Retraction notice to "Non-neuronal cholinergic system delays cardiac remodelling in type 1 diabetes" [Heliyon 9 (2023) e17434].

[This retracts the article DOI: 10.1016/j.heliyon.2023.e17434.].

The molecular immune modulator adenosine deaminase-1 enhances HIV specific humoral and cellular responses to a native-like HIV envelope trimer DNA vaccine.

There is currently no prophylactic vaccine available for human immunodeficiency virus (HIV). Research efforts have resulted in improved immunogens that mimic the native envelope (Env) glycoprotein structure. Recently, a novel triple tandem trimer (TTT) platform has been used to generate a plasmid encoding Env immunogen (pBG505-TTT) that expresses only as trimers, making it more suitable for nucleic acid vaccines. We have previously demonstrated that adenosine deaminase-1 (ADA-1) is critical to the T follicular helper (TFH) function and improves vaccine immune responses in vivo. In this study, we demonstrate that co-delivery of plasmid-encoded adenosine deaminase 1 (pADA) with pBG505-TTT enhances the magnitude, durability, isotype switching and functionality of HIV-specific antibodies in a dose-sparing manner. Co-delivery of the molecular immune modulator ADA-1 also enhances HIV-specific T cell polyfunctionality, activation, and degranulation as well as memory B cell responses. These data demonstrate that pADA enhances HIV-specific cellular and humoral immunity, making ADA-1 a promising immune modulator for HIV-targeting vaccines.

Characteristics of Drug Poisonings Seen in the Emergency Department of an Urban Hospital.

Background: Drug poisoning, either intentional or non-intentional, is a frequent diagnosis in the emergency department (ED), necessitating patient management from multiple services. Objective: To describe the drug poisonings seen in the ED of a large academic urban hospital. Methods: This retrospective descriptive study used 3 years of data (2018-2020) abstracted from the hospital's electronic medical record system and linked to validated, coded extracts from the Canadian Institute for Health Information Discharge Abstract Database. Patients with a diagnosis of acute drug poisoning who presented to the ED were identified on the basis of International Statistical Classification of Diseases and Related Health Problems, 10th revision, Canada (ICD-10-CA) codes, and data were collected for demographic characteristics, the drugs involved, in-hospital management, and inpatient outcomes. Patients with diagnosis of an acute drug reaction, inebriation, or nondrug or in-hospital poisoning were excluded. Data were stratified and analyzed in relation to the intent of drug poisoning. Results: A total of 2983 visits for drug poisoning, involving 2211 unique patients (mean age 38.3 [standard deviation 16.2] years, 54.7% female), were included, yielding an overall incidence rate of 15.7 drug poisonings per 1000 ED visits (8.1 intentional, 6.4 non-intentional, and 1.3 unknown intent). Among the 1505 intentional drug poisonings, the most prevalent drug sources were antidepressants (n = 405, 26.9%), benzodiazepines (n = 375, 24.9%), and acetaminophen (n = 329, 21.9%); in contrast, opioids (n = 594, 48.1%) were most prevalent for the 1236 non-intentional poisonings. For 716 (24.0%) of the poisoning visits, the patient was admitted to acute care services, and the in-hospital mortality rate was 1.0% (n = 31). In addition, 111 patients (9.0%) with non-intentional drug poisoning left against medical advice. Finally, for 772 (25.9%) of the poisoning visits, the patient returned to the ED after discharge with a subsequent drug poisoning. Conclusions: Drug poisonings are a common cause of visits to urban EDs. They are rarely fatal but are associated with substantial utilization of hospital resources and considerable recidivism.

Contexte: L'intoxication médicamenteuse, intentionnelle ou non, est un diagnostic fréquent dans le service des urgences (SU); elle nécessite la prise en charge des patients par plusieurs services. Objectif: Décrire les intoxications médicamenteuses observées dans le SU d'un grand hôpital universitaire urbain. Méthodologie: Pour cette étude rétrospective et descriptive, des données contenues dans le système de dossiers médicaux électroniques de l'hôpital et liées à des extraits validés et codés de la base de données sur les congés des patients de l'Institut canadien d'information sur la santé pendant 3 ans (2018­2020) ont été utilisées. Les patients ayant reçu un diagnostic d'intoxication médicamenteuse aiguë qui se sont présentés à l'urgence ont été identifiés sur la base des codes de la Classification statistique internationale des maladies et des problèmes de santé connexes, 10e version, Canada (CIM-10-CA), et des données ont été recueillies pour les caractéristiques démographiques, les médicaments impliqués, la prise en charge à l'hôpital et les résultats pour les patients hospitalisés. Les patients présentant un diagnostic de réaction médicamenteuse aiguë, d'ébriété ou d'intoxication non médicamenteuse ou à l'hôpital ont été exclus. Les données ont été stratifiées et analysées en fonction de l'intention de l'empoisonnement médicamenteux. Résultats: Au total, 2983 cas mettant en cause 2211 patients (âge moyen 38,3 [écart type 16,2] ans, dont 54,7 % de femmes) ont été inclus; les résultats ont donné un taux d'incidence global de 15,7 intoxications médicamenteuses pour 1000 visites au SU (8,1 intentionnelles; 6,4 non intentionnelles; et 1,3 intention inconnue). Parmi les 1505 intoxications médicamenteuses intentionnelles, les médicaments les plus répandues étaient les antidépresseurs (n = 405, 26,9 %), les benzodiazépines (n = 375, 24,9 %) et l'acétaminophène (n = 329, 21,9 %); les opioïdes (n = 594, 48,1 %) étaient les plus répandus parmi les 1236 intoxications non intentionnelles. Dans 716 des cas (24,0 %), le patient a été admis dans les services de soins aigus. Le taux de mortalité hospitalière était de 1,0 % (n = 31). Par ailleurs, 111 patients (9,0 %) présentant une intoxication médicamenteuse non intentionnelle ont quitté l'hôpital contre avis médical. Enfin, dans 772 des cas d'intoxication (25,9 %), le patient est retourné à l'urgence après sa sortie à cause d'une intoxication médicamenteuse ultérieure. Conclusions: Les intoxications médicamenteuses sont une cause fréquente de visites dans les SU urbains. Ils sont rarement mortels, mais sont associés à une utilisation importante des ressources hospitalières et à une récidive considérable.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.

A Rare Case of Esophageal Carcinoma Cuniculatum Palliated by Esophageal and Endobronchial Stenting.

Carcinoma cuniculatum is a rare variant of well-differentiated squamous cell carcinoma. To date, there are less than 30 cases of esophageal carcinoma cuniculatum reported. It is frequently a diagnostic challenge: A definitive diagnosis typically cannot be made before esophagectomy. We present a uniquely aggressive case of esophageal carcinoma cuniculatum complicated by a bronchoesophageal fistula and successfully palliated with dual esophageal and endobronchial stenting.

Population Based Time Trends in the Epidemiology and Mortality of Gastroesophageal Junction and Esophageal Adenocarcinoma.

BACKGROUND: Limited data are available on the epidemiology of gastroesophageal junction adenocarcinoma (GEJAC), particularly in comparison to esophageal adenocarcinoma (EAC). With the advent of molecular non-endoscopic Barrett's esophagus (BE) detection tests which sample the esophagus and gastroesophageal junction, early detection of EAC and GEJAC has become a possibility and their epidemiology has gained importance. AIMS: We sought to evaluate time trends in the epidemiology and survival of patients with EAC and GEJAC in a population-based cohort. METHODS: EAC and GEJAC patients from 1976 to 2019 were identified using ICD 9 and 10 diagnostic codes from the Rochester Epidemiology Project (REP). Clinical data and survival status were abstracted. Poisson regression was used to calculate incidence rate ratios (IRR). Survival analysis and Cox proportional models were used to assess predictors of survival. RESULTS: We included 443 patients (287 EAC,156 GEJAC). The incidence of EAC and GEJAC during 1976-2019 was 1.40 (CI 1.1-1.74) and 0.83 (CI 0.61-1.11) per 100,000 people, respectively. There was an increase in the incidence of EAC (IRR = 2.45, p = 0.011) and GEJAC (IRR = 3.17, p = 0.08) from 2000 to 2004 compared to 1995-1999, plateauing in later time periods. Most patients had associated BE and presented at advanced stages, leading to high 5-year mortality rates (66% in EAC and 59% in GEJAC). Age and stage at diagnosis were predictors of mortality. CONCLUSION: The rising incidence of EAC/GEJAC appears to have plateaued somewhat in the last decade. However, both cancers present at advanced stages with persistently poor survival, underscoring the need for early detection.

Advanced glycated end-products inhibit dilation through constitutive endothelial RAGE and Nox1/4 in rat isolated skeletal muscle arteries.

OBJECTIVE: This study investigated the actions of advanced glycated end-products (AGE), their receptors (RAGE), and NAD(P)H oxidase (Nox) subtypes 1, 2, and 4 on mechanisms of endothelium-dependent dilation of the rat cremaster muscle artery (CMA). METHODS: Immunofluorescence studies were used to examine expression of RAGE in rat arteries. ROS accumulation was measured using luminescence and fluorescence assays. Functional studies were performed using pressure myography. RESULTS: High levels of RAGE expression were shown in the endothelial cells of the CMA, compared with low endothelial expression in middle cerebral and mesenteric arteries and the aorta. Exogenous AGE (in vitro glycated bovine serum albumin) stimulated H2O2 accumulation in CMA, which was prevented by the RAGE antagonist FPS-ZM1, the NAD(P)H oxidase (Nox) inhibitor apocynin and inhibited by the Nox1/4 inhibitor setanaxib, but not the Nox2 inhibitor GSK2795039. In functional studies, AGE inhibited vasodilation of CMA stimulated by acetylcholine, sodium nitroprusside, and the BKCa activator NS1619, but not adenosine-induced dilation. FPS-ZM1, apocynin, and setanaxib prevented the inhibitory effects of AGE on responses to acetylcholine and NS-1619. CONCLUSION: These observations suggest RAGE are constitutively expressed in the endothelium of the rat CMA and may be activated by AGE to stimulate Nox1/4 and ROS formation with resulting inhibition of NO and BKCa-mediated endothelium-dependent dilation.

Skin sensory alteration and kneeling ability following cruciate retaining total knee arthroplasty are not affected by the incision position: A randomised controlled trial of simultaneous bilateral surgery.

PURPOSE: The purpose of this randomised controlled trial was to assess the impact of skin incision location on the patients' ability to kneel. METHODS: A total of 29 patients undergoing bilateral total knee arthroplasty (58 knees) were randomised to receive a lateral or midline incision, with the contralateral limb receiving the alternative option. Cruciate retaining implants were used in all cases by three experienced arthroplasty surgeons. The primary outcome measures assessed functional ability to kneel using an innovative five-point kneeling scale, preferred knee to kneel on and the area of cutaneous sensory loss around the incision at 6 weeks, 6 months and 12 months. Secondary outcome measures were the OKS, KOOS JR, FJS and EQ5D patient reported outcome measures (PROMS), length of surgical scar, overall knee preference and range of motion (ROM). RESULTS: There were no significant differences between the two groups for any primary or secondary outcome measures. Flexion range however, had a significant positive correlation with kneeling score (r = 0.335, p = 0.010). The kneeling score increased at each time point after surgery and was significantly greater at 12 months than preoperatively (2.7 v 3.5, p = 0.015). The area of sensory loss lateral to the incision was significantly less at 6 and 12 months than at 6 weeks (43.6cm2 and 40.1cm2 v 84.1cm2, p < 0.0001). CONCLUSION: The ability to kneel following cruciate retaining total knee arthroplasty is not affected by the incision position but by time and flexion range. TKA improves the ability to kneel by 12 months post-surgery. Sensory loss lateral to the incision reduces with time. LEVEL OF EVIDENCE: Therapeutic Level 2.

Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling.

The limited availability of cytokines in solid tumours hinders maintenance of the antitumour activity of chimeric antigen receptor (CAR) T cells. Cytokine receptor signalling pathways in CAR T cells can be activated by transgenic expression or injection of cytokines in the tumour, or by engineering the activation of cognate cytokine receptors. However, these strategies are constrained by toxicity arising from the activation of bystander cells, by the suboptimal biodistribution of the cytokines and by downregulation of the cognate receptor. Here we show that replacement of the extracellular domains of heterodimeric cytokine receptors in T cells with two leucine zipper motifs provides optimal Janus kinase/signal transducer and activator of transcription signalling. Such chimeric cytokine receptors, which can be generated for common γ-chain receptors, interleukin-10 and -12 receptors, enabled T cells to survive cytokine starvation without induction of autonomous cell growth, and augmented the effector function of CAR T cells in vitro in the setting of chronic antigen exposure and in human tumour xenografts in mice. As a modular design, leucine zippers can be used to generate constitutively active cytokine receptors in effector immune cells.

Long-Term Outcomes and Risk of Pancreatic Cancer in Intraductal Papillary Mucinous Neoplasms.

Importance: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can give rise to pancreatic cancer (PC). Limited population data exist on their prevalence, natural history, or risk of malignant transformation (IPMN-PC). Objective: To fill knowledge gaps in epidemiology of IPMNs and associated PC risk by estimating population prevalence of IPMNs, associated PC risk, and proportion of IPMN-PC. Design, Setting, and Participants: : This retrospective cohort study was conducted in Olmsted County, Minnesota. Using the Rochester Epidemiology Project (REP), patients aged 50 years and older with abdominal computed tomography (CT) scans between 2000 and 2015 were randomly selected (CT cohort). All patients from the REP with PC between 2000 and 2019 were also selected (PC cohort). Data were analyzed from November 2021 through August 2023. Main outcomes and Measures: CIs for PC incidence estimates were calculated using exact methods with the Poisson distribution. Cox models were used to estimate age, sex, and stage-adjusted hazard ratios for time-to-event end points. Results: The CT cohort included 2114 patients (1140 females [53.9%]; mean [SD] age, 68.6 [12.1] years). IPMNs were identified in 231 patients (10.9%; 95% CI, 9.7%-12.3%), most of which were branch duct (210 branch-duct [90.9%], 16 main-duct [6.9%], and 5 mixed [2.2%] IPMNs). There were 5 Fukuoka high-risk (F-HR) IPMNs (2.2%), 39 worrisome (F-W) IPMNs (16.9%), and 187 negative (F-N) IPMNs (81.0%). After a median (IQR) follow-up of 12.0 (8.1-15.3) years, 4 patients developed PC (2 patients in F-HR and 2 patients in F-N groups). The PC incidence rate per 100 person years for F-HR IPMNs was 34.06 incidents (95% CI, 4.12-123.02 incidents) and not significantly different for patients with F-N IPMNs compared with patients without IPMNs (0.16 patients; 95% CI, 0.02-0.57 patients vs 0.11 patients; 95% CI, 0.06-0.17 patients; P = .62). The PC cohort included 320 patients (155 females [48.4%]; mean [SD] age, 72.0 [12.3] years), and 9.8% (95% CI, 7.0%-13.7%) had IPMN-PC. Compared with 284 patients with non-IPMN PC, 31 patients with IPMN-PC were older (mean [SD] age, 76.9 [9.2] vs 71.3 [12.5] years; P = .02) and more likely to undergo surgical resection (14 patients [45.2%] vs 60 patients [21.1%]; P = .003) and more-frequently had nonmetastatic PC at diagnosis (20 patients [64.5%] vs 130 patients [46.8%]; P = .047). Patients with IPMN-PC had better survival (adjusted hazard ratio, 0.62; 95% CI, 0.40-0.94; P = .03) than patients with non-IPMN PC. Conclusions and Relevance: In this study, CTs identified IPMNs in approximately 10% of patients aged 50 years or older. PC risk in patients with F-N IPMNs was low and not different compared with patients without IPMNs; approximately 10% of patients with PC had IPMN-PC, and they had better survival compared with patients with non-IPMN PC.

Using the power of innate immunoprofiling to understand vaccine design, infection, and immunity.

In the field of immunology, a systems biology approach is crucial to understanding the immune response to infection and vaccination considering the complex interplay between genetic, epigenetic, and environmental factors. Significant progress has been made in understanding the innate immune response, including cell players and critical signaling pathways, but many questions remain unanswered, including how the innate immune response dictates host/pathogen responses and responses to vaccines. To complicate things further, it is becoming increasingly clear that the innate immune response is not a linear pathway but is formed from complex networks and interactions. To further our understanding of the crosstalk and complexities, systems-level analyses and expanded experimental technologies are now needed. In this review, we discuss the most recent immunoprofiling techniques and discuss systems approaches to studying the global innate immune landscape which will inform on the development of personalized medicine and innovative vaccine strategies.

Low Risk for Ross River Virus Infection in Expeditionary Forces Training in Australia Demonstrated by a Serological Survey of Marine Rotational Force-Darwin, 2012-2018.

On an annual basis, approximately 2,500 U.S. Marines and Sailors deploy to Australia on 6-month training rotations. Active duty personnel are generally immunologically naïve to pathogens endemic to tropical Australia, a vulnerability that could significantly impact medical readiness. To estimate risk, we screened 628 post-deployment serum samples by ELISA for serological evidence of infection with Ross River virus (RRV), a mosquito-borne alphavirus endemic to tropical Australia. Samples that tested above the negative cutoff value were paired with their pre-deployment samples to identify deployment-related seroconversion. These paired samples were further investigated with a live virus neutralization assay to assess specificity. There was a single RRV seroconversion and 49 false-positive results. In the context of these analyses (i.e., limited sample numbers collected between the months of March and October), we assess the RRV risk to MRFD as low and encourage strategies such as avoiding and preventing mosquito bites to mitigate the existing risk over widespread vaccination programs, if an FDA-approved vaccine becomes available. The Panbio RRV ELISA lacks the specificity to draw conclusions based on seropositivity from large-scale surveys of U.S. personnel.

Non-neuronal cholinergic system delays cardiac remodelling in type 1 diabetes.

Aims: Type 1 diabetes mellitus (T1DM) is associated with increased risk of cardiovascular disease (CVD) and mortality. The underlying mechanisms for T1DM-induced heart disease still remains unclear. In this study, we aimed to investigate the effects of cardiac non-neuronal cholinergic system (cNNCS) activation on T1DM-induced cardiac remodelling. Methods: T1DM was induced in C57Bl6 mice using low-dose streptozotocin. Western blot analysis was used to measure the expression of cNNCS components at different time points (4, 8, 12, and 16 weeks after T1DM induction). To assess the potential benefits of cNNCS activation, T1DM was induced in mice with cardiomyocyte-specific overexpression of choline acetyltransferase (ChAT), the enzyme required for acetylcholine (Ac) synthesis. We evaluated the effects of ChAT overexpression on cNNCS components, vascular and cardiac remodelling, and cardiac function. Key findings: Western blot analysis revealed dysregulation of cNNCS components in hearts of T1DM mice. Intracardiac ACh levels were also reduced in T1DM. Activation of ChAT significantly increased intracardiac ACh levels and prevented diabetes-induced dysregulation of cNNCS components. This was associated with preserved microvessel density, reduced apoptosis and fibrosis, and improved cardiac function. Significance: Our study suggests that cNNCS dysregulation may contribute to T1DM-induced cardiac remodelling, and that increasing ACh levels may be a potential therapeutic strategy to prevent or delay T1DM-induced heart disease.

Image-derived instrumentation vs. conventional instrumentation with 3D planning for glenoid component placement in reverse total shoulder replacements: a randomized controlled trial.

Hypothesis: Glenoid baseplate positioning for reverse total shoulder arthroplasty (rTSA) is important for stability and longevity, with techniques such as image-derived instrumentation (IDI) developed for improving implant placement accuracy. We performed a single-blinded randomized controlled trial comparing glenoid baseplate insertion accuracy with 3D preoperative planning and IDI jigs vs. 3D preoperative planning and conventional instrumentation. Methods: All patients had a preoperative 3D computed tomography to create an IDI; then underwent rTSA according to their randomized method. Repeat computed tomography scans performed at six weeks postoperatively were compared to the preoperative plan to assess for accuracy of implantation. Patient-reported outcome measures and plain radiographs were collected with 2-year follow-up. Results: Forty-seven rTSA patients were included (IDI n = 24, conventional instrumentation n = 23). The IDI group was more likely to have a guidewire placement within 2mm of the preoperative plan in the superior/inferior plane (P = .01); and exhibited a smaller degree of error when the native glenoid retroversion was >10° (P = .047). There was no difference in patient-reported outcome measures or other radiographic parameters between the two groups. Conclusion: IDI is an accurate method for glenoid guidewire and component placement in rTSA, particularly in the superior/inferior plane and in glenoids with native retroversion >10°, when compared to conventional instrumentation.

Diffuse-Type Pancreatic Ductal Adenocarcinoma Mimicking Autoimmune Pancreatitis.

Pancreatic ductal adenocarcinoma (PDAC) classically presents as a solitary mass on cross-sectional imaging. Diffuse-type PDAC is an unusual variant that accounts for 1%-5% of PDACs. Owing to its rarity, there are no established radiographic or endosonographic definitions. We report a unique case of diffuse-type PDAC presenting with imaging findings of 2 distinct masses in the pancreatic head and tail and with endoscopic ultrasound findings of diffuse gland enlargement mimicking autoimmune pancreatitis. The case illustrates the importance of sampling several areas of the pancreas when diffuse enlargement is present on endoscopic ultrasound and multiple masses are seen on cross-sectional imaging.

The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential.

SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that treatment of human macrophages with the novel selective inhibitor of the SP140 protein (GSK761) reduced the expression of endotoxin-induced cytokines, implicating a role of SP140 in the function of inflammatory macrophages. In this study, we investigated the effects of GSK761 on in vitro human dendritic cell (DC) differentiation and maturation, assessing the expression of cytokines and co-stimulatory molecules and their capacity to stimulate T-cell activation and induce phenotypic changes. In DCs, lipopolysaccharide (LPS) stimulation induced an increase in SP140 expression and its recruitment to transcription start sites (TSS) of pro-inflammatory cytokine genes. Moreover, LPS-induced cytokines such as TNF, IL-6, and IL-1ß were reduced in GSK761- or SP140 siRNA- treated DCs. Although GSK761 did not significantly affect the expression of surface markers that define the differentiation of CD14+ monocytes into immature DCs (iDCs), subsequent maturation of iDCs to mature DCs was significantly inhibited. GSK761 strongly reduced expression of the maturation marker CD83, the co-stimulatory molecules CD80 and CD86, and the lipid-antigen presentation molecule CD1b. Finally, when the ability of DCs to stimulate recall T-cell responses by vaccine-specific T cells was assessed, T cells stimulated by GSK761-treated DCs showed reduced TBX21 and RORA expression and increased FOXP3 expression, indicating a preferential generation of regulatory T cells. Overall, this study suggests that SP140 inhibition enhances the tolerogenic properties of DCs, supporting the rationale of targeting SP140 in autoimmune and inflammatory diseases where DC-mediated inflammatory responses contribute to disease pathogenesis.

COVID-19, the Gut, and Nutritional Implications.

PURPOSE OF REVIEW: Our goal is to provide the most recent and accurate scientific evidence available regarding COVID-19's interaction with the human gut and the role of nutrition/nutritional supplementation in the prevention and treatment of the disease. RECENT FINDINGS: Gastrointestinal symptoms of COVID-19 are common and often persist even after classically defined illness resolution. Nutritional status and content have been shown to impact infection risk and severity. Well-balanced diets are associated with decreased infection risk/severity, and early nutrition is associated with better outcomes in the critically ill. No specific vitamin supplementation regimen has shown consistent benefit for infection treatment or prevention. The impact of COVID-19 extends far past the pulmonary system, and its impact on the gut should not be ignored. For those interested in adopting lifestyle modifications to prevent severe COVID-19 infection/side effects, consideration should be made for adoption of a well-balanced diet (e.g., Mediterranean style), utilization of probiotics, and addressing nutritional/vitamin deficiencies. Future, high-quality research is needed in this arena.

Adenosine deaminase augments SARS-CoV-2 specific cellular and humoral responses in aged mouse models of immunization and challenge.

Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of TH2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased TH2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function and expression. Here, we report that co-immunization with pADA enhanced IFNγ secretion while decreasing TNFα and IL-4 secretion. pADA expanded the breadth and affinity SARS-CoV-2 spike-specific antibodies while supporting TH1-type humoral responses in aged mice. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a TH1 gene profile and decreased FoxP3 gene expression. Upon challenge, pADA co-immunization decreased viral loads in aged mice. These data support the use of mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 vaccines and provide support for the use of adenosine deaminase as a molecular adjuvant in immune-challenged populations.