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Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

Since the realization that immature myeloid cells are powerful modulators of the immune response, many studies on \"myeloid-derived suppressor cells\" (MDSCs) have documented their ability to promote tumor progression in melanoma and other cancers. Whether MDSCs are induced solely pathologically in tumorigenesis, or whether they also represent physiological immune control mechanisms, is not well-understood, but is particularly important in the light of ongoing attempts to block their activities in order to enhance anti-tumor immunity. Here, we briefly review studies which explore (1) how best to identify MDSCs in the context of cancer and how this compares to other conditions in humans; (2) what the suppressive mechanisms of MDSCs are and how to target them pharmacologically; (3) whether levels of MDSCs with various phenotypes are informative for clinical outcome not only in cancer but also other diseases, and (4) whether MDSCs are only found under pathological conditions or whether they also represent a physiological regulatory mechanism for the feedback control of immunity. Studies unequivocally document that MDSCs strongly influence cancer outcomes, but are less informative regarding their relevance to infection, autoimmunity, transplantation and aging, especially in humans. So far, the results of clinical interventions to reverse their negative effects in cancer have been disappointing; thus, developing differential approaches to modulate MSDCs in cancer and other diseases without unduly comprising any normal physiological function requires further exploration.

Despite widespread influenza vaccination programs, influenza remains a major cause of morbidity and mortality in older adults. Age-related changes in multiple aspects of the adaptive immune response to influenza have been well-documented including a decline in antibody responses to influenza vaccination and changes in the cell-mediated response associated with immune senescence. This review will focus on T cell responses to influenza and influenza vaccination in older adults, and how increasing frailty or coexistence of multiple (≥2) chronic conditions contributes to the loss of vaccine effectiveness for the prevention of hospitalization. Further, dysregulation of the production of pro- and anti-inflammatory mediators contributes to a decline in the generation of an effective CD8 T cell response needed to clear influenza virus from the lungs. Current influenza vaccines provide only a weak stimulus to this arm of the adaptive immune response and rely on re-stimulation of CD8 T cell memory related to prior exposure to influenza virus. Efforts to improve vaccine effectiveness in older adults will be fruitless until CD8 responses take center stage.

Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C+ monocytes from old (18-22 mo) mice and CD14+CD16+ intermediate/inflammatory monocytes from older adults also contributed to this \"age-associated inflammation\" as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C+ monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C+ monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C+ monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity.

Background This study presents the prevalence of burnout among the Canadian public health workforce after three years of the COVID-19 pandemic and its association with work-related factors. Methods Data were collected using an online survey distributed through Canadian public health associations and professional networks between November 2022 and January 2023. Burnout was measured using a modified version of the Oldenburg Burnout Inventory (OLBI). Logistic regressions were used to model the relationship between burnout and work-related factors including years of work experience, redeployment to pandemic response, workplace safety and supports, and harassment. Burnout and the intention to leave or retire as a result of the COVID-19 pandemic was explored using multinomial logistic regressions. Results In 2,079 participants who completed the OLBI, the prevalence of burnout was 78.7%. Additionally, 49.1% of participants reported being harassed because of their work during the pandemic. Burnout was positively associated with years of work experience, redeployment to the pandemic response, being harassed during the pandemic, feeling unsafe in the workplace and not being offered workplace supports. Furthermore, burnout was associated with greater odds of intending to leave public health or retire earlier than anticipated. Conclusion The high levels of burnout among our large sample of Canadian public health workers and its association with work-related factors suggest that public health organizations should consider interventions that mitigate burnout and promote recovery.

Abstract Rationale The microbial communities inhabiting the upper respiratory tract protect from respiratory infection. The maturity of the immune system is a major influence on the composition of the microbiome and, in youth, the microbiota and immune system are believed to mature in tandem. With age, immune function declines and susceptibility to respiratory infection increases. Whether these changes contribute to the microbial composition of the respiratory tract is unknown. Objectives Our goal was to determine whether the microbes of the upper respiratory tract differ between mid-aged adults (18–40 yr) and the elderly (>65 yr). Methods Microbiomes of the anterior nares and oropharynx of elderly individuals were evaluated by 16S rRNA gene sequencing. These communities were compared with data on mid-aged adults obtained from the Human Microbiome Project. Measurements and Main Results The microbiota of the elderly showed no associations with sex, comorbidities, residence, or vaccinations. Comparisons of mid-aged adults and the elderly demonstrated significant differences in the composition of the anterior nares and oropharynx, including a population in the anterior nares of the elderly that more closely resembled the oropharynx than the anterior nares of adults. The elderly oropharyngeal microbiota were characterized by increased abundance of streptococci, specifically, Streptococcus salivarius group species, but not Streptococcus pneumoniae, carriage of which was low (<3% of participants), as demonstrated by PCR (n = 4/123). Conclusions Microbial populations of the upper respiratory tract in mid-aged adults and the elderly differ; it is possible that these differences contribute to the increased risk of respiratory infections experienced by the elderly.

Although the microneutralization (MN) assay has been shown to be more sensitive than the hemagglutination inhibition (HAI) assay for the measurement of humoral immunity against influenza viruses, further evidence relating MN titres to protective efficacy against infection is needed. Serum antibodies against seasonal H1N1 and H3N2 influenza were measured in children and adolescents (n = 656) by MN and hemagglutination inhibition (HAI) assays. Compared to HAI, the MN assay is more sensitive in detecting serum antibodies and estimates of protective effectiveness against PCR-confirmed infection were higher for both subtypes. Given our findings, the MN assay warrants further consideration as a formal tool for the routine evaluation of vaccine-induced antibody responses.

Background Quantitative PCR (qPCR) is a powerful tool that is particularly well-suited to measure mRNA levels in clinical samples, especially those with relatively low cell counts. However, a caveat of this approach is that reliable, stably expressed reference (housekeeping) genes are vital in order to ensure reproducibility and appropriate biological inference. In this study, we evaluated the expression stability of six reference genes in peripheral blood mononuclear cells (PBMCs) and isolated CD3 + T-cells from young and old adults ( n  = 10), following ex vivo stimulation with mock (unstimulated) or live influenza virus. Our genes included: β-actin ( ACTB ), glyercaldehyde-3-phostphate dehydrogenase ( GAPDH ), ribosomal protein L13a ( RPL13a ), ribosomal protein S18 ( RPS18 ), succinate dehydrogenase complex flavoprotein subunit A ( SDHA ), and ubiquitin-conjugating enzyme E2D2 ( UBE2D2 ). Results Reference gene expression varied significantly depending on cell type and stimulation conditions, but not age. Using the comparative ΔCt method, and the previously published software BestKeeper, NormFinder, and geNorm, we show that in PBMCs and T-cells, UBE2D2 and RPS18 were the most stable reference genes, followed by ACTB ; however, the expression of UBE2D2 and RPS18 was found to increase with viral stimulation in isolated T-cells, while ACTB expression did not change significantly. No age-related differences in stability were observed for any gene Conclusions This study suggests the use of a combination of UBE2D2 , RPS18 , and ACTB for the study of influenza responses in PBMCs and T-cells, although ACTB alone may be the most optimal choice if choosing to compare target gene expression before and after viral stimulation. Both GAPDH and RPL13a were found to be poor reference genes and should be avoided for studies of this nature.

Injection drug use poses a public health challenge. Clinical experience indicates that people who inject drugs (PWID) are hospitalized frequently for infectious diseases, but little is known about outcomes when admitted. Charts were identified from local hospitals between 2013-2018 using consultation lists and hospital record searches. Included individuals injected drugs in the past six months and presented with infection. Charts were accessed using the hospital information system, undergoing primary and secondary reviews using Research Electronic Data Capture (REDCap). The Wilcoxon rank-sum test was used for comparisons between outcome categories. Categorical data were summarized as count and frequency, and compared using Fisher's exact test. Of 240 individuals, 33% were admitted to the intensive care unit, 36% underwent surgery, 12% left against medical advice (AMA), and 9% died. Infectious diagnoses included bacteremia (31%), abscess (29%), endocarditis (29%), cellulitis (20%), sepsis (10%), osteomyelitis (9%), septic arthritis (8%), pneumonia (7%), discitis (2%), meningitis/encephalitis (2%), or other (7%). Sixty-six percent had stable housing and 60% had a family physician. Fifty-four percent of patient-initiated discharges were seen in the emergency department within 30 days and 29% were readmitted. PWID are at risk for infections. Understanding their healthcare trajectory is essential to improve their care.

A two-component vaccine comprised of a human adenovirus expressing the full spike protein and a recombinant spike protein receptor binding domain generated mucosal and systemic immunity against live viral challenge while preventing transmission in animal models, and was shown to be well-tolerated, safe, and effective at inducing antibody responses in humans (Fig. 1). [...]these vaccines often require supplementation with an adjuvant, such as purified saponin (i.e. Matrix-M) and cytosine phosphoguanine (CpG), which tend to increase the risk of acute adverse events.2 Although each vaccine platform targeting SARS-CoV-2 has a unique mixture of benefits and disadvantages, the vast majority employ an intramuscular route of administration, which is very safe and can be easily delivered in a variety of clinical settings. Mucosal vaccines, which are administered intranasally or through inhalation, have shown promise to generate strong mucosal immune responses; however, specific challenges exist when attempting to adapt intramuscular platforms for mucosal delivery, resulting in reduced vaccine effectiveness.3 In their recent publication in Nature Biomedical Engineering,1 Weiqi Hong and colleagues used a novel approach to overcome many of these challenges, developing a two-component COVID-19 intranasal vaccine comprised of a human Ad5 vector expressing the full spike protein of the Omicron XBB.1.5 variant (Ad5XBB.1.5) and a recombinant spike receptor binding domain (RBD) protein (RBDXBB.1.5-HR). Non-spike proteins, including envelope, membrane and nucleocapsid, are commonly targeted by antigen-specific T-cells generated following infection and have been shown to correlate with protection in individuals where exposure was likely.4 Further, vaccines coding both spike and nucleocapsid antigens have been demonstrated to provide long-term protection in mouse models of infection.5 Hence, the development of multi-antigenic COVID-19 mucosal vaccines that contain spike and non-spike proteins and target mucosal immunity could present a next-generation solution that offers broad and durable immunity against current and future variants of SARS-CoV-2.