Antibody Response to the Sneathia vaginalis Cytopathogenic Toxin A during Pregnancy.

Sneathia vaginalis is a Gram-negative vaginal species that is associated with pregnancy complications. It produces cytopathogenic toxin A (CptA), a pore-forming toxin. To determine whether CptA is expressed in vivo and to examine the mucosal Ab response to the toxin, we examined human midvaginal swab samples obtained during pregnancy for IgM, IgA, and IgG Abs with CptA affinity. This subcohort study included samples from 93 pregnant people. S. vaginalis relative abundance was available through 16S rRNA survey. There were 22 samples from pregnancies that resulted in preterm birth in which S. vaginalis relative abundance was <0.005%, 22 samples from pregnancies that resulted in preterm birth with S. vaginalis ≥0.005%, 24 samples from pregnancies that resulted in term birth with S. vaginalis <0.005%, and 25 samples from pregnancies that resulted in term birth with S. vaginalis ≥0.005%. IgM, IgA, and IgG with affinity for CptA were assessed by ELISA. The capacity for the samples to neutralize CptA was quantified by hemolysis assay. All three Ab isotypes were detectable within different subsets of the samples. There was no significant association between relative abundance of S. vaginalis and the presence of any Ab isotype. The majority of vaginal swab samples containing detectable levels of anti-CptA Abs neutralized the hemolytic activity of CptA, with the strongest correlation between IgA and neutralizing activity. These results demonstrate that S. vaginalis produces CptA in vivo and that CptA is recognized by the host immune defenses, resulting in the production of Abs with toxin-neutralizing ability.

Constructs of leading indicators: A synthesis of safety literature.

INTRODUCTION: Leading indicators represent an invaluable tool that offer organizations the capability to: track health and safety performance, not just failures and accidents; measure effectiveness of safety efforts adopted; and focus on undesired precursors, rather than undesired occurred events. Despite these palpable advantages associated with their adoption, leading indicator's definition, application, and function are mostly ambiguous and inconsistent within literature. Therefore, this study systematically reviews pertinent literature to identify the constructs of leading indicators and generates guidance for leading indicator implementation (as a conceptual model). METHOD: The overarching epistemological design adopted interpretivism and critical realism philosophical stances together with inductive reasoning to analyze 80 articles retrieved from the Scopus database, plus 13 more publications supplemented by the snowballing technique. Analysis of the safety discourse within literature (as secondary data) was undertaken in two stages, namely: (1) a cross-componential analysis identified the main features of leading indicators in comparison to lagging indicators; and (2) content analysis revealed prominent constructs of leading indicators. RESULTS AND CONCLUSION: Analysis results identify that the definition, types, and development methods represent the main constructs for understanding the concept of leading indicators. The study identifies that ambiguity around the definition and function of leading indicators is due to the lack of differentiation of its types, namely passive leading indicators and active leading indicators. PRACTICAL APPLICATION: As a practical contribution, the conceptual model, which introduces continuous learning through a perpetual loop of development and application of leading indicators, will help adopters create a knowledge repository of leading indicators and to continuously learn and improve their safety and safety performance. Specifically, the work clarifies their difference in terms of the timeframe passive leading indicators and active leading indicators take to measure different safety aspects, the functions they serve, the target they measure and their stage of development.

Pharmacist Disciplinary Action: What Do Pharmacists Get in Trouble for?

Objective: This study aims to determine the reasons for disciplinary action and resultant consequences for Canadian pharmacists and any associations with demographic factors. Methods: Regulatory body disciplinary action cases from 10 Canadian provinces were coded. Demographic information was coded. Results: There were 665 pharmacist cases from nine provinces between January 2010 and December 2020. The rate of disciplinary action was low (1.37 cases/1,000 practitioners/year). Professional misconduct was the most common category of violation. Male pharmacists were overrepresented in disciplinary action cases. Most cases involved community pharmacists. Conclusion: This study is the first, to our knowledge, in Canada to analyze the demographic factors of pharmacists subjected to disciplinary action. It updates a previous review of pharmacist disciplinary action (Foong et al. 2018).

Dentist Disciplinary Action: What Do Dentists Get in Trouble for?

Objective: This study aims to determine the reasons for disciplinary action, the consequences and any associations with demographic factors for Canadian dentists. Methods: Publicly available regulatory body disciplinary action cases from 10 Canadian provinces were coded. Demographic factors were also coded. Results: There were 344 dentist cases from five provinces between January 2010 and December 2020. The rate of disciplinary action was low (1.38 cases/1,000 practitioners/year). Clinical incompetence was the most common category of disciplinary action, followed by professional misconduct and dishonest business practices. Male dentists were overrepresented in the disciplinary action cases compared to the rest of the workforce. Conclusion: This study is the first, to our knowledge, to describe the outcomes of regulatory body disciplinary action for Canadian dentists.

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Toward an Integrated Context-Based Design Approach for Dementia Residential Care Homes: A Review of Key Operational Design Problems.

OBJECTIVES, PURPOSE, OR AIM: This article seeks to develop a context-based management system focusing on assessing key operational and design problems and affecting wayfinding in dementia residential care homes. BACKGROUND: Dementia is multifaceted neurocognitive impairments largely attributed to cognitive deterioration manifested in memory loss and visuospatial deficit which have wider practical implications to both environmental safety and wayfinding and navigation of dementia user. Two key questions were addressed in this context: (1) How can cognitively facilitating assistive technology (AT) be made more user-focused to mitigate the impacts of cognitive impairments on environmental safety and wayfinding? (2) How can design intervention and changes in design topology, colors and texture, and internal finishing aid wayfinding, navigation, and orientation in dementia residential care homes? METHOD: A systematic literature review and analysis was undertaken to assess the efficacy of key cognitively-related AT to support activities of daily living and environmental safety of dementia sufferers in a care home and aid wayfinding, navigation, and orientation. RESULTS: Several key design variables to facilitate wayfinding and spatial orientation were identified which include design topology, floor finishing, signposting, and use of color and texture strengthened by meaning, emotional connection to places and cognitively focused intervention via memory cueing and objects-centered recognition. CONCLUSIONS: Key operational and design guidelines were proposed to assist built environment, care home developers, clinicians and healthcare professionals, and care services providers. There is a need to move toward a dementia-centered design to address the challenges facing people living with dementia in care homes. This should be based on the interrelated behavioral, cognitive, and communication factors.

HeartMath as an Integrative, Personal, Social, and Global Healthcare System.

COVID-19 is a recent major event, adding to planet Earth's contexts of chaos, crime, injustice, illness, and violence. The HeartMath system has produced research evidence for scientific interventions that alter contexts characterized by chaos and stress, promoting health, coherence, and interconnectedness. This study provides an updated overview of HeartMath as an interdisciplinary, scientific, coherent, integral heart-based healthcare system, operated locally through various initiatives and globally through the Global Coherence Initiative. The HeartMath approach integrates ancient and contemporary, indigenous and mainstream, popular and folk, Eastern, Western, and African forms of healing. The HeartMath interdisciplinary, personal, social, and global vision and mission have considerable theoretical and practical potential for promoting planetary health, education, and development.

The vaginal microbiome in women of reproductive age with healthy weight versus overweight/obesity.

OBJECTIVE: The aim of this study was to evaluate the differences between the vaginal microbiome of reproductive-aged women with overweight and obesity (Ow/Ob) compared with healthy weight (HW). METHODS: In this case-control study, a cohort of 367 nonpregnant women (18 to 40 years) with Ow/Ob (BMI ≥25 kg/m2 ) was case-matched with 367 women with HW (BMI 18.0 to 24.9 kg/m2 ). The study was a secondary analysis of 16S rRNA vaginal microbiome surveys through the Vaginal Human Microbiome Study (VaHMP). Groups were matched on age, race/ethnicity, income, and nulliparity status. RESULTS: Mean age and BMI of Ow/Ob and HW groups were 26.8 versus 26.7 years and 37.0 versus 22.1 kg/m2 , respectively. The overall vaginal microbiome composition differed between groups (PERMANOVA, p = 0.035). Women with Ow/Ob had higher alpha diversity compared with women with HW (Wilcoxon test, Shannon index p = 0.025; inverse Simpson index p = 0.026). Lactobacillus dominance (≥30% proportional abundance) was observed in a greater proportion of women with HW (48.7%) compared with Ow/Ob (40.1%; p = 0.026). CONCLUSIONS: The vaginal microbiome differs in reproductive-aged women with Ow/Ob compared with women with HW, with increased alpha diversity and decreased predominance of Lactobacillus. Observed differences in the vaginal microbiome may partially explain differences in preterm birth and bacterial vaginosis risk between these populations.

Unique roles of vaginal Megasphaera phylotypes in reproductive health.

The composition of the human vaginal microbiome has been extensively studied and is known to influence reproductive health. However, the functional roles of individual taxa and their contributions to negative health outcomes have yet to be well characterized. Here, we examine two vaginal bacterial taxa grouped within the genus Megasphaera that have been previously associated with bacterial vaginosis (BV) and pregnancy complications. Phylogenetic analyses support the classification of these taxa as two distinct species. These two phylotypes, Megasphaera phylotype 1 (MP1) and Megasphaera phylotype 2 (MP2), differ in genomic structure and metabolic potential, suggestive of differential roles within the vaginal environment. Further, these vaginal taxa show evidence of genome reduction and changes in DNA base composition, which may be common features of host dependence and/or adaptation to the vaginal environment. In a cohort of 3870 women, we observed that MP1 has a stronger positive association with bacterial vaginosis whereas MP2 was positively associated with trichomoniasis. MP1, in contrast to MP2 and other common BV-associated organisms, was not significantly excluded in pregnancy. In a cohort of 52 pregnant women, MP1 was both present and transcriptionally active in 75.4 % of vaginal samples. Conversely, MP2 was largely absent in the pregnant cohort. This study provides insight into the evolutionary history, genomic potential and predicted functional role of two clinically relevant vaginal microbial taxa.

SNPPar: identifying convergent evolution and other homoplasies from microbial whole-genome alignments.

Homoplasic SNPs are considered important signatures of strong (positive) selective pressure, and hence of adaptive evolution for clinically relevant traits such as antibiotic resistance and virulence. Here we present a new tool, SNPPar, for efficient detection and analysis of homoplasic SNPs from large whole genome sequencing datasets (>1000 isolates and/or >100 000 SNPs). SNPPar takes as input an SNP alignment, tree and annotated reference genome, and uses a combination of simple monophyly tests and ancestral state reconstruction (ASR, via TreeTime) to assign mutation events to branches and identify homoplasies. Mutations are annotated at the level of codon and gene, to facilitate analysis of convergent evolution. Testing on simulated data (120 Mycobacterium tuberculosis alignments representing local and global samples) showed SNPPar can detect homoplasic SNPs with very high specificity (zero false-positives in all tests) and high sensitivity (zero false-negatives in 89 % of tests). SNPPar analysis of three empirically sampled datasets (Elizabethkingia anophelis, Burkholderia dolosa and M. tuberculosis) produced results that were in concordance with previous studies, in terms of both individual homoplasies and evidence of convergence at the codon and gene levels. SNPPar analysis of a simulated alignment of ~64 000 genome-wide SNPs from 2000 M. tuberculosis genomes took ~23 min and ~2.6 GB of RAM to generate complete annotated results on a laptop. This analysis required ASR be conducted for only 1.25 % of SNPs, and the ASR step took ~23 s and 0.4 GB of RAM. SNPPar automates the detection and annotation of homoplasic SNPs efficiently and accurately from large SNP alignments. As demonstrated by the examples included here, this information can be readily used to explore the role of homoplasy in parallel and/or convergent evolution at the level of nucleotide, codon and/or gene.

Reverse supply chain conceptual model for construction and demolition waste.

Construction and demolition waste (CDW) substantially contributes to environmental degradation because of its intrinsic characteristics of fast and high generation volume, low recycling rate, and low revenue margins. A systemic problem is that recycling facilities are not usually a part of a reverse supply chain (RSC) specific for CDW. This makes the recovery process costs prohibitive, especially where companies are unable to receive and process large volumes of waste continuously. This paper presents a systematic analysis of the extant literature and utilizes the results accrued to develop a conceptual RSC model for CDW. In so doing, the research seeks to provide clarity on this phenomenon, while simultaneously stimulating wider academic discourse and further research endeavours. A mixed philosophies epistemological design was adopted using both interpretavism and constructivism to undertake a qualitative systematic analysis of the literature. A process diagram was produced to represent the conceptual model (CM) and thematically group the nodes into three key swim lanes that delineate the boundaries between distribution, manufacturing, and sourcing and warehousing processes. Within each swim lane, stakeholders were incorporated as key actors. A further layer of nuanced complexity was added to illustrate the key actors involved in the process, government strategies, and activity flow paths. This novel CM offers both practical and theoretical contributions to existing knowledge and signposts a future research direction. Such work will demystify reverse logistics for managing CDW, and assist government policy-makers to develop informed policies that reduce the negative environmental impact of construction activities.

Sequence Comparison of Vaginolysin from Different Gardnerella Species.

Gardnerella vaginalis has recently been split into 13 distinct species. In this study, we tested the hypotheses that species-specific variations in the vaginolysin (VLY) amino acid sequence could influence the interaction between the toxin and vaginal epithelial cells and that VLY variation may be one factor that distinguishes less virulent or commensal strains from more virulent strains. This was assessed by bioinformatic analyses of publicly available Gardnerella spp. sequences and quantification of cytotoxicity and cytokine production from purified, recombinantly produced versions of VLY. After identifying conserved differences that could distinguish distinct VLY types, we analyzed metagenomic data from a cohort of female subjects from the Vaginal Human Microbiome Project to investigate whether these different VLY types exhibited any significant associations with symptoms or Gardnerella spp.-relative abundance in vaginal swab samples. While Type 1 VLY was most prevalent among the subjects and may be associated with increased reports of symptoms, subjects with Type 2 VLY dominant profiles exhibited increased relative Gardnerella spp. abundance. Our findings suggest that amino acid differences alter the interaction of VLY with vaginal keratinocytes, which may potentiate differences in bacterial vaginosis (BV) immunopathology in vivo.

A new method for determining the benchmark dose tolerable region and endpoint probabilities for toxicology experiments.

The increase of exposure to toxic materials and hazardous chemicals is a major concern due to the adverse effect on human health. Among the major concerns of toxicologists is to determine acceptable levels of exposure to hazardous substances. Current approaches often evaluate each endpoint and stressor individually. We propose a novel method to simultaneously determine the Benchmark Dose Tolerable Region (BMDTR) for multiple endpoint and multiple stressor studies by adopting a Bayesian approach. A main concern while assessing the combined toxicological effect of a chemical mixture is the anticipated type of the combined action (i.e. synergistic or antagonistic); thus it was essential to account for interaction effects to handle this situation, imposing more challenges due to the non-linearity of the tolerable region. The proposed method will be evaluated using two approaches, the first one using the estimated value of the posterior median and the second approach using all MCMC samples from the posterior distribution. Furthermore, we propose a new method to determine the endpoint probabilities for each endpoint, which reflects the importance of each endpoint in helping determining the boundaries of the benchmark dose tolerable region (BMDTR).

The vaginal microbiome and preterm birth.

The incidence of preterm birth exceeds 10% worldwide. There are significant disparities in the frequency of preterm birth among populations within countries, and women of African ancestry disproportionately bear the burden of risk in the United States. In the present study, we report a community resource that includes 'omics' data from approximately 12,000 samples as part of the integrative Human Microbiome Project. Longitudinal analyses of 16S ribosomal RNA, metagenomic, metatranscriptomic and cytokine profiles from 45 preterm and 90 term birth controls identified harbingers of preterm birth in this cohort of women predominantly of African ancestry. Women who delivered preterm exhibited significantly lower vaginal levels of Lactobacillus crispatus and higher levels of BVAB1, Sneathia amnii, TM7-H1, a group of Prevotella species and nine additional taxa. The first representative genomes of BVAB1 and TM7-H1 are described. Preterm-birth-associated taxa were correlated with proinflammatory cytokines in vaginal fluid. These findings highlight new opportunities for assessment of the risk of preterm birth.

Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy.

The microbiome of the female reproductive tract has implications for women's reproductive health. We examined the vaginal microbiome in two cohorts of women who experienced normal term births: a cross-sectionally sampled cohort of 613 pregnant and 1,969 non-pregnant women, focusing on 300 pregnant and 300 non-pregnant women of African, Hispanic or European ancestry case-matched for race, gestational age and household income; and a longitudinally sampled cohort of 90 pregnant women of African or non-African ancestry. In these women, the vaginal microbiome shifted during pregnancy toward Lactobacillus-dominated profiles at the expense of taxa often associated with vaginal dysbiosis. The shifts occurred early in pregnancy, followed predictable patterns, were associated with simplification of the metabolic capacity of the microbiome and were significant only in women of African or Hispanic ancestry. Both genomic and environmental factors are likely contributors to these trends, with socioeconomic status as a likely environmental influence.

Relationship between vitamin D status and the vaginal microbiome during pregnancy.

OBJECTIVE: Evidence supports an inverse association between vitamin D and bacterial vaginosis (BV) during pregnancy. Furthermore, both the vaginal microbiome and vitamin D status correlate with pregnancy outcome. Women of African ancestry are more likely to experience BV, to be vitamin D deficient, and to have certain pregnancy complications. We investigated the association between vitamin D status and the vaginal microbiome. STUDY DESIGN: Subjects were assigned to a treatment (4400 IU) or a control group (400 IU vitamin D daily), sampled three times during pregnancy, and vaginal 16S rRNA gene taxonomic profiles and plasma 25-hydroxyvitamin D [25(OH)D] concentrations were examined. RESULT: Gestational age and ethnicity were significantly associated with the microbiome. Megasphaera correlated negatively (p = 0.0187) with 25(OH)D among women of African ancestry. Among controls, women of European ancestry exhibited a positive correlation between plasma 25(OH)D and L. crispatus abundance. CONCLUSION: Certain vaginal bacteria are associated with plasma 25(OH)D concentration.

Quantitation of Purines from Pigeon Guano and Implications for Cryptococcus neoformans Survival During Infection.

The fertilizing properties of bird manure, or guano, have played an important role in plant cultivation for thousands of years. Research into its chemical composition by Unger in 1846 identified a novel compound, now known as guanine, a purine base that is essential for DNA and RNA biosynthesis and cell signalling. Nitrogen-rich guano can also harbour human pathogens, one significant example being the fungal pathogen Cryptococcus neoformans. Historically associated with pigeon droppings, C. neoformans is able to infect immunocompromised individuals with the aid of a number of adaptive virulence traits. To gain insight into this niche, a quantitative analysis of pigeon guano was performed by LC/MS to determine the concentrations of purines present. Guanine was found in abundance, in particular, in aged guano samples that contained 156-296 µg/g [w/w] compared to 75 µg/g in fresh guano. Adenine concentrations were more consistent between fresh and aged samples, 13 µg/g compared to 10-15 µg/g, respectively. C. neoformans strains that lack key enzymes of the de novo purine synthesis pathway and are guanine or adenine auxotrophs displayed differences in their ability to exploit this substrate: growth of a guanine auxotrophic mutant (gua1Δ) was partially restored on 30% pigeon guano media, but an adenine auxotrophic mutant (ade13Δ) was unable to grow. We conclude that while purine salvage is likely a useful resource-saving mechanism, alone it is not sufficient to fully provide the purines required by wild-type C. neoformans growing in its guano niche.

Frequent transmission of the Mycobacterium tuberculosis Beijing lineage and positive selection for the EsxW Beijing variant in Vietnam.

To examine the transmission dynamics of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients in Ho Chi Minh City, Vietnam, we sequenced the whole genomes of 1,635 isolates and compared these with 3,144 isolates from elsewhere. The data identify an underlying burden of disease caused by the endemic Mtb lineage 1 associated with the activation of long-term latent infection, and a threefold higher burden associated with the more recently introduced Beijing lineage and lineage 4 Mtb strains. We find that Beijing lineage Mtb is frequently transferred between Vietnam and other countries, and detect higher levels of transmission of Beijing lineage strains within this host population than the endemic lineage 1 Mtb. Screening for parallel evolution of Beijing lineage-associated SNPs in other Mtb lineages as a signal of positive selection, we identify an alteration in the ESX-5 type VII-secreted protein EsxW, which could potentially contribute to the enhanced transmission of Beijing lineage Mtb in Vietnamese and other host populations.