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Despite a lack of clinical data demonstrating the effectiveness of alcohol swab cleansing prior to vaccinations as a prophylactic measure to prevent skin infections, it is recommended for vaccine administration by the Canadian Immunization Guide. The objective of this study was to evaluate the risk of adverse events after omitting alcohol skin cleansing in long-term care (LTC) residents receiving vaccinations during the COVID-19 pandemic. Two medium-sized LTC homes participated in a cohort study, whereby one LTC used alcohol swab cleansing prior to resident vaccinations and the other did not. All residents received two doses of the BNT162b2 COVID-19 vaccine separated by an average (SD) 29.3 (8.5) days. The electronic chart records of participants were reviewed by researchers blinded to group allocation to assess for the presence of adverse events following immunization (AEFI), including reactogenicity, cellulitis, abscess, or systemic reactions. Log-binomial regression was used to compute risk ratios (with 95% confidence intervals) of an AEFI according to alcohol swab status. 189 residents were included, with a total of 56 AEFI between the two doses. The risk of reactogenicity (adjusted RR 0.54, 95% CI 0.17-1.73) or systemic reactions (adjusted RR 0.75, 95% CI 0.26-2.13) did not differ for the residents that received alcohol skin antisepsis compared to those that did not. There were no cases of cellulitis or abscess. This study did not demonstrate an elevated risk of AEFI in LTC residents receiving two doses of the BNT162b2 mRNA COVID vaccine without alcohol skin antisepsis.

Background: Oral mucositis is a painful and debilitating condition that occurs in the majority of head and neck cancer patients receiving radiation and/or chemotherapy. While some patient and treatment related factors are known to contribute to the incidence and severity of disease, reliable biomarkers remain elusive. In the following study, we investigated the association of salivary DNA methylation derived biological aging, cellular frequency and protein concentration measures with the severity of oral mucositis and overall survival in a cohort of head and neck cancer (HNC) patients (n = 103)., Methods: DNA methylation profiling was performed on saliva samples obtained prior to treatment. Biological aging measures included Horvath2, PhenoAge, FitAge and GrimAge, and cellular frequency included epithelial and specific immune cell populations., Results: Severe mucositis (i.e. grade 3 or 4) occurred in nearly half of patients. For malignant HNC patients (n = 84), every 1-SD increase in GrimAge was associated with 2.62-times risk of severe mucositis (95 % CI: 1.38, 5.57), while a 1-SD increase in monocyte frequency was associated with a decreased risk (OR [95 %CI]: 0.40 [0.18, 0.80]). Over a median follow-up of 53 months, 39 of 103 participants died. Six protein scores (TNFSF14, GCSF, MATN3, GDF8, nCDase, TNF-β) were associated with survival at q < 0.15., Conclusion: We provide evidence that the risk-related biological aging measure GrimAge may be a useful predictor of mucositis severity in HNC patients. Salivary monocyte frequency may be protective against mucositis, and this measure could be used as a predictive biomarker while also providing clues into the pathobiology of the disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Functional decline following hospitalization remains an important problem in health care, especially for frail older adults. Modifiable factors related to reduction in harms of hospitalization are not well described. One particularly pervasive factor is emergency department (ED) boarding time; time waiting from decision to admit, until transfer to an in-patient medical unit. We sought to investigate how the functional status of frail older adults correlated with the length of time spent boarded in the ED. We found that patients who waited for 24 hours or more exhibited functional decline in both the Barthel Index and Hierarchical Assessment of Balance and Mobility and an increase in the Clinical Frailty Scale from discharge to 6 months post discharge. In conclusion, there is a need for additional investigation into ED focused interventions to reduce ED boarding time for this population or to improve access to specialized geriatric services within the ED.

Aim: Transanal total mesorectal (taTME) excision is a method used to assist in the radical removal of the rectum. By adopting the concept of natural orifice surgery, it offers potential benefits over conventional techniques. Early enthusiasm for this strategy led to its rapid and widespread adoption. The imposing of a local moratorium was precipitated by the discovery in Norway of an uncommon multifocal pattern of locoregional recurrence. The aim of this systematic review and meta-analysis was to determine the incidence of local recurrence after taTME for rectal cancer., Method: Conforming to the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines checklist, a systematic review and meta-analysis was conducted. This included case series and comparative studies between taTME and preferentially laparoscopic procedures published between 2010 and 2021., Results: There were a total of 1175 studies retrieved. After removal and screening for quality and relevance, the final analysis contained 40 studies. The local recurrence rate following taTME was 3.4% (95% CI 2.9%-3.9%, I 2  = 0%) in 4987 patients with follow-up durations ranging from 0.7 to 5.5 years. Compared with laparoscopic TME, local recurrence was not statistically different for the taTME group (p = 0.076); however, it was less probable (OR = 0.51, 95% CI 0.24-1.09, I 2  = 0%). Systemic recurrence and circumferential resection margin status were secondary outcomes; however, the differences were not statistically significant., Conclusion: Our data suggest that the local recurrence for regular laparoscopic and transanal TME surgeries may be comparable, suggesting that taTME can be performed without influencing locoregional oncological outcomes in patients treated at specialized institutions and who have been cautiously selected., (© 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: Understanding how health trajectories are related to the likelihood of adverse outcomes and healthcare utilization is key to planning effective strategies for improving health span and the delivery of care to older adults. Frailty measures are useful tools for risk stratification in community-based and primary care settings, although their effectiveness in adults younger than 60 is not well described., Methods: We performed a 10-year retrospective analysis of secondary data from the Ontario Health Study, which included 161,149 adults aged ≥ 18. Outcomes including all-cause mortality and hospital admissions were obtained through linkage to ICES administrative databases with a median follow-up of 7.1-years. Frailty was characterized using a 30-item frailty index., Results: Frailty increased linearly with age and was higher for women at all ages. A 0.1-increase in frailty was significantly associated with mortality (HR = 1.47), the total number of outpatient (IRR = 1.35) and inpatient (IRR = 1.60) admissions over time, and length of stay (IRR = 1.12). However, with exception to length of stay, these estimates differed depending on age and sex. The hazard of death associated with frailty was greater at younger ages, particularly in women. Associations with admissions also decreased with age, similarly between sexes for outpatient visits and more so in men for inpatient., Conclusions: These findings suggest that frailty is an important health construct for both younger and older adults. Hence targeted interventions to reduce the impact of frailty before the age of 60 would likely have important economic and social implications in both the short- and long-term., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

A key hallmark in the age-related dysfunction of physiological systems is disruption related to the regulation of inflammation, often resulting in a chronic, low-grade inflammatory state (i.e., inflammaging). In order to understand the causes of overall system decline, methods to quantify the life-long exposure or damage related to chronic inflammation are critical. Here, we characterize a comprehensive epigenetic inflammation score (EIS) based on DNA methylation loci (CpGs) that are associated with circulating levels of C-reactive protein (CRP). In a cohort of 1446 older adults, we show that associations to age and health-related traits such as smoking history, chronic conditions, and established measures of accelerated aging were stronger for EIS than CRP, while the risk of longitudinal outcomes such as outpatient or inpatient visits and increased frailty were relatively similar. To determine whether variation in EIS actually reflects the cellular response to chronic inflammation we exposed THP1 myelo-monocytic cells to low levels of inflammatory mediators for 14 days, finding that EIS increased in response to both CRP (p = 0.011) and TNF (p = 0.068). Interestingly, a refined version of EIS based only on those CpGs that changed in vitro was more strongly associated with many of the aforementioned traits as compared to EIS. In conclusion, our study demonstrates that EIS outperforms circulating CRP with regard to its association to health-traits that are synonymous with chronic inflammation and accelerated aging, and substantiates its potential role as a clinically relevant tool for stratifying patient risk of adverse outcomes prior to treatment or following illness., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objectives: To identify factors that contribute to protection from infection with the Omicron variant of SARS-CoV-2 in older adults in nursing and retirement homes., Design: Longitudinal cohort study with retrospective analysis of infection risk., Setting and Participants: 997 residents of nursing and retirement homes from Ontario, Canada, in the COVID in LTC study., Methods: Residents with 3 messenger RNA (mRNA) dose vaccinations were included in the study. SARS-CoV-2 infection was determined by positive nasopharyngeal polymerase chain reaction test and/or circulating antinucleocapsid IgG antibodies. Cumulative probability of Omicron infection after recent COVID-19 was assessed by log-rank test of Kaplan-Meier curves. Cox regression was used to assess risk of Omicron infection by age, sex, mRNA vaccine combination, whether individuals received a fourth dose, as well as recent COVID-19., Results: In total, 171 residents (17.2%) had a presumed Omicron variant SARS-CoV-2 infection between December 15, 2021 (local start of the first Omicron wave) and May 3, 2022. Risk of Omicron infection was not different by age [hazard ratio (95% confidence interval) 1.01 (0.99‒1.02)], or in women compared with men [0.97 (0.70‒1.34)], but infection risk decreased 47% with 3 vaccine doses of mRNA-1273 (Moderna) compared with BNT162b2 (Pfizer) [0.53 (0.31-0.90)], 81% with any fourth mRNA vaccine dose [0.19 (0.12‒0.30)], and 48% with SARS-CoV-2 infection in the 3 months prior to beginning of the Omicron wave [0.52, (0.27‒0.99)]., Conclusions and Implications: Vaccine type (ie, mRNA-1273/Spikevax vs BNT162b2/Cominarty), any fourth vaccine dose, and hybrid immunity from recent COVID-19, were protective against infection with the Omicron variant. These data emphasize the importance of vaccine type, and number of vaccine doses, in maintenance of protective immunity and reduction of risk of Omicron variant breakthrough infection. These findings promote continued public health efforts to support vaccination programs and monitor vaccine immunogenicity in older adults., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Granzymes are a family of serine-proteases that act as critical mediators in the cytolytic and immunomodulatory activities of immune cells such as CD8 + T-cells and natural killer (NK) cells. Previous work indicates that both granzyme B (GZB) and K (GZK) are increased with age in CD8 + T-cells, and in the case of GZB, contribute to dysfunctional immune processes observed in older adults. Here, we sought to determine how GZB and GZK expression in NK-cells, and CD4 + , CD8 + , and gamma-delta T-cells, quantified in terms of positive cell frequency and mean fluorescence intensity (MFI), differed with age, age-related health-traits and the antibody response to high-dose influenza vaccine. We found that the frequency and MFI of GZB-expressing NK-cells, and CD8 + and Vδ1+ T-cells, and GZK-expressing CD8 + T-cells was significantly higher in older (66-97 years old; n = 75) vs. younger (24-37 years old; n = 10) adults by up to 5-fold. There were no significant associations of GZB/GZK expression with sex, frailty or plasma levels of TNF or IL-6 in older adults, but those who were seropositive for cytomegalovirus (CMV) exhibited significantly higher frequencies of GZB+ NK-cells, and CD4 + , CD8 + and Vδ1+ T-cells, and GZK+ CD8 + T-cells (Cohen's d = .5-1.5). Pre-vaccination frequencies of GZB+ NK-cells were positively correlated with vaccine antibody responses against A/H3N2 (d = .17), while the frequencies of GZK+ NK and CD8 + T-cells were inversely associated with A/H1N1 (d = -0.18 to -0.20). Interestingly, GZK+ NK-cell frequency was inversely correlated with pre-vaccination A/H1N1 antibody titres, as well as those measured over the previous 4 years, further supporting a role for this subset in influencing vaccine antibody-responses. These findings further our understanding of how granzyme expression in different lymphoid cell-types may change with age, while suggesting that they influence vaccine responsiveness in older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Verschoor, Picard, Andrew, Haynes, Loeb, Pawelec and Kuchel.)

Background: Rhino-enteroviruses, particularly enterovirus strain D68 (EV-D68), have been associated with severe respiratory distress in children. The goal of this study was to compare the long-term outcomes of children with EV-D68 infection to that of children with other enterovirus / rhinovirus., Methods: Nasopharyngeal swabs from 174 children presenting with respiratory distress were tested by PCR for respiratory viruses. The primary outcome was diagnosis of a chronic respiratory condition within the follow-up period. Admission to intensive care, and length of stay were recorded. Odds ratios were determined using multinomial logistic regression., Results: During 5 years of follow-up, the crude odds of diagnosis with a chronic respiratory condition were significantly more likely in EV-D68 cases (OR: 1.95, 95% CI: 1.02, 3.82), but failed to remain significant after adjusting for a past history of asthma. Upon admission for a primary concern of asthma, length of stay both in hospital and intensive care were significantly longer in EV-D68 cases (OR: 2.10 [95% CI: 1.56, 2.82, p < 0.001]) and (OR: 5.18 [95% CI: 1.90, 6.28, p < 0.001]), respectively. After adjustment for a history of asthma, EV-D68 cases had significantly longer length of stay in hospital, admitted for 1.94 days for each day that controls were admitted (95% CI: 1.40, 2.68). In admissions to intensive care, EV-D68 cases spent 2.74 days for each day of admission in controls (95% CI: 1.62, 4.97, p < 0.001)., Conclusions: Ours is first study to assess prognostic respiratory outcomes of patients infected with EV-D68 in childhood. Our study finds that EV-D68 cases were significantly more likely be hospitalized for longer than other enterovirus/rhinovirus controls in subsequent admissions for respiratory distress. Need for intensive care was significantly longer in EV-D68 infections. Our next steps will be validation in a larger sample size., (© 2022 The Author(s).)

Objectives: CARD (comfort, ask, relax, distract) is a vaccine delivery framework that includes interventions to improve the patient's experience. CARD has not been previously implemented in long-term care (LTC) settings. This study evaluated drivers to implementation for COVID-19 vaccinations in an LTC facility., Methods: Postimplementation interpretive evaluation including qualitative interviews and quantitative surveys with eight participants. The Consolidated Framework for Implementation Research (CFIR) was used for analysis. Adverse reactions to vaccinations and CARD interventions, including local reactogenicity and systemic reactions, were abstracted from medical charts of residents., Results: Eight CFIR constructs emerged. Staff perceived CARD was complex because it added steps to vaccination delivery. Motivated to meet residents' needs, a receptive implementation climate of support among staff led to using strategies within CARD, such as administering topical anesthetics and omitting alcohol skin antisepsis prior to injections. Having an effective network like the residents council positively influenced implementation by allowing residents to voice their opinions. Facilitators to implementation included staff knowledge and beliefs and staff's commitment to their organization, which was focused on person-centered care. Barriers included lack of available resources (inadequate staffing), insufficient communication between management and staff and lack of awareness of CARD, and external policies not aligned with CARD. Chart reviews conducted for 93 vaccinated residents corroborated perceptions of vaccination and CARD intervention safety, revealing a low rate of local and systemic adverse reactions and no cases of skin infection., Discussion: We identified positive and negative implementation drivers. Future research is recommended to expand the strategies employed and involve residents more directly., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Dyspnea is associated with functional impairment and impaired quality of life. There is limited information on the potential risk factors for dyspnea in an older adult population., Objectives: Among older adults aged 45 to 85 years of age, what sociodemographic, environmental, and disease related factors are correlated with dyspnea?, Design: We used cross-sectional questionnaire data collected on 28,854 participants of the Canadian Longitudinal Study of Aging (CLSA). Multinomial regression was used to assess the independent effect of individual variables adjusting for the other variables of interest., Key Results: The adjusted odds ratios for dyspnea "walking on flat surfaces" were highest for obesity (OR, 5.71; 95%CI, 4.71-6.93), lung disease (OR, 3.91; 95%CI, 3.41-4.49), and depression (OR, 3.68; 95%CI, 3.15-4.29), and were greater than 2 for lower income, and heart disease. The effect of diabetes remained significant after adjusting for sociodemographics, heart disease and BMI (OR, 1.61; 95%CI, 1.39-1.86). Those with both respiratory disease and depression had a 12.78-fold (95%CI, 10.09-16.19) increased odds of exertional dyspnea, while the corresponding OR for the combination of heart disease and depression was 18.31 (95%CI, 13.4-25.01)., Conclusions: In a community sample of older adults, many correlates of dyspnea exist which have significant independent and combined effects. These factors should be considered in the clinical context where dyspnea is out of proportion to the degree of heart and lung disease. Whether or not diabetes may possibly be a risk factor for dyspnea merits further investigation., (© 2022. Crown.)

Background: Young children are at high risk for developing complications of influenza, as well as severe clinical presentation of disease. Vaccination provides direct protection and reduces symptom severity in breakthrough infections. We assessed whether adjuvanted trivalent seasonal influenza vaccine is associated with symptom severity in children who developed laboratory-confirmed influenza, as compared to children who received quadrivalent inactivated influenza., Methods: A cluster randomized controlled trial of influenza vaccines in Canadian Hutterite colonies was conducted from the 2016-2017 to the 2018-2019 influenza season. Children were vaccinated with either quadrivalent inactivated influenza vaccine (QIV), or the MF59 adjuvanted trivalent influenza vaccine (aTIV). We assessed children who developed PCR-confirmed influenza infection for symptom severity outcomes using multivariable generalized negative binomial regression., Results: Among vaccinated children, 49 infections were observed across 1779 person-days. Vaccine formulation (aTIV vs QIV) was not significantly associated with composite symptom outcomes, including total number of symptoms or total duration of symptom presentation ( p > 0.05 for all outcomes). Receipt of aTIV vaccination was significantly associated with attenuation of fever, with an estimated 74% reduction in fever severity. In influenza A type infections, adjuvanted vaccination was significantly associated with reduced systemic symptoms (incidence rate ratios: 0.16, 95% confidence intervals: 0.03, 0.64, p  = 0.01). No associations were observed between vaccine formulation and symptom severity in influenza B infections., Conclusions: In vaccinated children who develop an influenza infection, vaccine formulation was associated with attenuated fever severity, leading to reduced systemic symptoms. In influenza A infections, adjuvanted vaccination was significantly associated with reduced systemic symptoms., Conclusions: Clinical Trials Registry: NCT02871206., (© 2022 The Author(s). Published by Elsevier Ltd on behalf of Tsinghua University Press.)

Background: Biological aging represents a loss of integrity and functionality of physiological systems over time. While associated with an enhanced risk of adverse outcomes such as hospitalization, disability and death following infection, its role in perceived age-related declines in vaccine responses has yet to be fully elucidated. Using data and biosamples from a 4-year clinical trial comparing immune responses of standard- and high-dose influenza vaccination, we quantified biological age (BA) prior to vaccination in adults over 65 years old (n = 292) using a panel of ten serological biomarkers (albumin, alanine aminotransferase, creatinine, ferritin, free thyroxine, cholesterol, high-density lipoprotein, triglycerides, tumour necrosis factor, interleukin-6) as implemented in the BioAge R package. Hemagglutination inhibition antibody titres against influenza A/H1N1, A/H3N2 and B were quantified prior to vaccination and 4-, 10- and 20- weeks post-vaccination., Results: Counter to our hypothesis, advanced BA was associated with improved post-vaccination antibody titres against the different viral types and subtypes. However, this was dependent on both vaccine dose and CMV serostatus, as associations were only apparent for high-dose recipients (d = 0.16-0.26), and were largely diminished for CMV positive high-dose recipients., Conclusions: These findings emphasize two important points: first, the loss of physiological integrity related to biological aging may not be a ubiquitous driver of immune decline in older adults; and second, latent factors such as CMV infection (prevalent in up to 90% of older adults worldwide) may contribute to the heterogeneity in vaccine responses of older adults more than previously thought., (© 2022. The Author(s).)

People exposed to adverse childhood experiences (ACEs) suffer from an increased risk of chronic disease and shorter lifespan. These individuals also tend to exhibit accelerated reproductive development and show signs of advanced cellular aging as early as childhood. These observations suggest that ACEs may accelerate biological processes of aging through direct or indirect mechanisms; however, few population-based studies have data to test this hypothesis. We analysed ACEs and biological aging data from the Canadian Longitudinal Study on Aging (CLSA; n = 23,354 adults aged 45-85) and used the BioAge R package to compute three indices of biological aging from blood-chemistry and organ-function data: Klemera-Doubal method (KDM) biological age, phenotypic age (PA), and homeostatic dysregulation (HD). Adults with ACEs tended to be biologically older than those with no ACEs, although the observed effect-sizes were small (Cohen's d<0.15), with the exception of neglect (d=0.35 for KDM and PA). Associations were similar for men and women and tended to be smaller for older as compared to midlife participants. Subtypes of ACEs perceived as being more severe (e.g., being pushed or kicked, experiencing forced sexual activity, witnessing physical violence) and more frequent and diverse exposures were associated with relatively larger effect-sizes. These findings support the hypothesis that ACEs contribute to accelerated biological aging, although replication is needed in studies with access to prospective records of ACEs and cellular-level measurements of biological aging. Furthermore, future work to better understand the degree to which associations between ACEs and biological aging are moderated by specific life-course pathways, and mediated by lifestyle and socioeconomic factors is warranted., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: We declare no competing interests.

Background: With increasing age, overall health declines while systemic levels of inflammatory mediators tend to increase. Although the underlying mechanisms are poorly understood, there is a wealth of data suggesting that this so-called "inflammaging" contributes to the risk of adverse outcomes in older adults. We sought to determine whether markers of systemic inflammation were associated with antibody responses to the seasonal influenza vaccine., Results: Over four seasons, hemagglutination inhibition antibody titres and ex vivo bulk peripheral blood mononuclear cell (PBMC) responses to live influenza viruses assessed via interferon (IFN)-γ/interleukin (IL)-10 production, were measured pre- and 4-weeks post-vaccination in young adults (n = 79) and older adults randomized to standard- or high-dose inactivated vaccine (n = 612). Circulating tumour necrosis factor (TNF), interleukin (IL)-6 and C-reactive protein (CRP) were also measured pre-vaccination. Post-vaccination antibody titres were significantly associated with systemic inflammatory levels; specifically, IL-6 was positively associated with A/H3N2 titres in young adults (Cohen's d = 0.36), and in older high-dose, but not standard-dose recipients, all systemic inflammatory mediators were positively associated with A/H1N1, A/H3N2 and B titres (d = 0.10-0.45). We further show that the frequency of ILT2(+)CD57(+) CD56-Dim natural killer (NK)-cells was positively associated with both plasma IL-6 and post-vaccination A/H3N2 titres in a follow-up cohort of older high-dose recipients (n = 63). Pathway analysis suggested that ILT2(+)CD57(+) Dim NK-cells mediated 40% of the association between IL-6 and A/H3N2 titres, which may be related to underlying participant frailty., Conclusions: In summary, our data suggest a complex relationship amongst influenza vaccine responses, systemic inflammation and NK-cell phenotype in older adults, which depends heavily on age, vaccine dose and possibly overall health status. While our results suggest that "inflammaging" may increase vaccine immunogenicity in older adults, it is yet to be determined whether this enhancement contributes to improved protection against influenza disease., (© 2022. The Author(s).)

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., Competing Interests: The authors have declared that no competing interests exist.

Aim: The main objective of this study was to compare the oncological outcomes of patients undergoing abdominoperineal resection (APR) versus low anterior resection (LAR) through a transanal total mesorectal excision (taTME) approach., Method: A total of 360 adult patients with a diagnosis of rectal cancer were enrolled at participating centres from the Canadian taTME Expert Collaboration. Forty-three patients received taTME-APR and received 317 taTME-LAR. Demographic, operative, pathological and follow-up data were collected and merged into a single database. Results are presented as hazard ratio (HR) and 95% confidence interval. All analyses were performed in the R environment (v.3.6)., Results: The proportion of patients with a positive circumferential radial margin status was higher in the taTME-APR group than the taTME-LAR group (21% vs. 9%, p = 0.001). Complete TME was achieved in 91% of those undergoing APR compared with 96% of those undergoing LAR (p = 0.25). APR was associated with a greater rate of local recurrence relative to LAR, although it was not significant [crude HR = 3.53 (95% CI 0.92-13.53)]. Circumferential margin positivity was significantly associated with a higher rate of systemic recurrence [crude HR = 3.59 (95% CI 1.38-9.3)]., Conclusion: Our results demonstrate inferior outcomes in those undergoing taTME-APR compared with taTME-LAR. The use of this technique for this particular indication needs to be carefully considered., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Competing Interests: We declare no competing interests.

Introduction: Frailty in older adults, characterized by a decline in multiple physiological systems and increasing vulnerability to loss of independence, disability, and death, is a public health priority in developed countries. Etiology of frailty extends across the lifespan and may begin in early life, but empirical evidence for this association is scarce. In this study, we examined whether adverse childhood experiences (ACEs) are associated with frailty in later life., Methods: We conducted a cross-sectional analysis of data for a population-based sample of 27,748 adults aged 45-85 years from the Canadian Longitudinal Study on Aging. The frailty index (FI) was computed with 76 health-related characteristics of physical and cognitive performance, self-rated health, chronic conditions, visual and hearing ability, activities of daily living, and well-being. Self-reported exposure to ACEs included physical, emotional, and sexual abuse, neglect, and witnessing intimate partner violence prior age of 16 and parental death, divorce, and living with a family member with mental illness prior age of 18. Generalized linear regression models with gamma error distribution and identity link function, adjusted for age and sex, were used to examine associations of each ACE type and the number of ACE types (0, 1, 2, or 3+) reported by an individual with FI. All models were adjusted for income, education, smoking, and alcohol consumption in sensitivity analysis., Results: Individuals exposed to ACEs had elevated levels of FI (mean = 0.13, SD = 0.09) than those unexposed, with the largest difference observed for neglect (B [95% CI]: 0.05 [0.04, 0.06]) and the smallest for parental death and divorce (0.015 [0.01,0.02]). The ACE count was associated with frailty in a graded manner, with the FI difference reaching 0.04 [0.037, 0.044] for participants exposed to 3+ ACE types. The association between ACEs and frailty tended to be stronger for women than men and for men aged 45-64 years than older men., Conclusions: Our study supports previous studies showing that exposure to ACEs is associated with frailty in adults. Our findings suggest that screening for ACEs involving childhood maltreatment may be useful for identifying individuals at risk of frailty and prevention of ACEs may have long-term benefits for healthy aging., (© 2021 S. Karger AG, Basel.)

Measures of obesity, including body mass index (BMI) and waist circumference (WC), do not fully capture the complexity of obesity-related health risks. This study identified distinct classes of obesity-related characteristics and evaluated their associations with BMI, WC, and percent body fat (%BF) using cross-sectional data from 30,096 participants aged 45-85 in the Canadian Longitudinal Study on Aging (2011-2015). Sixteen obesity-related variables, including behavioural, metabolic, physical health, and mental health/social factors, were included in a latent class analysis to identify distinct classes of participants. Adjusted odds ratios (OR) were estimated from logistic regression for associations between each class and obesity defined by BMI, WC and %BF. Six latent classes were identified: "low-risk" (39.8%), "cardiovascular risk" (19.4%), "metabolic risk" (16.9%), "sleep and mental health risk" (12.1%), "multiple and complex risk" (6.7%), and "cardiometabolic risk" (5.1%). Compared to "low-risk", all classes had increased odds of BMI-, WC- and %BF-defined obesity. For example, the "complex and multiple risk" class was associated with obesity by BMI (OR: 10.70, 95% confidence interval (CI): 9.51, 12.04), WC (OR: 9.21, 95% CI: 8,15, 10,41) and %BF (OR: 7.54, 95% CI: 6.21, 9.16). Distinct classes of obesity-related characteristics were identified and were strongly associated with obesity defined by multiple measures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Recent studies have demonstrated that even in the absence of lung impairment as determined by spirometry, smoking and respiratory symptoms are associated with poor overall health and well-being. However, this relationship is not well defined; and it remains unclear the degree to which symptoms are related to poor health, independent of smoking. This is of particular importance to older adults, as they are more likely to exhibit respiratory symptoms and are, therefore, at risk of not receiving appropriate treatment if they have never smoked and have normal spirometry., Methods: We performed a cross-sectional analysis of data from the Canadian Longitudinal Study on Aging to delineate the associations of respiratory symptoms and smoking on the health of participants age 45-86 who exhibited normal spirometry. Participant health was estimated using a frailty index, a multidimensional measure of vulnerability to adverse outcomes that has been validated in numerous health settings., Results: Of the 21,293 participants included in our analysis, 87% exhibited a normal FEV 1 , FVC, and FEV 1 /FVC; of those, 45% reported at least one respiratory symptom, and 50% were former or current smokers. Both respiratory symptoms and smoking were independently associated with frailty (median interquartile range [IQR] = 0.11 [0.07-0.15]), the most substantial associations observed for those having at least one respiratory symptom (adjusted β 0.023, 95% CI 0.022-0.025) and current smokers with > 10 pack-year exposure (adjusted β 0.014, 95% CI [0.010-0.019). Not only was the association between symptoms and frailty evident in never smokers, a significant proportion of the total effect of smoking on frailty was observed to be mediated by symptoms., Conclusions: Our data show that respiratory symptoms, regardless of smoking history, were a significant correlate of frailty in older adults with normal spirometry. Hence, they should not be simply regarded as a benign by-product of aging., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2021 by Daedalus Enterprises.)

Background: The trajectory of frailty in older adults is important to public health; therefore, markers that may help predict this and other important outcomes could be beneficial. Epigenetic clocks have been developed and are associated with various health-related outcomes and sociodemographic factors, but associations with frailty are poorly described. Further, it is uncertain whether newer generations of epigenetic clocks, trained on variables other than chronological age, would be more strongly associated with frailty than earlier developed clocks. Using data from the Canadian Longitudinal Study on Aging (CLSA), we tested the hypothesis that clocks trained on phenotypic markers of health or mortality (i.e., Dunedin PoAm, GrimAge, PhenoAge and Zhang in Nat Commun 8:14617, 2017) would best predict changes in a 76-item frailty index (FI) over a 3-year interval, as compared to clocks trained on chronological age (i.e., Hannum in Mol Cell 49:359-367, 2013, Horvath in Genome Biol 14:R115, 2013, Lin in Aging 8:394-401, 2016, and Yang Genome Biol 17:205, 2016)., Results: We show that in 1446 participants, phenotype/mortality-trained clocks outperformed age-trained clocks with regard to the association with baseline frailty (mean = 0.141, SD = 0.075), the greatest of which is GrimAge, where a 1-SD increase in ΔGrimAge (i.e., the difference from chronological age) was associated with a 0.020 increase in frailty (95% CI 0.016, 0.024), or ~ 27% relative to the SD in frailty. Only GrimAge and Hannum (Mol Cell 49:359-367, 2013) were significantly associated with change in frailty over time, where a 1-SD increase in ΔGrimAge and ΔHannum 2013 was associated with a 0.0030 (95% CI 0.0007, 0.0050) and 0.0028 (95% CI 0.0007, 0.0050) increase over 3 years, respectively, or ~ 7% relative to the SD in frailty change., Conclusion: Both prevalence and change in frailty are associated with increased epigenetic age. However, not all clocks are equally sensitive to these outcomes and depend on their underlying relationship with chronological age, healthspan and lifespan. Certain clocks were significantly associated with relatively short-term changes in frailty, thereby supporting their utility in initiatives and interventions to promote healthy aging., (© 2021. The Author(s).)

Previous studies have demonstrated that the status of the T cell compartment and inflammation-related factors are associated with the immunogenicity of the varicella-zoster virus (VZV) vaccine in older adults; however, little is known about the roles of other immune cell subsets known to influence the generation and maintenance of immunological memory. Responses to a live-attenuated VZV vaccine were studied in relation to peripheral blood mononuclear cell (PBMC) composition and function in a sample of 30 nursing home residents (aged 80-99 years). Interferon-gamma enzyme-linked immunospot (ELISPOT) was used to measure VZV responses at baseline and 6 weeks following vaccination, and associations were sought with the frequencies of monocytes and T, B and natural killer (NK) cells and the production and secretion of cytokines following their ex-vivo stimulation with different agents. While only the frequency of interleukin (IL)-6 + CD14 + monocytes was inversely associated with post-vaccination VZV response, amounts of IL-1β, IL-10, IL-17A and tumour necrosis factor (TNF) secreted by PBMCs and the frequency of IL-1β + CD14 + monocytes was positively correlated with pre-vaccination VZV response. Furthermore, both bivariate correlation and causal mediation analyses supported the notion that IL-1β + CD14 + monocytes were significant mediators of the associations between IL-1β and TNF secretion by PBMCs and pre-vaccination VZV responses. Our findings implicate a strong cytokine response mediated by inflammatory IL-1β + monocytes in coordinating responses of long-lived VZV-reactive memory T cells, but with an opposing effect of IL-6 + CD14 + monocytes. Whether monocyte status promotes or inhibits the induction and/or maintenance of these memory T cells later in life has yet to be determined., (© 2021 British Society for Immunology.)

Background: Efforts to improve influenza vaccine effectiveness in older adults have resulted in some successes, such as the introduction of high-dose split-virus influenza vaccine (HD-SVV), yet studies of cell-mediated immune responses to these vaccines remain limited. We have shown that the activity of the cytolytic mediator, granzyme B (GrB), in peripheral blood mononuclear cells (PBMC) challenged with influenza A/H3N2 virus, correlates with protection against influenza following standard dose vaccination (SD-SVV) in older adults. Further, the interferon-γ (IFNγ) to interleukin-10 (IL-10) ratio can be a correlate of protection depending on the timing of vaccination relative to exposure to influenza., Methods: In a double-blind trial (ClinicalTrials.gov NCT02297542) older adults (≥65 years, n=582) were randomized to receive SD-SVV or HD-SVV (Fluzone®) from 2014/15 to 2017/18. Young adults (20-40 years, n=79) received SD-SVV. At 0, 4, 10 and 20 weeks post-vaccination, serum antibody titers, IFNγ, IL-10, and inducible GrB (iGrB) were measured in ex vivo influenza virus-challenged PBMC. iGrB is defined as the fold change in GrB activity from baseline levels (bGrB) in circulating T cells. Responses of older adults were compared to younger controls, while specifically for older adults we analyzed effects of age, sex, cytomegalovirus (CMV) serostatus, frailty, and vaccine dose., Results: Prior to vaccination, younger adults produced significantly higher IFNγ, IL-10 and iGrB levels, but with no difference in the IFNγ:IL-10 ratio. Relative to SD-SVV recipients, older HD-SVV recipients exhibited significantly lower IFNγ:IL-10 ratios at 4 weeks post-vaccination. In contrast, IFNγ and iGrB levels were higher in younger SD vs. older SD or HD recipients; only the HD group showed a significant IFNγ response to vaccination compared to the SD groups while all three groups showed a significant iGrB response to vaccination. In a regression analysis, female sex and HD-SVV were associated with higher IL-10 levels, while SD-SVV was associated with lower iGrB levels. Prior season influenza vaccination showed a decline in iGrB levels but an increase in IFNγ and IL-10 levels, which correlated with influenza A/H3N2 hemagglutination inhibition antibody titers., Conclusions: Overall, HD-SVV amplified the IL-10 response consistent with enhanced antibody responses, with little effect on the iGrB response relative to SD-SVV in either younger or older adults. These results suggest that enhanced protection with HD-SVV is largely antibody-mediated.

The challenge of distinguishing between changes attributable to ageing and those attributable to pathology is even greater for the immune system than for many other organs, and this is especially true for myeloid-derived suppressor cells (MDSCs). Hematopoiesis is different in older adults with a bias towards myelopoiesis, and older adults also manifest "inflammageing" exacerbated by disease and contributing to MDSC induction. Hence, at least in humans, one can only investigate MDSCs in the context of ageing and disease states, and not in the context of ageing processes per se. This contribution provides a brief overview of the literature on MDSCs and ageing in humans., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Transanal total mesorectal excision can be a technically challenging operation to master. While many early adopters have reported adequate outcomes, others have failed to reproduce these results. There are contradicting data on oncologic outcomes during the learning phase of this technique. Thus, our objective was to perform a multicentered assessment of oncological outcomes in patients undergoing transanal total mesorectal excision during the learning phase in a sample of successful adopting centers., Methods: Surgeons from 8 centers with experience in the management of rectal cancer were invited to participate. The initial 51 consecutive benign and malignant cases of the participating units were retrospectively reviewed, but only 366 cancer cases were included in the analysis. Procedures were divided into implementation (ie, the first 10 cases) and postimplementation (ie, case 11 on onwards) groups, and the main outcome was the incidence of local recurrence., Results: The overall prevalence of local recurrence was 4.1% at a median follow-up of 35 months (interquartile range 20.3-44.2); among implementation and postimplementation groups local recurrence was 7.5% and 3.1%, respectively, and the rate of local recurrence was observed to be nearly 60% lower in the postimplementation group (hazard ratio [95% confidence interval] = 0.43 [0.26-0.72]) Total mesorectal excision specimens were complete or nearly complete in 87.7% of cases, and the circumferential and distal margins were clear in 93.2% and 92.6%, respectively CONCLUSION: Local recurrence rate was low during the learning phase of the transanal total mesorectal excision in a sample of rectal cancer surgeons with acceptable surgical and oncologic outcomes. Both the prevalence and rate of local recurrence were markedly lower in the postimplementation phase, indicating improvement as experience accumulated., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1 tm1Mom Il2rg tm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women.

Medroxyprogesterone acetate (MPA) is a frequently used hormonal contraceptive that has been shown to significantly increase HIV-1 susceptibility by approximately 40 %. However, the underlying mechanism by which this occurs remains unknown. Here, we examined the biological response to MPA by vaginal epithelial cells, the first cells to encounter HIV-1 during sexual transmission, in order to understand the potential mechanism(s) of MPA-mediated increase of HIV-1 infection. Using microarray analysis and in vitro assays, we characterized the response of vaginal epithelial cells, grown in biologically relevant air-liquid interface (ALI) cultures, to physiological levels of female sex hormones, estradiol (E2), progesterone (P4), or MPA. Transcriptional profiling of E2, P4 or MPA-treated vaginal epithelial cells indicated unique transcriptional profiles associated with each hormone. MPA treatment increased transcripts of genes related to cholesterol/sterol synthesis and decreased transcripts related to cell division and cell-cell adhesion, results not seen with E2 or P4 treatments. MPA treatment also resulted in unique gene expression indicative of decreased barrier integrity. Functional assays confirmed that MPA, but not E2 or P4 treatments, resulted in increased epithelial barrier permeability and inhibited cell cycle progression. The effects of MPA on vaginal epithelial cells seen in this study may help explain the increase of HIV-1 infection in women who use MPA as a hormonal contraceptive., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Proponents of novel transanal total mesorectal excision (TME) suggest the procedure overcomes the technical and oncologic challenges of conventional approaches for treating rectal cancer. Recently, however, there has been controversy regarding the oncologic safety of the procedure., Objective: To assess the association of transanal TME with the incidence of local recurrence (LR) of cancer and the probability of remaining free of LR during follow-up., Design, Setting, and Participants: This multicenter cohort study used data from 8 high-volume rectal cancer academic institutions from across Canada on all consecutive patients with primary rectal cancer treated by transanal TME at the participating centers. The study was conducted between January 2014 and December 2018, and data were analyzed from April 1, 2020, to September 15, 2020., Exposure: Transanal TME., Main Outcomes and Measures: The incidence of LR was reported as a direct measure of quality of resection. The cumulative probability of LR- and systemic recurrence (SR)-free survival at 36 months was estimated. Local recurrence and SR were defined as radiologic or endoscopic evidence of 1 or more new lesions in or outside the pelvis, respectively, documented during surveillance after the removal of the primary tumor., Results: Of 608 total patients included in the analysis, 423 (69.6%) were male; the median age was 63 years (interquartile range [IQR], 54-70 years). Local recurrence was identified in 22 patients (3.6%) after a median follow-up of 27 months (IQR, 18-38 months). The median time to LR was 13 months (IQR, 9-19 months). Sixteen of the 22 patients with LR (72.7%) were male, 14 (63.6%) received neoadjuvant chemoradiation, and 12 (54.5%) had American Joint Committee on Cancer stage III disease. Of those with LR, 16 (72.7%) had a negative circumferential radial margin and 20 (90.9%) had a negative distal resection margin, 2 (9.1%) experienced conversion to open surgery, and 15 (68.2%) also developed SR. The probability of LR-free survival at 36 months was 96% (95% CI, 94%-98%). According to the Cox proportional hazards regression model, the hazard ratio of LR was estimated to be 4.2 (95% CI, 2.9-6.2) times higher among patients with a positive circumferential radial margin than among those with a negative circumferential radial margin., Conclusions and Relevance: In this cohort study, transanal TME performed by experienced surgeons was associated with an incidence of LR and SR that is in line with the published literature on open and laparoscopic TME, suggesting that transanal TME may be an acceptable approach for management of rectal cancer.

Many studies have shown that estimates of biological age (BA) can predict health-related outcomes in older adults. Often, researchers employ multiple measures belonging to a variety of biological/physiological systems, and assess the validity of BA estimates by how well they approximate chronological age (CA). However, it is not clear whether this is the best approach for judging a BA estimate, or whether certain groups of measures are more informative to this end. Using data from the Canadian Longitudinal Study on Aging, we composed panels of biological measures based on the physiological systems/domains they belong to (blood, organ function, physical/cognitive performance), and also composed a panel of measures that optimized the association of BA with CA. We then compared BA estimates for each according to their association with CA and health-related outcomes, including frailty, multimorbidity, chronic condition domains, disability, and health care utilization. Although BA estimated using all 40 measures (r = 0.74) or our age-optimized panel (r = 0.77) most closely approximated CA, the strength of associations to health-related outcomes was comparable or weaker than that of our panel composed only of physical performance measures (CA r = 0.59). All BA estimates were significantly associated to the outcomes considered, with exception to the neurological and musculoskeletal disease domains, and only varied slightly by sex. In summary, while the approximation of CA is important to consider when estimating BA, the strength of associations to prospective outcomes may be of greater importance. Hence, the context in which BA is estimated should be influenced by an investigator's specific research goals., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite efforts to design better vaccines for older adults, the risk for serious complications of influenza remains disproportionately high. Identifying correlates of vaccine effectiveness and understanding the heterogeneity of health outcomes in older adults are key to the vaccine development pipeline. We sought correlates of protection against laboratory-confirmed influenza illness (LCII) in a 4-year randomized trial of standard versus high-dose influenza vaccination of adults 65 years and older. To this end, we quantified serum hemagglutination-inhibition (HAI) titers and interferon-gamma (IFNγ) and interleukin-10 (IL-10) secretion by virus-challenged peripheral blood mononuclear cells. Of the 608 participants included, 26 developed either A/H3N2-( n = 17) or B-LCII ( n = 9) at 10-20 weeks post-vaccination. Antibody titres for A/H3N2 at 4-weeks post-vaccination were significantly associated with protection against LCII, where every 1-standard deviation increase reduced the odds of A/H3N2-LCII by 53%. Although B-titres did not correlate with protection against B-LCII, the fold-increase in IFNγ:IL-10 ratios from pre- to 4-weeks post-vaccination was significantly associated with protection against B-LCII, where every 1-standard deviation increase reduced the odds by 71%. Our results suggest that both antibody and cell-mediated immune measures are valuable and potentially complementary correlates of protection against LCII in vaccinated older adults, although this may depend on the viral type causing infection.

Background: Influenza-specific cytolytic T lymphocytes (CTL) have a critical role in clearing the virus from the lungs, but are poorly stimulated by current inactivated influenza vaccines. Our previous work suggests that granzyme B (GrB) activity predicts protection against laboratory-confirmed influenza infection (LCII) in older adults. However, basal GrB (bGrB) activity increases with age and the frequency of GrB + CTL that do not co-express perforin increases following influenza infection, thereby acting as a potential contributor to immune pathology., Objectives: Using data from a 4-year randomized trial of standard- versus high-dose influenza vaccination, we sought to determine whether measurements of GrB activity alone indicate a protective vs. pathologic response to influenza infection. We compared LCII to No-LCII subsets according to: pre-vaccination bGrB activity; and induced GrB activity in ex vivo influenza-challenged peripheral blood mononuclear cells (PBMC) at 4- and 20-weeks post-vaccination., Results: Over four influenza seasons (2014-2018), 27 of 608 adult participants aged 65 years and older developed influenza A/H3N2-LCII (n=18) or B-LCII (n=9). Pre-vaccination, there was a significant correlation between bGrB and ex vivo GrB activity in each of the H3N2-LCII, B-LCII, and No-LCII subsets. Although pre-vaccination ex vivo GrB activity was significantly higher in B-LCII vs. No-LCII with a trend for H3N2-LCII vs. No-LCII, there was no difference in the response to vaccination. In contrast, there was a trend toward increased pre-vaccination bGrB activity and LCII: Odds Ratio (OR) (95% confidence intervals) OR = 1.46 (0.94, 2.33). By 20-weeks post-vaccination, there were significant fold-increases in ex vivo GrB activity specific for the infecting subtype in H3N2-LCII: OR = 1.63 (1.35, 2.00) and B-LCII: OR = 1.73 (1.34, 2.23)., Conclusions: Our results suggest that the poor GrB responses to influenza vaccination that led to development of LCII can be attributed to inactivated formulations rather than the aging immune system since LCII cases generated robust ex vivo GrB responses following natural infection. Further, we identified bGrB as a biomarker of those who remain at risk for LCII following vaccination. Future studies will focus on understanding the mechanisms responsible for the shift in GrB-mediated protection vs. potential immune pathology caused by GrB release., Competing Interests: Conflict of Interest Statement: JEM’s institution has received honoraria for her participation in advisory boards and data safety and monitoring boards from Sanofi, GSK, Seqirus, Merck, Medicago and ResTORbio, and grant funding from the Public Health Agency of Canada. CPV declares no competing interest. GP has received honoraria and research support from Immatics Biotechnologies, Astellas, Celgene, Clasado, GSK, Pfizer, 4D-Pharma, Sanofi, Novovax and Seqirus. LH serves as a paid consultant for Spring Discovery. ML has received honoraria for participation in advisory boards from Seqirus, Sanofi, Merck, Medicago, Pfizer and research support from Seqirus. MKA has received honoraria for advisory activities from Sanofi, Pfizer and Seqirus and grant funding from GSK, Sanofi, Pfizer, Public Health Agency of Canada, Canadian Immunity Task Force and Canadian Frailty Network. GAK has served as consultant for ResTORbio, Janssen and Spring Discovery.

Background: Management of rectal cancer has a number of potentially appropriate alternatives for each patient. Despite acceptance of standards, practices may vary among regions. There is significant paucity of data in this area. The objective was to create a snapshot of the regional differences., Design: This online survey included 10 questions. Enquiries focused on controversial topics, on surgeon and hospital volume, surgical margins, appropriateness of surgical approaches and techniques, watch-and-wait strategies, and total neoadjuvant therapy. Major colorectal surgery societies around the world were asked to invite their members to complete the survey., Outcome Measures: Frequency of responses across regions within each question was compared by Fisher's exact test., Results: Seven hundred and fifty-three participants from 60 countries responded. Eight regions were identified, and four had sufficient representation for comparisons. Similarities and differences in the therapies among these regions were identified. Robotic surgery penetrance is higher in North America, and watch and wait is more accepted in South America. Patients in Oceania are more likely to be diverted; Europe has more usage of taTME., Discussion: This online survey was practical as a mean to provide a rapid assessment of the international picture on consistency and variability of rectal cancer patients' care, and to potentially identify opportunities to standardized care to patients. Medical surveys have inherent limitations; pertinence to our study is selection bias., Conclusions: The management of rectal cancer varies among different regions. Identification of differences is important when considering global efforts to improve management and interpret data.

Circulating concentrations of brain-derived neurotrophic factor (BDNF) have been linked to cancer, neuropsychiatric, diabetes, and gynecological disorders. However, factors influencing plasma storage and subsequent BDNF quantification are incompletely understood. Therefore, the anticoagulant used in plasma separator tubes, storage-time, storage-temperature, and repeated freeze-thaw cycles on circulating BDNF concentrations was evaluated. Peripheral blood samples were collected from healthy women (n = 14) and men (n = 10) recruited prospectively from McMaster University (August 2014). Blood was collected from the cubital vein into plasma separator tubes containing five different anticoagulant systems [K2EDTA, Li-Hep, Li-Hep (gel), Na-Hep, Na-Hep (glass)], and placed on ice for transport to the lab for centrifugation. Plasma samples (n = 16) collected in K2EDTA tubes from women recruited to a previous study (April 2011 to December 2012) were used to determine the effect of multiple freeze-thaw cycles. Plasma BDNF was quantified using a commercially available ELISA kit. Plasma concentrations of BDNF were significantly affected by the type of plasma separator tube, storage-time, and number of freeze-thaw cycles. Storage temperature (- 20 vs. - 80 °C) did not significantly affect the quantity of BDNF measured as mean BDNF concentrations generally fell within our calculated acceptable change limit up to 6 months in the freezer. Our results suggest that for quantification of circulating BDNF blood collected in K2EDTA tubes and plasma stored up to 6 months at either - 20 or - 80 °C produces reproducible results that fall within an acceptable range. However, plasma samples stored beyond 6 months and repeated freeze-thaw cycles should be avoided.

Maintenance of lung function is an often underappreciated, yet critical component of healthy aging. Given the unprecedented shift in the average age of Canadians over the next half century, it will be important to investigate the determinants of lung function in the elderly. In the following study, we estimated the association between lung function and a broad array of factors related to sociodemographics, lifestyle, chronic medical conditions and psychosocial factors in older adults aged 45-86 years old using cross-sectional data from the Canadian Longitudinal Study of Aging (n = 21,338). In addition to examining the entire cohort, we also performed stratified analyses within men/women, adults aged 45-64/65+, and healthy/comorbid. In multivariable regression, our explanatory factors (excluding age, sex, height and ethnicity) were able to explain 17% and 11% of the total variance in FEV 1 and FEV 1 /FVC, respectively. Notable and significant contributions were observed for respiratory disease, smoking, obesity, income, and physical activity, while psychosocial factors mainly exhibited non-significant associations. Generally, these associations were stronger for males than females, and adults 65 and older as compared to those aged 45-64. Our findings indicate that there are pervasive and generally under-recognized sociodemographic and lifestyle factors that exhibit significant associations with FEV 1 and FEV 1 /FVC in older adults. While implication of causality in these relationships is not possible due to the cross-sectional nature of the study, future work aiming to investigate determinants of lung health in older adults may choose to target these factors, given that many are modifiable., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Despite the use of antiretroviral therapy (ART) in HIV-1 infected mothers approximately 5% of new HIV-1 infections still occur in breastfed infants annually, which warrants for the development of novel strategies to prevent new HIV-1 infections in infants. Human milk (HM) exosomes are highly enriched in microRNAs (miRNAs), which play an important role in neonatal immunity. Furthermore, HM exosomes from healthy donors are known to inhibit HIV-1 infection and transmission; however, the effect of HIV-1 on HM exosomal miRNA signatures remains unknown. In this study, we used nCounter NanoString technology and investigated miRNAs expression profiles in first week postpartum HM exosomes from HIV-1 infected and uninfected control mothers (n = 36). Our results indicated that HIV-1 perturbed the differential expression patterns of 19 miRNAs (13 upregulated and 6 downregulated) in HIV-1 infected women compared to healthy controls. DIANA-miR functional pathway analyses revealed that multiple biological pathways are involved including cell cycle, pathways in cancer, TGF-β signaling, FoxO signaling, fatty acid biosynthesis, p53 signaling and apoptosis. Moreover, the receiver operating characteristics (ROC) curve analyses of miR-630 and miR-378g yielded areas under the ROC curves of 0.82 (95% CI 0.67 to 0.82) and 0.83 (95% CI 0.67 to 0.83), respectively highlighting their potential to serve as biomarkers to identify HIV-1 infection in women. These data may contribute to the development of new therapeutic strategies in prevention of mother-to-child transmission (MTCT) of HIV-1.

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., Competing Interests: Competing interestsJEM’s institution has received honoraria for presentations and participation in advisory boards and data safety and monitoring boards and related travel reimbursements from Sanofi, GSK, Pfizer and Merck outside of the submitted work. CPV has no competing interests. MKA has received grant funding from GSK, Sanofi and Pfizer and honoraria from Sanofi and the Canadian Frailty Network. LH and GAK declare no competing interest. GP has received honoraria and research support from Immatics Biotechnologies, Celgene, Pfizer, Sanofi, 4D-Pharma, Clasado and The Croeni Foundation, and consults for Repair Biotechnologies, Inc., (© The Author(s) 2020.)

Objectives: Poor diet due to poor oral health was proposed as a potential mediator of the association between poor oral health and frailty. This study explores the cross-sectional associations between poor oral health, poor diet, and frailty in Canadian adults, aged 45 to 85 years, and then tests whether the expected oral health-frailty association is changed by taking into account the pathway through poor diet., Design: Cross-sectional study., Setting: The baseline wave of the Canadian Longitudinal Study on Aging, a nationally representative population study., Participants: Data from 28 738 community-dwelling participants, aged 45 to 85 years., Measurements: We characterized poor oral health (cumulative count of 24 items of oral health problems), poor diet (scale of poor food consumption from 7 healthy foods groups), and frailty (cumulative frailty index of 76 items). Regression-based path analyses were used to investigate associations between poor oral health, poor diet, and frailty, adjusted for age group, sex, income, smoking, living alone, education, physical activity, social support, and dental visit., Results: Poorer oral health was associated with low income, smoking, low physical activity, low social support, and no dental visit. There were associations between poorer oral health and poorer diet (effect size β adjusted = .40; 95% confidence interval [CI] = .20-.61) and between poorer oral health and increased frailty (β adjusted = .85; 95% CI = .68-1.02). The indirect effect through the path of poor diet was approximately 0.01 (95% CI = 0.01-0.02) (ie, explaining ∼1% of the effect of poor oral health on frailty)., Conclusions: Poor oral health was associated with poor diet and frailty. Each additional oral health problem was associated with an increase of approximately 1 frailty index point, even after full adjustment for poor diet. The indirect effect of poor oral health through poor diet was modest. Though poor oral health was associated with poorer diet quality, a more direct effect of poor oral health on increasing frailty may be indicated. J Am Geriatr Soc 68:959-966, 2020., (© 2020 The American Geriatrics Society.)

Background: Although high-dose (HD) vaccines have been reported to stimulate higher antibody responses compared with standard-dose (SD) influenza vaccines, there have been limited studies on the impact of frailty on such responses., Methods: We conducted a randomized, double-blind trial (2014/2015 to 2017/2018) of SD versus HD trivalent split-virus vaccine (Fluzone) in 612 study participants aged 65+ over 4 influenza seasons. Hemagglutination inhibition antibody titers for influenza H1N1, H3N2, and B vaccine subtypes were measured at baseline and at 4, 10, and 20 weeks postvaccination and frailty was measured using a validated frailty index., Results: Geometric mean antibody titers were significantly higher in HD compared with SD vaccine recipients for all influenza subtypes at all time points postvaccination. However, frailty was positively correlated with 4-week titers and was associated with increased odds of being a vaccine responder. For influenza A subtypes, this was mostly limited to HD recipients., Conclusions: Frailty was associated with higher titers and increased antibody responses at 4 weeks after influenza vaccination, which was partially dependent on vaccine dosage. Chronic inflammation or dysregulated immunity, both of which are commonly observed with frailty, may be responsible, but it requires further investigation., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The most important advancement in the surgical management of rectal cancer has been the introduction of total mesorectal excision (TME). Technical limitations to approaching mid and distal lesions remain. The recently described transanal TME makes it possible to minimize some of the difficulties by improving access. Anastomotic leak is a persistent concern after colorectal surgery no matter what technique is used. The objective of this study was to explore the impact of experience on the incidence of anastomotic leak after transanal TME. Secondary endpoints were local recurrence and margin status., Methods: A retrospective cohort study was conducted over a period of 3 years at a tertiary care center in Northern Ontario with high volume of rectal cancer patients. The initial 100 consecutive patients with rectal neoplasia who had transanal TME surgery were included. All cases were performed by a single team. The main outcome assessed was the incidence of anastomotic leak beyond a pre-determined learning curve, as previously established in the literature. For statistical analysis, associations between patient characteristics and outcomes were estimated using ordinary least squares and logistic regression., Results: Six cases of anastomotic leak occurred over the course of the study, the last of which occurred in the 37th patient. Relative to a baseline anastomotic leak rate of 7.8%, cumulative sum (CUSUM) analysis indicated that a 50% improvement in risk occurred at trial 50 of 85 patients that had an anastomosis performed. Two patients developed local recurrence during the study period. No correlation between learning curve and oncologic outcomes was identified., Conclusions: Proficiency is likely to have a positive effect on the 30-day occurrence of anastomotic leak. Larger studies are required to explore the impact of experience on local recurrence.

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., (Copyright © 2020 Picard, Verschoor, Ma and Pawelec.)

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.

Purpose: The purpose of this review is to investigate the relationship between life-space mobility and cognition in older adults., Methods: MEDLINE, Embase, CINAHL, and PsycINFO were searched through December 2018 for studies containing measures of life-space mobility and cognitive function. Two independent reviewers screened studies. Eligible studies were combined using a random-effects model, and heterogeneity was assessed using the I 2 ., Results: Thirty-five articles were identified for review. A moderate and statistically significant association (pooled r  = 0.30, 95% confidence interval 0.19 to 0.40.) was observed between life-space mobility and cognition among nine studies. Life-space mobility demonstrated small-to-moderate associations with domain-specific cognitive functioning, particularly executive function, learning, memory, and processing speed. Furthermore, individuals who had restricted life-space mobility (Life-Space Assessment ≤ 40) experienced a steeper decline in cognition ( β  = 0.56 and p  = 0.0471) compared to those who did not (Life-Space Assessment ≥ 41)., Conclusion: This review examined the association between life-space mobility and cognitive function in older adults. The results suggest that a moderate relationship between life-space mobility and cognition exists, whether adjusted or unadjusted for covariates such as sociodemographics, mental health, functional capacity, and comorbidities.

Soluble amyloid beta assemblies (Aβ n ) are neurotoxic and play a central role in the early phases of the pathogenesis cascade leading to Alzheimer's disease. However, the current knowledge about the molecular determinants of Aβ n toxicity is at best scant. Here, we comparatively analyze Aβ n prepared in the absence or presence of a catechin library that modulates cellular toxicity. By combining solution NMR with dynamic light scattering, fluorescence spectroscopy, electron microscopy, wide-angle X-ray diffraction and cell viability assays, we identify a cluster of unique molecular signatures that distinguish toxic vs. nontoxic Aβ assemblies. These include the exposure of a hydrophobic surface spanning residues 17-28 and the concurrent shielding of the highly charged N-terminus. We show that the combination of these two dichotomous structural transitions promotes the colocalization and insertion of β-sheet rich Aβ n into the membrane, compromising membrane integrity. These previously elusive toxic surfaces mapped here provide an unprecedented foundation to establish structure-toxicity relationships of Aβ assemblies.

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.