Showing papers by "Mark Walker published in 2022"

A saturated map of common genetic variants associated with human height

Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study

Abstract: The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments.

Pharmacogenomics of GLP-1 Receptor Agonists: A genome-wide analysis of observational data and large randomized controlled trials

Abstract: Background: In the treatment of type 2 diabetes (T2D), GLP-1 Receptor Agonists (GLP-1RA) lower glucose levels and body weight, and have cardiovascular benefits. GLP-1RA efficacy and side effects vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insights into drug action and provide biomarkers to inform clinical decision-making. We, therefore, aimed to identify genetic variants associated with glycaemic response to GLP-1RA treatment. Methods: We studied HbA1c reduction at 6 months after starting GLP-1RA in 4,571 subjects with T2D from four prospective observational cohorts and two randomized clinical trials. We evaluated variants in GLP-1R, then undertook a genome-wide association study (GWAS) and gene-based burden test. Findings: Variation in HbA1c reduction with GLP-1RA treatment was associated with rs6923761G>A (Gly168Ser) in the GLP-1R (0.9 mmol/mol lower reduction in HbA1c per Serine, p=6.0e-05) and low-frequency variants in ARRB1 (pskato=6.72e-08), largely driven by rs140226575G>A (Thr370Met) (2.7mmol/mol greater HbA1c reduction per Methionine, p=5.2e-06). Similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian populations who have a higher frequency of this variant (6-11%) than in white populations. A genetic risk score derived from these two genes identified around 5% of the population who had a ~30% greater reduction in HbA1c than the ~43% of the population with the worse response. Interpretation: This first genome-wide pharmacogenomic study of GLP-1RA has provided novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants may benefit from earlier initiation of GLP-1RA. Funding: Innovative Medicines Initiative, Wellcome Trust

Rescuing Tetracycline Class Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii Pulmonary Infection

Abstract: Within intensive care unit settings, multidrug-resistant (MDR) Acinetobacter baumannii is a major cause of ventilator-associated pneumonia, and hospital-associated outbreaks are becoming increasingly widespread. Antibiotic treatment of A. baumannii infection is often compromised by MDR strains resistant to last-resort β-lactam (e.g., carbapenems), polymyxin, and tetracycline class antibiotics. ABSTRACT Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients, and antibiotic treatment is compromised by multidrug-resistant strains resistant to β-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines. Among COVID-19 patients receiving ventilator support, a multidrug-resistant A. baumannii secondary infection is associated with a 2-fold increase in mortality. Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in A. baumannii, increasing cellular zinc and copper while decreasing magnesium accumulation. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multidrug-resistant A. baumannii infections. IMPORTANCE Within intensive care unit settings, multidrug-resistant (MDR) Acinetobacter baumannii is a major cause of ventilator-associated pneumonia, and hospital-associated outbreaks are becoming increasingly widespread. Antibiotic treatment of A. baumannii infection is often compromised by MDR strains resistant to last-resort β-lactam (e.g., carbapenems), polymyxin, and tetracycline class antibiotics. During the on-going COVID-19 pandemic, secondary bacterial infection by A. baumannii has been associated with a 2-fold increase in COVID-19-related mortality. With a rise in antibiotic resistance and a reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. Rescuing the efficacy of existing therapies for the treatment of MDR A. baumannii infection represents a financially viable pathway, reducing time, cost, and risk associated with drug innovation.

Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion

Abstract: During infection, microbes must escape host immune responses and survive exposure to reactive oxygen species produced by immune cells. Here, we identify the ABC transporter substrate binding protein GshT as a key component of the glutathione salvage pathway in glutathione-auxotrophic GAS. ABSTRACT The nasopharynx and the skin are the major oxygen-rich anatomical sites for colonization by the human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]). To establish infection, GAS must survive oxidative stress generated during aerobic metabolism and the release of reactive oxygen species (ROS) by host innate immune cells. Glutathione is the major host antioxidant molecule, while GAS is glutathione auxotrophic. Here, we report the molecular characterization of the ABC transporter substrate binding protein GshT in the GAS glutathione salvage pathway. We demonstrate that glutathione uptake is critical for aerobic growth of GAS and that impaired import of glutathione induces oxidative stress that triggers enhanced production of the reducing equivalent NADPH. Our results highlight the interrelationship between glutathione assimilation, carbohydrate metabolism, virulence factor production, and innate immune evasion. Together, these findings suggest an adaptive strategy employed by extracellular bacterial pathogens to exploit host glutathione stores for their own benefit. IMPORTANCE During infection, microbes must escape host immune responses and survive exposure to reactive oxygen species produced by immune cells. Here, we identify the ABC transporter substrate binding protein GshT as a key component of the glutathione salvage pathway in glutathione-auxotrophic GAS. Host-acquired glutathione is crucial to the GAS antioxidant defense system, facilitating escape from the host innate immune response. This study demonstrates a direct link between glutathione assimilation, aerobic metabolism, and virulence factor production in an important human pathogen. Our findings provide mechanistic insight into host adaptation that enables extracellular bacterial pathogens such as GAS to exploit the abundance of glutathione in the host cytosol for their own benefit.

Thrice daily consumption of a novel, premeal shot containing a low dose of whey protein increases time in euglycemia during 7 days of free-living in individuals with type 2 diabetes

Abstract: Introduction During acute feeding trials, consuming a large dose of whey protein (WP) before meals improves postprandial glucose regulation in people with type 2 diabetes. It is unclear if the reported benefits of premeal WP supplementation are translatable to everyday care or are associated with clinically meaningful, real-world glycemic outcomes. This study examined the application of a novel, premeal shot containing a low dose of WP on parameters of free-living glycemic control in people with type 2 diabetes. Research design and methods In a randomized, placebo-controlled, single-blind crossover design, 18 insulin naive individuals with type 2 diabetes ((mean±SD) age, 50±6 years; HbA1c (glycated hemoglobin), 7.4%±0.8%; duration of diabetes, 6±5 years) consumed a ready-to-drink WP shot (15 g of protein) or a nutrient-depleted placebo beverage 10 min before breakfast, lunch, and dinner over a 7-day free-living period. Free-living glucose control was measured by blinded continuous glucose monitoring and determined by the percentage of time spent above range (>10 mmol/L), in euglycemic range (3.9–10.0 mmol/L), below range (<3.9 mmol/L) and mean glucose concentrations. Results Mealtime WP supplementation reduced the prevalence of daily hyperglycemia by 8%±19% (30%±25% vs 38%±28%, p<0.05), thereby enabling a 9%±19% (~2 hours/day) increase in the time spent in euglycemia (p<0.05). Mean 24-hour blood glucose concentrations were 0.6±1.2 mmol/L lower during WP compared with placebo (p<0.05). Similar improvements in glycemic control were observed during the waken period with premeal WP supplementation (p<0.05), whereas nocturnal glycemic control was unaffected (p>0.05). Supplemental compliance/acceptance was high (>98%), and no adverse events were reported. Conclusions Consuming a novel premeal WP shot containing 15 g of protein before each main meal reduces the prevalence of daily hyperglycemia, thereby enabling a greater amount of time spent in euglycemic range per day over 7 days of free-living in people with type 2 diabetes. Trial registration number ISRCTN17563146; www.isrctn.com/ISRCTN17563146

Vancomycin Resistance in Enterococcus and Staphylococcus aureus

Abstract: Enterococcus faecalis, Enterococcus faecium and Staphylococcus aureus are both common commensals and major opportunistic human pathogens. In recent decades, these bacteria have acquired broad resistance to several major classes of antibiotics, including commonly employed glycopeptides. Exemplified by resistance to vancomycin, glycopeptide resistance is mediated through intrinsic gene mutations, and/or transferrable van resistance gene cassette-carrying mobile genetic elements. Here, this review will discuss the epidemiology of vancomycin-resistant Enterococcus and S. aureus in healthcare, community, and agricultural settings, explore vancomycin resistance in the context of van and non-van mediated resistance development and provide insights into alternative therapeutic approaches aimed at treating drug-resistant Enterococcus and S. aureus infections.

Association of maternal socioeconomic status and race with risk of congenital heart disease: a population-based retrospective cohort study in Ontario, Canada

Abstract: Objective To investigate the interrelationships between maternal socioeconomic status (SES), race and congenital heart diseases (CHD) among infants. Design Retrospective cohort study. Study setting Ontario, Canada. Study population All singleton stillbirths and live births born in hospitals between 1 April 2012 and 31 March 2018 in Ontario, Canada (n=804 292). Outcome CHD. Analysis Multivariable logistic regression models were performed to assess associations between maternal neighbourhood household income, education level, race and CHD while adjusting for maternal age at birth, assisted reproductive technology, obesity, pre-existing health conditions, substance use during pregnancy, maternal rural residence and infant’s sex. Results Compared with infants whose mothers lived in the highest median household income neighbourhoods, infants whose mothers lived in the lowest median income neighbourhoods had a higher likelihood of having CHD (adjusted OR 1.15, 95% CI 1.06 to 1.24). Compared with infants whose mothers lived in neighbourhoods with more people with a university or higher degree, those infants whose mothers lived in neighbourhoods with less people with a university or higher degree had a higher chance of developing CHD (adjusted OR 1.26, 95% CI 1.16 to 1.36). Compared with white mothers, black mothers had a higher odds of giving birth to a child with CHD (adjusted OR 1.40, 95% CI 1.27 to 1.54). No association was detected between White and Asian mothers and CHD among infants. Conclusions Our study indicates that there are inequities in CHD burden by maternal SES and race in Ontario, Canada. Further investigation is needed to examine racial variation in CHD using more detailed ethnic data.

Racial Differences in Patient-Reported Symptoms and Adherence to Adjuvant Endocrine Therapy Among Women With Early-Stage, Hormone Receptor–Positive Breast Cancer

Abstract: This cohort study evaluates the differences in patient-reported symptoms and adherence to adjuvant endocrine therapy by race among women with early-stage breast cancer.

The influence of maternal and paternal education on birth outcomes: an analysis of the Ottawa and Kingston (OaK) birth cohort

Abstract: Abstract Background Education is considered one of the most robust determinants of health. However, it is unclear whether maternal education and paternal education have differential impacts on perinatal health outcomes. We assess maternal and paternal education differences and their association with adverse birth outcomes in a large birth cohort from Ontario, Canada. Methods The OaK Birth Cohort recruited patients from Ontario, Canada, between October 2002 and April 2009. We recruited mothers were recruited between 12 and 20 weeks’ gestation and collected both mother and infant data. The final sample size of the cohort was 8,085 participants. We use logistic regression to model the probability of preterm birth (less than 34 and 37 weeks’ gestation), small-for-gestational-age (SGA), or stillbirth as a function of maternal and paternal educational attainment. We adjust for household-level income, maternal and paternal race and ethnicity, and compare the strength of the association between maternal and paternal education on outcomes using Wald tests. Results 7,928 mother-father-offspring triads were available for the current analysis. 75% of mothers and fathers had college or university level education, and 8.7% of mothers experienced preterm delivery. Compared to mothers with college or university education, mothers with a high school education had an odds ratio of 1.37 (95% CI: 1.01–1.87) for SGA. Paternal education was not associated with infant outcomes. Comparing the odds ratios for maternal education and paternal education showed a stronger association than paternal education at the high school level for SGA birth (difference in odds ratio: 1.95, 95% CI: 1.13–3.36, p = .016) among women at least 25 years old. Conclusion Maternal education was associated with SGA, and this effect was more robust than paternal education, but both associations were weaker than previously reported.

Presentation and management of spinal meningioma and its association with breast carcinoma-case series and systematic review.

Abstract: OBJECTIVE Benign spinal intradural tumors are rare entities and there have been relatively few case series describing the epidemiology and characteristics of these tumors. Here, we evaluate the presentation, demographics, pathology and outcomes associated with the surgical management of spinal meningioma in our unit over a 6-year period. RESULTS A total of 68 cases presented to the operating surgeon during a 6-year period. Of these, over 80% (n = 55) were in females. Seventy-nine percent of the meningiomas were observed in the thoracic region (n = 54). Weakness and gait disturbance were the most common presenting complaints. Surgery significantly improved both motor outcome (p < 0.001) and health related qualities of life (SF36, p < 0.01).Seventeen percent of spinal meningioma cases (n = 12) had a preceding cancer diagnosis. Of these 75% (n = 9/12) were attributable to breast cancer. Overall, breast cancer preceded a diagnosis of a spinal meningioma in 16.4% of female cases (9/55). This is higher than expected number of breast cancer based on UK population and those reported in literature for breast cancer and intracranial meningioma. CONCLUSION Spinal meningioma is disproportionately over-represented in females. Patients present with neurological deficits and surgery improved both neurology and patient reported quality of life. Relative to the known UK prevalence of breast cancer, there is a significantly higher than expected association between spinal meningioma and a preceding history of breast cancer.

Genome-wide analysis of Structural Variants in Parkinson’s Disease using Short-Read Sequencing data

Abstract: Parkinson’s disease is a complex neurodegenerative disorder, affecting approximately one million individuals in the USA alone. A significant proportion of risk for Parkinson’s disease is driven by genetics. Despite this, the majority of the common genetic variation that contributes to disease risk is unknown, in-part because previous genetic studies have focussed solely on the contribution of single nucleotide variants. Structural variants represent a significant source of genetic variation in the human genome. However, because assay of this variability is challenging, structural variants have not been cataloged on a genome-wide scale, and their contribution to the risk of Parkinson’s disease remains unknown. In this study, we 1) leveraged the GATK-SV pipeline to detect and genotype structural variants in 7,772 short-read sequencing data and 2) generated a subset of matched whole-genome Oxford Nanopore Technologies long-read sequencing data from the PPMI cohort to allow for comprehensive structural variant confirmation. We detected, genotyped, and tested 3,154 “high-confidence” common structural variant loci, representing over 412 million nucleotides of non-reference genetic variation. Using the long-read sequencing data, we validated three structural variants that may drive the association signals at known Parkinson’s disease risk loci, including a 2kb intronic deletion within the gene LRRN4. Further, we confirm that the majority of structural variants in the human genome cannot be detected using short-read sequencing alone, encompassing on average around 4 million nucleotides of inaccessible sequence per genome. Therefore, although these data provide the most comprehensive survey of the contribution of structural variants to the genetic risk of Parkinson’s disease to date, this study highlights the need for large-scale long-read datasets to fully elucidate the role of structural variants in Parkinson’s disease.

Blood metals and vitamin D status in a pregnancy cohort: A bidirectional biomarker analysis.

Abstract: Low 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status, is associated with reduced immune function and adverse pregnancy outcomes, such as preterm birth. Observational studies indicate that long-term, high level exposure to metals such as cadmium (Cd) and lead (Pb) can impact a person's vitamin D status. However, the directionality of the association is uncertain, particularly for low-level exposures. We used three distinct longitudinal data analysis methods to investigate cross-sectional, longitudinal and bidirectional relationships of Cd and Pb biomarkers with 25-hydroxyvitamin D (25OHD) in a Canadian pregnancy cohort. Maternal whole blood Cd and Pb and plasma 25OHD concentrations were measured in the 1st (n = 1905) and 3rd (n = 1649) trimester and at delivery (25OHD only, n = 1542). Our multivariable linear regression analysis showed weak inverse associations between Cd and 25OHD concentrations cross-sectionally and longitudinally while the latent growth curve models showed weak associations with Pb on the 25OHD intercept. In the bidirectional analysis, using cross lagged panel models, we found no association between 1st trimester metals and 3rd trimester 25OHD. Instead, 1st trimester 25OHD was associated with 9% (-15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. These findings suggest the 25OHD may modify metal concentrations in pregnancy and demonstrates the value of controlling for contemporaneous effects and the persistence of a biomarker over time, in order to rule out reverse causation.

Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria

Abstract: Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of the lipopolysaccharide modification pathways that confer polymyxin resistance. Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillin-resistant S. aureus), and vancomycin-resistant Enterococcus faecium. Using the globally disseminated M1T1 GAS strain 5448 as a proof of principle model, colistin in the presence of PBT2 + zinc was shown to be bactericidal in activity. Any resistance that did arise imposed a substantial fitness cost. PBT2 + zinc dysregulated GAS metal ion homeostasis, notably decreasing the cellular manganese content. Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection. These findings provide a foundation from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections.

Survey of mode of delivery and maternal and perinatal outcomes in Canada.

Abstract: Objective To identify determinants of cesarean delivery (CD) and examine associations between mode of delivery (MOD) and maternal and perinatal outcomes. Methods We conducted a retrospective analysis of a Canadian multicentre birth cohort derived from provincial data collected in 2008/2009. Maternal and perinatal characteristics and outcomes were compared between vaginal and cesarean birth and between the following MOD subgroups: spontaneous vaginal delivery (VD), assisted VD, planned cesarean delivery (CD), and intrapartum CD. Multivariate regression identified determinants of CD and the effects of MOD and previous CD on maternal and perinatal outcomes. Results The cohort included 264 755 births (72.1% VD and 27.9% CD) from 91 participating institutions. Determinants of CD included maternal age, parity, previous CD, chronic hypertension, diabetes, urinary tract infection or pyelonephritis, gestational hypertension, vaginal bleeding, labour induction, pre-term gestational age, low birth weight, large for gestational age, malpresentation, and male sex. CD was associated with greater risk of maternal and perinatal morbidity and mortality. Subgroup analysis demonstrated higher risk of adverse pregnancy outcomes with assisted VD and intrapartum CD than spontaneous VD. Planned CD reduced the risk of obstetric wound hematoma and perinatal mortality but increased maternal and neonatal morbidity. Previous CD increased the risk of maternal and neonatal morbidity among multiparous women. Conclusions The CD rate in Canada is consistent with global trends reflecting demographic and obstetric intervention factors. The risk of adverse pregnancy outcomes with CD warrants evaluation of interventions to safely prevent nonessential cesarean birth.

Race differences in patient-reported symptoms during chemotherapy among women with early-stage hormone receptor positive breast cancer.

Abstract: BACKGROUND Symptom burden differences may contribute to racial disparities in breast cancer survival. We compared symptom changes from before to during chemotherapy among women with breast cancer. METHODS This observational study followed a cohort of Black and White women diagnosed with Stage I-III, hormone-receptor positive breast cancer from a large cancer center in 2007-2015, and reported symptoms before and during chemotherapy. We identified patients who experienced a one-standard deviation (SD) increase in symptom burden after starting chemotherapy using four validated composite scores (General Physical Symptoms, Treatment Side-Effects, Acute Distress, and Despair). Kitagawa-Blinder-Oaxaca decomposition was used to quantify race differences in symptom changes explained by baseline characteristics (sociodemographic, baseline scores, cancer stage) and first-line chemotherapy regimens. RESULTS Among 1,273 patients, Black women (n=405, 31.8%) were more likely to report one-SD increase in General Physical Symptoms (55.6% vs. 48.2%, p=0.015), Treatment Side-Effects (74.0% vs. 63.4%, p<0.001), and Acute Distress (27.4% vs. 20.0%, p=0.015) than White women. Baseline characteristics and first-line chemotherapy regimens explained a large and significant proportion of the difference in Acute Distress changes (93.7%, p=0.001), but not General Physical Symptoms (25.7%, p=0.25) or Treatment Side-Effects (16.4%, p=0.28). CONCLUSIONS Black women with early-stage breast cancer were more likely to experience significant increases in physical and psychological symptom burden during chemotherapy. Most of the difference in physical symptom changes remained unexplained by baseline characteristics, which suggests inadequate symptom management among Black women. IMPACT Future studies should identify strategies to improve symptom management among Black women and reduce differences in symptom burden.

Issues associated with possible implementation of Non‐Invasive Prenatal Testing (NIPT) in first‐tier screening: A rapid scoping review

Abstract: In recent years, as the implementation and use of Non‐Invasive Prenatal Testing (NIPT) have increased, the cost of the test has been decreasing. The cost of NIPT is expected to fall further in the upcoming years. As a result of the decreasing cost of NIPT, many jurisdictions may change their prenatal screening policies toward abandoning serum‐based screening and instead, implement and support NIPT as the first‐tier screening for all women. There are several concerns in replacing first‐trimester screening with NIPT. In this scoping review, we aimed to map the existing knowledge about possible issues in the systematic implementation of NIPT as the primary method of first‐tier screening and to assess if any jurisdiction has altered its policy and discontinued serum‐based prenatal screening in exchange for NIPT. The Medline database (Ovid) and Google Scholar was searched and all the studies discussing, investigating, or reporting on the systematic implementation of NIPT as the primary method of first‐tier screening were included. All the studies went through a two‐stage screening process and included full‐text articles were reviewed. We did not find any articles indicating a country or region that replaced traditional prenatal screening by NIPT. The included articles were charted, and the data about the possible issues in the systematic implementation of NIPT as the primary method of first‐tier screening are summarized narratively and presented in tables in four categories. The findings of this scoping review may be informative for stakeholders and policymakers regarding recent changes in NIPT implementation policies around the world and may aid with developing policy for NIPT implementation with a broader perspective.

An ionophore breaks the multi-drug-resistance of Acinetobacter baumannii

Abstract: Within intensive care units, multi-drug resistant Acinetobacter baumannii outbreaks are a frequent cause of ventilator-associated pneumonia. During the on-going COVID-19 pandemic, patients who receive ventilator support experience a 2-fold increased risk of mortality when they contract a secondary A. baumannii pulmonary infection. In our recent paper (De Oliveira et al. (2022), Mbio, doi: 10.1128/mbio.03517-21), we demonstrate that the 8-hydroxquinoline ionophore, PBT2 breaks the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multi-drug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multi-drug resistant A. baumannii infections.

Folic Acid Supplementation in Early Pregnancy, Homocysteine Concentration, and Risk of Gestational Diabetes Mellitus.

Abstract: We used a prospective cohort of pregnant women at 12 to 20 weeks gestation between 2002 and 2008 in Ottawa and Kingston to evaluate the impact of early pregnancy folic acid supplementation on the risk of gestational diabetes mellitus. Among 7552 eligible women, 84 (1.11%) were diagnosed of gestational diabetes mellitus. Non-significant associations were observed between gestational diabetes mellitus and folate supplementation, homocysteine levels, and methylenetetrahydrofolate reductase 677 TT genotype. Although we found no significant associations between folic acid supplementation and the risk of gestational diabetes mellitus, genetic associations were not confounded by lifestyle or socioeconomic factors, which may have biased previous studies.

Repurposing the Ionophore, PBT2, for Treatment of Multidrug-Resistant Neisseria gonorrhoeae Infections

Abstract: Multidrug-resistant (MDR) N. gonorrhoeae is a current public health threat. New therapies are urgently needed. PBT2 is an ionophore that disrupts metal homeostasis. PBT2 administered with zinc is shown to reverse resistance to antibiotics in several bacterial pathogens. Here we show that both N. meningitidis and MDR N. gonorrhoeae are sensitive to killing by PBT2 alone. PBT2 is, thus, a candidate therapeutic for MDR N. gonorrhoeae infections. ABSTRACT Multidrug-resistant (MDR) N. gonorrhoeae is a current public health threat. New therapies are urgently needed. PBT2 is an ionophore that disrupts metal homeostasis. PBT2 administered with zinc is shown to reverse resistance to antibiotics in several bacterial pathogens. Here we show that both N. meningitidis and MDR N. gonorrhoeae are sensitive to killing by PBT2 alone. PBT2 is, thus, a candidate therapeutic for MDR N. gonorrhoeae infections.

Associations of congenital heart disease with deprivation index by rural-urban maternal residence: a population-based retrospective cohort study in Ontario, Canada

Abstract: Abstract Background The risk of congenital heart disease (CHD) has been found to vary by maternal socioeconomic status (SES) and rural-urban residence. In this study, we examined associations of CHD with two maternal SES indicators and stratified the analysis by maternal rural-urban residence. Methods This was a population-based retrospective cohort study. We included all singleton stillbirths and live hospital births from April 1, 2012 to March 31, 2018 in Ontario, Canada. We linked the BORN Information System and Canadian Institute for Health Information databases. Multivariable logistic regression models were used to examine associations of CHD with material deprivation index (MDI), social deprivation index (SDI), and maternal residence while adjusting for maternal age at birth, assisted reproductive technology, obesity, pre-pregnancy maternal health conditions, mental health illness before and during pregnancy, substance use during pregnancy, and infant’s sex. MDI and SDI were estimated at a dissemination area level in Ontario and were categorized into quintiles (Q1-Q5). Results This cohort study included 798,173 singletons. In maternal urban residence, the p trend (Cochran–Armitage test) was less than 0.0001 for both MDI and SDI; while for rural residence, it was 0.002 and 0.98, respectively. Infants living in the most materially deprived neighbourhoods (MDI Q5) had higher odds of CHD (aOR: 1.21, 95% CI: 1.12–1.29) compared to Q1. Similarly, infants living in the most socially deprived neighbourhoods (SDI Q5) had an 18% increase in the odds of CHD (aOR: 1.18, 95% CI: 1.1–1.26) compared to Q1. Rural infants had a 13% increase in the odds of CHD compared to their urban counterparts. After stratifying by maternal rural-urban residence, we still detected higher odds of CHD with two indices in urban residence but only MDI in rural residence. Conclusion Higher material and social deprivation and rural residence were associated with higher odds of CHD. Health interventions and policies should reinforce the need for optimal care for all families, particularly underprivileged families in both rural and urban regions. Future studies should further investigate the effect of social deprivation on the risk of CHD development.

The association between metals, vitamin D and preterm birth in the MIREC Cohort Study

Abstract: BACKGROUND Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have explored this association at the low levels currently found in the Canadian population. Conversely, studies suggest that vitamin D may have antioxidant activity and protect against PTB. In this study, we sought to investigate associations between toxic metals (lead, mercury, cadmium and arsenic) and PTB, and to determine if maternal plasma vitamin D concentrations modify these associations. METHODS We investigated whether metals in whole blood measured in early and late pregnancy were associated with PTB (&#x3c;37 weeks) and spontaneous PTB (a subset of PTBs with spontaneous labour) in 1,851 pregnancies resulting in live births from the Maternal-Infant Research on Environmental Chemicals Study (MIREC) using discrete time survival analysis. In addition, we investigated whether the risk of PTB was modified by plasma 25OHD concentration measured in the 1st trimester. RESULTS Six percent (n=117) of live births in the MIREC study were PTBs; 4% (n=89) were spontaneous PTBs. A 1 &#x3bc;g/dL increase in blood lead concentrations during pregnancy was associated with increased risk of PTB (OR=1.5, 95% CI: 1.0, 2.3) and spontaneous PTB (OR=1.7, 95% CI: 1.1, 2.8). In stratified analysis, the risk of PTB (OR=2.7, 95% CI: 1.0, 7.2) and spontaneous PTB (OR=3.4, 95% CI: 1.1, 10.8) was higher in women with insufficient vitamin D concentrations (25OHD &#x3c;50 nmol/L). However, a statistical interaction was not seen. Arsenic was associated with a higher risk of PTB (OR=1.1, 95% CI: 1.0, 1.2) and spontaneous PTB (OR=1.1, 95% CI: 1.0, 1.2) per µg/L, but these associations were not modified by vitamin D. CONCLUSIONS Low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; the association with lead was stronger in participants with insufficient plasma vitamin D. Replication of these findings is warranted.

Single Dose of Antenatal Corticosteroids (SNACS) Non-Inferiority Randomized Controlled Trial for Pregnancies at Risk of Preterm Delivery

Abstract: Antenatal corticosteroids (ACS) given to infants born preterm, are associated with a decrease in infant mortality and morbidity. However, these neonatal benefits decrease with increasing gestational age. Importantly, recent long term studies suggest that ACS may be associated with long term neurodevelopmental harm. Research suggests that a single dose of ACS matures preterm lungs similar to double doses. This CIHR funded RCT will test this question. Our research Question: In pregnancies at risk of preterm birth, between 22+0 to 34+6 weeks, is 12 mg vs. 24 mg Betamethasone: non-inferior for the primary neonatal composite outcome of 1) perinatal mortality (fetal or neonatal), 2) severe respiratory morbidity (need for surfactant within 48 hours of life), 3) grade 3–4 intraventricular hemorrhage or 4) stage 2–3 necrotizing enterocolitis (and superior for secondary neurosensory and developmental long-term outcome assessed at 24 months corrected age).

Paramedic Endotracheal Intubation Success Rates Before and After an Intensive Airway Management Education Session

Abstract: Introduction Advanced airway management by paramedics is potentially life-saving, but carries a significant risk to patient safety and can be associated with poor clinical outcome if performed incorrectly. Previously, our team had found that an intensive education intervention demonstrated an improvement in paramedic performance on a written exam and increased confidence in airway skills. This study measured intubation success and the number of attempts per patient before and after intensive paramedic airway management education intervention. Methods A 10-hour mandatory course was taken by all advanced life support (ALS) paramedics in a provincial system (2009/04-07, n=~395). The course was done during semi-annual continuing education Emergency Health Services (EHS) in-services. These day-long courses were held in person over four months. The electronic charting database was queried for intubation attempts and successful placements 12 months before the training, during the four months of training, and 12 months post-training. The primary outcome is the difference in success rates between the before (pre-intervention) and after (post-intervention) periods. The secondary outcome is the number of attempts per patient. Stationarity of success in pre- and post-periods was tested. The model was fit tested using Maximum Likelihood regression, and variables were tested using the Wald test. Results A sample size of 476 intubation attempts in each of the pre- and post-periods was required to detect a 10% improvement with the pre-intervention success of 60%. A total of 1421 intubation attempts occurred; 674 pre-intervention, 604 post-intervention, and 143 during teaching. Seven attempts were excluded (success unknown). Intubation success rates improved, from 0.68 (95% CI 0.64-0.71) to 0.75 (95% CI 0.72-0.78); a difference of 0.076 (95% CI 0.03-0.12) (p = 0.001). Intubation success rates in the pre-intervention and post-intervention periods were found to be static. A significant decrease was found in the number of attempts per patient in the post-period (p = 0.005). Conclusion Intubation success increased from 68% to 75% and was maintained over the 12-month post-period. There is a potential that judgment may also have improved, based on the decreased number of attempts per patient. Limitations include missing values, paramedics’ self-reported number of attempts, and the definition of what is considered to be an attempt. In addition to previously demonstrated improvements in paramedic exam and scenario performance, this airway education intervention appears to have made a significant improvement to patient outcomes. These findings support the value of such education interventions to improve performance.

Validation of gestational age determination from ultrasound or a metabolic gestational age algorithm using exact date of conception in a cohort of newborns conceived using assisted reproduction technologies

Abstract: Accurate estimates of gestational age in pregnancy are important for the provision of optimal care. Although current guidelines generally recommend estimating gestational age via first-trimester ultrasound measurement of crown–rump length, error associated with this method can range from 3 to 8 days of gestation. In pregnancies resulting from assisted reproductive technology, estimated due date can be calculated on the basis of the age of the embryo and the date of embryo transfer, arguably providing the most accurate estimates possible. We have developed and extensively validated statistical models to estimate gestational age postnatally using metabolomic markers from blood samples in combination with clinical and demographic data. These models have shown high accuracy compared with first-trimester ultrasound, the recommended method for estimating gestational age in spontaneous pregnancies. We hypothesized that gestational age derived from date and stage of embryo at transfer in newborns conceived using assisted reproduction therapy would provide the most accurate reference standard possible to evaluate and compare the accuracy of both first-trimester ultrasound and metabolomic model–based gestational dating. This study aimed to validate both first-trimester ultrasound dating and postnatal metabolomic gestational age estimation models against gestational age derived from date and stage of embryo at transfer in a cohort of newborns conceived via assisted reproductive technology, both overall and in important subgroups of interest (preterm birth, small for gestational age, and multiple birth). This was a retrospective cohort study of infants born in Ontario, Canada between 2015 and 2017 and captured in the provincial birth registry. Spontaneous conceptions were randomly partitioned into a model derivation sample (80%) and a test sample (20%) for model validation. A cohort of assisted conceptions resulting from fresh embryo transfers was derived to evaluate the accuracy of both ultrasound and model-based gestational dating. Postnatal gestational age estimation models were developed with multivariable linear regression using elastic-net regularization. Gestational age estimates from dating ultrasound and from postnatal metabolomic models were compared with date of embryo transfer reference gestational age in the independent test cohorts. Accuracy was quantified by calculating mean absolute error and the square root of mean squared error. Our model derivation cohort included 202,300 spontaneous conceptions, and the testing cohorts included 50,735 spontaneous conceptions and 1924 assisted conceptions. In the assisted conception cohort, first-trimester dating ultrasound was accurate to within approximately ±1.5 days compared with date of embryo transfer reference overall (mean absolute error, 0.21 [95% confidence interval, 0.20–0.23]). When compared with gestational age derived from date of embryo transfer, the metabolomic estimation models were accurate to within approximately ±5 days overall (0.79 [0.76–0.81] weeks). When ultrasound was used as the reference in validating the metabolomic model, the mean absolute error was slightly higher overall (0.81 [0.78–0.84] weeks). In general, the accuracy of gestational age estimates derived from ultrasound or metabolomic models was highest in term infants and lower in preterm and small-for-gestational-age newborns. Our findings support the accuracy of ultrasound as a gestational age dating tool. They also support the potential utility of metabolic gestational age dating algorithms in settings where ultrasound or other accurate methods of estimating gestational age are not available because of lack of infrastructure or specialized training (eg, low-income countries). However, the accuracy of metabolomic model–based dating was generally lower than that of ultrasound.

Lifestyle improvement reduces the consumption of ultra-processed foods in adults with metabolic syndrome.

Abstract:

Abstract

Background and aims:

The high consumption of ultra-processed products is a concern because it is positively associated with the incidence of chronic non-communicable diseases, as metabolic syndrome (MetS). The aim is to evaluate the effects of three different interventions to modify lifestyle on the consumption of ultra-processed foods in adults with MetS.

Methods and results:

This was a randomized clinical trial, in which the participants were divided into three groups: Standard Intervention (SI), Group Intervention (GI) and Individual Intervention (II). The interventions were carried out over a three-month period and the data was collected in a 24-h food record, taken at the beginning and end of the intervention. The food they ate was classified into four groups according to the degree of processing (unprocessed or minimally processed foods, processed culinary ingredients, processed foods, and ultra-processed foods) in accordance with the NOVA food classification. Seventy adults took part in the study with a mean age of 51.2 ± 6.6 years old; most of whom were female (55.7%). The amount of ultra-processed food consumed by the three groups (SI, GI and II) was significantly reduced (46%, 34%, and 33%, respectively). The amount of processed food consumed only reduced in the II group. The Total Energy Value (TEV) consumed by the SI and II groups decreased.

Conclusions

The interventions that were intended to alter lifestyles were able to reduce the amount of ultra-processed food consumed, which can have an impact on the prevention and treatment of MetS.

Registration

registered in the Brazilian Registry of Clinical Trials, ReBEC, under number: RBR-9wz5fc.

Peripartum Outcomes Following COVID-19 Vaccination in Late Pregnancy: Findings from a Population-Based Retrospective Cohort Study in Ontario, Canada

Abstract: Evaluate peripartum outcomes following COVID-19 vaccination during pregnancy. Ontario population-based retrospective cohort between December 14, 2020 and September 30, 2021 using linkage of provincial birth registry and COVID-19 immunization databases. Poisson regression was used to generate risk ratios (RR) and 95% confidence intervals (CI), adjusted for temporal, socio-demographic, and clinical factors using propensity scores. Obstetric (postpartum hemorrhage, chorioamnionitis, cesarean birth) and newborn (NICU admission and 5-minute Apgar<7) outcomes were compared for those who received ≥1 dose of COVID-19 vaccine during pregnancy with 2 unexposed groups—Group 1: individuals vaccinated postpartum, Group 2: never vaccinated. Among 97 590 individuals, 22 660 (23%) received ≥1 dose of vaccine during pregnancy (64% received dose 1 in 3rd trimester). Compared with those vaccinated postpartum, we found no increased risks of postpartum hemorrhage (aRR 0.91, 95% CI 0.82–1.02); chorioamnionitis (aRR 0.92, 95% CI 0.70–1.21); or cesarean (aRR 0.92, 95% CI 0.89–0.95) following COVID-19 vaccination, nor any increased risk of NICU admission or 5-minute Apgar <7. All findings were similar when compared with individuals who did not receive COVID-19 vaccination at any point. We did not observe any difference according to vaccine product, number of doses received during pregnancy, or trimester of dose 1. As of late 2021, there is limited evidence from comparative studies in large populations on outcomes following COVID-19 vaccination during pregnancy. Our study of births up to September 30, 2021 did not identify any increased adverse peripartum outcomes associated with later pregnancy COVID-19 vaccination. Once more individuals vaccinated earlier in pregnancy deliver, we will report on other important obstetric and perinatal outcomes.