The majority of Canadians likely behaved as myopic rationalists rather than success-based learners when deciding on their first dose of COVID-19 vaccine.

Introduction: Successful vaccine promotion communication strategies require knowing how eligible recipients will respond to the opportunity to get vaccinated. Two main classes of recipients are myopic rationalists, those who receive a dose of vaccine only if it maximizes their own instant benefit and if so, do it as soon as possible, and success-based learners, those who learn from others that they perceive to be most successful. Methods: A recent study models these two decision-making types, and estimates the population proportion of myopic rationalists in each U.S. state. In this report, we fit a similar model to data on COVID-19 vaccine uptake across the Canadian provinces and territories. Results: We estimated that 64% of Canadians behaved as myopic rationalists in taking the first dose of a COVID-19 vaccine, compared to an estimated 47% in the United States. Among the provinces, the lowest proportion of myopic rationalists was 0.51 in Saskatchewan, while the highest was 0.74 in Prince Edward Island. The correlation analysis suggested a positive correlation between the proportion of myopic rationalists and the average age across the Canadian provinces (Pearson-r = 0.71). Discussion: Canadian health management may benefit from these results in tailoring the vaccine promotion communication strategies.

Comparison of the immunogenicity of mRNA-encoded and protein HIV-1 Env-ferritin nanoparticle designs.

Nucleoside-modified mRNA technology has revolutionized vaccine development with the success of mRNA COVID-19 vaccines. We used modified mRNA technology for the design of envelopes (Env) to induce HIV-1 broadly neutralizing antibodies (bnAbs). However, unlike SARS-CoV-2 neutralizing antibodies that are readily made, HIV-1 bnAb induction is disfavored by the immune system because of the rarity of bnAb B cell precursors and the cross-reactivity of bnAbs targeting certain Env epitopes with host molecules, thus requiring optimized immunogen design. The use of protein nanoparticles (NPs) has been reported to enhance B cell germinal center responses to HIV-1 Env. Here, we report our experience with the expression of Env-ferritin NPs compared with membrane-bound Env gp160 when encoded by modified mRNA. We found that well-folded Env-ferritin NPs were a minority of the protein expressed by an mRNA design and were immunogenic at 20 µg but minimally immunogenic in mice at 1 µg dose in vivo and were not expressed well in draining lymph nodes (LNs) following intramuscular immunization. In contrast, mRNA encoding gp160 was more immunogenic than mRNA encoding Env-NP at 1 µg dose and was expressed well in draining LN following intramuscular immunization. Thus, analysis of mRNA expression in vitro and immunogenicity at low doses in vivo are critical for the evaluation of mRNA designs for optimal immunogenicity of HIV-1 immunogens.IMPORTANCEAn effective HIV-1 vaccine that induces protective antibody responses remains elusive. We have used mRNA technology for designs of HIV-1 immunogens in the forms of membrane-bound full-length envelope gp160 and envelope ferritin nanoparticle. Here, we demonstrated in a mouse model that the membrane-bound form induced a better response than envelope ferritin nanoparticle because of higher in vivo protein expression. The significance of our research is in highlighting the importance of analysis of mRNA design expression and low-dose immunogenicity studies for HIV-1 immunogens before moving to vaccine clinical trials.

NK cells modulate in vivo control of SARS-CoV-2 replication and suppression of lung damage.

Natural killer (NK) cells play a critical role in virus control. However, it has remained largely unclear whether NK cell mobilization in SARS-CoV-2 infections is beneficial or pathologic. To address this deficit, we employed a validated experimental NK cell depletion non-human primate (NHP) model with SARS-CoV-2 Delta variant B.1.617.2 challenge. Viral loads (VL), NK cell numbers, activation, proliferation, and functional measures were evaluated in blood and tissues. In non-depleted (control) animals, infection rapidly induced NK cell expansion, activation, and increased tissue trafficking associated with VL. Strikingly, we report that experimental NK cell depletion leads to higher VL, longer duration of viral shedding, significantly increased levels of pro-inflammatory cytokines in the lungs, and overt lung damage. Overall, we find the first significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data indicate that adjunct therapies for infection could largely benefit from NK cell-targeted approaches.

Extracellular vesicles may provide an alternative detoxification pathway during skeletal muscle myoblast ageing.

Skeletal muscle (SM) acts as a secretory organ, capable of releasing myokines and extracellular vesicles (SM-EVs) that impact myogenesis and homeostasis. While age-related changes have been previously reported in murine SM-EVs, no study has comprehensively profiled SM-EV in human models. To this end, we provide the first comprehensive comparison of SM-EVs from young and old human primary skeletal muscle cells (HPMCs) to map changes associated with SM ageing. HPMCs, isolated from young (24 ± 1.7 years old) and older (69 ± 2.6 years old) participants, were immunomagnetically sorted based on the presence of the myogenic marker CD56 (N-CAM) and cultured as pure (100% CD56+) or mixed populations (MP: 90% CD56+). SM-EVs were isolated using an optimised protocol combining ultrafiltration and size exclusion chromatography (UF + SEC) and their biological content was extensively characterised using Raman spectroscopy (RS) and liquid chromatography mass spectrometry (LC-MS). Minimal variations in basic EV parameters (particle number, size, protein markers) were observed between young and old populations. However, biochemical fingerprinting by RS highlighted increased protein (amide I), lipid (phospholipids and phosphatidylcholine) and hypoxanthine signatures for older SM-EVs. Through LC-MS, we identified 84 shared proteins with functions principally related to cell homeostasis, muscle maintenance and transcriptional regulation. Significantly, SM-EVs from older participants were comparatively enriched in proteins involved in oxidative stress and DNA/RNA mutagenesis, such as E3 ubiquitin-protein ligase TTC3 (TTC3), little elongation complex subunit 1 (ICE1) and Acetyl-CoA carboxylase 1 (ACACA). These data suggest SM-EVs could provide an alternative pathway for homeostasis and detoxification during SM ageing.

Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways.

SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta-the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

An early warning indicator trained on stochastic disease-spreading models with different noises.

The timely detection of disease outbreaks through reliable early warning signals (EWSs) is indispensable for effective public health mitigation strategies. Nevertheless, the intricate dynamics of real-world disease spread, often influenced by diverse sources of noise and limited data in the early stages of outbreaks, pose a significant challenge in developing reliable EWSs, as the performance of existing indicators varies with extrinsic and intrinsic noises. Here, we address the challenge of modelling disease when the measurements are corrupted by additive white noise, multiplicative environmental noise and demographic noise into a standard epidemic mathematical model. To navigate the complexities introduced by these noise sources, we employ a deep learning algorithm that provides EWS in infectious disease outbreaks by training on noise-induced disease-spreading models. The indicator's effectiveness is demonstrated through its application to real-world COVID-19 cases in Edmonton and simulated time series derived from diverse disease spread models affected by noise. Notably, the indicator captures an impending transition in a time series of disease outbreaks and outperforms existing indicators. This study contributes to advancing early warning capabilities by addressing the intricate dynamics inherent in real-world disease spread, presenting a promising avenue for enhancing public health preparedness and response efforts.

Arenavirus-Based Vectors Generate Robust SIV Immunity in Non-Human Primates.

Arenavirus-based vectors are being investigated as therapeutic vaccine candidates with the potential to elicit robust CD8 T-cell responses. We compared the immunogenicity of replicating (artPICV and artLCMV) and non-replicating (rPICV and rLCMV) arenavirus-based vectors expressing simian immunodeficiency virus (SIV) Gag and Envelope (Env) immunogens in treatment-naïve non-human primates. Heterologous regimens with non-replicating and replicating vectors elicited more robust SIV IFN-γ responses than a homologous regimen, and replicating vectors elicited significantly higher cellular immunogenicity than non-replicating vectors. The heterologous regimen elicited high anti-Env antibody titers when administered intravenously, with replicating vectors inducing significantly higher titers than non-replicating vectors. Intramuscular immunization resulted in more durable antibody responses than intravenous immunization for both vector platforms, with no difference between the replicating and non-replicating vectors. Overall, both replicating and non-replicating arenavirus vectors generated robust T- and B-cell-mediated immunity to SIV antigens in treatment-naïve non-human primates, supporting further evaluation of these vectors in a clinical setting for HIV therapy.

Environmental enrichment reduces restricted repetitive behavior by altering gray matter microstructure.

Restricted, repetitive behaviors are common symptoms in neurodevelopmental disorders including autism spectrum disorder. Despite being associated with poor developmental outcomes, repetitive behaviors remain poorly understood and have limited treatment options. Environmental enrichment attenuates the development of repetitive behaviors, but the exact mechanisms remain obscure. Using the C58 mouse model of repetitive behavior, we performed diffusion tensor imaging to examine microstructural alterations associated with the development of repetitive behavior and its attenuation by environmental enrichment. The C57BL/6 mouse strain, which displays little or no repetitive behavior, was used as a control group. We observed widespread differences in diffusion metrics between C58 mice and C57BL/6 mice. In juvenile C58 mice, repetitive motor behavior displayed strong negative correlations with fractional anisotropy in multiple gray matter regions, whereas in young adult C58 mice, high repetitive motor behavior was most strongly associated with lower fractional anisotropy and higher radial diffusivity in the striatum. Environmental enrichment increased fractional anisotropy and axial diffusivity throughout gray matter regions in the brains of juvenile C58 mice and overlapped predominantly with cerebellar and sensory regions associated with repetitive behavior. Our results suggest environmental enrichment reduces repetitive behavior development by altering gray matter microstructure in the cerebellum, medial entorhinal cortex, and sensory processing regions in juvenile C58 mice. Under standard laboratory conditions, early pathology in these regions appears to contribute to later striatal and white matter dysfunction in adult C58 mice. Future studies should examine the role these regions play in the development of repetitive behavior and the relationship between sensory processing and cerebellar deficits and repetitive behavior.

Pyridostigmine to Reduce the duration of postoperative Ileus after Colorectal surgery (PyRICo-RCT): randomized clinical trial.

BACKGROUND: Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting acetylcholinesterase, pyridostigmine can potentially modulate the cholinergic anti-inflammatory pathway and accelerate gastrointestinal recovery. This study aimed to assess the efficacy of pyridostigmine in improving gastrointestinal recovery after colorectal surgery. METHODS: This double-blinded RCT enrolled adult patients undergoing elective colorectal surgery at two hospitals in South Australia. Patients were randomized to 60 mg oral pyridostigmine or placebo twice daily starting 6 h after surgery until the first passage of stool. The primary outcome was GI-2, a validated composite measure of time to first stool and tolerance of oral diet. Secondary outcomes included incidence of postoperative ileus (defined as GI-2 greater than 4 days), duration of hospital stay, and 30-day complications, evaluated by intention-to-treat univariate analysis. RESULTS: Of 130 patients recruited (mean(s.d.) age 58.4(16.4) years; 73 men, 56%), 65 were allocated to each arm. The median GI-2 was 1 day shorter with pyridostigmine compared with placebo (2 (i.q.r. 1-3) versus 3 (2-4) days; P = 0.015). However, there were no significant differences in postoperative ileus (17.2 versus 21.5%; P = 0.532) or duration of hospital stay (median 5 (i.q.r. 4-8.75) versus 5 (4-7.5) days; P = 0.921). Similarly, there were no significant differences in overall complications, anastomotic leak, cardiac complications, or patient-reported side effects. CONCLUSION: Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal dosing and evaluate the impact of pyridostigmine in different surgical settings. Registration number: ACTRN12621000530820 (https://anzctr.org.au).

Intradiscal Steroid Injections for Degenerative Disc Disease With Modic Changes: A Retrospective Study of Therapeutic and Diagnostic Features.

PURPOSE: Anterior column pain refers to axial low back pain (LBP) originating from the intervertebral disc or vertebral endplates (discogenic or vertebrogenic pain). We sought to assess the safety and effectiveness of intradiscal steroid injection (IDSI) in diagnosing and treating patients with LBP arising from the anterior column. PATIENTS AND METHODS: This is a retrospective chart review of 66 patients who underwent 77 injections in an outpatient, private practice setting for the treatment of chronic lower back with history and physical exam findings indicating an origin within the anterior column and magnetic resonance imaging (MRI) findings of Modic changes associated with disc degeneration of grade 4 or above on the modified Pfirrmann scale. Patients reported pain as measured by the numerical rating scale (NRS) before the injection, at the time of their follow-up, and their maximum pain relief. The primary outcome was the change in NRS before and after the injections. The secondary outcome determined if the changes in the subjects' NRS met the minimal clinically important change (MCIC) criteria for LBP. We conducted a statistical analysis using a paired sample t-test. RESULTS: There was a statistically significant difference between the pre-injection and follow-up NRS scores (p < 0.001) and a significant difference between pre-injection and maximum relief NRS scores (p < 0.001). Most subjects (55/77, 71.4%) met the MCIC to relieve their chronic LBP at the time of the follow-up evaluation. CONCLUSION: For patients with chronic LBP and degenerative endplate changes, IDSIs provided these patients with significant short-term pain relief from pain arising from the anterior column.

Revealing Decision-Making Strategies of Americans in Taking COVID-19 Vaccination.

Efficient coverage for newly developed vaccines requires knowing which groups of individuals will accept the vaccine immediately and which will take longer to accept or never accept. Of those who may eventually accept the vaccine, there are two main types: success-based learners, basing their decisions on others' satisfaction, and myopic rationalists, attending to their own immediate perceived benefit. We used COVID-19 vaccination data to fit a mechanistic model capturing the distinct effects of the two types on the vaccination progress. We proved the identifiability of the population proportions of each type and estimated that 47 % of Americans behaved as myopic rationalists with a high variation across the jurisdictions, from 31 % in Mississippi to 76 % in Vermont. The proportion was correlated with the vaccination coverage, proportion of votes in favor of Democrats in 2020 presidential election, and education score.

Comparison of the immunogenicity and protective efficacy of ACAM2000, MVA, and vectored subunit vaccines for Mpox in rhesus macaques.

The 2022-2023 mpox outbreak triggered vaccination efforts using smallpox vaccines that were approved for mpox, including modified vaccinia Ankara (MVA; JYNNEOS), which is a safer alternative to live replicating vaccinia virus (ACAM2000). Here, we compare the immunogenicity and protective efficacy of JYNNEOS by the subcutaneous or intradermal routes, ACAM2000 by the percutaneous route, and subunit Ad35 vector-based L1R/B5R or L1R/B5R/A27L/A33R vaccines by the intramuscular route in rhesus macaques. All vaccines provided robust protection against high-dose intravenous mpox virus challenge with the current outbreak strain, with ACAM2000 providing near complete protection and JYNNEOS and Ad35 vaccines providing robust but incomplete protection. Protection correlated with neutralizing antibody responses as well as L1R/M1R- and B5R/B6R-specific binding antibody responses, although additional immune responses likely also contributed to protection. This study demonstrates the protective efficacy of multiple vaccine platforms against mpox virus challenge, including both current clinical vaccines and vectored subunit vaccines.

Simultaneous estimation of the temporal and spatial extent of animal migration using step lengths and turning angles.

BACKGROUND: Animals of many different species, trophic levels, and life history strategies migrate, and the improvement of animal tracking technology allows ecologists to collect increasing amounts of detailed data on these movements. Understanding when animals migrate is important for managing their populations, but is still difficult despite modelling advancements. METHODS: We designed a model that parametrically estimates the timing of migration from animal tracking data. Our model identifies the beginning and end of migratory movements as signaled by change-points in step length and turning angle distributions. To this end, we can also use the model to estimate how an animal's movement changes when it begins migrating. In addition to a thorough simulation analysis, we tested our model on three datasets: migratory ferruginous hawks (Buteo regalis) in the Great Plains, barren-ground caribou (Rangifer tarandus groenlandicus) in northern Canada, and non-migratory brown bears (Ursus arctos) from the Canadian Arctic. RESULTS: Our simulation analysis suggests that our model is most useful for datasets where an increase in movement speed or directional autocorrelation is clearly detectable. We estimated the beginning and end of migration in caribou and hawks to the nearest day, while confirming a lack of migratory behaviour in the brown bears. In addition to estimating when caribou and ferruginous hawks migrated, our model also identified differences in how they migrated; ferruginous hawks achieved efficient migrations by drastically increasing their movement rates while caribou migration was achieved through significant increases in directional persistence. CONCLUSIONS: Our approach is applicable to many animal movement studies and includes parameters that can facilitate comparison between different species or datasets. We hope that rigorous assessment of migration metrics will aid understanding of both how and why animals move.

BIPOC experiences of (anti-)racist patient engagement in adolescent and young adult oncology research: an electronic Delphi study.

Aims: To characterize Black, Indigenous and People of Color (BIPOC) adolescent and young adult (AYA) cancer patients' experiences of patient engagement in AYA oncology and derive best practices that are co-developed by BIPOC AYAs and oncology professionals. Materials & methods: Following a previous call to action from AYA oncology professionals, a panel of experts composed exclusively of BIPOC AYA cancer patients (n = 32) participated in an electronic Delphi study. Results: Emergent themes described BIPOC AYA cancer patients' direct experiences and consensus opinion on recommendations to advance antiracist patient engagement from BIPOC AYA cancer patients and oncology professionals. Conclusion: The findings reveal high-priority practices across all phases of research and are instructional for advancing health equity.

Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques.

The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the occlusion of CD4bs by glycans, expansion of appropriate naive B cells with immunogens, and selection of functional antibody mutations. Here, we demonstrate that immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAb bound to HIV-1 Env demonstrated binding angles and heavy-chain interactions characteristic of all known human CD4-mimicking bnAbs. Macaque nAb were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAb. This vaccine study initiated in primates the B cells from which CD4bs bnAbs can derive, accomplishing the key first step in the development of an effective HIV-1 vaccine.

Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.

Regular Medications in the Emergency Department Short Stay Unit (ReMedIES): Can Prescribing be Improved Without Increasing Resources?

Background: Hospital medication errors are frequent and may result in adverse events. Data on non-prescription of regular medications to emergency department short stay unit patients is lacking. In response to local reports of regular medication omissions, a multi-disciplinary team was tasked to introduce corrective emergency department (ED) process changes, but with no additional financing or resources. Aim: To reduce the rate of non-prescription of regular medications for patients admitted to the ED Short Stay Unit (SSU), through process change within existing resource constraints. Methods: A pre- and post-intervention observational study compared regular medication omission rates for patients admitted to the ED SSU. Included patients were those who usually took regular home medications at 08:00 or 20:00. Omissions were classified as clinically significant medications (CSMs) or non-clinically significant medications (non-CSMs). The intervention included reinforcement that the initially treating acute ED doctor was responsible for prescription completion, formal checking of prescription presence at SSU handover rounds, double-checking of prescription completeness by the overnight SSU lead nurse and junior doctor, and ED pharmacist medication reconciliation for those still identified as having regular medication non-prescription at 07:30. Results: For the 110 and 106 patients in the pre- and post-intervention periods, there was a non-significant reduction in the CSM omission rate of -11% (95% CI: -23 to 2), from 41% (95% CI: 32-50) to 30% (95% CI: 21-39). Conclusion: Non-prescription of regular CSMs for SSU patients was not significantly reduced by institution of work practice changes within existing resource constraints.

Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder.

BACKGROUND: Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB. METHODS: We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB. RESULTS: Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FAT) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FAT and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes. LIMITATIONS: The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated. CONCLUSIONS: These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FAT was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.