Comparative analysis of human gut- and blood-derived mononuclear cells: contrasts in function and phenotype.

Introduction: Alterations in the gut immune system have been implicated in various diseases.The challenge of obtaining gut tissues from healthy individuals, commonly performed via surgical explants, has limited the number of studies describing the phenotype and function of gut-derived immune cells in health. Methods: Here, by means of recto-sigmoid colon biopsies obtained during routine care (colon cancer screening in healthy adults), the phenotype and function of immune cells present in the gut were described and compared to those found in blood. Results: The proportion of CD4+, CD8+, MAIT, γδ+ T, and NK cells phenotype, expression of integrins, and ability to produce cytokine in response to stimulation with PMA and ionomycin. T cells in the gut were found to predominantly have a memory phenotype as compared to T cells in blood where a naïve phenotype predominates. Recto-sigmoid mononuclear cells also had higher PD-1 and Ki67 expression. Furthermore, integrin expression and cytokine production varied by cell type and location in blood vs. gut. Discussion: These findings demonstrate the differences in functionality of these cells when compared to their blood counterparts and validate previous studies on phenotype within gut-derived immune cells in humans (where cells have been obtained through surgical means). This study suggests that recto-sigmoid biopsies collected during colonoscopy can be a reliable yet more accessible sampling method for follow up of alterations of gut derived immune cells in clinical settings.

Levels of immunoglobulin isotypes in serum and respiratory samples of patients with chronic obstructive pulmonary disease: protocol for a systematic review and meta-analysis.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is an inflammatory respiratory disorder characterised by the progressive worsening of lung function. Acute exacerbation of COPD (AECOPD) is a leading contributor to patient morbidity, mortality and hospitalisations. The clinical significance of immunoglobulin (Ig) levels in COPD patients is not well established and is in need of further investigation. METHODS AND ANALYSIS: We will conduct a systematic review to describe levels of different Ig isotypes (IgG, IgA and IgM) in various samples (serum, sputum and bronchoalveolar lavage) of patients with COPD. IgE levels in COPD patients have been researched and reviewed extensively and hence will be excluded from this review. IgD levels will also be excluded from the review as there is a paucity of data on IgD levels in COPD patients. The primary outcome of interest in this systematic review is assessing Ig isotype levels in patients with COPD. Secondary outcomes that will be assessed include the differences between Ig isotype levels in COPD patients compared with healthy controls, as well as the relationships between Ig isotype levels and key clinical variables, including COPD severity, incidence of AECOPD and AECOPD severity. Embase and Ovid MEDLINE will be used to search for non-randomised studies published from 1946 to October 2022 that report our prespecified primary and secondary outcomes. As per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol, retrieved studies will undergo a two-phase screening process conducted by two independent reviewers. Prespecified primary and secondary outcomes will be extracted from eligible studies, and descriptive statistics will be used to analyse extracted outcomes. The risk of bias will be assessed using the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. ETHICS AND DISSEMINATION: Ethics approval is not required as this is a protocol for a systematic review and meta-analysis. Findings will be disseminated through peer-reviewed publications and other formats including conference presentations. PROSPERO REGISTRATION NUMBER: CRD42020192220.

Cutaquig® Is Well Tolerated in Immunodeficient Patients Who Did Not Tolerate Other Subcutaneous Immunoglobulin Products.

OBJECTIVE: Subcutaneous immunoglobulin (SCIG) treatment is generally tolerable, but some patients may experience adverse events to one or more SCIG products. We investigated whether 16.5% Cutaquig® treatment offered a tolerable and safe alternative treatment for immunodeficient patients. METHODS: A one-year prospective cohort study was conducted at a single center in Ottawa, Canada. Adult immunodeficient patients who reported previous intolerability, adverse events, or other difficulty to other 20% SCIG product(s) were recruited to start on 16.5% Cutaquig®. Treatment tolerability, safety, and quality of life were observed and described. RESULTS: Seven out of ten patients tolerated Cutaquig®. There were no serious or severe adverse events related to the treatment. Three moderate infections were reported (two urinary tract infections and one injection site infection). The mean serum IgG level at the end of the study was comparable to baseline levels recorded before the study: 9.6 ± 4.5 vs. 7.6 ± 4.3 g/L, p = 0.07. The overall health and health domain changes in the SF-36 and quality of life tests using the EQ visual analog scale improved by 21.5% (p = 0.38), 16.7% (p = 0.29), and 7.7% (p = 0.23), respectively. CONCLUSIONS: Cutaquig® may be used as an alternative treatment option for patients who did not tolerate 20% SCIG products.

Enhancing COVID Rehabilitation with Technology (ECORT): protocol for an open-label, single-site randomized controlled trial evaluating the effectiveness of electronic case management for individuals with persistent COVID-19 symptoms.

BACKGROUND: As of May 2022, Ontario has seen more than 1.3 million cases of COVID-19. While the majority of individuals will recover from infection within 4 weeks, a significant subset experience persistent and often debilitating symptoms, known as "post-COVID syndrome" or "Long COVID." Those with Long COVID experience a wide array of symptoms, with variable severity, including fatigue, cognitive impairment, and shortness of breath. Further, the prevalence and duration of Long COVID is not clear, nor is there evidence on the best course of rehabilitation for individuals to return to their desired level of function. Previous work with chronic conditions has suggested that the addition of electronic case management (ECM) may help to improve outcomes. These platforms provide enhanced connection with care providers, detailed symptom tracking and goal setting, and access to relevant resources. In this study, our primary aim is to determine if the addition of ECM with health coaching improves Long COVID outcomes at 3 months compared to health coaching alone. METHODS: The trial is an open-label, single-site, randomized controlled trial of ECM with health coaching (ECM+) compared to health coaching alone (HC). Both groups will continue to receive usual care. Participants will be randomized equally to receive health coaching (± ECM) for a period of 8 weeks and a 12-week follow-up. Our primary outcome is the WHO Disability Assessment Scale (WHODAS), 36-item self-report total score. Participants will also complete measures of cognition, fatigue, breathlessness, and mental health. Participants and care providers will be asked to complete a brief qualitative interview at the end of the study to evaluate acceptability and implementation of the intervention. DISCUSSION: There is currently little evidence about the optimal treatment of Long COVID patients or the use of digital health platforms in this population. The results of this trial could result in rapid, scalable, and personalized care for people with Long COVID which will decrease morbidity after an acute infection. Results from this study will also inform decision making in Long COVID and treatment guidelines at provincial and national levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT05019963. Registered on 25 August 2021.

A randomized control trial of high-dose micronutrient-antioxidant supplementation in healthy persons with untreated HIV infection.

BACKGROUND: Although micronutrient and antioxidant supplementation are widely used by persons with human immunodeficiency virus (HIV), a therapeutic role beyond recommended daily allowances (RDA) remains unproven. An oral high-dose micronutrient and antioxidant supplement (Treatment) was compared to an RDA supplement (Control) for time to progressive immunodeficiency or initiation of antiretroviral therapy (ART) in people living with HIV (PLWH). METHODS: This study was a randomized, double-blind, placebo-controlled multicenter clinical trial. PLWH were recruited from Canadian HIV Trials Network sites, and followed quarterly for two years. Eligible participants were asymptomatic, antiretroviral treatment (ART)-naïve, HIV-seropositive adults with a CD4 T lymphocyte count (CD4 count) between 375-750 cells/µL. Participants were randomly allocated 1:1 to receive Treatment or Control supplements. The primary outcome was a composite of time-to-first of confirmed CD4 count below 350 cells/µL, initiation of ART, AIDS-defining illness or death. Primary analysis was by intention-to-treat. Secondary outcomes included CD4 count trajectory from baseline to ART initiation or two years. A Data and Safety Monitoring Board reviewed the study for safety, recruitment and protocol adherence every six months. RESULTS: Of 171 enrolled participants: 66 (38.6%) experienced a primary outcome: 27 reached a CD4 count below 350 cells/µL, and 57 started ART. There was no significant difference in time-to-first outcome between groups (Hazard Ratio = 1.05; 95%CI: 0.65, 1.70), or in time to any component outcome. Using intent-to-treat censoring, mean annualized rates of CD4 count decline were -42.703 cells/µL and -79.763 cells/µL for Treatment and Control groups, with no statistical difference in the mean change between groups (-37.06 cells/µL/52 weeks, 95%CI: (-93.59, 19.47); p = 0.1993). Accrual was stopped at 171 of the 212 intended participants after an interim analysis for futility, although participant follow-up was completed. CONCLUSIONS: In ART-naïve PLWH, high-dose antioxidant, micronutrient supplementation compared to RDA supplementation had no significant effect on disease progression or ART initiation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00798772.

Building knowledge, optimising physical and mental health and setting up healthier life trajectories in South African women (Bukhali): a preconception randomised control trial part of the Healthy Life Trajectories Initiative (HeLTI).

INTRODUCTION: South Africa's evolving burden of disease is challenging due to a persistent infectious disease, burgeoning obesity, most notably among women and rising rates of non-communicable diseases (NCDs). With two thirds of women presenting at their first antenatal visit either overweight or obese in urban South Africa (SA), the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and NCDs. METHODS AND ANALYSIS: Bukhali is the first individual randomised controlled trial in Africa to test the efficacy of a complex continuum of care intervention and forms part of the Healthy Life Trajectories Initiative (HeLTI) consortium implementing harmonised trials in Canada, China, India and SA. Starting preconception and continuing through pregnancy, infancy and childhood, the intervention is designed to improve nutrition, physical and mental health and health behaviours of South African women to offset obesity-risk (adiposity) in their offspring. Women aged 18-28 years (n=6800) will be recruited from Soweto, an urban-poor area of Johannesburg. The primary outcome is dual-energy X-ray absorptiometry derived fat mass index (fat mass divided by height2) in the offspring at age 5 years. Community health workers will deliver the intervention randomly to half the cohort by providing health literacy material, dispensing a multimicronutrient supplement, providing health services and feedback, and facilitating behaviour change support sessions to optimise: (1) nutrition, (2) physical and mental health and (3) lay the foundations for healthier pregnancies and early child development. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Ethics Research Committee University of the Witwatersrand, Johannesburg, South Africa (M1811111), the University of Toronto, Canada (19-0066-E) and the WHO Ethics Committee (ERC.0003328). Data and biological sample sharing policies are consistent with the governance policy of the HeLTI Consortium (https://helti.org) and South African government legislation (POPIA). The recruitment and research team will obtain informed consent. TRIAL REGISTRATION: This trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871). PROTOCOL VERSION: 20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries.

Spatiotemporal trends and socioecological factors associated with Lyme disease in eastern Ontario, Canada from 2010-2017.

Currently, there is limited knowledge about socioeconomic, neighbourhood, and local ecological factors that contribute to the growing Lyme disease incidence in the province of Ontario, Canada. In this study, we sought to identify these factors that play an important role at the local scale, where people are encountering ticks in their communities. We used reported human Lyme disease case data and tick surveillance data submitted by the public from 2010-2017 to analyze trends in tick exposure, spatiotemporal clusters of infection using the spatial scan statistic and Local Moran's I statistic, and socioecological risk factors for Lyme disease using a multivariable negative binomial regression model. Data were analyzed at the smallest geographic unit, consisting of 400-700 individuals, for which census data are disseminated in Canada. We found significant heterogeneity in tick exposure patterns based on location of residence, with 65.2% of Lyme disease patients from the city of Ottawa reporting tick exposures outside their health unit of residence, compared to 86.1%-98.1% of patients from other, largely rural, health units, reporting peri-domestic exposures. We detected eight spatiotemporal clusters of human Lyme disease incidence in eastern Ontario, overlapping with three clusters of Borrelia burgdorferi-infected ticks. When adjusting for population counts, Lyme disease case counts increased with larger numbers of Borrelia burgdorferi-infected ticks submitted by the public, higher proportion of treed landcover, lower neighbourhood walkability due to fewer intersections, dwellings, and points of interest, as well as with regions of higher residential instability and lower ethnic concentration (Relative Risk [RR] = 1.25, 1.02, 0.67-0.04, 1.34, and 0.57, respectively, p < .0001). Our study shows that there are regional differences in tick exposure patterns in eastern Ontario and that multiple socioecological factors contribute to Lyme disease risk in this region.

Effect of implementation of a 12-dose once-weekly treatment (3HP) in addition to standard regimens to prevent TB on completion rates: Interrupted time series design.

OBJECTIVES: We aimed to determine if offering a 12-dose once-weekly treatment (3HP) as an additional treatment option would result in an increase in the overall proportion of patients completing TB preventive treatment (TPT) above the baseline rate. METHODS: We analyzed outcomes in consecutive adults referred to a TB clinic from January 2010 to May 2019. Starting December 2016, 3HP was offered as an alternative to standard clinic regimens which included 9 months of daily isoniazid or 4 months of daily rifampin. The primary outcome was the proportion of patients who completed TPT among all patients who started treatment. Using segmented autoregression analysis, we compared completion at the end of the study with projected completion had the intervention not been introduced. RESULTS: A total of 2803 adults were referred for assessment over the study period. There was an absolute increase in completions among those who started a treatment of 19.0% at the end of the study between the observed intervention completion rate and the projected completion rate from the baseline study period (the completion rate had the 3HP intervention not been introduced) (76% observed vs 57% projected; 95% CI 6.6 to 31.4%; p = 0.004) and an absolute increase among those who were offered treatment (17.3%; 95% CI, 2.3 to 32.3%; p = 0.025). CONCLUSIONS: The introduction of 3HP for TPT as an alternative to the regular regimens offered resulted in a significant increase in the proportion of patients completing treatment. Our study provides evidence to support accelerated use of 3HP in Canada.

Single-dose replicating poxvirus vector-based RBD vaccine drives robust humoral and T cell immune response against SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic requires the continued development of safe, long-lasting, and efficacious vaccines for preventive responses to major outbreaks around the world, and especially in isolated and developing countries. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we characterize a temperature-stable vaccine candidate (TOH-Vac1) that uses a replication-competent, attenuated vaccinia virus as a vector to express a membrane-tethered spike receptor binding domain (RBD) antigen. We evaluate the effects of dose escalation and administration routes on vaccine safety, efficacy, and immunogenicity in animal models. Our vaccine induces high levels of SARS-CoV-2 neutralizing antibodies and favorable T cell responses, while maintaining an optimal safety profile in mice and cynomolgus macaques. We demonstrate robust immune responses and protective immunity against SARS-CoV-2 variants after only a single dose. Together, these findings support further development of our novel and versatile vaccine platform as an alternative or complementary approach to current vaccines.

A Randomized Double-Blind Placebo-Control Feasibility Trial of Immunoglobulin Treatment for Prevention of Recurrent Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that immunoglobulin treatment may reduce the frequency of acute exacerbations of COPD (AECOPD). OBJECTIVE: To inform the design of a future randomised control trial (RCT) of intravenous immunoglobulin (IVIG) treatment efficacy for AECOPD prevention. METHODS: A pilot RCT was conducted. We recruited patients with COPD hospitalized for AECOPD, or from ambulatory clinics with one severe, or two moderate AECOPD in the previous year regardless of their serum IgG level. Patients were allocated in a 1:1 ratio with balanced randomisation to monthly IVIG or normal saline for 1 year. The primary outcome was feasibility defined as pre-specified accrual, adherence, and follow-up rates. Secondary outcomes included safety, tolerance, AECOPD rates, time to first AECOPD, quality of life, and healthcare costs. RESULTS: Seventy patients were randomized (37 female; mean age 67.7; mean FEV1 35.1%). Recruitment averaged 4.5±0.9 patients per month (range 0-8), 34 (49%) adhered to at least 80% of planned treatments, and four (5.7%) were lost to follow-up. There were 35 serious adverse events including seven deaths and one thromboembolism. None was related to IVIG. There were 56 and 48 moderate and severe AECOPD in the IVIG vs control groups. In patients with at least 80% treatment adherence, median time to first moderate or severe AECOPD was 275 vs 114 days, favoring the IVIG group (HR 0.76, 95% CI 0.3-1.92). CONCLUSION: The study met feasibility criteria for recruitment and retention, but adherence was low. A trend toward more robust treatment efficacy in adherent patients supports further study, but future trials must address treatment adherence. TRIAL REGISTRATION NUMBER: NCT0290038, registered 24 February 2016, https://clinicaltrials.gov/ct2/show/NCT02690038 and NCT03018652, registered January 12, 2017, https://clinicaltrials.gov/ct2/show/NCT03018652.

Impact of in-utero antiretroviral drug exposure on expression of membrane-associated transporters in mouse placenta and fetal brain.

OBJECTIVE: Although antiretroviral therapy (ART) during pregnancy is effective in limiting vertical HIV transmission, adverse outcomes persist amongst uninfected children exposed to antiretroviral drugs in utero. Membrane-associated drug transporters, metabolic enzymes, and tight junction proteins play important roles in adult antiretroviral drug disposition and toxicity; however, the fetal expression of these proteins in the context of ART, and their impact on in-utero antiretroviral drug distribution remain poorly understood. This study aimed to characterize the role of these proteins in modulating in-utero antiretroviral drug exposure. METHODS: Pregnant mice were exposed to an ART regimen consisting of lamivudine, abacavir, atazanavir, and ritonavir, at clinically relevant doses. Fetal brain, liver, placenta amniotic fluid, and maternal plasma were collected on gestational day 18.5 and concentration of antiretroviral drugs in fetal tissues was measured by LC/MS/MS, whereas transporter expression was assessed by qPCR. RESULTS: Abacavir and lamivudine were detected in fetal brain and amniotic fluid, whereas atazanavir and ritonavir were detected in amniotic fluid only. Robust mRNA expression of key transporters was observed in adult and fetal tissues, and sex differences were identified in the expression of Abcc1 and Slc29a1 in the placenta. Antiretroviral drug exposure was associated with a reduction in relative placental Abcg2, Abcc1, and Slc29a1 expression. CONCLUSION: These findings identify a novel effect of fetal sex and antiretroviral drug treatment on the expression of placental transporters in a mouse model, and characterize the penetration of lamivudine and abacavir into fetal brain, uncovering a potential role of transporters in modulating fetal exposure to antiretroviral drugs.

Polyvalent Immunoglobulin as a Potential Treatment Option for Patients with Recurrent COPD Exacerbations.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and episodes of worsening respiratory symptoms and pulmonary function, termed acute exacerbations of COPD (AECOPD). AECOPD episodes are associated with heightened airway inflammation and are often triggered by infection. A subset of COPD patients develops frequent exacerbations despite maximal existing standard medical therapy. It is therefore clear that a targeted and more effective prevention strategy is needed. Immunoglobulins are glycoprotein molecules that are secreted by B lymphocytes and plasma cells and play a critical role in the adaptive immune response against many pathogens. Altered serum immunoglobulin levels have been observed in patients with immunodeficiencies and inflammatory diseases. Serum immunoglobulin has also been identified as potential biomarkers of AECOPD frequency. Since plasma-derived polyvalent immunoglobulin treatment is effective in preventing recurrent infections in immunodeficient patients and in suppressing inflammation in many inflammatory diseases, it may be conceivable that immunoglobulin treatment may be effective in preventing recurrent AECOPD. In this article, we provide a review of the current knowledge on immunoglobulin treatment in patients with COPD and discuss plausible mechanisms as to how immunoglobulin treatment may work to reduce AECOPD frequency.

Evaluation of the protein gap for detection of abnormal serum gammaglobulin level: an imperfect predictor.

OBJECTIVES: The value of the serum protein gap (PG, difference between total protein and albumin) in the detection of hyper- or hypogammaglobulinemia is not well established. We assessed the performance of PG for the detection of hyper- or hypogammaglobulinemia in a large sample of patients. METHODS: We reviewed all paired measurements of serum total protein, albumin, quantitative immunoglobulins, and serum protein electrophoresis tested between March 2014 and June 2017 at the Eastern Ontario Regional Laboratory Association. Sensitivity, specificity, positive predictive value, negative predictive value and likelihood ratios of PG at thresholds between 18 and 44 g/L for the detection of hyper- and hypogammaglobulinemia were assessed. RESULTS: There were 19,575 and 5,426 simultaneous paired data points to assess hyper- and hypogammaglobulinemia identified by serum protein electrophoresis (SPE) and nephelometry, respectively. The mean PG was 36.3 g/L (SD 8.6). The prevalence of hypergammaglobulinemia (>16 g/L by SPE) and hypogammaglobulinemia (IgG <7 g/L) was 21.9 and 5.5%, respectively. High PG (≥38 g/L) had sensitivity and specificity of 76.2 and 71.5% respectively for hypergammaglobulinemia. PG ≥38 g/L had a negative predictive value (NPV) of 93.1% for monoclonal, and 96.9% for polyclonal gammopathy. A PG threshold of ≤18 g/L had of sensitivity of 0.4%, specificity of 100%, PPV of 100% and NPV of 80.1% to detect hypogammaglobulinemia (IgG <7 g/L). CONCLUSIONS: High and low PG values were not sensitive in detecting hyper- or hypogammaglobulinemia, although negative predictive values were high for both. Performance of PG should be further evaluated prospectively in specific populations at risk of for abnormal IgG levels.

Nanoluciferase complementation-based bioreporter reveals the importance of N-linked glycosylation of SARS-CoV-2 S for viral entry.

The ongoing COVID-19 pandemic has highlighted the immediate need for the development of antiviral therapeutics targeting different stages of the SARS-CoV-2 life cycle. We developed a bioluminescence-based bioreporter to interrogate the interaction between the SARS-CoV-2 viral spike (S) protein and its host entry receptor, angiotensin-converting enzyme 2 (ACE2). The bioreporter assay is based on a nanoluciferase complementation reporter, composed of two subunits, large BiT and small BiT, fused to the S receptor-binding domain (RBD) of the SARS-CoV-2 S protein and ACE2 ectodomain, respectively. Using this bioreporter, we uncovered critical host and viral determinants of the interaction, including a role for glycosylation of asparagine residues within the RBD in mediating successful viral entry. We also demonstrate the importance of N-linked glycosylation to the RBD's antigenicity and immunogenicity. Our study demonstrates the versatility of our bioreporter in mapping key residues mediating viral entry as well as screening inhibitors of the ACE2-RBD interaction. Our findings point toward targeting RBD glycosylation for therapeutic and vaccine strategies against SARS-CoV-2.

Molecular Epidemiology of Mycobacterium tuberculosis To Describe the Transmission Dynamics Among Inuit Residing in Iqaluit Nunavut Using Whole-Genome Sequencing.

BACKGROUND: In the last decade, tuberculosis (TB) incidence among Inuit in the Canadian Arctic has been rising. Our aim was to better understand the transmission dynamics of TB in this remote region of Canada using whole-genome sequencing. METHODS: Isolates from patients who had culture-positive pulmonary TB in Iqaluit, Nunavut, between 2009 and 2015 underwent whole-genome sequencing (WGS). The number of transmission events between cases within clusters was calculated using a threshold of a ≤3 single nucleotide polymorphism (SNP) difference between isolates and then combined with detailed epidemiological data using a reproducible novel algorithm. Social network analysis of epidemiological data was used to support the WGS data analysis. RESULTS: During the study period, 140 Mycobacterium tuberculosis isolates from 135 cases were sequenced. Four clusters were identified, all from Euro-American lineage. One cluster represented 62% of all cases that were sequenced over the entire study period. In this cluster, 2 large chains of transmission were associated with 3 superspreading events in a homeless shelter. One of the superspreading events was linked to a nonsanctioned gambling house that resulted in further transmission. Shelter to nonshelter transmission was also confirmed. An algorithm developed for the determination of transmission events demonstrated very good reproducibility (κ score .98, 95% confidence interval, .97-1.0). CONCLUSIONS: Our study suggests that socioeconomic factors, namely residing in a homeless shelter and spending time in a gambling house, combined with the superspreading event effect may have been significant factors explaining the rise in cases in this predominantly Inuit Arctic community.

The Effects of Traditional Chinese Medicine as an Auxiliary Treatment for COVID-19: A Systematic Review and Meta-Analysis.

Background: Coronavirus disease 2019 (COVID-19) has become a pandemic with no specific and widely accepted effective drug or vaccine. However, studies have shown that Traditional Chinese Medicine (TCM) may play a significant role as an auxiliary treatment for COVID-19. Objective: This study aimed to assess the effects of TCM as an auxiliary treatment for COVID-19 through a systematic review of randomized-controlled trials (RCTs). Methods: Four English and three Chinese language databases were searched from December 1, 2019, to June 30, 2020. RCTs comparing TCM in combination with Western medicine (WM) with the same WM therapies alone for confirmed COVID-19 patients were included. The outcome measures were cure rate, lowering of body temperature, cough relief, improvement in chest computed tomography (CT) images, deterioration of condition, and adverse effects. Methodological quality was assessed using the Cochrane risk-of-bias tool. A series of meta-analyses were conducted for selected outcomes using RevMan 5.3 software. The quality of evidence was appraised using the grading of recommendation, assessment, development, and evaluation (GRADE) recommendations. Results: Ten RCTs with a total of 1,285 patients were included. Compared with WM alone in treating COVID-19, WM with auxiliary treatment by TCM appears to have increased the cure rate (risk ratio [RR] 1.15 [95% confidence interval (CI) 1.04-1.26]), relieved cough (RR 1.32 [95% CI 1.15-1.52]), improved chest CT images (RR 1.23 [95% CI 1.11-1.37]), and reduced the number of cases transitioning from a moderate to severe condition (RR 0.58 [95% CI 0.43-0.77]). The authors are uncertain whether TCM combined WM has effects on fever normalization (RR 1.10 [95% CI 0.94-1.29]) or adverse effects (RR 0.81 (95% CI 0.42-1.57]). Although they evaluated the certainty of evidence for lowering body temperature and adverse effects as very low, and low for cure rate, certainty was evaluated as moderate for improvement in chest CT images, cough relief, and deterioration of condition. Conclusion: TCM may be an effective auxiliary treatment for COVID-19 patients, which is likely to help improve the main symptoms and reduce disease progression. However, due to the limited number of studies and apparent heterogeneity among them, a more definitive conclusion on the effect of TCM on lowering body temperature and adverse effects cannot be drawn at this time.

Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity.

INTRODUCTION: Continuous antiretroviral therapy (ART) suppresses HIV plasma viral load (pVL) to very low levels, which allows for some immune recovery. Discontinuation of ART leads to pVL rebound from reservoirs of persistence and latency, and progressive immunodeficiency. One promising but controversial strategy targeting CD4+ T lymphocytes with a monoclonal antibody (mAb) against α4ß7 integrin has shown promise through sustained virological remission of pVL (SVR) in SIV239-infected rhesus macaques. We propose to assess the safety and tolerability of vedolizumab, a licensed humanised mAb against human α4ß7 integrin, in healthy HIV-infected adults on ART. This study will also assess, by analytical treatment interruption (ATI), whether vedolizumab treatment can induce SVR beyond ART and vedolizumab treatment. METHODS AND ANALYSIS: The HIV-ART-vedolizumab-ATI (HAVARTI) trial is a single-arm, dose-ranging pilot trial in healthy HIV-positive adult volunteers receiving ART. Twelve consenting persons will be enrolled in sequential groups of 4 to each serial dosing vedolizumab regimen (300 mg, 150 mg, 75 mg). The primary outcomes are: (1) to assess the safety and tolerability of seven serial infusions of vedolizumab at each of three doses; (2) to identify the immunovirological measures, including pVL and T-cell kinetics, that characterise HIV/ART cases before, during, after vedolizumab treatment and ATI; and (3) to seek SVR of pVL after ATI. Secondary outcomes will include immune reconstitution and pVL suppression as well as immune reconstitution and long-term safety following re-initiation of ART in the absence of SVR. ETHICS AND DISSEMINATION: The study protocol was approved by the Ottawa Health Science Network-REB and by the Health Canada Therapeutic Products Directorate. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open access journal within a year of study completion. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03147859; https://clinicaltrials.gov/ct2/show/NCT03147859.

Bacille Calmette-Guérin Vaccine Strain Modulates the Ontogeny of Both Mycobacterial-Specific and Heterologous T Cell Immunity to Vaccination in Infants.

Differences in Bacille Calmette-Guérin (BCG) immunogenicity and efficacy have been reported, but various strains of BCG are administered worldwide. Since BCG immunization may also provide protection against off-target antigens, we sought to identify the impact of different BCG strains on the ontogeny of vaccine-specific and heterologous vaccine immunogenicity in the first 9 months of life, utilizing two African birth cohorts. A total of 270 infants were studied: 84 from Jos, Nigeria (vaccinated with BCG-Bulgaria) and 187 from Cape Town, South Africa (154 vaccinated with BCG-Denmark and 33 with BCG-Russia). Infant whole blood was taken at birth, 7, 15, and 36 weeks and short-term stimulated (12 h) in vitro with BCG, Tetanus and Pertussis antigens. Using multiparameter flow cytometry, CD4+ T cell memory subset polyfunctionality was measured by analyzing permutations of TNF-α, IL-2, and IFN-γ expression at each time point. Data was analyzed using FlowJo, SPICE, R, and COMPASS. We found that infants vaccinated with BCG-Denmark mounted significantly higher frequencies of BCG-stimulated CD4+ T cell responses, peaking at week 7 after immunization, and possessed durable polyfunctional CD4+ T cells that were in a more early differentiated memory stage when compared with either BCG-Bulgaria and BCG-Russia strains. The latter responses had lower polyfunctional scores and tended to accumulate in a CD4+ T cell naïve-like state (CD45RA+CD27+). Notably, BCG-Denmark immunization resulted in higher magnitudes and polyfunctional cytokine responses to heterologous vaccine antigens (Tetanus and Pertussis). Collectively, our data show that BCG strain was the strongest determinant of both BCG-stimulated and heterologous vaccine stimulated T cell magnitude and polyfunctionality. These findings have implications for vaccine policy makers, manufacturers and programs worldwide and also suggest that BCG-Denmark, the first vaccine received in many African infants, has both specific and off-target effects in the first few months of life, which may provide an immune priming benefit to other EPI vaccines.

Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: A systematic review and meta-analysis - Part II: Non-kidney transplant.

Immunoglobulin (IG) is commonly used to desensitize and treat antibody-mediated rejection in solid organ transplant (SOT) recipients. The impact of IG on other outcomes such as infection, all-cause mortality, graft rejection, and graft loss is not clear. We conducted a similar systematic review and meta-analysis to our previously reported Part I excluding kidney transplant. A comprehensive literature review found 16 studies involving the following organ types: heart (6), lung (4), liver (4), and multiple organs (2). Meta-analysis could only be performed on mortality outcome in heart and lung studies due to inadequate data on other outcomes. There was a significant reduction in mortality (OR 0.34 [0.17-0.69]; 4 studies, n = 455) in heart transplant with hypogammaglobulinemia receiving IVIG vs no IVIG. Mortality in lung transplant recipients with hypogammaglobulinemia receiving IVIG was comparable to those of no hypogammaglobulinemia (OR 1.05 [0.49, 2.26]; 2 studies, n = 887). In summary, IVIG targeted prophylaxis may decrease mortality in heart transplant recipients as compared to those with hypogammaglobulinemia not receiving IVIG, or improve mortality to the equivalent level with those without hypogammaglobulinemia in lung transplant recipients, but there is a lack of data to support physicians in making decisions around using immunoglobulins in all SOT recipients for infection prophylaxis.