Effectiveness of interventions to address different types of vulnerabilities in community-dwelling older adults: An umbrella review.

Background: Frailty, social isolation, loneliness, and poverty may render older adults vulnerable to social or health stressors. It is imperative to identify effective interventions to address them especially in the context of COVID-19 pandemic. Objective: To identify effective community-based interventions to address frailty, social isolation, loneliness, and poverty among community-dwelling older adults. Design: Umbrella review. Data Source: We systematically searched PubMed, Ovid MEDLINE, Embase, Cochrane CENTRAL, EBM-Reviews, CINAHL via EBSCO, and APA PsycInfo via Ovid from January 2009 to December 2022. Eligibility Criteria: We included systematic reviews or quantitative reviews of non-pharmacologic interventions targeting community-dwelling older adults. Data Selection Extraction and Management: Two review authors independently screened the titles and abstracts, performed data extraction and appraised the methodological quality of the reviews. We used a narrative synthesis approach to summarize and interpret the findings. We assessed the methodological quality of the studies using AMSTAR 2.0 tool. Results: We identified 27 reviews incorporating 372 unique primary studies that met our inclusion criteria. Ten of the reviews included studies conducted in low-middle-income countries. Twelve reviews (46%, 12/26) included interventions that addressed frailty. Seventeen reviews (65%, 17/26) included interventions that addressed either social isolation or loneliness. Eighteen reviews included studies with single component interventions, while 23 reviews included studies with multi-component interventions. Interventions including protein supplementation combined with physical activity may improve outcomes including frailty status, grip strength, and body weight. Physical activity alone or in combination with diet may prevent frailty. Additionally, physical activity may improve social functioning and interventions using digital technologies may decrease social isolation and loneliness. We did not find any review of interventions addressing poverty among older adults. We also noted that few reviews addressed multiple vulnerabilities within the same study, specifically addressed vulnerability among ethnic and sexual minority groups, or examined interventions that engaged communities and adapted programs to local needs. Conclusion: Evidence from reviews support diets, physical activity, and digital technologies to improve frailty, social isolation or loneliness. However, interventions examined were primarily conducted under optimal conditions. There is a need for further interventions in community settings and conducted under real world settings in older adults living with multiple vulnerabilities.

Expression of Inhibitory Receptors TIGIT, TIM-3, and LAG-3 on CD4+ T Cells from Patients with Different Clinical Forms of Chronic Chagas Disease.

T cells are central to the adaptive immune response against Trypanosoma cruzi infection. In chronic Chagas disease (CCD), circulating parasite-specific memory T cells show reduced functionality and increased expression of inhibitory receptors as a result of persistent antigenic stimulation. This phenotype has been linked to progression of cardiac pathology, whereas the presence of polyfunctional T cells shows association with therapeutic success. In this study, we demonstrate that T. cruzi-specific human CD4+ T cells can be identified by their expression of OX40 and CD25 upon in vitro stimulation. We characterized the expression of the inhibitory receptors T cell immunoreceptor with Ig and ITIM domains (TIGIT), T cell Ig and mucin-domain containing-3 (TIM-3), and lymphocyte activation gene 3 (LAG-3) in CD4+ T cells from CCD patients with and without cardiac alterations. Our results show that, independently of their clinical stage, CCD patients present an increased frequency of CD4+ T cells expressing TIGIT in comparison with non-T. cruzi-infected donors. Exposure to parasite Ags increases the expression of TIM-3 in CD4+ T cells from CCD patients, especially in those with cardiac compromise. Upregulation of LAG-3 was also detected in CCD individuals without cardiac manifestations, predominantly within the subpopulation of cells that did not become activated upon stimulation. Further differences were found between groups in the coexpression of these receptors. Blockade of each individual receptor did not affect activation or the production of IFN-γ and IL-10 by CD4+ T cells in response to parasite Ags. Our results suggest a role for TIGIT, TIM-3, and LAG-3 in the modulation of inflammatory phenomena thought to ultimately lead to tissue damage and cardiac pathology.

Trypanosoma cruzi Induces Regulatory B Cell Alterations in Patients With Chronic Chagas Disease.

The clinical evolution of patients with chronic Chagas disease (CCD) is mainly associated with an excessive inflammation and a defective immunomodulatory profile caused by the interaction between T. cruzi and the host. Regulatory B (Breg) cells exert immune suppression mostly through IL-10 production (B10 cells), but also through IL-10-independent mechanisms. Previously, we demonstrated that CCD patients with cardiomyopathy show changes in the ex vivo Breg cell phenotypic distribution although maintain IL-10 production capacity. Here, we sought to identify potential alterations on Breg cells upon in vitro stimulation. Isolated B cells from CCD patients with or without cardiomyopathy and non-infected (NI) donors were stimulated with T. cruzi lysate or CpG + CD40L, and characterized by flow cytometry based on the expression of CD24, CD27, CD38, and the regulatory molecules IL-10 and PD-L1. IL-10 and IL-17 secretion in the supernatant of B cells was evaluated by ELISA. Data showed that T. cruzi stimulation diminished the expression of CD24 and CD38 on CD27- B cells while reducing the percentage of CD24high inside CD27+ B cells. Furthermore, T. cruzi induced a regulatory B cell phenotype by increasing B10 cells and IL-10 secretion in all the groups. The innate-like B10 cells expansion observed in patients with cardiomyopathy would be associated with CD27- B10 cell subsets, while no predominant phenotype was found in the other groups. Patients with cardiomyopathy also displayed higher IL-17 secretion levels in T. cruzi-activated B cells. CpG + CD40L stimulation revealed that B cells from CCD patients and NI donors had the same ability to differentiate into B10 cells and secrete IL-10 in vitro. Additionally, CCD patients showed an increased frequency of CD24-CD27- B cells and a reduction in the percentage of CD24highCD27+ Breg cells, which appeared to be inversely correlated with the presence of T. cruzi DNA in blood. Finally, CCD patients exhibited a higher frequency of PD-L1+ B cells in T. cruzi-stimulated samples, suggesting that IL-10-independent mechanisms could also be tangled in the control of inflammation. Altogether, our results provide evidence about the potential role of Breg cells in the immune response developed against T. cruzi and its contribution to chronic Chagas cardiomyopathy.

Ex vivo characterization of Breg cells in patients with chronic Chagas disease.

Despite the growing importance of the regulatory function of B cells in many infectious diseases, their immunosuppressive role remains elusive in chronic Chagas disease (CCD). Here, we studied the proportion of different B cell subsets and their capacity to secrete IL-10 ex vivo in peripheral blood from patients with or without CCD cardiomyopathy. First, we immunophenotyped peripheral blood mononuclear cells from patients according to the expression of markers CD19, CD24, CD38 and CD27 and we showed an expansion of total B cell and transitional CD24highCD38high B cell subsets in CCD patients with cardiac involvement compared to non-infected donors. Although no differences were observed in the frequency of total IL-10 producing B cells (B10) among the groups, CCD patients with cardiac involvement showed an increased proportion of naïve B10 cells and a tendency to a higher frequency of transitional B10 cells compared to non-infected donors. Our research demonstrates that transitional B cells are greatly expanded in patients with the cardiac form of CCD and these cells retain the ability to secrete IL-10. These findings provide insight into the phenotypic distribution of regulatory B cells in CCD, an important step towards new strategies to prevent cardiomyopathy associated with T. cruzi infection.

Attendance, activation and health profiles of participants, a prospective study on a regional cardiometabolic disease self-management program in Laval, Canada.

BACKGROUND: Chronic diseases are responsible for over 70% of all deaths globally. While some self-management programs have been shown to be efficacious in preventing or altering trajectories for some chronic conditions, scaling-up and sustaining such programs beyond tightly-controlled study conditions remain a major challenge. CISSS-Laval partnered with the Cardiovascular Health Awareness Program team to co-develop Cible-santé/prévention and evaluate the first cohort of participants enrolled in the program, in order to better understand the program's implementation and scope. The objective of the current study was to describe the profile of attendees and the level of engagement of participants in a new, region-wide cardiometabolic disease self-management program offered in Laval, Canada. METHODS: This was a prospective study with no comparison group. Potential participants were identified and referred to the program from April to December 2015 by their primary care health professional practicing in one of the city's interdisciplinary primary care clinics. They had their blood pressure, waist circumference and body mass index measured by trained volunteers, and completed a questionnaire on health habits, level of activation and the risk of developing prediabetes and type 2 diabetes over the next 10 years. RESULTS: A descriptive analysis of the first cohort of 141 Cible-Santé/prévention participants showed very low attendance. Furthermore, only 1 in 10 of enrolled participants completed the full program. The program typically attracted adults with some risk factors associated with their conditions (high waist circumference, obesity), but with an already high level of knowledge, skills and confidence to participate in self-management activities. CONCLUSION: This study provides a portrait of new participants to a self-management cardiometabolic disease program, which highlights the potential of supporting patients ready to make changes but also exposes the difficulty of attracting a larger number and diversity of participants and in encouraging completion of the program.

The cytosolic tryparedoxin peroxidase from Trypanosoma cruzi induces a pro-inflammatory Th1 immune response in a peroxidatic cysteine-dependent manner.

Trypanosoma cruzi cytosolic tryparedoxin peroxidase (c-TXNPx) is a 2-Cys peroxiredoxin (Prx) with an important role in detoxifying host cell oxidative molecules during parasite infection. c-TXNPx is a virulence factor, as its overexpression enhances parasite infectivity and resistance to exogenous oxidation. As Prxs from other organisms possess immunomodulatory properties, we studied the effects of c-TXNPx in the immune response and analysed whether the presence of the peroxidatic cysteine is necessary to mediate these properties. To this end, we used a recombinant c-TXNPx and a mutant version (c-TXNPxC52S) lacking the peroxidatic cysteine. We first analysed the oligomerization profile, oxidation state and peroxidase activity of both proteins by gel filtration, Western blot and enzymatic assay, respectively. To investigate their immunological properties, we analysed the phenotype and functional activity of macrophage and dendritic cells and the T-cell response by flow cytometry after injection into mice. Our results show that c-TXNPx, but not c-TXNPxC52S, induces the recruitment of IL-12/23p40-producing innate antigen-presenting cells and promotes a strong specific Th1 immune response. Finally, we studied the cellular and humoral immune response developed in the context of parasite natural infection and found that only wild-type c-TXNPx induces proliferation and high levels of IFN-γ secretion in PBMC from chronic patients without demonstrable cardiac manifestations. In conclusion, we demonstrate that c-TXNPx possesses pro-inflammatory properties that depend on the presence of peroxidatic cysteine that is essential for peroxidase activity and quaternary structure of the protein and could contribute to rational design of immune-based strategies against Chagas disease.

Participation in the Cardiovascular Health Awareness Program (CHAP) by older adults residing in social housing in Quebec: Social network analysis.

BACKGROUND: The Cardiovascular Health Awareness Program (CHAP) is as a community-based cardiovascular disease prevention program recently adapted to target older adults living in 14 social housing buildings in Ontario (7) and Quebec (7). Social network analysis (SNA) has been used successfully to assess and strengthen participation in health promotion programs. We applied SNA methods to investigate whether interpersonal relationships among residents within buildings influenced their participation in CHAP. METHODS: Our aim was to examine relational dynamics in two social housing buildings in Quebec with low and high CHAP attendance rates, respectively. We used sociometric questionnaires and network analysis for the quantitative phase of the study, supplemented by a phase of qualitative interviews. All residents of both buildings were eligible for the sociometric questionnaire. Respondents for the qualitative interviews were purposively selected to represent the different attendance situations following the principle of content saturation. RESULTS: In total, 69 residents participated in the study, 37 through sociometric questionnaires and 32 in qualitative interviews. Of the latter, 10 attended almost all CHAP sessions, 10 attended once, and 12 attended none. Results of the quantitative analysis phase identified well-known and appreciated local leaders. In Building 1, which had a high attendance rate (34.3%), there was a main leader (in-degree or 'named by others' frequency 23.2%) who had attended all CHAP sessions. In Building 2, which had a low attendance rate (23.9%), none of the leaders had attended CHAP sessions. Results of the qualitative analysis phase showed that residents who did not attend CHAP sessions (or other activities in the building) generally preferred to avoid conflicts, vindictiveness, and gossip and did not want to get involved in clans and politics within their building. CONCLUSION: We identified four potential strategies to increase attendance at CHAP sessions by residents of subsidized housing for older adults: strengthen confidentiality for those attending the sessions; use community peer networks to enhance recruitment; pair attendees to increase the likelihood of participation; and intervene through opinion leaders or bridging individuals.

Implementation of Modified Cardiovascular Health Awareness Program for Canadian Adults on a Waiting List for a Family Physician.

INTRODUCTION: The Cardiovascular Health Awareness Program (CHAP) was originally developed and evaluated as a community-based cardiovascular diseases (CVD) prevention program in communities where access to family physicians was not a significant issue. Many Canadians now face sub-optimal access to a regular source of primary care. Centralized waiting lists and prioritization based on urgency of medical need were created to address this problem. We aimed to assess the acceptability, CVD risk profile, and potential benefits of offering a modified version of CHAP to adults on the waiting list. METHODS: The implementation was conducted in Laval (Canada) between March and June 2016, targeting individuals 40 years of age or older who were registered on the waiting list (GACO) and had a priority code of 3. Participants were invited through a personalized letter to attend sessions in community health centers. During the sessions, participants completed CVD risk profiles, risk of type 2 diabetes questionnaire (CANRISK); had their blood pressure, height and weight as well as waist circumference measured. They also received targeted healthy lifestyle and patient education materials and were referred to local programs including a medical follow-up, when required. RESULTS: A total of 1976 invitation letters were sent resulting in 281 (14.2%) participants. The average age of attendees was 58.1 (SD = 8.2) and a majority were female (58%, n = 163). A third of participants (34.2%, n = 96) had BP ≥140/90 and 11.4% (n = 32) were classified as having a very high risk for developing diabetes. Almost half (41.6%, n = 117) of participants were referred either to health promotion programs offered by local health authorities, to family physicians (4.6%, n = 13) or emergency departments (1.8%, n = 5) for short-term medical assistance. CONCLUSION: Despite low participation rate, many adults on a waiting list had elevated risk for CVD and would greatly benefit from having a regular source of primary care.

Volunteer engagement to inform research on cardiovascular health awareness, Canada.

Volunteers have been extensively used in health promotion programmes. However, they have been less frequently involved in the research process. In its most recent iterations, the Cardiovascular Health Awareness Program (CHAP) integrated volunteers (i) to facilitate CHAP sessions with participating patients for data collection and (ii) to evaluate the intervention. Drawing on the patient and public involvement literature, our research team included volunteers in the data collection and evaluation of CHAP sessions as part of the programme's implementation in the province of Quebec (Canada). We sought volunteers' formal feedback through individual online and phone interviews and through focus groups for each of the four projects conducted in Quebec. We found that volunteers provide valuable insight on the research protocol as well as patient needs. Their feedback led to several modifications to the research protocol and procedures of subsequent CHAP sessions. Changes included involving volunteers at earlier stages of the research process, adding more learning modules and practice sessions during the volunteer training and defining research priorities according to patient needs. Our methodology of engaging volunteers in the research process was useful to gain important and unique insight on patient needs and for future programme planning to modify the research process.

In Silico Guided Discovery of Novel Class I and II Trypanosoma cruzi Epitopes Recognized by T Cells from Chagas' Disease Patients.

T cell-mediated immune response plays a crucial role in controlling Trypanosoma cruzi infection and parasite burden, but it is also involved in the clinical onset and progression of chronic Chagas' disease. Therefore, the study of T cells is central to the understanding of the immune response against the parasite and its implications for the infected organism. The complexity of the parasite-host interactions hampers the identification and characterization of T cell-activating epitopes. We approached this issue by combining in silico and in vitro methods to interrogate patients' T cells specificity. Fifty T. cruzi peptides predicted to bind a broad range of class I and II HLA molecules were selected for in vitro screening against PBMC samples from a cohort of chronic Chagas' disease patients, using IFN-γ secretion as a readout. Seven of these peptides were shown to activate this type of T cell response, and four out of these contain class I and II epitopes that, to our knowledge, are first described in this study. The remaining three contain sequences that had been previously demonstrated to induce CD8+ T cell response in Chagas' disease patients, or bind HLA-A*02:01, but are, in this study, demonstrated to engage CD4+ T cells. We also assessed the degree of differentiation of activated T cells and looked into the HLA variants that might restrict the recognition of these peptides in the context of human T. cruzi infection.

Design and rationale for a pragmatic cluster randomized trial of the Cardiovascular Health Awareness Program (CHAP) for social housing residents in Ontario and Quebec, Canada.

BACKGROUND: The Cardiovascular Health Awareness Program (CHAP) uses volunteers to provide cardiovascular disease (CVD) and diabetes screening in a community setting, referrals to primary care providers, and locally available programs targeting lifestyle modification. CHAP has been adapted to target older adults residing in social housing, a vulnerable segment of the population. Older adults living in social housing report poorer health status and have a higher burden of a multitude of chronic illnesses, such as CVD and diabetes. The study objective is to evaluate whether there is a reduction in unplanned CVD-related Emergency Department (ED) visits and hospital admissions among residents of social seniors' housing buildings receiving the CHAP program for 1 year compared to residents in matched buildings not receiving the program. METHODS/DESIGN: This is a pragmatic, cluster randomized controlled trial in community-based social (subsidized) housing buildings in Ontario and Quebec. All residents of 14 matched pairs (intervention/control) of apartment buildings will be included. Buildings with 50-200 apartment units with the majority of residents aged 55+ and a unique postal code are included. All individuals residing within the buildings at the start of the intervention period are included (intention to treat, open cohort). The intervention instrument consists of CHAP screens for high blood pressure using automated blood pressure monitors and for diabetes using the Canadian Diabetes Risk (CANRISK) assessment tool. Monthly drop-in sessions for screening/monitoring are held within a common area of the building. Group health education sessions are also held monthly. Reports are sent to family doctors, and attendees are encouraged to visit their family doctor. The primary outcome measure is monthly CVD-related ED visits and hospitalizations over a 1-year period post randomization. Secondary outcomes are all ED visits, hospitalizations, quality of life, cost-effectiveness, and participant experience. DISCUSSION: It is anticipated that CVD-related ED visits and hospitalizations will decrease in the intervention buildings. Using the volunteer-led CHAP program, there is significant opportunity to improve the health of older adults in social housing. TRIAL REGISTRATION: ClinicalTrials.gov,NCT03549845. Registered on 15 May 2018. Updated on 21 May 2019.

The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease.

Trypanosoma cruzi interacts with the different arms of the innate and adaptive host's immune response in a very complex and flowery manner. The history of host-parasite co-evolution has provided this protozoan with means of resisting, escaping or subverting the mechanisms of immunity and establishing a chronic infection. Despite many decades of research on the subject, the infection remains incurable, and the factors that steer chronic Chagas disease from an asymptomatic state to clinical onset are still unclear. As the relationship between T. cruzi and the host immune system is intricate, so is the amount and diversity of scientific knowledge on the matter. Many of the mechanisms of immunity are fairly well understood, but unveiling the factors that lead each of these to success or failure, within the coordinated response as a whole, requires further research. The intention behind this Review is to compile the available information on the different aspects of the immune response, with an emphasis on those phenomena that have been studied and confirmed in the human host. For ease of comprehension, it has been subdivided in sections that cover the main humoral and cell-mediated components involved therein. However, we also intend to underline that these elements are not independent, but function intimately and concertedly. Here, we summarize years of investigation carried out to unravel the puzzling interplay between the host and the parasite.

Evaluation of the immune response against Trypanosoma cruzi cytosolic tryparedoxin peroxidase in human natural infection.

Trypanosoma cruzi, the aetiological agent of Chagas disease, has a highly efficient detoxification system to deal with the oxidative burst imposed by its host. One of the antioxidant enzymes involved is the cytosolic tryparedoxin peroxidase (c-TXNPx), which catalyses the reduction to hydrogen peroxide, small-chain organic hydroperoxides and peroxynitrite. This enzyme is present in all parasite stages, and its overexpression renders parasites more resistant to the oxidative defences of macrophages, favouring parasite survival. This work addressed the study of the specific humoral and cellular immune response triggered by c-TXNPx in human natural infection. Thus, sera and peripheral blood mononuclear cells (PBMC) were collected from chronically infected asymptomatic and cardiac patients, and non-infected individuals. Results showed that levels of IgG antibodies against c-TXNPx were low in sera from individuals across all groups. B-cell epitope prediction limited immunogenicity to a few, small regions on the c-TXNPx sequence. At a cellular level, PBMC from asymptomatic and cardiac patients proliferated and secreted interferon-γ after c-TXNPx stimulation, compared with mock control. However, only proliferation was higher in asymptomatic patients compared with cardiac and non-infected individuals. Furthermore, asymptomatic patients showed an enhanced frequency of CD19+ CD69+ cells upon exposure to c-TXNPx. Overall, our results show that c-TXNPx fails to induce a strong immune response in natural infection, being measurable only in those patients without any clinical symptoms. The low impact of c-TXNPx in the human immune response could be strategic for parasite survival, as it keeps this crucial antioxidant enzyme activity safe from the mechanisms of adaptive immune response.

Ouabain Protects Human Renal Cells against the Cytotoxic Effects of Shiga Toxin Type 2 and Subtilase Cytotoxin.

Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children. The majority of cases are associated with Shiga toxin (Stx)-producing Escherichia coli (STEC). In Argentina, HUS is endemic and presents the highest incidence rate in the world. STEC strains expressing Stx type 2 (Stx2) are responsible for the most severe cases of this pathology. Subtilase cytotoxin (SubAB) is another STEC virulence factor that may contribute to HUS pathogenesis. To date, neither a licensed vaccine nor effective therapy for HUS is available for humans. Considering that Ouabain (OUA) may prevent the apoptosis process, in this study we evaluated if OUA is able to avoid the damage caused by Stx2 and SubAB on human glomerular endothelial cells (HGEC) and the human proximal tubule epithelial cell (HK-2) line. HGEC and HK-2 were pretreated with OUA and then incubated with the toxins. OUA protected the HGEC viability from Stx2 and SubAB cytotoxic effects, and also prevented the HK-2 viability from Stx2 effects. The protective action of OUA on HGEC and HK-2 was associated with a decrease in apoptosis and an increase in cell proliferation. Our data provide evidence that OUA could be considered as a therapeutic strategy to avoid the renal damage that precedes HUS.

Prevention of renal damage caused by Shiga toxin type 2: Action of Miglustat on human endothelial and epithelial cells.

Typical hemolytic uremic syndrome (HUS) is responsible for acute and chronic renal failure in children younger than 5 years old in Argentina. Renal damages have been associated with Shiga toxin type 1 and/or 2 (Stx1, Stx2) produced by Escherichia coli O157:H7, although strains expressing Stx2 are highly prevalent in Argentina. Human glomerular endothelial cells (HGEC) and proximal tubule epithelial cells are very Stx-sensitive since they express high levels of Stx receptor (Gb3). Nowadays, there is no available therapy to protect patients from acute toxin-mediated cellular injury. New strategies have been developed based on the Gb3 biosynthesis inhibition through blocking the enzyme glucosylceramide (GL1) synthase. We assayed the action of a GL1 inhibitor (Miglustat: MG), on the prevention of the renal damage induced by Stx2. HGEC primary cultures and HK-2 cell line were pre-treated with MG and then incubated with Stx2. HK- 2 and HGEC express Gb3 and MG was able to decrease the levels of this receptor. As a consequence, both types of cells were protected from Stx2 cytotoxicity and morphology damage. MG was able to avoid Stx2 effects in human renal cells and could be a feasible strategy to protect kidney tissues from the cytotoxic effects of Stx2 in vivo.