Immune Epitopes of SARS-CoV-2 Spike Protein and Considerations for Universal Vaccine Development.

Despite the success of global vaccination programs in slowing the spread of COVID-19, these efforts have been hindered by the emergence of new SARS-CoV-2 strains capable of evading prior immunity. The mutation and evolution of SARS-CoV-2 have created a demand for persistent efforts in vaccine development. SARS-CoV-2 Spike protein has been the primary target for COVID-19 vaccine development, but it is also the hotspot of mutations directly involved in host susceptibility and virus immune evasion. Our ability to predict emerging mutants and select conserved epitopes is critical for the development of a broadly neutralizing therapy or a universal vaccine. In this article, we review the general paradigm of immune responses to COVID-19 vaccines, highlighting the immunological epitopes of Spike protein that are likely associated with eliciting protective immunity resulting from vaccination in humans. Specifically, we analyze the structural and evolutionary characteristics of the SARS-CoV-2 Spike protein related to immune activation and function via the TLRs, B cells, and T cells. We aim to provide a comprehensive analysis of immune epitopes of Spike protein, thereby contributing to the development of new strategies for broad neutralization or universal vaccination.

Th2 and Th17-associated immunopathology following SARS-CoV-2 breakthrough infection in Spike-vaccinated ACE2-humanized mice.

Vaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN. Subsequently, we exposed them to increasing doses of SARS-CoV-2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+ T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19 and to enhance vaccine formulations for broad protection and maximum safety.

Safety and care of no fasting prior to catheterization laboratory procedures: a non-inferiority randomized control trial protocol (SCOFF trial).

Aims: Cardiac catheterization procedures are typically performed with local anaesthetic and proceduralist guided sedation. Various fasting regimens are routinely implemented prior to these procedures, noting the absence of prospective evidence, aiming to reduce aspiration risk. However, there are additional risks from fasting including patient discomfort, intravascular volume depletion, stimulus for neuro-cardiogenic syncope, glycaemic outcomes, and unnecessary fasting for delayed/cancelled procedures. Methods and results: This is an investigator-initiated, multicentre, randomized trial with a prospective, open-label, blinded endpoint (PROBE) assessment based in New South Wales, Australia. Patients will be randomized 1:1 to fasting (6 h solid food and 2 h clear liquids) or to no fasting requirements. The primary outcome will be a composite of hypotension, hyperglycaemia, hypoglycaemia, and aspiration pneumonia. Secondary outcomes will include patient satisfaction, contrast-induced nephropathy, new intensive care admission, new non-invasive or invasive ventilation requirement post procedure, and 30-day mortality and readmission. Conclusions: This is a pragmatic and clinically relevant randomised trial designed to compare fasting verse no fasting prior to cardiac catheterisation procedures. Routine fasting may not reduce peri-procedural adverse events in this setting.

Immune Epitopes of SARS-CoV-2 Spike Protein and Considerations for Universal Vaccine Development.

Despite the success of global vaccination programs in slowing the spread of COVID-19, these efforts have been hindered by the emergence of new SARS-CoV-2 strains capable of evading prior immunity. The mutation and evolution of SARS-CoV-2 have created a demand for persistent efforts in vaccine development. SARS-CoV-2 Spike protein has been the primary target for COVID-19 vaccine development, but it is also the hotspot of mutations directly involved in host susceptibility and immune evasion. Our ability to predict emerging mutants and select conserved epitopes is critical for the development of a broadly neutralizing therapy or a universal vaccine. In this article, we review the general paradigm of immune responses to COVID-19 vaccines, highlighting the immunological epitopes of Spike protein that are likely associated with eliciting protective immunity resulting from vaccination. Specifically, we analyze the structural and evolutionary characteristics of the SARS-CoV-2 Spike protein related to immune activation and function via the toll-like receptors (TLRs), B cells, and T cells. We aim to provide a comprehensive analysis of immune epitopes of Spike protein, thereby contributing to the development of new strategies for broad neutralization or universal vaccination.

Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice.

Vaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN. Subsequently, we exposed them to increasing doses of SARS-CoV-2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+ T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19 and to enhance vaccine formulations for broad protection and maximum safety.

Correction: Magazine et al. Mutations and Evolution of the SARS-CoV-2 Spike Protein. Viruses 2022, 14, 640.

In the original publication [...].

Computed tomography Coronary angiography in rural referral hospitals: A single-Centre experience.

OBJECTIVE: To describe the first 9 months of a newly established computed tomography coronary angiogram (CTCA) over the period of the COVID-19 pandemic. METHODS: A retrospective analysis of the first 9 months of a CT-CA program. DESIGN: Data were collected for the period of June 2020 to March 2021. Information reviewed included demographics, risk factors, renal function, technical factors and outcomes including Calcium Score and Coronary Artery Disease Reporting and Data System (CAD-RADS). SETTING: A single Rural Referral Hospital in regional New South Wales. PARTICIPANTS: Ninety-six CTCAs were reviewed. Ages ranged from 29 to 81 years. 37 (39%) male, 59 (61%) female. 15 (15.6%) identified as Aboriginal and/or Torres Strait Islander. MAIN OBJECTIVE OUTCOMES: CTCA is a viable alternative to invasive coronary angiogram in appropriate populations for regional areas. RESULTS: Eighty-eight (91.6%) were considered technically satisfactory. Mean heart rate was 57 beats per minute with a range of 108. Cardiovascular risk factors included hypertension, dyslipidemia, smoking status, family history and diabetes mellitus. Of patients with CAD-RADS scores 3 or 4 who underwent subsequent invasive coronary angiogram (ICA), 80% were determined to have operator-defined significant stenosis. Significant cardiac and non-cardiac findings were extensive. CONCLUSIONS: CTCA is a safe and efficacious imaging modality for low- to moderate-risk chest pain patients. There was acceptable diagnostic accuracy and the investigation was safe.

Development of the Illinois Surgical Quality Improvement Collaborative (ISQIC): Implementing 21 Components to Catalyze Statewide Improvement in Surgical Care.

INTRODUCTION: In 2014, 56 Illinois hospitals came together to form a unique learning collaborative, the Illinois Surgical Quality Improvement Collaborative (ISQIC). Our objectives are to provide an overview of the first three years of ISQIC focused on (1) how the collaborative was formed and funded, (2) the 21 strategies implemented to support quality improvement (QI), (3) collaborative sustainment, and (4) how the collaborative acts as a platform for innovative QI research. METHODS: ISQIC includes 21 components to facilitate QI that target the hospital, the surgical QI team, and the peri-operative microsystem. The components were developed from available evidence, a detailed needs assessment of the hospitals, reviewing experiences from prior surgical and non-surgical QI Collaboratives, and interviews with QI experts. The components comprise 5 domains: guided implementation (e.g., mentors, coaches, statewide QI projects), education (e.g., process improvement (PI) curriculum), hospital- and surgeon-level comparative performance reports (e.g., process, outcomes, costs), networking (e.g., forums to share QI experiences and best practices), and funding (e.g., for the overall program, pilot grants, and bonus payments for improvement). RESULTS: Through implementation of the 21 novel ISQIC components, hospitals were equipped to use their data to successfully implement QI initiatives and improve care. Formal (QI/PI) training, mentoring, and coaching were undertaken by the hospitals as they worked to implement solutions. Hospitals received funding for the program and were able to work together on statewide quality initiatives. Lessons learned at one hospital were shared with all participating hospitals through conferences, webinars, and toolkits to facilitate learning from each other with a common goal of making care better and safer for the surgical patient in Illinois. Over the first three years, surgical outcomes improved in Illinois. DISCUSSION: The first three years of ISQIC improved care for surgical patients across Illinois and allowed hospitals to see the value of participating in a surgical QI learning collaborative without having to make the initial financial investment themselves. Given the strong support and buy-in from the hospitals, ISQIC has continued beyond the initial three years and continues to support QI across Illinois hospitals.

Determining the optimal radiation-surgery interval (RSI) for oncologic proctectomy following radiotherapy for rectal adenocarcinoma.

Preoperative radiotherapy has improved outcomes in rectal cancer patients, however, the optimal interval between radiation and proctectomy is unknown. A review of contemporary literature suggests an 8-12 week interval between radiation and surgery likely improves tumor response rates for rectal cancer patients undergoing proctectomy, which may convey modest improvements in long-term oncologic outcomes. Prolonged radiation-surgery intervals may expose surgeons to pelvic fibrosis, however, which may impact later-term proctectomies and compromise perioperative and oncologic outcomes.

Changes in Surgical Outcomes in a Statewide Quality Improvement Collaborative with Introduction of Simultaneous, Comprehensive Interventions.

BACKGROUND: Surgical quality improvement collaboratives (QICs) aim to improve patient outcomes through coaching, benchmarked data reporting, and other activities. Although other regional QICs have formed organically over time, it is unknown whether a comprehensive quality improvement program implemented simultaneously across hospitals at the formation of a QIC would improve patient outcomes. STUDY DESIGN: Patients undergoing surgery at 48 hospitals in the Illinois Surgical Quality Improvement Collaborative (ISQIC) were included. Risk-adjusted rates of postoperative morbidity and mortality were compared from baseline to year 3. Difference-in-differences analyses compared ISQIC hospitals with hospitals in the NSQIP Participant Use File (PUF), which served as a control. RESULTS: There were 180,582 patients who underwent surgery at ISQIC-participating hospitals. Inpatient procedures comprised 100,219 (55.5%) cases. By year 3, risk-adjusted rates of death or serious morbidity decreased in both ISQIC (relative reduction 25.0%, p < 0.001) and PUF hospitals (7.8%, p < 0.001). Adjusted difference-in-differences analysis revealed that ISQIC participation was associated with a significantly greater reduction in death or serious morbidity (odds ratio 0.94, 95% CI 0.90 to 0.99, p = 0.01) compared with PUF hospitals. Relative reductions in risk-adjusted rates of other outcomes were also seen in both ISQIC and PUF hospitals (morbidity 22.4% vs 6.4%; venous thromboembolism 20.0% vs 5.0%; superficial surgical site infection 27.3% vs 7.7%, all p < 0.05), although these difference-in-differences did not reach statistical significance. CONCLUSIONS: Although complication rates decreased at both ISQIC and PUF hospitals, participation in ISQIC was associated with a significantly greater improvement in death or serious morbidity. These results underscore the potential of QICs to improve patient outcomes.

Mind The Gap, Aboriginal and Torres Strait Islander Cardiovascular Health: A Narrative Review.

Australia's First Nations Peoples, Aboriginal and Torres Strait Islanders, have reduced life expectancy compared to the wider community. Cardiovascular diseases, mainly driven by ischaemic heart disease, are the leading contributors to this disparity. Despite over a third of First Nations Peoples living in New South Wales, the bulk of the peer-reviewed literature is from Central Australia and Far North Queensland. Regardless of the site of publication, First Nations Peoples are significantly younger at disease onset and have higher rates of comorbidities, in turn driving adverse health events. On top of this, very few First Nations Peoples specific cardiovascular interventions or programs have been shown to improve outcomes. The traditional biomedical model of care is less efficacious and non-traditional models of communication such as clinical yarning may benefit both clinicians and patients. The key purpose of this review is to highlight the deficiencies of our knowledge of cardiovascular burden of disease for First Nations Peoples; and to serve as a catalyst for more dedicated research. We need to have relationships with communities and concentrate on community improvement and partnerships. By involving First Nations Peoples researchers in collaboration with local communities in all levels of health care design and intervention will improve outcomes.

Remote monitoring in patients with heart failure with cardiac implantable electronic devices: a systematic review and meta-analysis.

BACKGROUND: Remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) is now the standard of care, but whether the demonstrated benefits of RM translate into improvements in heart failure (HF) management is controversial. This systematic review addresses the role of RM in patients with HF with a CIED. METHODS AND RESULTS: A systematic search of the literature for randomised clinical trials in patients with HF and a CIED assessing efficacy/effectiveness of RM was performed using MEDLINE, PubMed and Embase. Meta-analysis was performed on the effects of RM of CIEDs in patients with HF on mortality and readmissions. Effects on implantable cardiac defibrillator (ICD) therapy, healthcare costs and clinic presentations were also assessed.607 articles were identified and refined to 10 studies with a total of 6579 patients. Implementation of RM was not uniform with substantial variation in methodology across the studies. There was no reduction in mortality or hospital readmission rates, while ICD therapy findings were inconsistent. There was a reduction in patient-associated healthcare costs and reduction in healthcare presentations. CONCLUSION: RM for patients with CIEDs and HF was not uniformly performed. As currently implemented, RM does not provide a benefit on overall mortality or the key metric of HF readmission. It does provide a reduction in healthcare costs and healthcare presentations. PROSPERO REGISTRATION NUMBER: CRD42019129270.

The Prevalence of Iron Deficiency in Atrial Fibrillation: Low Hanging Fruit?

Background and Objectives: Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide. The relationship between AF and iron deficiency is poorly understood. Materials and Methods: We conducted an observational study investigating the prevalence of iron deficiency in those with AF. Iron deficiency was defined by the American College of Cardiology (ACC) criteria for iron deficiency in heart failure. Results: Of 134 eligible subjects, 81 (60.4%) met the ACC definition of iron deficiency in heart failure. Those who were iron deficient were more likely to be female (OR 1.876, p = 0.005), have a history of diabetes mellitus (OR 3.085, p = 0.001) a history of stroke (OR 3.147, p = 0.016), and have higher CHA2DS2-VASc (p ≤ 0.0001) and Charlson Comorbidity Index scores (CCI) (p = 0.007). Conclusions: The prevalence of iron deficiency in those with AF appears high and warrants evaluation in a prospective study.

High-Efficiency Retroviral Transduction for Type 1 Regulatory T Cell Differentiation.

Type 1 regulatory T (Tr1) cells are an immunoregulatory CD4 + Foxp3- IL-10 high T cell subset with therapeutic potential for various inflammatory diseases. Retroviral (RV) transduction has been a valuable tool in defining the signaling pathways and transcription factors that regulate Tr1 differentiation and suppressive function. This protocol describes a method for RV transduction of naïve CD4 + T cells differentiating under Tr1 conditions, without the use of reagents such as polybrene or RetroNectin. A major advantage of this protocol over others is that it allows for the role of genes of interest on both differentiation and function of Tr1 cells to be interrogated. This is due to the high efficiency of RV transduction combined with the use of an IL10 GFP /Foxp3 RFP dual reporter mouse model, which enables successfully transduced Tr1 cells to be identified and sorted for functional assays. In addition, this protocol may be utilized for dual/multiple transduction approaches and transduction of other lymphocyte populations, such as CD8 + T cells.

PD-1 and ICOS counter-regulate tissue resident regulatory T cell development and IL-10 production during flu.

Regulatory T cells that express the transcription factor Foxp3 (Treg cells) are a highly heterogenous population of immunoregulatory cells critical for maintaining immune homeostasis and preventing immunopathology during infections. Tissue resident Treg (TR-Treg) cells are maintained within nonlymphoid tissues and have been shown to suppress proinflammatory tissue resident T cell responses and promote tissue repair. Human populations are repetitively exposed to influenza infections and lung tissue resident effector T cell responses are associated with flu-induced long-term pulmonary sequelae. The kinetics of TR-Treg cell development and molecular features of TR-Treg cells during repeated and/or long-term flu infections are unclear. Utilizing a Foxp3RFP/IL-10GFP dual reporter mouse model along with intravascular fluorescent in vivo labeling, we characterized the TR-Treg cell responses to repetitive heterosubtypic influenza infections. We found lung tissue resident Treg cells accumulated and expressed high levels of co-inhibitory and co-stimulatory receptors post primary and secondary infections. Blockade of PD-1 or ICOS signaling reveals that PD-1 and ICOS signaling pathways counter-regulate TR-Treg cell expansion and IL-10 production, during secondary influenza infection. Furthermore, the virus-specific TR-Treg cell response displayed distinct kinetics, when compared to conventional CD4+ tissue resident memory T cells, during secondary flu infection. Our results provide insight into the tissue resident Foxp3+ regulatory T cell response during repetitive flu infections, which may be applicable to other respiratory infectious diseases such as tuberculosis and COVID.

Comprehensive Evaluation of the Trends in Length of Stay and Post-discharge Complications After Colon Surgery in the USA.

INTRODUCTION: With widespread adoption of enhanced recovery protocols and a push toward shorter length of stay (LOS) following colon surgery, the extent to which complications have shifted to the post-discharge setting is unknown. The objectives of this study were to (1) characterize changes in LOS and post-discharge complications over time and (2) evaluate risk factors associated with post-discharge complications. METHODS: Patients who underwent elective colon resection from 2012 to 2018 were identified from the ACS NSQIP Colectomy-Targeted Dataset. Changes in LOS and the proportion of post-discharge complications were evaluated over time, and predictors of post-discharge complications were assessed using multivariable logistic regression. RESULTS: Of the 98,136 patients who underwent colon resection, median LOS decreased from 5 days in 2012 to 4 days in 2018. Overall, 30-day complication rate was 21.5%, which decreased during the study period (25.8 to 19.1%, p < 0.001). Of the 13 individual complications evaluated, 4 demonstrated a significant increase in the proportion of post-discharge events including overall SSI (55.8 to 63.3%, p = 0.002), superficial SSI (57.3 to 75.7%, p < 0.001), wound disruption (46.0 to 62.1%, p = 0.047), and UTI (41.5 to 62.7%, p < 0.001). Factors associated with the development of any post-discharge complication included female sex, ASA III/IV/V, dependent functional status, and higher BMI. Intraoperative factors included wound class, operation time, and approach. CONCLUSIONS: Although LOS and 30-day complications decreased over time, the proportion of events occurring post-discharge increased for several complications. We identified specific factors associated with post-discharge complications which emphasize the importance of a patient monitoring program to early identify and manage post-discharge complications.

Association between Patient and Hospital Characteristics and Adherence to a Surgical Site Infection Reduction Bundle in a Statewide Surgical Quality Improvement Collaborative.

BACKGROUND: Adherence to bundled interventions can reduce surgical site infection (SSI) rates; however, predictors of successful implementation are poorly characterized. We studied the association of patient and hospital characteristics with adherence to a colorectal SSI reduction bundle across a statewide surgical collaborative. STUDY DESIGN: A 16-component colorectal SSI reduction bundle was introduced in 2016 across a statewide quality improvement collaborative. Bundle adherence was measured for patients who underwent colorectal operations at participating institutions. Multivariable mixed-effects logistic regression models were constructed to estimate associations of patient and hospital factors with bundle adherence and quantify sources of variation. RESULTS: Among 2,403 patients at 35 hospitals, a median of 11 of 16 (68.8%, interquartile range 8 to 13) bundle elements were completed. The likelihood of completing 11 or more elements was increased for obese patients (56.8% vs 51.5%, odds ratio [OR] 1.39, 95% CI 1.05 to 1.86, p = 0.022) but reduced for underweight patients (31.0% vs 51.5%, OR 0.51, 95% CI 0.26 to 1.00, p = 0.048) compared with patients with a normal BMI. Lower adherence was noted for patients treated at safety net hospitals (n = 9 hospitals, 24.4% vs 54.4%, OR 0.08, 95% CI 0.01 to 0.44, p = 0.004). The largest proportion of adherence variation was attributable to hospital factors for six bundle elements, surgeon factors for no elements, and patient factors for nine elements. CONCLUSION: Adherence to an SSI reduction bundle is associated with patient BMI and hospital safety net status. Quality improvement groups should consider institutional traits for optimal implementation of SSI bundles. Safety net hospitals may require additional focus to overcome unique implementation barriers.

Severe Chest Pain in a Young Patient with Behçet's Disease: A Rare Manifestation.

A 32-year-old man with a background of Behçet's disease developed severe chest pain. The onset coincided with an episode of sacroiliitis. The patient was diagnosed with pericarditis and was successfully treated with a combination of anti-inflammatory agents. Pericarditis is a rare manifestation of Behçet's disease.

Mutations and Evolution of the SARS-CoV-2 Spike Protein.

The SARS-CoV-2 spike protein mediates target recognition, cellular entry, and ultimately the viral infection that leads to various levels of COVID-19 severities. Positive evolutionary selection of mutations within the spike protein has led to the genesis of new SARS-CoV-2 variants with greatly enhanced overall fitness. Given the trend of variants with increased fitness arising from spike protein alterations, it is critical that the scientific community understand the mechanisms by which these mutations alter viral functions. As of March 2022, five SARS-CoV-2 strains were labeled "variants of concern" by the World Health Organization: the Alpha, Beta, Gamma, Delta, and Omicron variants. This review summarizes the potential mechanisms by which the common mutations on the spike protein that occur within these strains enhance the overall fitness of their respective variants. In addressing these mutations within the context of the SARS-CoV-2 spike protein structure, spike/receptor binding interface, spike/antibody binding, and virus neutralization, we summarize the general paradigms that can be used to estimate the effects of future mutations along SARS-CoV-2 evolution.