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.

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.

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.

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.

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.

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

Polyvalent immunoglobulin is commonly used for desensitization and treatment of antibody-mediated rejection in kidney transplantation but its impact on other outcomes is not known. This systematic review investigated the impact of immunoglobulin prophylaxis on infection, rejection, graft loss, and death following kidney transplantation. A comprehensive literature search located 18 studies (n = 8 randomized controlled trials). None examined the effect of immunoglobulin prophylaxis in transplant recipients with hypogammaglobulinemia. Quality of included studies was variable with high to very high risk of bias. In the randomized trials, immunoglobulin use did not reduce cytomegalovirus infection (OR 0.68 [0.39, 1.21]; 6 studies, n = 295), rejection (OR 0.96 [0.50, 1.82]; 4 studies, n = 187), or graft loss (OR 1.03 [0.46, 2.30]; 6 studies, n = 265). In non-randomized studies, immunoglobulin did not reduce cytomegalovirus infection (OR 0.63 [0.20, 1.94]; 6 studies, n = 361) or death (OR 1.32 [0.05, 38.79]; 3 studies, n = 222) but reduce rejection (OR 0.47 [0.24, 0.94]; 4 studies, n = 268) and graft loss (OR 0.15 [0.05, 0.43]; 2 studies, n = 118). Data were scarce and sample size of current evidence was small. Adequately powered randomized trials are needed to determine if immunoglobulin is an effective intervention to reduce infection, rejection, graft loss, or death following kidney transplantation with and without hypogammaglobulinemia.

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.

Evaluation of a Personalized Subcutaneous Immunoglobulin Treatment Program for Neurological Patients.

BACKGROUND: Subcutaneous immunoglobulin (SCIg) treatment has been shown to control symptoms and improve overall satisfaction in patients with neurological disorders. However, a large injection volume can be overwhelming and a barrier to successful SCIg treatment. We established a nurse-led individualized approach program to facilitate a smooth and successful treatment transition from intravenous immunoglobulin (IVIg) to SCIg. The program involved a lead nurse to provide two or more individual educational sessions on SCIg administration, establish a written transition plan, and liaise care with physicians. OBJECTIVES: We aimed to evaluate the impact of our program to a successful transition defined as SCIg retention or adherence without a need to restart IVIg by six or twelve months. METHODS: We reviewed medical charts of all patients with immune-mediated neuromuscular disorders who were in our program during January 2010 to Dec 2016. RESULTS: Nineteen patients were identified. Mean IVIg treatment duration was 31.5 months (range 4-98) before the transition. Mean steady state SCIg dosage was 26.2 g/week (SD 10.3). All patients were initially able to switch to SCIg, with a retention rate of 17/19 (89.5%) at six months and 15/19 (78.9%) at twelve months. Two patients reverted back to IVIg treatment due to worsening of their symptoms at two and three months, while two required supplemental IVIg infusions. There were no major adverse events reported during the twelve-month period, but one minor cutaneous adverse event (redness around the injection site). CONCLUSIONS: Successful treatment transition may be achieved with the nurse led individualized approach program.

CONTEXTE: Il a été prouvé que les traitements à l'immunoglobuline par voie sous-cutanée (IgSC) permettent de contrôler les symptômes qui affectent des patients atteints de troubles neurologiques et d'améliorer leur satisfaction générale. Toutefois, de grands volumes injectés peuvent devenir accablants et représenter un obstacle à un traitement par IgSC qui soit efficace. Nous avons ainsi mis sur pied un programme reposant sur une approche individuelle et dirigé par du personnel infirmier afin de favoriser une transition en douceur efficace entre les traitements d'immunoglobuline par voie intraveineuse (IgIV) et ceux par IgSC. Un tel programme impliquait la présence d'une infirmière en chef chargée d'offrir deux séances de formation ou plus en ce qui concerne l'administration d'un traitement par IgSC mais aussi d'établir un plan écrit de transition entre les deux traitements et d'assurer une liaison avec les médecins traitants. OBJECTIFS: Nous avons cherché à évaluer l'impact de notre programme en matière de transition. C'est ainsi que nous avons voulu savoir dans quelle mesure un traitement par IgSC entraînait une forme d'adhésion thérapeutique en vertu de laquelle un traitement par IgIV n'était plus nécessaire au bout de six ou de 12 mois. MÉTHODES: Nous avons passé en revue les dossiers médicaux de tous les patients atteints de troubles neuromusculaires d'origine auto-immune ayant fait partie de notre programme de janvier 2010 à décembre 2016. RÉSULTATS: Au total, dix-neuf patients ont été sélectionnés. Avant d'amorcer notre transition, la durée moyenne d'un traitement par IgIV était de 31,5 mois (étendue : 4-98). La posologie moyenne à l'équilibre d'un traitement par IgSC était de 26,2 g/semaine (écart-type : 10,3). Au début, tous les patients ont été en mesure de passer à un traitement par IgSC, le taux d'adhésion étant de 89,5 % (17/19) au bout de six mois et de 78,9 % (15/19) au bout de douze mois. Deux patients ont recommencé à suivre un traitement par IgIV en raison d'une détérioration de leurs symptômes au bout de deux et de trois mois tandis que deux autres ont eu besoin d'injections à l'immunoglobuline additionnelles. Outre un seul événement indésirable mineur de nature cutanée, à savoir de la rougeur autour de la zone d'injection, aucun événement indésirable majeur n'a été signalé au cours de la période de transition de douze mois. CONCLUSIONS: Il est possible, au moyen d'un programme dirigé par une infirmière chef dont l'approche est individuelle, d'effectuer une transition efficace entre les deux traitements évoqués ci-dessus.

Type of Pelvic Disease as a Risk Factor for Surgical Site Infectionin Women Undergoing Hysterectomy.

STUDY OBJECTIVE: To quantify the relationship between type of benign pelvic disease and risk of surgical site infection (SSI) after hysterectomy. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP). PATIENTS: Women who underwent hysterectomy from 2006-2015 and recorded in NSQIP database. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: SSI risk was compared for type of benign pelvic disease, patient characteristics (i.e., age, race, and selected comorbidities) and process of care variables (i.e., admission status, type of hysterectomy, and operative time). SSI occurred in 2.48% of the 125,337 women who underwent hysterectomy. SSI was most frequent in patients with endometriosis and least frequent in those with genital prolapse (3.13% vs 1.39%; p <.0001). Following adjustment for potential confounders, the odds of SSI were higher in women undergoing hysterectomy for endometriosis (adjusted odds ratio [aOR], 1.79; 95% confidence interval [CI], 1.43- 2.25), uterine myomas (aOR, 1.28; 95% CI, 1.05-1.55), menstrual disorders (aOR, 1.46; 95% CI, 1.20-1.78), and pelvic pain (aOR, 1.75; 95% CI, 1.34-2.27) compared with women undergoing hysterectomy for genital prolapse. Other patient factors associated with SSI included age, body mass index, smoking, diabetes mellitus, chronic obstructive pulmonary disease, hypertension, and American Society of Anesthesiologists classification. Among process-of-care factors, inpatient status, route of hysterectomy, total vs subtotal hysterectomy, and operative time were also associated with SSI. CONCLUSION: In addition to various patient and process-of-care factors known to be associated with SSI, type of underlying pelvic disease is an independent risk factor for SSI in women undergoing hysterectomy for benign indications.

Landscape review of current HIV 'kick and kill' cure research - some kicking, not enough killing.

BACKGROUND: Current antiretroviral therapy (ART) used to treat human immunodeficiency virus (HIV) patients is life-long because it only suppresses de novo infections. Recent efforts to eliminate HIV have tested the ability of a number of agents to reactivate ('Kick') the well-known latent reservoir. This approach is rooted in the assumption that once these cells are reactivated the host's immune system itself will eliminate ('Kill') the virus. While many agents have been shown to reactivate large quantities of the latent reservoir, the impact on the size of the latent reservoir has been negligible. This suggests that the immune system is not sufficient to eliminate reactivated reservoirs. Thus, there is a need for more emphasis on 'kill' strategies in HIV cure research, and how these might work in combination with current or future kick strategies. METHODS: We conducted a landscape review of HIV 'cure' clinical trials using 'kick and kill' approaches. We identified and reviewed current available clinical trial results in human participants as well as ongoing and planned clinical trials. We dichotomized trials by whether they did not include or include a 'kill' agent. We extracted potential reasons why the 'kill' is missing from current 'kick and kill' strategies. We subsequently summarized and reviewed current 'kill' strategies have entered the phase of clinical trial testing in human participants and highlighted those with the greatest promise. RESULTS: The identified 'kick' trials only showed promise on surrogate measures activating latent T-cells, but did not show any positive effects on clinical 'cure' measures. Of the 'kill' agents currently being tested in clinical trials, early results have shown small but meaningful proportions of participants remaining off ART for several months with broadly neutralizing antibodies, as well as agents for regulating immune cell responses. A similar result was also recently observed in a trial combining a conventional 'kick' with a vaccine immune booster ('kill'). CONCLUSION: While an understanding of the efficacy of each individual component is crucial, no single 'kick' or 'kill' agent is likely to be a fully effective cure. Rather, the solution is likely found in a combination of multiple 'kick and kill' interventions.

Increasing Number and Proportion of Adverse Obstetrical Outcomes among Women Living with HIV in the Ottawa Area: A 20-Year Clinical Case Series.

Background. The prevalence and associated risks with adverse obstetrical outcomes among women living with HIV are not well measured. The objective of this study was to longitudinally investigate the prevalence and correlates of adverse obstetrical outcomes among women with HIV. Methods. This 20-year (1990-2010) clinical case series assessed the prevalence of adverse obstetrical outcomes among pregnant women with HIV receiving care at The Ottawa Hospital (TOH). General estimating equation modeling was used to identify factors independently associated with adverse obstetrical outcomes, while controlling for year of childbirth clustering. Results. At TOH, there were 127 deliveries among 94 women (1990-2010): 22 preterm births, 9 births with low birth weight, 12 births small for gestational age, and 4 stillbirths. Per year, the odds of adverse obstetrical outcomes increased by 15% (OR: 1.15, 95% CI: 1.03-1.30). Psychiatric illness (AOR: 2.64, 95% CI: 1.12-6.24), teen pregnancy (AOR: 3.35, 95% CI: 1.04-1.46), and recent immigrant status (AOR: 7.24, 95% CI: 1.30-40.28) were the strongest correlates of adverse obstetrical outcomes. Conclusions. The increasing number and proportion of adverse obstetrical outcomes among pregnant women with HIV over the past 20 years highlight the need for social supports and maternal and child health interventions, especially among adolescents, new immigrants, and those with a history of mental illness.

Oral antibiotic therapy for the treatment of infective endocarditis: a systematic review.

BACKGROUND: The role of oral antibiotic therapy in treating infective endocarditis (IE) is not well established. METHODS: We searched MEDLINE, EMBASE and Scopus for studies in which oral antibiotic therapy was used for the treatment of IE. RESULTS: Seven observational studies evaluating the use oral beta-lactams (five), oral ciprofloxacin in combination with rifampin (one), and linezolid (one) for the treatment of IE caused by susceptible bacteria reported cure rates between 77% and 100%. Two other observational studies using aureomycin or sulfonamide, however, had failure rates >75%. One clinical trial comparing oral amoxicillin versus intravenous ceftriaxone for streptococcal IE reported 100% cure in both arms but its reporting had serious methodological limitations. One small clinical trial (n = 85) comparing oral ciprofloxacin and rifampin versus conventional intravenous antibiotic therapy for uncomplicated right-sided S. aureus IE in intravenous drug users (IVDUs) reported cure rates of 89% and 90% in each arm, respectively (P =0.9); however, drug toxicities were more common in the latter group (62% versus 3%; P <0.01). Major limitations of this trial were lack of allocation concealment and blinding at the delivery of the study drug(s) and assessment of outcomes. CONCLUSION: Reported cure rates for IE treated with oral antibiotic regimens vary widely. The use of oral ciprofloxacin in combination with rifampin for uncomplicated right-sided S. aureus IE in IVDUs is supported by one small clinical trial of relatively good quality and could be considered when conventional IV antibiotic therapy is not possible.

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.

Inaccuracy of death certificate diagnosis of tuberculosis and potential underdiagnosis of TB in a region of high HIV prevalence.

UNLABELLED: Despite the South African antiretroviral therapy rollout, which should reduce the incidence of HIV-associated tuberculosis (TB), the number of TB-attributable deaths in KwaZuluNatal (KZN) remains high. TB is often diagnosed clinically, without microbiologic confirmation, leading to inaccurate estimates of TB-attributed deaths. This may contribute to avoidable deaths, and impact population-based TB mortality estimates. OBJECTIVES: (1) To measure the number of cases with microbiologically confirmed TB in a retrospective cohort of deceased inpatients with TB-attributed hospital deaths. (2) To estimate the rates of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB in this cohort. RESULTS: Of 2752 deaths at EDH between September 2006 and March 2007, 403 (15%) were attributed to TB on the death certificate. 176 of the TB-attributed deaths (44%) had a specimen sent for smear or culture; only 64 (36%) had a TB diagnosis confirmed by either test. Of the 39 culture-confirmed cases, 27/39 (69%) had fully susceptible TB and 27/39 (69%) had smear-negative culture-positive TB (SNTB). Two patients had drug monoresistance, three patients had MDR-TB, and one had XDR-TB. CONCLUSIONS: Most TB-attributed deaths in this cohort were not microbiologically confirmed. Of confirmed cases, most were smear-negative, culture positive and were susceptible to all first line drugs.

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.

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.

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.