A multi-bin rarefying method for evaluating alpha diversities in TCR sequencing data.

MOTIVATION: T cell receptors (TCRs) constitute a major component of our adaptive immune system, governing the recognition and response to internal and external antigens. Studying the TCR diversity via sequencing technology is critical for a deeper understanding of immune dynamics. However, library sizes differ substantially across samples, hindering the accurate estimation/comparisons of alpha diversities. To address this, researchers frequently use an overall rarefying approach in which all samples are sub-sampled to an even depth. Despite its pervasive application, its efficacy has never been rigorously assessed. RESULTS: In this paper, we develop an innovative "multi-bin" rarefying approach that partitions samples into multiple bins according to their library sizes, conducts rarefying within each bin for alpha diversity calculations, and performs meta-analysis across bins. Extensive simulations using real-world data highlight the inadequacy of the overall rarefying approach in controlling the confounding effect of library size. Our method proves robust in addressing library size confounding, outperforming competing normalization strategies by achieving better-controlled type-I error rates and enhanced statistical power in association tests. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/mli171/MultibinAlpha. The datasets are freely available at https://doi.org/10.21417/B7001Z and https://doi.org/10.21417/AR2019NC.

A Spatial Omnibus Test (SPOT) for Spatial Proteomic Data.

MOTIVATION: Spatial proteomics can reveal the spatial organization of immune cells in the tumor immune microenvironment. Relating measures of spatial clustering, such as Ripley's K or Besag's L, to patient outcomes may offer important clinical insights. However, these measures require pre-specifying a radius in which to quantify clustering, yet no consensus exists on the optimal radius which may be context-specific. RESULTS: We propose a SPatial Omnibus Test (SPOT) which conducts this analysis across a range of candidate radii. At each radius, SPOT evaluates the association between the spatial summary and outcome, adjusting for confounders. SPOT then aggregates results across radii using the Cauchy combination test, yielding an omnibus p-value characterizing the overall degree of association. Using simulations, we verify that the type I error rate is controlled and show SPOT can be more powerful than alternatives. We also apply SPOT to an ovarian and lung cancer study. AVAILABILITY: An R package and tutorial is provided at https://github.com/sarahsamorodnitsky/SPOT.

The Study of the Epidemiology of Pediatric Hypertension Registry (SUPERHERO): Rationale and Methods.

Despite increasing prevalence of hypertension in youth and high adult cardiovascular mortality rates, the long-term consequences of youth-onset hypertension remain unknown. This is due to limitations of prior research such as small sample sizes, reliance on manual record review, and limited analytic methods that did not address major biases. The Study of the Epidemiology of Pediatric Hypertension (SUPERHERO) is a multisite retrospective Registry of youth evaluated by subspecialists for hypertension disorders. Sites obtain harmonized electronic health record data using standardized biomedical informatics scripts validated with randomized manual record review. Inclusion criteria are index visit for International Classification of Diseases Diagnostic Codes, 10th Revision (ICD-10 code)-defined hypertension disorder ≥January 1, 2015 and age <19 years. We exclude patients with ICD-10 code-defined pregnancy, kidney failure on dialysis, or kidney transplantation. Data include demographics, anthropomorphics, U.S. Census Bureau tract, histories, blood pressure, ICD-10 codes, medications, laboratory and imaging results, and ambulatory blood pressure. SUPERHERO leverages expertise in epidemiology, statistics, clinical care, and biomedical informatics to create the largest and most diverse registry of youth with newly diagnosed hypertension disorders. SUPERHERO's goals are to (i) reduce CVD burden across the life course and (ii) establish gold-standard biomedical informatics methods for youth with hypertension disorders.

A Comprehensive Review of Lyme Disease: A Focus on Cardiovascular Manifestations.

Lyme disease is a tick-borne illness known for its ability to cause multi-systemic manifestations. It can affect several different systems, including neurological, musculoskeletal, and dermatological systems. However, one of the most concerning biological systems affected is the cardiac system. Lyme carditis typically presents with varying degrees of atrioventricular (AV) block. Additionally, current literature also endorses atypical manifestations, including but not limited to atrial fibrillation and bundle branch blocks. These atypical manifestations are important as they can be the first presenting symptoms in patients with Lyme disease. Therefore, educating clinicians on various signs, symptoms, and manifestations of Lyme carditis remains paramount in reducing morbidity and mortality. We conducted a literature review using PubMed, MEDLINE, and CINAHL, collecting a total of 13 articles to gather information on atypical manifestations of Lyme carditis. This literature review serves to summarize the current research and studies describing these cardiac manifestations and the cardiac pathophysiology associated with Lyme disease. These findings aim to contribute to the expanding understanding of Lyme carditis, subsequently preventing long-term effects through prompt diagnosis and treatment.

Salvage surgery for recurrent or residual hypopharyngeal squamous cell carcinoma: A systematic review.

BACKGROUND: This systematic review aggregates the data of studies that include site-specific analyses of patients undergoing salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma. METHODS: The primary outcomes are disease-free, disease-specific, and overall survival (DFS, DSS, and OS, respectively). Secondary outcomes include complications and postoperative feeding requirements. RESULTS: Fifteen studies met the inclusion criteria with a total of 442 patients. Two-year DFS is reported from 30.0 to 50.0% and 5-year DFS ranges from 15.0 to 57.1%. Five-year DSS ranges from 28.0 to 57.1%. Two-year OS ranges from 38.8 to 52.0% and 5-year OS ranges from 15.5 to 57.1%. Complications include pharyngocutaneous fistula (0.0-71.4%), carotid artery rupture (2.9-13.3%), and stomal stenosis (4.2-20.0%). Complete oral feeding achieved following surgery ranges from 61.9 to 100.0%, while complete gastrostomy tube dependence ranges from 0.0 to 28.6%. CONCLUSIONS: Salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma has a relatively high complication rate and should be offered to patients with the understanding of a guarded prognosis.

Viral genomic variation and the severity of genital HSV-2 infection as quantified by shedding rate: a viral genome-wide association study.

BACKGROUND: The clinical severity of genital HSV-2 infection varies widely among infected persons with some experiencing frequent genital lesions while others are asymptomatic. The viral genital shedding rate is closely associated with and has been established as a surrogate marker of clinical severity. METHODS: To assess the relationship between viral genetics and shedding, we assembled a set of 145 persons who had the severity of their genital herpes quantified through determination of their HSV genital shedding rate. An HSV-2 sample from each person was sequenced and biallelic variants among these genomes were identified. RESULTS: We found no association between metrics of genome-wide variation in HSV-2 and shedding rate. A viral genome-wide association study (vGWAS) identified the minor alleles of three individual unlinked variants as significantly associated with higher shedding rate (p<8.4x10-5): C44973T (A512T), a non-synonymous variant in UL22 (glycoprotein H); A74534G, a synonymous variant in UL36 (large tegument protein); and T119283C, an intergenic variant. We also found an association between the total number of minor alleles for the significant variants and shedding rate (p=6.6x10-7). CONCLUSIONS: These results add to a growing body of literature for HSV suggesting a connection between viral genetic variation and clinically important phenotypes of infection.

A Scoping Review of the Positive and Negative Bacteria Associated With the Gut Microbiomes of Systemic Lupus Erythematosus Patients.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple systems of the body. Recent research on the gut microbiota dysbiosis associated with SLE patients has gained traction and warranted further exploration. It has not been determined whether the change in the gut microbiota is a cause of SLE or a symptom of SLE. However, based on the physiological and pathophysiological role of the bacteria in the gut microbiome, as levels of the bacteria rise or fall, symptomatology in SLE patients could be affected. This review analyzes the recent studies that examined the changes in the gut microbiota of SLE patients and highlights the correlations between gut dysbiosis and the clinical manifestations of SLE. A systematic search strategy was developed by combining the terms "SLE," "systemic lupus erythematosus," and "gut microbiome." Biomedical Reference Collection, CINAHL, Medline ProQuest, and PubMed Central databases were searched by combining the appropriate keywords with "AND." Only full-text, English-language articles were searched. The articles were restricted from 2013 to 2023. Only peer-reviewed controlled studies with both human and animal trials were included in this scoping review. Review articles, non-English articles, editorials, case studies, and duplicate articles from the four databases were excluded. Various species of bacteria were found to be positively or negatively associated with SLE gut microbiomes. Among the bacterial species increased were Clostridium, Lactobacilli, Streptococcus, Enterobacter, and Klebsiella. The bacterial species that decreased were Bifidobacteria, Prevotella, and the Firmicutes/Bacteroidetes ratio. Literature shows that Clostridium is one of several bacteria found in abundance, from pre-disease to the diseased state of SLE. Lachnospiraceae and Ruminococcaceae are both part of the family of butyrate-producing anaerobes that are known for their role in strengthening the skin barrier function and, therefore, may explain the cutaneous manifestations of SLE patients. Studies have also shown that the Firmicutes/Bacteroidetes ratio is significantly depressed, which may lead to appetite changes and weight loss seen in SLE patients. Based on the established role of these bacteria within the gut microbiome, the disruption in the gut ecosystem could explain the symptomatology common in SLE patients. By addressing these changes, our scoping review encourages further research to establish a true causal relationship between the bacterial changes in SLE patients as well as furthering the scope of microbiota changes in other systems and autoimmune diseases.

Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper.

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

Association between vaginal microbiota and vaginal inflammatory immune markers in postmenopausal women.

OBJECTIVE: In premenopausal individuals, vaginal microbiota diversity and lack of Lactobacillus dominance are associated with greater mucosal inflammation, which is linked to a higher risk of cervical dysplasia and infections. It is not known if the association between the vaginal microbiota and inflammation is present after menopause, when the vaginal microbiota is generally higher-diversity and fewer people have Lactobacillus dominance. METHODS: This is a post hoc analysis of a subset of postmenopausal individuals enrolled in a randomized trial for treatment of moderate-severe vulvovaginal discomfort that compared vaginal moisturizer, estradiol, or placebo. Vaginal fluid samples from 0, 4, and 12 weeks were characterized using 16S rRNA gene sequencing (microbiota) and MesoScale Discovery (vaginal fluid immune markers: IL-1b, IL-1a, IL-2, IL-6, IL-18, IL-10, IL-9, IL-13, IL-8, IP10, MIP1a, MIP1b, MIP3a). Global associations between cytokines and microbiota (assessed by relative abundance of individual taxa and Shannon index for alpha, or community, diversity) were explored, adjusting for treatment arm, using linear mixed models, principal component analysis, and Generalized Linear Mixed Model + Microbiome Regression-based Kernel Association Test (GLMM-MiRKAT). RESULTS: A total of 119 individuals with mean age of 61 years were included. At baseline, 29.5% of participants had a Lactobacillus -dominant vaginal microbiota. Across all timepoints, alpha diversity (Shannon index, P = 0.003) was highly associated with immune markers. Individual markers that were associated with Lactobacillus dominance were similar to those observed in premenopausal people: IL-10, IL-1b, IL-6, IL-8 (false discovery rate [FDR] < 0.01), IL-13 (FDR = 0.02), and IL-2 (FDR = 0.09). Over 12 weeks, change in alpha diversity was associated with change in cytokine concentration (Shannon, P = 0.018), with decreased proinflammatory cytokine concentrations observed with decreasing alpha diversity. CONCLUSIONS: In this cohort of postmenopausal individuals, Lactobacillus dominance and lower alpha diversity were associated with lower concentrations of inflammatory immune markers, as has been reported in premenopausal people. This suggests that after menopause lactobacilli continue to have beneficial effects on vaginal immune homeostasis, despite lower prevalence.

"Multiplexed screen identifies a Pseudomonas aeruginosa -specific small molecule targeting the outer membrane protein OprH and its interaction with LPS".

The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa , a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT 1 , a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM ß-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal novel pathogen biology.

Syphilis and cardiovascular risk: a Taiwanese registry.

BACKGROUND AND AIMS: Studies on the impact of syphilis on the cardiovascular system in large populations are limited. This study investigated the effects of syphilis on cardiovascular outcomes. METHODS: Medical records from 2010 to 2015 were retrieved from the Taiwan National Health Insurance Research Database, linked to the Notifiable Infectious Diseases database from the Taiwan Centers for Disease Control. Patients with syphilis were identified, excluding those with missing information, under 20 years of age, or with a history of human immunodeficiency virus infection, acute myocardial infarction, heart failure, aortic regurgitation, replacement of the aortic valve, aneurysm and/or dissection of the aorta, atrial fibrillation, ischaemic stroke, haemorrhagic stroke, and venous thromboembolism. Primary outcomes included new-onset acute myocardial infarction, heart failure, aortic regurgitation, aneurysm and dissection of the aorta, atrial fibrillation, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, cardiovascular death, and all-cause mortality. RESULTS: A total of 28 796 patients with syphilis were identified from 2010 to 2015. After exclusions and frequency matching, 20 601 syphilis patients and 20 601 non-syphilis patients were analysed. The relative rate (RR) was utilized in the analysis, as the competing risk of death was not considered. Compared with patients without syphilis, patients with syphilis had increased risks of acute myocardial infarction (RR 38%, 95% confidence interval [CI] 1.19-1.60, P < .001), heart failure (RR 88%, 95% CI 1.64-2.14, P < .001), aortic regurgitation (RR 81%, 95% CI 1.18-2.75, P = .006), atrial fibrillation (RR 45%, 95% CI 1.20-1.76, P < .001), ischaemic stroke (RR 68%, 95% CI 1.52-1.87, P < .001), haemorrhagic stroke (RR 114%, 95% CI 1.74-2.64, P < .001), venous thromboembolism (RR 67%, 95% CI 1.23-2.26, P = .001), cardiovascular death (RR 155%, 95% CI 2.11-3.08, P < .001), and all-cause death (RR 196%, 95% CI 2.74-3.19, P < .001) but not for aneurysm and dissection of the aorta. CONCLUSIONS: This study demonstrates that patients with syphilis have a higher risk of cardiovascular events and all-cause mortality compared with those without syphilis.

Durability of Original Monovalent mRNA Vaccine Effectiveness Against COVID-19 Omicron-Associated Hospitalization in Children and Adolescents - United States, 2021-2023.

Pediatric COVID-19 vaccination is effective in preventing COVID-19-related hospitalization, but duration of protection of the original monovalent vaccine during SARS-CoV-2 Omicron predominance merits evaluation, particularly given low coverage with updated COVID-19 vaccines. During December 19, 2021-October 29, 2023, the Overcoming COVID-19 Network evaluated vaccine effectiveness (VE) of ≥2 original monovalent COVID-19 mRNA vaccine doses against COVID-19-related hospitalization and critical illness among U.S. children and adolescents aged 5-18 years, using a case-control design. Too few children and adolescents received bivalent or updated monovalent vaccines to separately evaluate their effectiveness. Most case-patients (persons with a positive SARS-CoV-2 test result) were unvaccinated, despite the high frequency of reported underlying conditions associated with severe COVID-19. VE of the original monovalent vaccine against COVID-19-related hospitalizations was 52% (95% CI = 33%-66%) when the most recent dose was administered <120 days before hospitalization and 19% (95% CI = 2%-32%) if the interval was 120-364 days. VE of the original monovalent vaccine against COVID-19-related hospitalization was 31% (95% CI = 18%-43%) if the last dose was received any time within the previous year. VE against critical COVID-19-related illness, defined as receipt of noninvasive or invasive mechanical ventilation, vasoactive infusions, extracorporeal membrane oxygenation, and illness resulting in death, was 57% (95% CI = 21%-76%) when the most recent dose was received <120 days before hospitalization, 25% (95% CI = -9% to 49%) if it was received 120-364 days before hospitalization, and 38% (95% CI = 15%-55%) if the last dose was received any time within the previous year. VE was similar after excluding children and adolescents with documented immunocompromising conditions. Because of the low frequency of children who received updated COVID-19 vaccines and waning effectiveness of original monovalent doses, these data support CDC recommendations that all children and adolescents receive updated COVID-19 vaccines to protect against severe COVID-19.

The Efficacy of Metformin as a Therapeutic Agent in the Treatment of Acne Vulgaris: A Systematic Review.

A large portion of the world's population is affected by acne vulgaris (AV), with many of these individuals being adolescents. The underlying mechanism of AV is hyperkeratinization and Cutibacterium acnes infection of the pilosebaceous follicle secondary to excessive stimulation of sebaceous glands by androgens. Metformin is a biguanide medication primarily used in efforts to lower patients' sugar levels in the management of type 2 diabetes. It has been proven to reduce levels of circulating androgens in patients with insulin resistance, indicating its potential for treating AV. A search strategy was developed and performed using the databases Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Controlled Register of Trials (CENTRAL), and Web of Science. The keywords "metformin" and "acne" were searched, along with related Medical Subject Headings (MeSH) and other subject headings. Studies that met the inclusion criteria were controlled trials, published after 2010, and in the English language. Participants with and without comorbidities such as polycystic ovary syndrome (PCOS) were considered. Two independent reviewers screened studies based on predefined criteria and extracted data from each study, which were quantitatively combined. A total of 15 studies were included in this systematic review. Across the 15 studies, there were 1,046 participants, with 13 studies looking exclusively at women with PCOS. Of the remaining two studies, one examined males with altered metabolic profiles, while the other included men and women with moderate AV. Notable risks of bias included studies that did not exclusively state the blindness of the study. Of the studies that were examined, 13 showed that metformin reduces AV, with seven studies showing statistical significance. Acne vulgaris is an inflammatory condition that has plagued patients for years due to the limited treatment options available. The hyperglycemic medication metformin, used in the management of type 2 diabetes, is being explored as a novel therapeutic that can possibly be repurposed for the treatment of AV. The use of metformin in AV is hypothesized to disrupt the proposed linkage between insulin resistance and AV proliferation. This proposed research could offer physicians a new option for the treatment of AV as well as render an alternative AV treatment for patients.

A Spatial Omnibus Test (SPOT) for Spatial Proteomic Data.

Spatial proteomics can reveal the spatial organization of immune cells in the tumor immune microenvironment. Relating measures of spatial clustering, such as Ripley's K or Besag's L, to patient outcomes may offer important clinical insights. However, these measures require pre-specifying a radius in which to quantify clustering, yet no consensus exists on the optimal radius which may be context-specific. We propose a SPatial Omnibus Test (SPOT) which conducts this analysis across a range of candidate radii. At each radius, SPOT evaluates the association between the spatial summary and outcome, adjusting for confounders. SPOT then aggregates results across radii using the Cauchy combination test, yielding an omnibus p-value characterizing the overall degree of association. Using simulations, we verify that the type I error rate is controlled and show SPOT can be more powerful than alternatives. We also apply SPOT to an ovarian cancer study. An R package and tutorial is provided at https://github.com/sarahsamorodnitsky/SPOT.

Tailoring Strength Training Prescriptions for People with Rheumatoid Arthritis: A Scoping Review.

Introduction: Prescribing strength training (ST) for people with rheumatoid arthritis (RA) is complicated by factors (barriers and facilitators) that affect participation. It is unclear whether guidelines include recommendations beyond prescription parameters (frequency, intensity, time, type, volume, and progression) and adequately incorporate participation factors tailored to people with RA. Objective: To summarize available recommendations to aid in the tailoring of ST prescriptions for people with RA. Methods: Medline, Embase, and CINAHL databases and gray literature were searched for guidelines, recommendations, and review articles containing ST prescription recommendations for RA. Article screening and data extraction were performed in duplicate by two reviewers. Results: Twenty-seven articles met the inclusion criteria. The recommendations address RA-specific ST participation factors including: knowledge gaps (of equipment, ST benefits, disease), memory problems, the management of joint deformity, comorbidity, the fluctuating nature of the disease and symptoms (pain, stiffness, flares), fear avoidance, motivation, need for referral to other professionals, and provision of RA-specific resources. Conclusion: This review summarizes recommendations for tailoring ST prescriptions for people with RA. Future research is required to understand how pain, symptom assessment, and unaddressed ST participation factors like sleep and medication side effects can be addressed to support ST participation amongst people with RA.

Guanfacine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Down Syndrome: A Retrospective Chart Review.

Study Design: Retrospective case series. Objectives: The objective of this study was to provide naturalistic data on the use of guanfacine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a clinically referred sample of youth with Down syndrome (DS). Methods: The medical records of children and adolescents with DS who received guanfacine for the treatment of ADHD from a multidisciplinary neurodevelopmental disorder clinic between September 1, 2011, and September 10, 2021, were reviewed. Demographic and clinical characteristics, guanfacine dose and treatment duration, and adverse effects were recorded. Clinical Global Impression Scale (CGI) scores for ADHD symptom severity (S) and improvement (I) were retrospectively assigned by a child and adolescent psychiatrist based on review of the clinic notes. Response to guanfacine was defined as completion of at least 12 weeks of treatment and a Clinical Global Impression Improvement subscale rating ≤2 (1 = "very much improved" or 2 = "much improved"). Results: Twenty-one patients were eligible for inclusion, of whom 17 (81%) completed at least 12 weeks of guanfacine. Ten of the 21 patients (48%; 95% confidence interval [CI]: 28%-68%) responded to treatment. The median time on guanfacine treatment covered by the clinic notes was 50.4 weeks, with a range of 0.3 weeks to 7.5 years. Thirteen patients (62%) remained on guanfacine at the time of their most recent clinic note. Nine patients had adverse events documented in their clinic notes (43%; 95% CI: 24%-63%), most commonly sleepiness (n = 7) and constipation (n = 2). Conclusion: About half of patients with DS responded to guanfacine for the treatment of ADHD and many tolerated long-term use. Study limitations primarily relate to the retrospective nature of the study and small sample size.

Temporal Trends in Practice Patterns After Introduction of Pediatric Hypertension Guidelines in Canada.

Importance: In 2016 and 2017, respectively, new Canadian and US guidelines for diagnosis and management of pediatric hypertension (HTN) were published. Six years after their publication, it is unknown whether the recommendations have led to changes in primary care practice patterns. Objectives: To determine whether HTN guidelines are associated with changes in practice patterns among primary care clinicians. Design, Setting, and Participants: This retrospective, multicenter, population-based cohort study was conducted across 3 phases: January 1, 2011, to December 31, 2015 (era 1), January 1, 2016, to December 31, 2017 (washout period), and January 1, 2018, to December 31, 2019 (era 2). Data were collected from 7 Canadian provinces using the Canadian Primary Care Sentinel Surveillance Network Electronic Medical Record database. Eligible participants included children and adolescents (aged ≥3 to <18 years) with 1 or more encounters in the database. Data analysis was conducted from February 2022 to February 2023. Exposure: Implementation of the 2016 Hypertension Canada and 2017 American Academy of Pediatrics guidelines. Main Outcomes and Measures: The primary outcomes were annual BP screening documentation, high BP follow-up documentation at 6 months and 1-year, HTN prevalence, laboratory testing rates, and medication prescription rates. Interrupted time series analysis was used to assess the association of the introduction of the Canadian and US guidelines with outcomes. Results: The study included 343 191 children and adolescents (mean [SD] age at first encounter, 6.7 (4.6) years; 173 290 female [50.5%]; 169 901 male [49.5%]), including 235 094 patients in era 1 and 193 473 patients in era 2. In era 1, 55 550 patients (23.6%) had at least 1 BP measurement, and in era 2, 45 006 patients (23.3%) had at least 1 BP measurement. There was a significant increase in BP screening in era 2 from 26 876 of 148 554 screenings (18.1%) to 28 556 of 141 192 screenings (20.2%; ß = 0.202; 95% CI, 0.009 to 0.390; P = .04), and the increasing trend was sustained. There was a significant decrease in the trend of follow-up of high BP measurement at 6 months (1265 of 4941 patients with BP measurements [25.6%] to 1718 of 7321 patients with BP measurements [23.5%]; ß = -0.490; 95% CI, -0.758 to -0.223; P = .001) and 1 year (1974 of 4941 measurements [40.0%] to 2314 of 7321 measurements [31.6%]; ß = -1.392; 95% CI, -1.573 to -1.212; P < .001) in era 2. The proportion of patients meeting HTN criteria significantly increased from 2540 of 55 550 patients (4.6%) in era 1 to 5690 of 45 006 patients (12.6%) in era 2 (ß = 0.0210; 95% CI, 0.0021 to 0.0410; P = .03). There was no significant change in the trend of laboratory testing rates in era 2 (949 of 4941 patients tested [19.2%] to 1149 of 7321 patients tested [15.7%]; ß = -0.159; 95% CI, -0.364 to 0.046; P = .12). The trend in prescribing of medications to patients with HTN also decreased in era 2 (1305 of 4941 patients prescribed medication [26.4%] to 1415 of 7321 patients prescribed medication [19.3%]; ß = -0.605; 95% CI, -0.830 to -0.358; P < .001). Conclusions and Relevance: The findings of this cohort study within the Canadian primary care setting suggest that there was a significant increase in BP screening and HTN prevalence after the publication of national and international HTN guidelines; however, the follow-up of high BP was still suboptimal. Increasing rates of pediatric HTN emphasize the need for better adherence to pediatric HTN guidelines to improve care and outcomes.

Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition of Pseudomonas aeruginosa Virulence Phenotypes.

Bacterial resistance to antibiotics is a rapidly increasing threat to human health. New strategies to combat resistant organisms are desperately needed. One potential avenue is targeting two-component systems, which are the main bacterial signal transduction pathways used to regulate development, metabolism, virulence, and antibiotic resistance. These systems consist of a homodimeric membrane-bound sensor histidine kinase, and a cognate effector, the response regulator. The high sequence conservation in the catalytic and adenosine triphosphate-binding (CA) domain of histidine kinases and their essential role in bacterial signal transduction could enable broad-spectrum antibacterial activity. Through this signal transduction, histidine kinases regulate multiple virulence mechanisms including toxin production, immune evasion, and antibiotic resistance. Targeting virulence, as opposed to development of bactericidal compounds, could reduce evolutionary pressure for acquired resistance. Additionally, compounds targeting the CA domain have the potential to impair multiple two-component systems that regulate virulence in one or more pathogens. We conducted structure-activity relationship studies of 2-aminobenzothiazole-based inhibitors designed to target the CA domain of histidine kinases. We found these compounds have anti-virulence activities in Pseudomonas aeruginosa, reducing motility phenotypes and toxin production associated with the pathogenic functions of this bacterium.