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Abstract Background Adolescents are increasingly susceptible to obesity, and thus at risk of later non-communicable diseases, due to changes in food choices, physical activity levels and exposure to an obesogenic environment. This review aimed to synthesize the literature investigating the effectiveness of health education interventions delivered in school settings to prevent overweight and obesity and/ or reduce BMI in adolescents, and to explore the key features of effectiveness. Methods A systematic search of electronic databases including MEDLINE, CINAHL, PsychINFO and ERIC for papers published from Jan 2006 was carried out in 2020, following PRISMA guidelines. Studies that evaluated health education interventions in 10–19-year-olds delivered in schools in high-income countries, with a control group and reported BMI/BMI z-score were selected. Three researchers screened titles and abstracts, conducted data extraction and assessed quality of the full text publications. A third of the papers from each set were cross-checked by another reviewer. A meta-analysis of a sub-set of studies was conducted for BMI z-score. Results Thirty-three interventions based on 39 publications were included in the review. Most studies evaluated multi-component interventions using health education to improve behaviours related to diet, physical activity and body composition measures. Fourteen interventions were associated with reduced BMI/BMI z-score. Most interventions (n = 22) were delivered by teachers in classroom settings, 19 of which trained teachers before the intervention. The multi-component interventions (n = 26) included strategies such as environment modifications (n = 10), digital interventions (n = 15) and parent involvement (n = 16). Fourteen studies had a low risk of bias, followed by 10 with medium and nine with a high risk of bias. Fourteen studies were included in a random-effects meta-analysis for BMI z-score. The pooled estimate of this meta-analysis showed a small difference between intervention and control in change in BMI z-score (− 0.06 [95% CI -0.10, − 0.03]). A funnel plot indicated that some degree of publication bias was operating, and hence the effect size might be inflated. Conclusions Findings from our review suggest that school-based health education interventions have the public health potential to lower BMI towards a healthier range in adolescents. Multi-component interventions involving key stakeholders such as teachers and parents and digital components are a promising strategy.

Abstract Background Historically, Indigenous voices have been silent in health research, reflective of colonial academic institutions that privilege Western ways of knowing. However, Indigenous methodologies and methods with an emphasis on the active involvement of Indigenous peoples and centering Indigenous voices are gaining traction in health education and research. In this paper, we map each phase of our scoping review process and weave Indigenous research methodologies into Arksey and O’Malley’s (2005) framework for conducting scoping reviews. Methods Guided by an advisory circle consisting of Indigenous Knowledge Keepers and allied scholars, we utilized both Indigenous and Western methods to conduct a scoping review. As such, a circle of Knowledge Keepers provided guidance and informed our work, while our methods of searching and scoping the literature remained consistent with PRISMA-ScR guidelines. In keeping with an Indigenous methodology, the scoping review protocol was not registered allowing for an organic development of the research process. Results We built upon Arksey and O’Malley’s 5-stages and added an additional 3 steps for a combined 8-stage model to guide our research: (1) Exploration and Listening, (2) Doing the Groundwork, (3) Identifying and Refining the Research Question, (4) Identifying Relevant Studies, (5) Study Selection, (6) Mapping Data, (7) Collating, Summarizing and Synthesizing the Data, and lastly, (8) Sharing and Making Meaning. Engagement and listening, corresponding to Arksey and O’Malley (2005)’s optional “consultation stage,” was embedded throughout, but with greater intensity in stages 1 and 8. Conclusion An Indigenous approach to conducting a scoping review includes forming a team with a wide array of experience in both Indigenous and Western methodologies, meaningful Indigenous representation, and inclusion of Indigenous perspectives to shape the analysis and presentation of findings. Engaging Indigenous peoples throughout the entire research process, listening, and including Indigenous voices and perspectives is vital in reconciliation research, producing both credible and useable information for both Indigenous communities and academia. Our Indigenous methodology for conducting a scoping review can serve as a valuable framework for summarizing Indigenous health-related research.

Background Indigenous data sovereignty applies to the collection, ownership, and application of data about Indigenous peoples, lands, and resources. Objectives To support and expand Manitoba First Nations (FNs) data sovereignty by strengthening capacity and policies related to the ownership, repatriation, and governance of FNs health data. Approach In March of 2022, the Chiefs of the 63 First Nations in Manitoba adopted a resolution to mandate FNHSSM to implement the First Nations Data Governance Strategy. FNHSSM Data Sovereignty Team has conducted extensive engagement with FNs (including youth, Knowledge Keepers, urban members, 2SLGBTQIA+ members, health directors, and more) to identify current priorities for data collection, research, policy, and training. Basic analysis was done to determine the frequency with which each theme and sub-theme were discussed. Results Based on the engagement sessions themes that refer to traditional FNs cultural practices and knowledge represented a major priority for all groups, including the integration of strength-based indicators of wellbeing. Overall, FNs have reinforced the urgent need to exert ownership over community health data under the principles of data sovereignty. The health directors top three themes include: (1) data repatriation, (2) governance, ethics, and privacy and, (3) mental health, substance use, violence and poverty. Conclusions Through engagement, we have identified data needs (including access, training, policies), data topics (health priorities, traditional practices), and data uses (advocacy, repatriation, research) that are unique to FNs in Manitoba. Our team is working in collaboration with FNs to gain greater control over their data, enhance their data analysis capabilities, and ensure the protection of privacy and culture. Implications Operationalizing data sovereignty will support evidence-based decision making, research capacity, governance, and ultimately, self-determination.

Introduction: Daptomycin (DAP) is a cyclic lipopeptide that exhibits potent in vitro activity against many drug-resistant gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Despite substantial reports evaluating the clinical outcomes of DAP within the adult population, real-world data are lacking in children. The primary goal of this evaluation was to describe the clinical characteristics and outcomes of DAP use in pediatric patients across a wide range of infections. Methods: This retrospective evaluation included patients < 18 years of age who were treated with DAP from January 2014 to May 2023. The primary objective was to evaluate the composite clinical success, which was defined as a 30-day survival, the lack of a 30-day microbiological recurrence, and the resolution of signs and symptoms of an acute infection without therapy modifications based on clinical failures. Secondary objectives included adverse effects potentially attributable to DAP and reasons for DAP utilization. Results: Forty patients were included, which were predominately male (62.5%) and white (52.5%), with a median age of 8.7 [IQR, 4.4–16.0] years. DAP was used for a wide range of infections, including central line-associated bloodstream infections (CLABSIs; 32.5%), infective endocarditis (15.0%), surgical-site infections (12.5%), and osteomyelitis (12.5%). The most common pathogen isolated was MRSA (37.5%), and most patients were bacteremic (60.0%). The median DAP dose was 8 [IQR, 6–10] mg/kg, and the median duration of the DAP therapy was 11.5 [IQR, 4.8–18.8] days. Most patients achieved composite clinical success (75.0%). An adverse effect occurred in 5.0% of the patients. DAP was prescribed the most for its ease of use/ability to facilitate discharge (40.0%) and/or for issues with alternative therapies (37.5%). Conclusion: Most pediatric patients that received DAP demonstrated clinical success with a low incidence of adverse effects. Larger, real-world studies of DAP use are necessary to further assess clinical outcomes.

ABSTRACT Eravacycline is a synthetic fluorocycline approved by the U.S. Food and Drug Administration in 2018. This study aimed to describe clinical and microbiological outcomes in addition to associated adverse effects of eravacycline used in U.S. hospitals. Real-world, observational study involving patients receiving ≥72 h of eravacycline at 19 medical centers located in all 5 regions of the United States between October 2018 and August 2022. The primary outcome was clinical success, defined as survival and absence of microbiological recurrence at 30 days from the end of eravacycline therapy and clinical improvement within 96 h of eravacycline initiation. In total, 416 patients met study criteria and were evaluated. Index culture specimens were most often isolated from the respiratory tract (24.8%, n = 103/416), wound(s) (20.9%, n = 87/416), or blood (19.5%, n = 81/416). As definitive therapy, eravacycline was most often used to treat infections caused by Enterobacterales spp. (42.3%, n = 176/416; 24.4%, n = 43/176 carbapenem-resistant), Enterococci spp. (24.0%, n = 100/416; 49.0%, 49/100 vancomycin-resistant), and Acinetobacter spp. (23.3%, n = 97/416; 47.4%, n = 46/97 carbapenem-resistant). Clinical success occurred in 75.7% of patients (n = 315/416). Thirty-nine (9.4%, n = 39/416) patients experienced a treatment emergent adverse event (TEAE) potentially related to eravacycline with the majority (51.3%, n = 20/39) being gastrointestinal intolerance. Only 27 isolates (6.5%, n = 27/416) underwent eravacycline susceptibility testing. Eravacycline is being used to treat a broad range of Gram-negative and Gram-positive bacteria in the United States including those demonstrating multidrug-resistance with consistently low reported drug-related TEAE; however, antimicrobial susceptibility testing and subsequent in vitro susceptibility data of clinical isolates was sparingly performed. IMPORTANCE The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline’s efficacy in addressing the pressing global challenge of MDR bacterial infections.

Abstract Objectives: Evaluate system-wide antimicrobial stewardship program (ASP) update impact on intravenous (IV)-to-oral (PO) antimicrobial conversion in select community hospitals through pre- and postimplementation trend analysis. Methods: Retrospective study across seven hospitals: region one (four hospitals, 827 beds) with tele-ASP managed by infectious diseases (ID)-trained pharmacists and region two (three hospitals, 498 beds) without. Data were collected pre- (April 2022–September 2022) and postimplementation (April 2023–September 2023) on nine antimicrobials for the IV to PO days of therapy (DOTs). Antimicrobial administration route and (DOTs)/1,000 patient days were extracted from the electronical medical record (EMR). Primary outcome: reduction in IV DOTs/1,000 patient days. Secondary outcomes: decrease in IV usage via PO:total antimicrobial ratios and cost reduction. Results: In region one, IV usage decreased from 461 to 209/1,000 patient days (P = < .001), while PO usage increased from 289 to 412/1,000 patient days (P = < .001). Total antimicrobial use decreased from 750 to 621/1,000 patient days (P = < .001). In region two, IV usage decreased from 300 to 243/1,000 patient days (P = .005), and PO usage rose from 154 to 198/1,000 patient days (P = .031). The PO:total antimicrobial ratios increased in both regions, from .42–.52 to .60–.70 in region one and from .36–.55 to .46–.55 in region two. IV cost savings amounted to $19,359.77 in region one and $4,038.51 in region two. Conclusion: The ASP intervention improved IV-to-PO conversion rates in both regions, highlighting the contribution of ID-trained pharmacists in enhancing ASP initiatives in region one and suggesting tele-ASP expansion may be beneficial in resource-constrained settings.

Antimicrobial resistance is a global public health threat due to its associated increase in mortality, and the most appropriate treatment algorithms for resistant and persistent Gram-positive and Gram-negative infections have yet to be elucidated. Whilst combination therapy has been touted as a viable method to overcome prominent resistant mechanisms represented amongst these microbes, the optimal agents to utilize remains controversial. Beta-lactams have a safe profile and are bactericidal against most Gram-positive and Gram-negative microorganisms. Thus, the use of dual beta-lactam therapy to overcome multidrug-resistant pathogens is of supreme interest. This article reviews the mechanisms of beta-lactam resistance in Gram-positive and Gram-negative bacteria, discusses the rationale for dual beta-lactam use against multidrug-resistant infections (and other scenarios in which this strategy may be most utilized in clinical practice), explores the available in vitro, in vivo and clinical data, and provides considerations for the use of dual beta-lactam therapy against Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii pathogens.

ABSTRACT Forty-six patients were treated with eravacycline (ERV) for Acinetobacter baumannii infections, where 69.5% of isolates were carbapenem resistant (CRAB). Infections were primarily pulmonary (58.3%), and most patients received combination therapy (84.4%). The median (IQR) ERV duration was 6.9 days (5.1 to 11.1). Thirty-day mortality was 23.9% in the cohort and 21.9% in CRAB patients. One patient experienced an ERV-possible adverse event. IMPORTANCE Acinetobacter baumannii, particularly when carbapenem resistant (CRAB), is one of the most challenging pathogens in the health care setting. This is complicated by the fact that there is no consensus guideline regarding management of A. baumannii infections. However, the recent Infectious Diseases Society of America guidelines for treatment of resistant Gram-negative infections provided expert recommendations for CRAB management. The panel suggest using minocycline among tetracycline derivatives rather than eravacycline (ERV) until sufficient clinical data are available. Therefore, we present the largest multicenter real-world cohort in patients treated with ERV for A. baumannii, where the majority of isolates were CRAB (69.5%). Our analysis demonstrate that patients treated with ERV-based regimens achieved a 30-day mortality of 23.9% and had a low incidence of ERV-possible adverse events (2.1%). This study is important as it fills the gap in the literature regarding the use of a novel tetracycline (i.e., ERV) in the treatment of this challenging health care infection.

Abstract Coronavirus disease 2019 (COVID-19), caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a global pandemic. To date, only remdesivir and dexamethasone have demonstrated a positive response in a prospective, randomized trial for the treatment of patients with COVID-19. Hydroxychloroquine (HCQ) is an agent available in an oral formulation with in vitro activity against SARS-CoV-2 that has been suggested as a potential agent. Unfortunately, results of randomized trials evaluating HCQ as treatment against a control group are lacking, and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) profile against SARS-CoV-2. The objective of this review was to describe the current understanding of the PK/PD and dose selection of HCQ against SARS-CoV-2, discuss knowledge gaps, and identify future studies that are needed to optimize the efficacy and safety of treatments against COVID-19.

Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with high morbidity and mortality. More in vitro, in vivo, and clinical data suggest that vancomycin (VAN) or daptomycin (DAP) combination therapy with β-lactams (BL) improves outcomes of MRSA infections. We hypothesize that BL combination with VAN or DAP would reduce the odds of clinical failure compared to VAN or DAP monotherapy. Methods A retrospective cohort study of adult patients ≥ 18 years treated with VAN or DAP for MRSA BSI from 2006 to 2019 at Detroit Medical Center. Combination therapy (CT) was defined as VAN or DAP plus any BL for ≥ 24 h within 72 h of index culture. Monotherapy (MT) was defined as ≥ 72 h VAN or DAP within 72 h of index culture and no BL for ≥ 24 h up to 7 days following VAN/DAP initiation. Primary outcome was composite endpoint of clinical failure defined as: (1) 30-day mortality, (2) 60-day recurrence, or (3) persistent bacteremia (PB). PB was defined as bacteremia > 5 days. Multivariable logistic regression was used to evaluate the association between CT and the primary outcome. Results Overall, 597 patients were included in this analysis, 153 in the MT group and 444 in the CT group. CT was independently associated with reduced odds of clinical failure (adjusted odds ratio, 0.523; 95% confidence interval, 0.348–0.787). The composite endpoint was driven by 60-day recurrence and PB but not 30-day mortality. There were no difference in adverse events including nephrotoxicity between the two study arms. Conclusions In hospitalized adults with MRSA BSI, CT with any BL was independently associated with improved clinical outcomes and may ultimately be selected as preferred therapy.

ABSTRACT Bacterial biofilms are difficult to eradicate and can complicate many infections by forming on tissues and medical devices. Phage+antibiotic combinations (PAC) may be more active on biofilms than either type of agent alone, but it is difficult to predict which PAC regimens will be reliably effective. To establish a method for screening PAC combinations against Staphylococcus aureus biofilms, we conducted biofilm time-kill analyses (TKA) using various combinations of phage Sb-1 with clinically relevant antibiotics. We determined the activity of PAC against biofilm versus planktonic bacteria and investigated the emergence of resistance during (24 h) exposure to PAC. As expected, fewer treatment regimens were effective against biofilm than planktonic bacteria. In experiments with isogenic strain pairs, we also saw less activity of PACs against DNS-VISA mutants versus their respective parentals. The most effective treatment against both biofilm and planktonic bacteria was the phage+daptomycin+ceftaroline regimen, which met our stringent definition of bactericidal activity (>3 log10 CFU/mL reduction). With the VISA-DNS strain 8015 and DNS strain 684, we detected anti-biofilm synergy between Sb-1 and DAP in the phage+daptomycin regimen (>2 log10 CFU/mL reduction versus best single agent). We did not observe any bacterial resensitization to antibiotics following treatment, but phage resistance was avoided after exposure to PAC regimens for all tested strains. The release of bacterial membrane vesicles tended to be either unaffected or reduced by the various treatment regimens. Interestingly, phage yields from certain biofilm experiments were greater than from similar planktonic experiments, suggesting that Sb-1 might be more efficiently propagated on biofilm. IMPORTANCE Biofilm-associated multidrug-resistant infections pose significant challenges for antibiotic therapy. The extracellular polymeric matrix of biofilms presents an impediment for antibiotic diffusion, facilitating the emergence of multidrug-resistant populations. Some bacteriophages (phages) can move across the biofilm matrix, degrade it, and support antibiotic penetration. However, little is known about how phages and their hosts interact in the biofilm environment or how different phage+antibiotic combinations (PACs) impact biofilms in comparison to the planktonic state of bacteria, though scattered data suggest that phage+antibiotic synergy occurs more readily under biofilm-like conditions. Our results demonstrated that phage Sb-1 can infect MRSA strains both in biofilm and planktonic states and suggested PAC regimens worthy of further investigation as adjuncts to antibiotics.

Abstract Background The aim of this study was to evaluate the predictive performance of the INCREMENT-CPE (ICS), Pitt bacteremia score (PBS) and qPitt for mortality among patients treated with ceftazidime–avibactam for carbapenem-resistant Enterobacteriaceae (CRE) infections. Methods Retrospective, multicenter, cohort study of patients with CRE infections treated with ceftazidime–avibactam between 2015 and 2019. The primary outcome was 30-day all-cause mortality. Predictive performance was determined by assessing discrimination, calibration and precision. Results In total, 109 patients were included. Thirty-day mortality occurred in 18 (16.5%) patients. There were no significant differences in discrimination of the three scores [area under the curve (AUC) ICS 0.7039, 95% CI 0.5848–0.8230, PBS 0.6893, 95% CI 0.5709–0.8076, and qPitt 0.6847, 95% CI 0.5671–0.8023; P > 0.05 all pairwise comparisons]. All scores showed adequate calibration and precision. When dichotomized at the optimal cut-points of 11, 3, and 2 for the ICS, PBS, and qPitt, respectively, all scores had NPV > 90% at the expense of low PPV. Patients in the high-risk groups had a relative risk for mortality of 3.184 (95% CI 1.35–8.930), 3.068 (95% CI 1.094–8.606), and 2.850 (95% CI 1.016–7.994) for the dichotomized ICS, PBS, and qPitt, scores respectively. Treatment-related variables (early active antibiotic therapy, combination antibiotics and renal ceftazidime–avibactam dose adjustment) were not associated with mortality after controlling for the risk scores. Conclusions In patients treated with ceftazidime–avibactam for CRE infections, mortality risk scores demonstrated variable performance. Modifications to scoring systems to more accurately predict outcomes in the era of novel antibiotics are warranted.

Multidrug-resistant (MDR) Enterococcus faecium is a challenging nosocomial pathogen known to colonize medical device surfaces and form biofilms. Bacterio (phages) may constitute an emerging anti-infective option for refractory, biofilm-mediated infections. This study evaluates eight MDR E. faecium strains for biofilm production and phage susceptibility against nine phages. Two E. faecium strains isolated from patients with bacteremia and identified to be biofilm producers, R497 (daptomycin (DAP)-resistant) and HOU503 (DAP-susceptible dose-dependent (SDD), in addition to four phages with the broadest host ranges (ATCC 113, NV-497, NV-503-01, NV-503-02) were selected for further experiments. Preliminary phage-antibiotic screening was performed with modified checkerboard minimum biofilm inhibitory concentration (MBIC) assays to efficiently screen for bacterial killing and phage-antibiotic synergy (PAS). Data were compared by one-way ANOVA and Tukey (HSD) tests. Time kill analyses (TKA) were performed against R497 and HOU503 with DAP at 0.5× MBIC, ampicillin (AMP) at free peak = 72 µg/mL, and phage at a multiplicity of infection (MOI) of 0.01. In 24 h TKA against R497, phage-antibiotic combinations (PAC) with DAP, AMP, or DAP + AMP combined with 3- or 4-phage cocktails demonstrated significant killing compared to the most effective double combination (ANOVA range of mean differences 2.998 to 3.102 log10 colony forming units (CFU)/mL; p = 0.011, 2.548 to 2.868 log10 colony forming units (CFU)/mL; p = 0.023, and 2.006 to 2.329 log10 colony forming units (CFU)/mL; p = 0.039, respectively), with preserved phage susceptibility identified in regimens with 3-phage cocktails containing NV-497 and the 4-phage cocktail. Against HOU503, AMP combined with any 3- or 4-phage cocktail and DAP + AMP combined with the 3-phage cocktail ATCC 113 + NV-497 + NV-503-01 demonstrated significant PAS and bactericidal activity (ANOVA range of mean differences 2.251 to 2.466 log10 colony forming units (CFU)/mL; p = 0.044 and 2.119 to 2.350 log10 colony forming units (CFU)/mL; p = 0.028, respectively), however, only PAC with DAP + AMP maintained phage susceptibility at the end of 24 h TKA. R497 and HOU503 exposure to DAP, AMP, or DAP + AMP in the presence of single phage or phage cocktail resulted in antibiotic resistance stabilization (i.e., no antibiotic MBIC elevation compared to baseline) without identified antibiotic MBIC reversion (i.e., lowering of antibiotic MBIC compared to baseline in DAP-resistant and DAP-SDD isolates) at the end of 24 h TKA. In conclusion, against DAP-resistant R497 and DAP-SDD HOU503 E. faecium clinical blood isolates, the use of DAP + AMP combined with 3- and 4-phage cocktails effectively eradicated biofilm-embedded MDR E. faecium without altering antibiotic MBIC or phage susceptibility compared to baseline.

A disproportionate number of Greenland's Inuit population are chronically infected with Hepatitis B virus (HBV; 5–10%). HBV genotypes B and D are most prevalent in the circumpolar Arctic. Here, we report 39 novel HBV/D sequences from individuals residing in southwestern Greenland. We performed phylodynamic analyses with ancient HBV DNA calibrators to investigate the origin and relationship of these taxa to other HBV sequences. We inferred a substitution rate of 1.4 × 10−5 [95% HPD 8.8 × 10−6, 2.0 × 10−5] and a time to the most recent common ancestor of 629 CE [95% HPD 37–1138 CE]. The Greenland taxa form a sister clade to HBV/D2 sequences, specifically New Caledonian and Indigenous Taiwanese sequences. The Greenland sequences share amino acid signatures with subgenotypes D1 and D2 and ~97% sequence identity. Our results suggest the classification of these novel sequences does not fit within the current nomenclature. Thus, we propose these taxa be considered a novel quasi-subgenotype.