Showing papers by "Mark Walker published in 2023"

Detection of Streptococcus pyogenes M1UK in Australia and characterization of the mutation driving enhanced expression of superantigen SpeA

Abstract: A new variant of Streptococcus pyogenes serotype M1 (designated 'M1UK') has been reported in the United Kingdom, linked with seasonal scarlet fever surges, marked increase in invasive infections, and exhibiting enhanced expression of the superantigen SpeA. The progenitor S. pyogenes 'M1global' and M1UK clones can be differentiated by 27 SNPs and 4 indels, yet the mechanism for speA upregulation is unknown. Here we investigate the previously unappreciated expansion of M1UK in Australia, now isolated from the majority of serious infections caused by serotype M1 S. pyogenes. M1UK sub-lineages circulating in Australia also contain a novel toxin repertoire associated with epidemic scarlet fever causing S. pyogenes in Asia. A single SNP in the 5' transcriptional leader sequence of the transfer-messenger RNA gene ssrA drives enhanced SpeA superantigen expression as a result of ssrA terminator read-through in the M1UK lineage. This represents a previously unappreciated mechanism of toxin expression and urges enhanced international surveillance.

Pathogenesis, epidemiology and control of Group A Streptococcus infection

Abstract: Streptococcus pyogenes (Group A Streptococcus; GAS) is exquisitely adapted to the human host, resulting in asymptomatic infection, pharyngitis, pyoderma, scarlet fever or invasive diseases, with potential for triggering post-infection immune sequelae. GAS deploys a range of virulence determinants to allow colonization, dissemination within the host and transmission, disrupting both innate and adaptive immune responses to infection. Fluctuating global GAS epidemiology is characterized by the emergence of new GAS clones, often associated with the acquisition of new virulence or antimicrobial determinants that are better adapted to the infection niche or averting host immunity. The recent identification of clinical GAS isolates with reduced penicillin sensitivity and increasing macrolide resistance threatens both frontline and penicillin-adjunctive antibiotic treatment. The World Health Organization (WHO) has developed a GAS research and technology road map and has outlined preferred vaccine characteristics, stimulating renewed interest in the development of safe and effective GAS vaccines.

Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Abstract: Abstract The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Individual, Independent, and Joint Associations of Toxic Metals and Manganese on Hypertensive Disorders of Pregnancy: Results from the MIREC Canadian Pregnancy Cohort

Abstract: Background: Toxic metals, such as lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), may be associated with a higher risk of gestational hypertension and preeclampsia, whereas manganese (Mn) is an essential metal that may be protective. Objectives: We estimated the individual, independent, and joint associations of Pb, Cd, As, Hg, and Mn on the risk of developing gestational hypertension and preeclampsia in a cohort of Canadian women. Methods: Metal concentrations were analyzed in first and third trimester maternal blood (n=1,560). We measured blood pressure after 20 wk gestation to diagnose gestational hypertension, whereas proteinuria and other complications defined preeclampsia. We estimated individual and independent (adjusted for coexposure) relative risks (RRs) for each doubling of metal concentrations and examined interactions between toxic metals and Mn. We used quantile g-computation to estimate the joint effect of trimester-specific exposures. Results: Each doubling of third trimester Pb (RR=1.54; 95% CI: 1.06, 2.22) and first trimester blood As (RR=1.25; 95% CI: 1.01, 1.58) was independently associated with a higher risk of developing preeclampsia. First trimester blood As (RR=3.40; 95% CI: 1.40, 8.28) and Mn (RR=0.63; 95% CI: 0.42, 0.94) concentrations were associated with a higher and lower risk, respectively, of developing gestational hypertension. Mn modified the association with As such that the deleterious association with As was stronger at lower concentrations of Mn. First trimester urinary dimethylarsinic acid concentrations were not associated with gestational hypertension (RR=1.31; 95% CI: 0.60, 2.85) or preeclampsia (RR=0.92; 95% CI: 0.68, 1.24). We did not observe overall joint effects for blood metals. Discussion: Our results confirm that even low blood Pb concentrations are a risk factor for preeclampsia. Women with higher blood As concentrations combined with lower Mn in early pregnancy were more likely to develop gestational hypertension. These pregnancy complications impact maternal and neonatal health. Understanding the contribution of toxic metals and Mn is of public health importance. https://doi.org/10.1289/EHP10825

Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria

Abstract: Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20-40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research.

Genome‐Wide Analysis of Structural Variants in Parkinson Disease

Abstract: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large‐scale characterization of SVs in PD.

Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Abstract: Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists

Abstract: Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam-knockout mice, display increased resistance to GLP-1 in vivo. Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44% and 20% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.

Challenges, Job Satisfiers, and Self-Care among Perinatal Nurses in the United States during the COVID-19 Pandemic

Abstract: Abstract Purpose: To explore the perceived challenges, job satisfiers, and self-care of perinatal nurses in the United States during the COVID-19 pandemic. Study Design and Methods: In May of 2021, a cross-sectional survey was distributed online to members of the Association of Women's Health, Obstetric, and Neonatal Nurses and the National Association of Neonatal Nurses. We calculated descriptive statistics on respondent characteristics and applied conventional content analysis to free-text comments. Results: Perinatal nurses (N = 297) responded to three open-ended questions on their perceived challenges, job satisfiers, and self-care. Frequently reported challenges included changing guidelines and policies (n = 101, 34%), personal protective equipment as a barrier (n = 73, 24.6%), and visitor restrictions (n = 64, 21.5%). Frequently reported job satisfiers were provision of high-quality care (n = 137, 46.1%) and visitor restrictions (n = 77, 25.9%). Respondents reported using mental (n = 152, 51.2%) and physical (n = 145, 48.8%) self-care strategies and 12.8% (n = 38) reported using no self-care strategies. Clinical Implications: The ability to provide high-quality care was reported as a leading job satisfier. Poor communication of consistent, evidence-based guidelines, lack of personal protective equipment, and inadequate unit staffing were leading challenges. Visitor restrictions were a challenge and a job satisfier, suggesting opportunities to better include visitors as support people. Most respondents reported engaging in one or more types of self-care outside of the hospital setting. Future research is needed to examine strategies for self-care among perinatal nurses when at work in the hospital setting. Perinatal nurses, like other nurses in the United States and around the world, have faced many challenges in providing high quality nursing care during the COVID-19 pandemic. In this study, members of the Association of Women's Health, Obstetric, and Neonatal Nurses and the National Association of Neonatal Nurses participated in an online survey about their experiences during the pandemic. Ability to provide high-quality care was reported as a leading job satisfier, while poor communication of consistent, evidence-based guidelines, lack of personal protective equipment, and inadequate unit staffing were leading challenges. Visitor restrictions were a challenge and a job satisfier, suggesting opportunities to better include visitors as support people. This study adds important information about maternity nursing practice in the United States during the COVID-19 pandemic.

Pre-Meal Whey Protein Alters Postprandial Insulinemia by Enhancing β-Cell Function and Reducing Insulin Clearance in T2D.

Abstract: CONTEXT Treatments that reduce postprandial glycaemia [PPG] independent of stimulating insulin secretion are appealing for the management of type 2 diabetes. Consuming pre-meal whey protein [WP] reduces PPG by delaying gastric emptying and increasing plasma insulin concentrations. However, its effects on β-cell function and insulin kinetics remains unclear. OBJECTIVE To examine the PPG-regulatory effects of pre-meal WP by modelling insulin secretion, insulin clearance, and β-cell function. DESIGN Single-blind, randomized, placebo-controlled, crossover design. SETTING Two 240min mixed-meal tolerance tests. PATIENTS OR OTHER PARTICIPANTS Eighteen adults with type 2 diabetes (HbA1c, 56.7 ± 8.8 mmol/mol). INTERVENTION Participants consumed WP (15g protein) or placebo (0g protein) 10min before a mixed-macronutrient breakfast meal. PPG, pancreatic islet, and incretin hormones were measured throughout. Insulin secretion rates [ISR] were calculated by C-peptide deconvolution. Estimates of insulin clearance and β-cell function were modelled from glucose, insulin and ISR. MAIN OUTCOME MEASURE(S) Changes in PPG incremental area under the curve (iAUC; prespecified) and insulin clearance (post-hoc). RESULTS β-cell function was 40% greater after WP (p=0.001) and was accompanied with a -22% reduction in postprandial insulin clearance, compared to placebo (p<0.0001). Both the peak change and PPG iAUC were reduced by WP (-1.5 mmol/L and -16%, respectively; both p<0.05). Pre-meal WP augmented a 5.9-fold increase in glucagon and glucagon-like peptide 1 iAUC (both p<0.0001), and a 1.5-fold increase in insulin iAUC (p<0.001). Although the plasma insulin response was greater following WP, ISR was unaffected (p=0.133). CONCLUSION In adults with type 2 diabetes, pre-meal WP reduced PPG by coordinating an enhancement in β-cell function with a reduction in insulin clearance. This enabled an efficient postprandial insulinemic profile to be achieved without requiring further β-cell stimulation.

Clinical index to quantify the 1-year risk for common postpartum mental disorders at the time of delivery (PMH CAREPLAN): development and internal validation.

Abstract: BACKGROUND Common postpartum mental health (PMH) disorders such as depression and anxiety are preventable, but determining individual-level risk is difficult. AIMS To create and internally validate a clinical risk index for common PMH disorders. METHOD Using population-based health administrative data in Ontario, Canada, comprising sociodemographic, clinical and health service variables easily collectible from hospital birth records, we developed and internally validated a predictive model for common PMH disorders and converted the final model into a risk index. We developed the model in 75% of the cohort (n = 152 362), validating it in the remaining 25% (n = 75 772). RESULTS The 1-year prevalence of common PMH disorders was 6.0%. Independently associated variables (forming the mnemonic PMH CAREPLAN) that made up the risk index were: (P) prenatal care provider; (M) mental health diagnosis history and medications during pregnancy; (H) psychiatric hospital admissions or emergency department visits; (C) conception type and complications; (A) apprehension of newborn by child services (newborn taken into care); (R) region of maternal origin; (E) extremes of gestational age at birth; (P) primary maternal language; (L) lactation intention; (A) maternal age; (N) number of prenatal visits. In the index (scored 0-39), 1-year common PMH disorder risk ranged from 1.5 to 40.5%. Discrimination (C-statistic) was 0.69 in development and validation samples; the 95% confidence interval of expected risk encompassed observed risk for all scores in development and validation samples, indicating adequate risk index calibration. CONCLUSIONS Individual-level risk of developing a common postpartum mental health disorder can be estimated with data feasibly collectable from birth records. Next steps are external validation and evaluation of various cut-off scores for their utility in guiding postpartum individuals to interventions that reduce their risk of illness.

Real-world outcomes in metastatic HR+/HER2-, HER2+ and triple negative breast cancer after start of first-line therapy.

Abstract: Aim: We evaluated outcomes of first-line (1L) treatment of metastatic breast cancer (mBC) by biomarker subtype in the community setting over the last decade. Methods: Eligible patients (N = 1,518) were female, ≥18 years, diagnosed with mBC 2010 or later, had documented HR+/HER2-, HER2+, or triple negative breast cancer (TNBC); and initiated 1L therapy. Kaplan-Meier and Cox methods were used to evaluate 1L real-world progression-free survival (rwPFS) and overall survival (OS) from start of 1L. Results: TNBC was diagnosed at an earlier stage and had higher tumor grade at initial diagnosis. 1L rwPFS and OS from start of 1L were shorter for TNBC than HR+/HER2- or HER2+. Conclusion: Overall prognosis for patients with metastatic TNBC remains poor, and new therapies are needed to improve clinical outcomes.

Use of tranexamic acid (TXA) to reduce preterm birth and other adverse obstetrical outcomes among pregnant individuals with placenta previa: a systematic review protocol

Abstract: Introduction Placenta previa is a placental implantation pathology where the placenta overlies the internal endocervical os. Placenta previa affects approximately 4 per 1000 pregnancies and increases the risk of antepartum bleeding, emergent preterm labour and emergency caesarean sections. Currently, placenta previa is managed through expectant management. Guidelines primarily revolve around the mode and timing of delivery, in-hospital admissions and surveillance. However, the methods to prolong pregnancy have not proven to be clinically effective. Tranexamic acid (TXA), an antifibrinolytic agent, is effectively used to prevent and treat postpartum haemorrhage as well as menorrhagia, with limited adverse effect, and may prove to be an effective treatment for placenta previa. The objective of this systematic review protocol is to review and synthesise the evidence of TXA use for antepartum haemorrhage in placenta previa. Methods and analysis Preliminary searches were conducted on 12 July 2022. We will search MEDLINE, EMBASE, CINAHL, Scopus and the Cochrane Central Register of Controlled Trials. Grey literature resources such as clinical trials registries (ClinicalTrials.gov and the WHO’s International Clinical Trials Registry) and preprint servers (Europe PMC and Open Science Framework) will also be searched. The search terms will comprise of index headings and keyword searches related to TXA and the placenta or antepartum bleeding. Cohort and randomised and non-randomised trials will be considered. The target population is pregnant people, of any age, with placenta previa. The intervention is TXA given in the antepartum period. The main outcome of interest is preterm birth before 37 weeks, however, all perinatal outcomes will be collected. Title and abstract will be screened by two reviewers and any conflict will be discussed and evaluated by a third reviewer. The literature will be summarised in narrative form. Ethics and dissemination No ethics approval is required for this protocol. Findings will be disseminated through peer-review publication, lay summaries and conference presentations. PROSPERO registration number CRD42022363009).

Establishing cutting conditions for dry drilling of aluminium alloy stack materials

Abstract: Aside from their remarkable lightness, high strength and corrosion resistance, aluminium alloys have dominated aircraft manufacturing for decades. The combination of aluminium alloys 2024 and 7150 is widely used in the fabrication of airframe structures. Numerous holes must be drilled through the materials in order for them to be connected. Due to structure size and use of mobile drilling machines, lubricant oil is released during the drilling operation and either becomes airborne or accumulates on the floor. The primary motivation for dry drilling development is to avoid this oil discharge. A significant disadvantage of the drilling process for aluminium alloys is the workpiece’s proclivity to stick to the cutting tool, especially when temperatures are high. This research investigated the selection of cutting conditions that enable dry drilling of stack aluminium panels. The selection of cutting parameters for experiment use was made based on the assessment of literature pertaining to drilling with carbide cutting tools. Apart from literature, the assessment of cutting parameters also took into consideration existing practices in Airbus UK. Results indicated that optimum cutting performance was achieved by drilling at higher feedrates and lower interaction time compared to existing fluid based processes. In addition, this paper outlines the aspects of energy and cutting forces in current cutting processes as well as focuses on determining optimum conditions that minimise energy input.

Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts.

Abstract: The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC.We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2).A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2.A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

Association between maternal marginalization and infants born with congenital heart disease in Ontario Canada

Abstract: This study aims to evaluate the impact of socioeconomic status (SES) on the risk of congenital heart disease (CHD) since previous studies have yielded inconsistent results.We conducted a population-based retrospective cohort study, including all singleton live and still births in Ontario hospitals from April 1, 2012, to March 31, 2018. We used linked records from the Better Outcomes Registry & Network Information System, the Canadian Institute for Health Information databases, and the Ontario Marginalization Index (ON_Marg). ON_Marg was estimated at a dissemination area level using Canadian Census 2016 data and categorized into quintiles. Multivariable logistic regression models were performed to examine the relationships between four ON_Marg indices (material deprivation, dependency, ethnic concentration, residential instability), as proxies for maternal SES and the risk of infant CHD. We adjusted for maternal age at birth, assisted reproductive technology, obesity, pre-existing health conditions, substance use during pregnancy, mental health conditions before and during pregnancy, rural residence, and infant's sex in the analysis.Among the cohort of 776,799 singletons, 9,359 infants had a diagnosis of CHD. Of those, 3,069 were severe CHD and 493 cases were single ventricle CHD. The prevalence of all infant CHD types was higher for males relative to females. Compared to mothers living in neighbourhoods with the lowest material deprivation, mothers with highest material deprivation had a 27% (adjusted OR = 1.27; 95% CI: 1.18-1.37) higher odds of having an infant diagnosed with CHD. Mothers living in neighbourhoods with the highest minority ethnic and immigrant concentration tend to have infants with 11% lower odds of CHD (adjusted OR = 0.89; 95% CI: 0.82-0.97) as compared to those living in the least ethnically diverse communities. Maternal dependency and residential stability quintiles were not significantly associated with the risk of CHD.Higher maternal material deprivation was associated with increasing odds of infant CHD, whereas neighbourhood minority ethnic concentration was inversely associated with the odds of infant CHD. Our study further confirms that poverty is associated with CHD development. Future investigations might focus on the causal pathways between social deprivation, immigrant status, ethnicity, and the risk of infant CHD.

First and second trimester maternal serum markers for prenatal aneuploidy screening: an update on the adjustment factors for race, smoking, and insulin dependent diabetes mellitus.

Abstract: The concentrations of maternal serum markers for aneuploidy screening are influenced by maternal characteristics such as race, smoking, insulin dependent diabetes mellitus (IDDM), and in vitro fertilization (IVF). Accurate risk estimation requires adjustment of initial values for these characteristics. This study aims to update and validate adjustment factors for race, smoking, and IDDM. The study included singleton pregnancies that received multiple marker screening in Ontario, Canada between January 2012, and December 2018, and had their information collected in the Better Outcomes Registry & Network (BORN) Ontario. Serum markers assessed included first trimester pregnancy-associated plasma protein A (PAPP-A), free β and total human chorionic gonadotropin (hCG), placental growth factor (PlGF) and αlpha-fetoprotein (AFP); second trimester AFP, unconjugated estriol (uE3), total hCG and inhibin A. The Mann-Whitney U test was used to assess the differences in the median multiple of the median (MoM) of serum markers between study and reference groups. New adjustment factors were generated by dividing the median MoM of a particular race, individuals who smoke tobacco, or have IDDM by those of the reference groups. The study included 624,789 pregnancies. There were statistically significant differences in serum marker concentrations among pregnant individuals who were Black, Asian, or First Nations compared to a White group, those who smoked compared to Non-smoking individuals, and those with IDDM compared to Non-IDDM group. New adjustment factors for race, smoking, and IDDM were validated by comparing median MoM of serum markers corrected using the current adjustment factors and new adjustment factors generated in this study. The adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

Association between toxic metals, vitamin D and preterm birth in the Maternal-Infant research on environmental chemicals study.

Abstract: BACKGROUND Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have examined low levels found in most Canadians. Vitamin D, which may have antioxidant activity, protects against PTB. OBJECTIVES In this study, we investigated the impact of toxic metals (lead, mercury, cadmium and arsenic) on PTB and examined if maternal plasma vitamin D concentrations modify these associations. METHODS We investigated whether concentrations of metals in whole blood measured in early and late pregnancy were associated with PTB (<37 weeks) and spontaneous PTB in 1851 live births from the Maternal-Infant Research on Environmental Chemicals Study using discrete time survival analysis. We also investigated whether the risk of PTB was modified by first-trimester plasma 25-hydroxyvitamin D (25OHD) concentrations. RESULTS Of 1851 live births, 6.1% (n = 113) were PTBs and 4.9% (n = 89) were spontaneous PTB. A 1 μg/dL increase in blood lead concentrations during pregnancy was associated with an increased risk of PTB (relative risk [RR] 1.48, 95% confidence interval [CI] 1.00, 2.20) and spontaneous PTB (RR 1.71, 95% CI 1.13, 2.60). The risk was higher in women with insufficient vitamin D concentrations (25OHD <50 nmol/L) for both PTB (RR 2.42, 95% CI 1.01, 5.79) and spontaneous PTB (RR 3.04, 95% CI 1.15, 8.04). However, an interaction on the additive scale was not present. Arsenic was associated with a higher risk of PTB (RR 1.10, 95% CI 1.02, 1.19) and spontaneous PTB (RR 1.11, 95% CI 1.03, 1.20) per 1 μg/L. CONCLUSIONS Gestational exposure to low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; individuals with insufficient vitamin D may be more susceptible to the adverse effects of lead. Given our relatively small number of cases, we encourage testing of this hypothesis in other cohorts, especially those with vitamin D-deficient populations.

Streptolysin O Deficiency in Streptococcus pyogenes M1T1 covR/S Mutant Strain Attenuates Virulence in In Vitro and In Vivo Infection Models

Abstract: Streptococcus pyogenes is responsible for significant numbers of invasive and noninvasive infections which cause significant morbidity and mortality globally. Strep A isolates with mutations in the covR/S system display greater propensity to cause severe invasive diseases, which are responsible for more than 163,000 deaths each year. ABSTRACT Mutation within the Streptococcus pyogenes (Streptococcus group A; Strep A) covR/S regulatory system has been associated with a hypervirulent phenotype resulting from the upregulation of several virulence factors, including the pore-forming toxin, streptolysin O (SLO). In this study, we utilized a range of covR/S mutants, including M1T1 clonal strains (5448 and a covS mutant generated through mouse passage designated 5448AP), to investigate the contribution of SLO to the pathogenesis of covR/S mutant Strep A disease. Up-regulation of slo in 5448AP resulted in increased SLO-mediated hemolysis, decreased dendritic cell (DC) viability post coculture with Strep A, and increased production of tumor necrosis factor (TNF) and monocyte chemoattractant protein 1 (MCP-1) by DCs. Mouse passage of an isogenic 5448 slo-deletion mutant resulted in recovery of several covR/S mutants within the 5448Δslo background. Passage also introduced mutations in non-covR/S genes, but these were considered to have no impact on virulence. Although slo-deficient mutants exhibited the characteristic covR/S-controlled virulence factor upregulation, these mutants caused increased DC viability with reduced inflammatory cytokine production by infected DCs. In vivo, slo expression correlated with decreased DC numbers in infected murine skin and significant bacteremia by 3 days postinfection, with severe pathology at the infection site. Conversely, the absence of slo in the infecting strain (covR/S mutant or wild-type) resulted in detection of DCs in the skin and attenuated virulence in a murine model of pyoderma. slo-sufficient and -deficient covR/S mutants were susceptible to immune clearance mediated by a combination vaccine consisting of a conserved M protein peptide and a peptide from the CXC chemokine protease SpyCEP. IMPORTANCE Streptococcus pyogenes is responsible for significant numbers of invasive and noninvasive infections which cause significant morbidity and mortality globally. Strep A isolates with mutations in the covR/S system display greater propensity to cause severe invasive diseases, which are responsible for more than 163,000 deaths each year. This is due to the upregulation of virulence factors, including the pore-forming toxin streptolysin O. Utilizing covR/S and slo-knockout mutants, we investigated the role of SLO in virulence. We found that SLO alters interactions with host cell populations and increases Strep A viability at sterile sites of the host, such as the blood, and that its absence results in significantly less virulence. This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis. This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs.

Bayesian Integrated Reservoir Characterization, BIRCh, and its Application to the Raven Field

Abstract: Summary Bayesian Integrated Reservoir Characterization (BIRCh), ( Biswas et. al., 2023 ; Walker et. al., 2023 ) is a new technology designed to provide probabilistic outputs of different subsurface properties utilizing Bayesian inference and advanced optimization algorithms such as Stein Variational Gradient Descent, SVGD, ( Biswas et. al., 2023 ; Liu and Wang, 2016 ). The technology integrates seismic data and a priori knowledge of elastic parameters in the subsurface in a Bayesian framework, in an objective and data driven approach which does not require any interpreted input such as reservoir horizons and fluid contacts. During this study we show and discuss results of the application of BIRCh to a real data example in the Raven field, Egypt. The resulting subsurface predictions have helped locate with confidence unpenetrated Gas Water Contacts (GWCs) in the field and have highlighted areas with poor and good reservoir quality for future well placement.

Gaussian Mixture Models as Priors in a Gradient-Based Variational Algorithm for Bayesian Elastic Inversion

Abstract: Summary We describe a scheme based on Gaussian Mixture Models (GMMs) for defining the prior used in trace-by-trace Bayesian elastic inversion of Amplitude Versus Angle (AVA) data. We show that this approach can successfully capture statistical information about the distribution of elastic parameters in well log data. The scheme is suitable for use in Bayesian inference algorithms which rely on gradient calculations, and in particular Stein Variational Gradient Descent, which is utilised by the Bayesian Integrated Reservoir Characterization (BIRCh) workflow ( Biswas et. al 2023. ; Paramo et al. 2023 ). We therefore demonstrate the use of our GMM-based prior scheme in the BIRCh workflow for a real-data case study, where good posterior solutions at blind well locations were obtained. We also demonstrate that use of the GMM provides superior results to simpler models (e.g., a single Gaussian). Limitations and potential extensions to the method are discussed.

Promiscuous evolution of Group A Streptococcal M and M-like proteins

Abstract: Group A Streptococcus (GAS) M and M-like proteins are essential virulence factors and represent the primary epidemiological marker of this pathogen. Protein sequences encoding 1054 M, Mrp and Enn proteins, from 1668 GAS genomes, were analysed by SplitsTree4, partitioning around medoids and co-occurrence. The splits network and groups-based analysis of all M and M-like proteins revealed four large protein groupings, with multiple evolutionary histories as represented by multiple edges for most splits, leading to ‘M-family-groups’ (FG) of protein sequences: FG I, Mrp; FG II, M protein and Protein H; FG III, Enn; and FG IV, M protein. M and Enn proteins formed two groups with nine sub-groups and Mrp proteins formed four groups with ten sub-groups. Discrete co-occurrence of M and M-like proteins were identified suggesting that while dynamic, evolution may be constrained by a combination of functional and virulence attributes. At a granular level, four distinct family-groups of M, Enn and Mrp proteins are observable, with Mrp representing the most genetically distinct of the family-group of proteins. While M and Enn protein families generally group into three distinct family-groups, horizontal and vertical gene flow between distinct GAS strains is ongoing.

617-P: Time in Range following Mealtime Protein Supplementation Is Predicted by Liver Health and ß-Cell Function in Adults with Type 2 Diabetes

Abstract: Background: Consuming mealtime whey protein supplementation increases daily time in euglycemic range [TIR] in adults with type 2 diabetes [T2D] with inter-individual responses. The present post-hoc analysis aimed to identify metabolic predictors to the effectiveness of pre-meal whey protein. Methods: In a randomized-crossover design, 16 individuals with T2D [HbA1c 57±9 mmol/mol) underwent two 7d free-living periods where they consumed a whey protein (15g) or placebo beverage before each main meal. Glucose control was captured by blinded continuous glucose monitoring. Patient anthropometric and fasting markers of liver health and glucose metabolism were obtained at baseline. β-cell function was determined by the ratio of the incremental changes in insulin secretion to glucose during a feeding test. The relationship between TIR and clinical markers were analyzed by correlational analysis, and predictors of TIR were determined by multiple regression. Results: β-cell function was a strong determinant to TIR during both the whey (rs=0.615; p=0.011) and placebo (rs=0.598; p=0.019) weeks. Around 76% of the variance in TIR during the whey week was accounted by β-cell function, and fasting insulin and alanine aminotransferase concentrations (adj R2=0.760; p<0.001). During the whey intervention, TIR was inversely associated with aspartate aminotransferase (rs=−0.506; p=0.046) and tended to be related to fasting glucagon (rs=−0.482; p=0.058), whereas there were no associations between liver health or fasting hormonal markers with TIR during placebo (p>0.05). Conclusions: In a small cohort of people with T2D, our data indicates that those with compromised liver health and reduced β-cell function may experience a reduction in TIR when consuming mealtime protein supplementation. This is possibly due to disruptions in the liver-α-cell axis, which may be further aggravated by increasing plasma amino acid availability from protein supplementation. K.Smith: None. G.Taylor: None. M.Walker: None. K.A.Bowden davies: None. E.J.Stevenson: None. D.J.West: None. Francis James Bell Endowment Fund; County Durham Community Foundation