Toward a pan-SARS-CoV-2 vaccine targeting conserved epitopes on spike and non-spike proteins for potent, broad and durable immune responses.

BACKGROUND: The SARS-CoV-2 non-Spike (S) structural protein targets on nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, are grossly overlooked in COVID vaccine development. The current Spike-only vaccines bear an intrinsic shortfall for promotion of a fuller T cell immunity. Vaccines designed to target conserved epitopes could elicit strong cellular immune responses that would synergize with B cell responses and lead to long-term vaccine success. We pursue a universal (pan-SARS-CoV-2) vaccine against Delta, Omicrons and ever-emergent new mutants. METHODS AND FINDINGS: We explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation (N = 1,478) of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). This UB-612 booster vaccination is safe and well tolerated without SAEs. CONCLUSIONS: By targeting conserved epitopes on viral S2, M and N proteins, UB-612 could provide potent, broad and long-lasting B-cell and T-cell memory immunity and offers the potential as a universal vaccine to fend off Omicrons and new VoCs without resorting to Omicron-specific immunogens. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04773067; ClinicalTrials.gov ID: NCT05293665; ClinicalTrials.gov ID: NCT05541861.

Recommendations to Enhance Physical Health for Individuals with Severe Mental Illness in Canadian Healthcare Organizations.

As Canadians with severe mental illness remain underserved and experience a high burden of physical health challenges and premature mortality, there is an unprecedented need to provide better physical healthcare to this population. Ways of addressing this gap include the delivery of physical healthcare in mental health settings ("reverse integration"). However, there is limited guidance on how to enact this integration. In this article, we outline the development of an integrated care strategy in Canada's largest mental health hospital and discuss system- and policy-level recommendations that healthcare organizations could consider in their initiatives.

Biowaste Eggshell Membranes for Bio-triboelectric Nanogenerators and Smart Sensors.

In this study, we used a simple and cost-effective method to fabricate triboelectric nanogenerators (TENGs) based on biowaste eggshell membranes (EMs). We prepared stretchable electrodes with various types of EMs (hen, duck, goose, and ostrich) and employed them as positive friction materials for bio-TENGs. A comparison of the electrical properties of the hen, duck, goose, and ostrich EMs revealed that the output voltage of the ostrich EM could reach up to 300 V, due to its abundant functional groups, natural fiber structure, high surface roughness, high surface charge, and high dielectric constant. The output power of the resulting device reached 0.18 mW, sufficient to power 250 red light-emitting diodes simultaneously, as well as a digital watch. This device also displayed good durability when subjected to 9000 cycles at 30 N at a frequency of 3 Hz. Furthermore, we designed an ostrich EM-TENG as a smart sensor for the detection of body motion, including leg movement and the pressing of different numbers of fingers.

A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants.

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 µg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 µg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 µg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

The Topographical Mapping in Drosophila Central Complex Network and Its Signal Routing.

Neural networks regulate brain functions by routing signals. Therefore, investigating the detailed organization of a neural circuit at the cellular levels is a crucial step toward understanding the neural mechanisms of brain functions. To study how a complicated neural circuit is organized, we analyzed recently published data on the neural circuit of the Drosophila central complex, a brain structure associated with a variety of functions including sensory integration and coordination of locomotion. We discovered that, except for a small number of "atypical" neuron types, the network structure formed by the identified 194 neuron types can be described by only a few simple mathematical rules. Specifically, the topological mapping formed by these neurons can be reconstructed by applying a generation matrix on a small set of initial neurons. By analyzing how information flows propagate with or without the atypical neurons, we found that while the general pattern of signal propagation in the central complex follows the simple topological mapping formed by the "typical" neurons, some atypical neurons can substantially re-route the signal pathways, implying specific roles of these neurons in sensory signal integration. The present study provides insights into the organization principle and signal integration in the central complex.

The proper use of coronary calcium score and coronary computed tomography angiography for screening asymptomatic patients with cardiovascular risk factors.

Early detection and treatment of coronary artery disease (CAD) can reduce incidences of acute myocardial infarction. In this study, we determined the proper use of contributing risk factors and coronary artery calcium score (CACS) when screening asymptomatic patients with coronary arterial stenoses using coronary computed tomography angiography (CCTA). We reviewed 934 consecutive patients who received CACS and CCTA between December 2013 and November 2016. At least one cardiovascular disease risk factor was present in each of the 509 asymptomatic participants. Patients were grouped based on CACS into "zero," "minimal" (0 < CACS ≤ 10), "mild" (10 < CACS ≤ 100), "moderate" (100 < CACS ≤ 400), and "excessive" (CACS > 400). Males over 45 years old with diabetes mellitus and hypertension had a higher risk of significant coronary stenosis. In multivariate analysis, age, sex, hypertension, and diabetes mellitus remained significant predictors of stenosis. A CACS of zero occurred in 227 patients (44.6%). There were no significant differences between the "zero" and "minimal" groups (p = 0.421), but the "mild," "moderate," and "excessive" groups showed correlations with significant coronary stenosis. Age, sex, diabetes mellitus, and hypertension were associated with higher risk of significant coronary stenosis. Asymptomatic patients with CACSs of zero do not require CCTA, and thereby avoid unnecessary radiation exposure.

Assessment of radiation safety in cardiac CT angiography.

This study investigates the radiation dose and image quality of patients not receiving ß-blockers for cardiac CT angiography (CCTA) with or without the optimization of electrocardiographic (ECG) pulsing window. The differences in patient characteristics are also characterized.Normal-weight and obese patients (n = 154) with heart rates between 65 and 80 beats per minutes (bpm) during the prospective axial scanning were enrolled retrospectively. The ECG pulsing windows were set at 50% to 75% (Group A) or 60% to 75% (Group B) of the R-R interval for patients with heart rate variability higher than or not exceeding ±5 bpm, respectively. The effective doses of individual patient were estimated from the dose length product of the CCTA scan. Two radiologists independently reviewed the images and applied a 4-point Likert scale for image quality assessment. The patients' characteristics were compared along with the patients' effective doses between groups.The optimized pulsing window significantly reduced the average radiation dose for normal-weight and obese patients by 33% and 27%, respectively. The CCTA image quality of patients in Group A was not different overall from those obtained from Group B. Nondiabetic obese patients were more likely to be accepted for the use of the optimized pulsing window. Unlike obese patients, normal-weight patients revealed no characteristic difference between Groups A and B.This study indicates an equivalent efficacy of using optimized pulsing windows for reducing the radiation dose for patients without ß-blocker administration between different body weight groups. Nevertheless, gender and diabetic status became prominent characteristics in the obese group when matching up with the optimized pulsing window.

Polarity-specific high-level information propagation in neural networks.

Analyzing the connectome of a nervous system provides valuable information about the functions of its subsystems. Although much has been learned about the architectures of neural networks in various organisms by applying analytical tools developed for general networks, two distinct and functionally important properties of neural networks are often overlooked. First, neural networks are endowed with polarity at the circuit level: Information enters a neural network at input neurons, propagates through interneurons, and leaves via output neurons. Second, many functions of nervous systems are implemented by signal propagation through high-level pathways involving multiple and often recurrent connections rather than by the shortest paths between nodes. In the present study, we analyzed two neural networks: the somatic nervous system of Caenorhabditis elegans (C. elegans) and the partial central complex network of Drosophila, in light of these properties. Specifically, we quantified high-level propagation in the vertical and horizontal directions: the former characterizes how signals propagate from specific input nodes to specific output nodes and the latter characterizes how a signal from a specific input node is shared by all output nodes. We found that the two neural networks are characterized by very efficient vertical and horizontal propagation. In comparison, classic small-world networks show a trade-off between vertical and horizontal propagation; increasing the rewiring probability improves the efficiency of horizontal propagation but worsens the efficiency of vertical propagation. Our result provides insights into how the complex functions of natural neural networks may arise from a design that allows them to efficiently transform and combine input signals.

Conservative treatment of concomitant extraperitoneal bladder rupture and intrabladder blood clot formation: Case report of application of ureteral catheterization.

Most extraperitoneal bladder ruptures can be treated conservatively with catheter drainage only. However, in patients with concomitant intrabladder blood clot formation and extraperitoneal bladder rupture, surgery for blood clot evacuation and bladder repair are usually needed due to occlusion of the urinary catheter. In our patient, we used a ureteral catheter to bypass the clots in the bladder to provide adequate urinary drainage. This procedure serves as a valuable tool in the conservative treatment of extraperitoneal bladder injury.

Role of three-dimensional rotational venography in evaluation of the left iliac vein in patients with chronic lower limb edema.

The aim of this study was to assess the role of three-dimensional rotational venography (3D RV) supplementary to two-dimensional (2D) digital subtraction venography (DSV) in evaluation of the left iliac vein in patients with chronic lower limb edema. We reviewed 34 patients with chronic lower limb edema who had undergone bilateral iliac 2D DSV and 3D RV of the left common iliac vein and had surgery in our institution. The presence, anatomical location, and size of the venous narrowing were assessed. Stenosis was defined as luminal narrowing of 50% or more compared with the prestenotic or poststenotic lumen by visual assessment. A measured pressure gradient of 2 mm Hg or more at surgery was considered a positive result. The diagnostic accuracy was higher for the 3D images (88.2%) than for the 2D images alone (70.6%). 3D images provided higher sensitivity (90%) than the 2D images alone (66.7%). The 2D images alone had excellent specificity (100%) and positive predictive value (100%) in the diagnosis of venous narrowing. 2D DSV images provide specificity in diagnosis of venous stenosis of the left iliac vein in patients with chronic lower limb edema. In patients with negative 2D images, additional 3D RV leads to higher diagnostic sensitivity, thereby providing a powerful tool for planning surgical and endovascular treatment.