A prospective pre- and post-design with a self-report survey including retrospective pre-training assessment and a 3-month follow-up was conducted. Statistical analysis was performed using descriptive statics and non-parametric methods. RESULTS: 321 (97.9%) of the course participants enrolled in the study and completed the confidence survey and SPICE-R2 tool pre-course. Nurses (113, 35.4%) and physicians (110, 34.4%) made up the largest groups of participants, although physician assistants and paramedics were also well represented. Confidence in recognition and management of critical illness significantly improved across all studied domains after course completion, with the mean total confidence score improving from 32.96 pre-course to 41.10 post-course, P < 0.001. Attitudes towards multidisciplinary education and interprofessional care also improved (mean score 41.37 pre-course vs 42.71 post-course, P < 0.001), although pre-course numbers were higher than expected which limited the significance to only certain domains. DISCUSSION: In a multidisciplinary group, completion of FCCS training led to increased confidence in all aspects of critical illness measured. A modest increase in attitudes regarding multidisciplinary education and interprofessional care was also demonstrated. Further study is needed to assess whether this increased confidence translates to improvements in patient care and outcomes.

Studying moral distress (MD) and moral injury (MI) among inpatient and outpatient healthcare professionals during the COVID-19 pandemic.

BACKGROUND: COVID-19 increased moral distress (MD) and moral injury (MI) among healthcare professionals (HCPs). MD and MI were studied among inpatient and outpatient HCPs during March 2022. OBJECTIVES: We sought to examine (1) the relationship between MD and MI; (2) the relationship between MD/MI and pandemic-related burnout and resilience; and (3) the degree to which HCPs experienced pandemic-related MD and MI based on their background. METHODS: A survey was conducted to measure MD, MI, burnout, resilience, and intent to leave healthcare at 2 academic medical centers during a 4-week period. A convenience sample of 184 participants (physicians, nurses, residents, respiratory therapists, advanced practice providers) completed the survey. In this mixed-methods approach, researchers analyzed both quantitative and qualitative survey data and triangulated the findings. RESULTS: There was a moderate association between MD and MI (r = .47, P < .001). Regression results indicated that burnout was significantly associated with both MD and MI (P = .02 and P < .001, respectively), while intent to leave was associated only with MD (P < .001). Qualitative results yielded 8 sources of MD and MI: workload, distrust, lack of teamwork/collaboration, loss of connection, lack of leadership, futile care, outside stressors, and vulnerability. CONCLUSIONS: While interrelated conceptually, MD and MI should be viewed as distinct constructs. HCPs were significantly impacted by the COVID-19 pandemic, with MD and MI being experienced by all HCP categories. Understanding the sources of MD and MI among HCPs could help to improve well-being and work satisfaction.

The two faces of intentional self-inflicted injury: High in-hospital mortality, low postdischarge mortality, but high readmission rates.

BACKGROUND: Intentional self-inflicted injuries present unique challenges in treatment and prevention. We hypothesized intentional self-inflicted injuries would have higher in-hospital and postdischarge mortality than nonintentional self-inflicted injuries trauma. METHODS: Adult patients evaluated 2008 to 2012 were identified in our trauma registry and matched with mortality data from the National Death Index. Intentional self-inflicted injuries were identified using E-Codes. Readmissions were identified and analyzed. Intentional self-inflicted injuries patients who died in-hospital were compared with those surviving to discharge. Univariate analysis was performed using nonparametric tests. Kaplan-Meier curves were plotted to compare mortality ≤5 years postdischarge between intentional self-inflicted injuries and non-intentional self-inflicted injuries patients. RESULTS: In the study, 8,716 patient records were evaluated with 245 (2.8%) classified as intentional self-inflicted injuries. Eighteen (7.8%) patients with intentional self-inflicted injuries had multiple admissions, compared with 352 (4.4%) patients with nonintentional self-inflicted injuries with readmissions (P = .0210). In-hospital mortality was higher for intentional self-inflicted injuries compared with patients with non-intentional self-inflicted injuries (18.7% vs 4.9%, P < .0001). Survival analysis demonstrated that patients with intentional self-inflicted injuries had significantly lower postdischarge mortality at multiple time points. CONCLUSION: Patients with intentional self-inflicted injuries trauma have high in-hospital mortality, but low postdischarge mortality. We attribute this to high lethality mechanisms but appropriate psychiatric treatment and rehabilitation. However, the high intentional self-inflicted injuries readmission rate indicates further study of intentional self-inflicted injuries follow-up is warranted. Better prevention strategies are needed to identify and intervene in patients at-risk for intentional self-inflicted injuries.

The impact of perception and knowledge on the treatment and prevention of intestinal worms in the Manikganj district of Bangladesh.

Soil transmitted helminths (STHs) affect more than one billion of the world's population and are very prevalent in regions with high poverty rates and poor sanitation. Efforts to achieve Millennium Development Goals, such as combating diseases and increasing the number of people with access to safe drinking water and proper sanitation facilities, will directly help in eliminating STHs. The Plains regions of Bangladesh has one of the highest prevalence rates of STHs, and the efforts made by the World Health Organization might not be enough to eradicate these diseases in this region before the 2015 goal. This survey was conducted in the Manikganj district of Central Bangladesh to evaluate local awareness about the transmission and prevention of STHs. The results from this survey show that although a large percentage of the respondents were knowledgeable about the spread and impact of intestinal worms, the majority of individuals still do not take the necessary steps to prevent infection. Our findings demonstrate the complexity of controlling and eliminating STHs and show that concluding efforts should incorporate additional measures for vaccine development as well as improved educational efforts that are sensitive to the region's traditions and cultures.

Identification of a secreted fatty acid and retinol-binding protein (Hp-FAR-1) from Heligmosomoides polygyrus.

Hp-FAR-1 is a major, secreted antigen of the parasitic nematode Heligmosomoides polygyrus, a laboratory mouse model frequently used to study the cellular mechanisms of chronic helminth infections. The DNA encoding Hp-FAR-1 was recovered by screening a fourth larval (L4) H. polygyrus cDNA expression library using antibodies raised against L4 stage excretory/secretory (E/S) proteins. Predictions of secondary structure based on the Hp-FAR-1 amino acid sequence indicated that an alpha-helix predominates in Hp-FAR-1, possibly with some coiled-coil conformation, with no beta-structure. Fluorescence-based ligand binding analysis confirmed that the recombinant Hp-FAR-1 (rHp-FAR-1) binds the fluorescent fatty acid analog 11-((5-[dimethylaminoaphthalene-1-sulfonyl)amino)undecanoic acid (DAUDA), and by competition oleic acid. RT-PCR amplification of the hp-far-1 gene indicated that the gene is transcribed in all parasitic stages of the organism's life cycle. The presence of a secreted FAR protein in the well-defined laboratory model of H. polygyrus provides an excellent model for the further study and analysis of the in vivo role of secreted FAR proteins in parasitism, and supports the mounting evidence that secreted FAR proteins play a major role in nematode parasitism.