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Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. CAP can trigger acute cardiac events. We sought to determine the incidence of major cardiac complications in CAP patients to characterize the magnitude of this problem. Two investigators searched MEDLINE, Scopus, and EMBASE for observational studies of immunocompetent adults with clinical and radiological evidence of CAP that reported any of the following: overall cardiac complications, incident heart failure, acute coronary syndromes (ACS), or incident cardiac arrhythmias occurring within 30 days of CAP diagnosis. At a minimum, studies had to establish enrolment procedures and inclusion and exclusion criteria, enroll their patients sequentially, and report the incidence of cardiac complications as a function of their entire cohorts. Studies with focus on nosocomial or health care-associated pneumonia were not included. Review of 2,176 citations yielded 25 articles that met eligibility and minimum quality criteria. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates for overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eight cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7% (confidence interval [CI] 13.9-22.2), 14.1% (9.3-20.6), 5.3% (3.2-8.6), and 4.7% (2.4-8.9), respectively. One article reported cardiac complications in CAP outpatients, four in low-risk (not severely ill) inpatients, and three in high-risk inpatients. The incidences for all outcomes except overall cardiac complications were lower in the two former groups and higher in the latter. One additional study reported on CAP outpatients and low-risk inpatients without discriminating between these groups. Twelve studies (48%) asserted the evaluation of cardiac complications in their methods but only six (24%) provided a definition for them. Only three studies, all examining ACS, carried out risk factor analysis for these events. No study analyzed the association between cardiac complications and other medical complications or their impact on other CAP outcomes. Major cardiac complications occur in a substantial proportion of patients with CAP. Physicians and patients need to appreciate the significance of this association for timely recognition and management of these events. Strategies aimed at preventing pneumonia (i.e., influenza and pneumococcal vaccination) in high-risk populations need to be optimized. Further research is needed to understand the mechanisms underlying this association, measure the impact of cardiac complications on other CAP outcomes, identify those patients with CAP at high risk of developing cardiac complications, and design strategies to prevent their occurrence in this population.

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.

Recurrent acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, debilitating, costly and often difficult to prevent. We reviewed records of patients who had COPD and immunoglobulin (Ig) treatment as adjunctive preventative treatment for AECOPD, and documented all AECOPD episodes for one year before and after initiation of Ig treatment. We graded AECOPD episodes as moderate for prescription of antibiotics and/or corticosteroids or for visit to the Emergency Department, and as severe for hospital admission. We conducted a retrospective within-subject self-controlled risk interval analysis to compare the outcome of annual AECOPD rate before and after treatment. We identified 22 cases of certain COPD, of which three had early discontinuation of Ig treatment due to rash and local swelling to subcutaneous Ig, and five had incomplete records leaving 14 cases for analyses. The median baseline IgG level was 5.9 g/L (interquartile range 4.1-7.4). Eight had CT radiographic bronchiectasis. Overall, the incidence of AECOPD was consistently and significantly reduced in frequency from mean 4.7 (± 3.1) per patient-year before, to 0.6 (± 1.0) after the Ig treatment (p = 0.0001). There were twelve episodes of severe AECOPD (in seven cases) in the year prior, and one in the year after Ig treatment initiation (p = 0.016). Ig treatment appears to decrease the frequency of moderate and severe recurrent AECOPD. A prospective, controlled evaluation of adjunctive Ig treatment to standard therapy of recurrent AECOPD is warranted.

IntroductionChronic 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 analysisWe 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 disseminationEthics 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 numberCRD42020192220.

We describe the first use of phage therapy in Canada for the treatment of a life-threatening periprosthetic joint infection (PJI), with successful outcome. PJI is a devastating complication of joint replacement surgery, with high morbidity and mortality. Our patient presented with early sepsis from a chronic recalcitrant multidrug-resistant (MDR) Staphylococcus epidermidis hip PJI which had repeatedly failed standard therapy. She had previously undergone 10 operations of the right hip, and only three weeks after completing a prolonged course of daptomycin following her most recent hip revision, she developed a draining sinus tract. Given the high burden of disease, inability to achieve surgical source control, and lack of antibiotic treatment options for long-term suppressive therapy, bacteriophage (phage) therapy was pursued. The patient underwent irrigation and debridement with complex flap reconstruction: intraoperative tissue cultures again yielded MDR S. epidermidis. We developed a novel phage therapy protocol for this patient, with twice daily, intra-articular and intravenous (7 × 109 PFU/dose) phage delivery over a planned 14-day course. Complete healing of the wound with cessation of drainage occurred within one month after treatment. A marked improvement in right hip pain and mobility occurred within three months after treatment. Twelve months following phage treatment, there is normalization of serum inflammatory markers with diminished pain, increased mobility, and no recurrent surgery. Our patient continues to improve and is currently living independently at home, with sustained clinical control of infection.

We aimed to determine the mental health and cognitive outcomes at six months in people who had not been hospitalized with COVID-19 and who had tested positive or negative for COVID-19 in Eastern Ontario, Canada. Participants were matched 1:1 six months following their COVID-19 polymerase chain reaction test. X2, t-test, and Mann–Whitney U tests were conducted to compare self-report and observer-rated mental health and cognitive outcomes between the two groups. We also conducted an age and gender-adjusted logistic regression analysis to explore risk factors associated with depression, anxiety, and cognitive impairment among those who had tested positive for COVID-19. A total of 324 participants were enrolled (n = 162 per arm). Overall, 40.7% of those in the COVID-positive group were men, with an average age of 37.9 (SD 13.2) years. In the COVID-negative group, 41.4% were men, with an average age of 36.7 (SD 12.8). There were no statistically significant differences in mental health outcomes between the groups. On cognitive testing, while 21% of the COVID-positive participants and 14% of the COVID-negative participants had scores indicating significant cognitive impairment, the difference between groups was not significant, though this warrants further investigation in future research. In non-hospitalized patients who have tested positive for COVID-19, there is no evidence of an increase in mental health disorders compared to people who tested negative. Any increases in mental health disorders during the pandemic may be the effect of social changes rather than an effect of the virus itself. The exception may be the cognitive changes in those who tested positive.

IntroductionSouth 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 analysisBukhali 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 disseminationEthical 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 registrationThis trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871).Protocol version20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries.

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.

IntroductionRaltegravir is a potent HIV-integrase strand transfer inhibitor (INSTI). Despite its strong activity against HIV-1 strains resistant to other antiretroviral drug classes, it is usually used in combination with other antiretroviral drugs due to the empirical requirement for anti-HIV drug combinations to ensure effective anti-retroviral therapy (ART). As an early-arriving INSTI, raltegravir is clinically familiar for its safety, tolerability and treatment effectiveness. High-dose calcium carbonate formulated as an antacid (as opposed to a supplement formulation) taken orally together with raltegravir is known to reduce systemic raltegravir exposure due to chelation and reduced absorption. This study aims to assess the effect of daily calcium carbonate antacid as TUMS Ultra Strength (US) administration in lower doses, as currently used for oral calcium supplementation, on the steady-state pharmacokinetics (PKs) of once-daily oral raltegravir.Methods and analysisThis is an open-label, three-treatment series in three periods in a single group, fixed-sequence PK study in 12 healthy adult volunteers with HIV on ART. Subjects will take 1200 mg of raltegravir single QD oral dose alone for 7 days (period one), then raltegravir 1200 mg with calcium carbonate 500 mg from day 8 to day 14 (period two) and raltegravir 1200 mg with calcium carbonate 1000 mg from day 15 to day 22 (period three). We will conduct serial PK sampling from observed dosing on days 7, 14 and 21, with 24-hour PK sampling scheduled for days 8, 15 and 22. Follow-up will continue until day 51.Ethics and disseminationThis study will adhere to the ICH GCP Guidelines and the Declaration of Helsinki. Ethics approval was obtained from the Ottawa Health Science Network Research Ethics Board under study ID 20190750–01 hour. Informed consent will be obtained from all participants prior to enrolment. This protocol will be published in a peer-reviewed journal prior to the study’s completion and closure. Results generated from this activity will also be reported in a peer-reviewed journal.Trial registration numberNCT04258475.

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. 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. 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. 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.