Mutations, substitutions, and selection: Linking mutagenic processes to cancer using evolutionary theory.

Cancers are the product of evolutionary events, where molecular variation occurs and accumulates in tissues and tumors. Sequencing of this molecular variation informs not only which variants are driving tumorigenesis, but also the mechanisms behind what is fueling mutagenesis. Both of these details are crucial for preventing premature deaths due to cancer, whether it is by targeting the variants driving the cancer phenotype or by measures to prevent exogenous mutations from contributing to somatic evolution. Here, we review tools to determine both molecular signatures and cancer drivers, and avenues by which these metrics may be linked.

Distal Clavicular Resection Worsens Outcomes in Rotator Cuff Repair: A National Database Study.

Introduction: Distal clavicular resection (DCR) is a procedure used to alleviate acromioclavicular joint (ACJ) pain, often done alongside rotator cuff repair (RCR). This investigation explored the relationships between DCR and RCR, outcomes of DCR during RCR, and complication rates of DCR. Methods: This retrospective study used electronic medical record data from the TriNetX database. Cohorts were subdivided based on the timeline of DCR in comparison to RCR, as well as comparing RCR with DCR against RCR without DCR. Results: In total 46 534 patients underwent RCR with 14.8% (6898) of these patients also undergoing DCR. And 72.8% (5021) had DCR during RCR, and 10.7% (740) had DCR after RCR. Less than 5% (<10) of patients with preexisting ACJ pain required DCR 3 years postoperatively, and 0.002% (78) patients without ACJ pain developed ACJ pain within 3 years. Less that 20 patients underwent DCR within 3 years of being diagnosed with ACJ pain. Patients who had RCR with DCR were more likely to have chronic pain postoperatively (P < .0001). Conclusion: Patients undergoing RCR do not require subsequent DCR. Performing DCR does not offer significant benefit when compared to performing isolated RCR without DCR in patients with preexisting ACJ pain, but increases risk for ACJ instability and chronic pain.

Prevalence of and Annual Conversion Rates to Mild Cognitive Impairment and Dementia: Prospective, Longitudinal Study of an Essential Tremor Cohort.

OBJECTIVE: Despite recent attention to cognitive impairment in essential tremor, few studies examine rates of conversion to diagnoses of mild cognitive impairment and dementia. Development of dementia in essential tremor is associated with loss of functional ability and a doubling of mortality rate. This prospective, longitudinal study comprehensively reports the prevalence and incidence of, and the annual rates of conversion to, mild cognitive impairment and dementia in an essential tremor cohort. METHODS: Patients underwent detailed cognitive assessments and were assigned diagnoses of normal cognition, mild cognitive impairment, or dementia. There were 222 patients at baseline (mean age = 79.3 ± 9.7 years), and 177 patients participated in follow-up evaluations at 18, 36, 54, and 72 months (mean years of observation = 5.1 ± 1.7). Data were compared to those of historical controls and Parkinson disease patients. RESULTS: The cumulative prevalence of dementia and average annual conversion rate of mild cognitive impairment to dementia were 18.5% and 12.2%, nearly three times higher than rates in the general population, and approximately one half the magnitude of those reported for Parkinson disease patients. The cumulative prevalence of mild cognitive impairment (26.6%) was almost double that of the general population, but less than that in Parkinson disease populations. INTERPRETATION: We present the most complete exposition of the longitudinal trajectory of cognitive impairment in an essential tremor cohort yet presented. The prevalence of and conversion rates to dementia in essential tremor fall between those associated with the natural course of aging and the more pronounced rates observed in Parkinson disease. ANN NEUROL 2024;95:1193-1204.

Mesenchymal Stromal Cell Senescence Induced by Dnmt3a -Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy.

Clonal hematopoiesis (CH) can predispose to blood cancers due to enhanced fitness of mutant hematopoietic stem and progenitor cells (HSPCs), but the mechanisms driving this progression are not understood. We hypothesized that malignant progression is related to microenvironment-remodelling properties of CH-mutant HSPCs. Single-cell transcriptomic profiling of the bone marrow microenvironment in Dnmt3a R878H/+ mice revealed signatures of cellular senescence in mesenchymal stromal cells (MSCs). Dnmt3a R878H/+ HSPCs caused MSCs to upregulate the senescence markers SA-ß-gal, BCL-2, BCL-xL, Cdkn1a (p21) and Cdkn2a (p16), ex vivo and in vivo . This effect was cell contact-independent and can be replicated by IL-6 or TNFα, which are produced by Dnmt3a R878H/+ HSPCs. Depletion of senescent MSCs in vivo reduced the fitness of Dnmt3a R878H/+ hematopoietic cells and the progression of CH to myeloid neoplasms using a sequentially inducible Dnmt3a ; Npm1 -mutant model. Thus, Dnmt3a -mutant HSPCs reprogram their microenvironment via senescence induction, creating a self-reinforcing niche favoring fitness and malignant progression. Statement of Significance: Mesenchymal stromal cell senescence induced by Dnmt3a -mutant hematopoietic stem and progenitor cells drives clonal hematopoiesis and initiation of hematologic malignancy.

The ß2-adrenergic receptor (ADRB2) entrains circadian gene oscillation and diurnal responses to virus infection in CD8 + T cells.

Adaptive immune cells are regulated by circadian rhythms (CR) under both steady state conditions and during responses to infection. Cytolytic CD8 + T cells display variable responses to infection depending upon the time of day of exposure. However, the neuronal signals that entrain these cyclic behaviors remain unknown. Immune cells express a variety of neurotransmitter receptors including nicotinic, glucocorticoid, and adrenergic receptors. Here, we demonstrate that the ß2-adrenergic receptor (ADRB2) regulates the periodic oscillation of select core clock genes, such as Per2 and Bmal1 , and selective loss of the Adrb2 gene dramatically perturbs the normal diurnal oscillation of clock gene expression in CD8 + T cells. Consequently, their circadian-regulated anti-viral response is dysregulated, and the diurnal development of CD8 + T cells into variegated populations of cytolytic T cell (CTL) effectors is dramatically altered in the absence of ADRB2 signaling. Thus, the Adrb2 directly entrains core clock gene oscillation and regulates CR-dependent T cell responses to virus infection as a function of time-of-day of pathogen exposure. One Sentence Summary: The ß2-adrenergic receptor regulates circadian gene oscillation and downstream daily timing of cytolytic T cell responses to virus infection.

Variation in mesenchymal KITL/SCF and IGF1 expression in middle age underlies steady-state hematopoietic stem cell aging.

ABSTRACT: Intrinsic molecular programs and extrinsic factors including proinflammatory molecules are understood to regulate hematopoietic aging. This is based on foundational studies using genetic perturbation to evaluate causality. However, individual organisms exhibit natural variation in the hematopoietic aging phenotypes and the molecular basis of this heterogeneity is poorly understood. Here, we generated individual single-cell transcriptomic profiles of hematopoietic and nonhematopoietic cell types in 5 young adult and 9 middle-aged C57BL/6J female mice, providing a web-accessible transcriptomic resource for the field. Among all assessed cell types, hematopoietic stem cells (HSCs) exhibited the greatest phenotypic variation in expansion among individual middle-aged mice. We computationally pooled samples to define modules representing the molecular signatures of middle-aged HSCs and interrogated, which extrinsic regulatory cell types and factors would predict the variance in these signatures between individual middle-aged mice. Decline in signaling mediated by adiponectin, kit ligand (KITL) and insulin-like growth factor 1 (IGF1) from mesenchymal stromal cells (MSCs) was predicted to have the greatest transcriptional impact on middle-aged HSCs, as opposed to signaling mediated by endothelial cells or mature hematopoietic cell types. In individual middle-aged mice, lower expression of Kitl and Igf1 in MSCs was highly correlated with reduced lymphoid lineage commitment of HSCs and increased signatures of differentiation-inactive HSCs. These signatures were independent of expression of aging-associated proinflammatory cytokines including interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor α and RANTES. In sum, we find that Kitl and Igf1 expression are coregulated and variable between individual mice at the middle age and expression of these factors is predictive of HSC activation and lymphoid commitment independently of inflammation.

Understanding ion-transfer reactions in silver electrodissolution and electrodeposition from first-principles calculations and experiments.

The electrified aqueous/metal interface is critical in controlling the performance of energy conversion and storage devices, but an atomistic understanding of even basic interfacial electrochemical reactions challenges both experiment and computation. We report a combined simulation and experimental study of (reversible) ion-transfer reactions involved in anodic Ag corrosion/deposition, a model system for interfacial electrochemical processes generating or consuming ions. With the explicit modeling of the electrode potential and a hybrid implicit-explicit solvation model, the density functional theory calculations produce free energy curves predicting thermodynamics, kinetics, partial charge profiles, and reaction trajectories. The calculated (equilibrium) free energy barriers (0.2 eV), and their asymmetries, agree with experimental activation energies (0.4 eV) and transfer coefficients, which were extracted from temperature-dependent voltage-step experiments on Au-supported, Ag-nanocluster substrates. The use of Ag nanoclusters eliminates the convolution of the kinetics of Ag+(aq.) generation and transfer with those of nucleation or etch-pit formation. The results indicate that the barrier is controlled by the bias-dependent competition between partial solvation of the incipient ion, metal-metal bonding, and electrostatic stabilization by image charge, with the latter two factors weakened by stronger positive biases. We also report simulations of the bias-dependence of defect generation relevant to nucleating corrosion by removing an atom from a perfect Ag(100) surface, which is predicted to occur via a vacancy-adatom intermediate. Together, these experiments and calculations provide the first validated, accurate, molecular model of the central steps that govern the rates of important dissolution/deposition reactions broadly relevant across the energy sciences.

Metacognition and Self-Efficacy in Action: How First-Year Students Monitor and Use Self-Coaching to Move Past Metacognitive Discomfort During Problem Solving.

Stronger metacognitive regulation skills and higher self-efficacy are linked to increased academic achievement. Metacognition and self-efficacy have primarily been studied using retrospective methods, but these methods limit access to students' in-the-moment metacognition and self-efficacy. We investigated first-year life science students' metacognition and self-efficacy while they solved challenging problems, and asked: 1) What metacognitive regulation skills are evident when first-year life science students solve problems on their own? and 2) What aspects of learning self-efficacy do first-year life science students reveal when they solve problems on their own? Think-aloud interviews were conducted with 52 first-year life science students across three institutions and analyzed using content analysis. Our results reveal that while first-year life science students plan, monitor, and evaluate when solving challenging problems, they monitor in a myriad of ways. One aspect of self-efficacy, which we call self-coaching, helped students move past the discomfort of monitoring a lack of understanding so they could take action. These verbalizations suggest ways we can encourage students to couple their metacognitive skills and self-efficacy to persist when faced with challenging problems. Based on our findings, we offer recommendations for helping first-year life science students develop and strengthen their metacognition to achieve improved problem-solving performance.

From wolves to humans: oral microbiome resistance to transfer across mammalian hosts.

The mammalian mouth is colonized by complex microbial communities, adapted to specific niches, and in homeostasis with the host. Individual microbes interact metabolically and rely primarily on nutrients provided by the host, with which they have potentially co-evolved along the mammalian lineages. The oral environment is similar across mammals, but the diversity, specificity, and evolution of community structure in related or interacting mammals are little understood. Here, we compared the oral microbiomes of dogs with those of wild wolves and humans. In dogs, we found an increased microbial diversity relative to wolves, possibly related to the transition to omnivorous nutrition following domestication. This includes a larger diversity of Patescibacteria than previously reported in any other oral microbiota. The oral microbes are most distinct at bacterial species or strain levels, with few if any shared between humans and canids, while the close evolutionary relationship between wolves and dogs is reflected by numerous shared taxa. More taxa are shared at higher taxonomic levels including with humans, supporting their more ancestral common mammalian colonization followed by diversification. Phylogenies of selected oral bacterial lineages do not support stable human-dog microbial transfers but suggest diversification along mammalian lineages (apes and canids). Therefore, despite millennia of cohabitation and close interaction, the host and its native community controls and limits the assimilation of new microbes, even if closely related. Higher resolution metagenomic and microbial physiological studies, covering a larger mammalian diversity, should help understand how oral communities assemble, adapt, and interact with their hosts.IMPORTANCENumerous types of microbes colonize the mouth after birth and play important roles in maintaining oral health. When the microbiota-host homeostasis is perturbed, proliferation of some bacteria leads to diseases such as caries and periodontitis. Unlike the gut microbiome, the diversity of oral microbes across the mammalian evolutionary space is not understood. Our study compared the oral microbiomes of wild wolves, dogs, and apes (humans, chimpanzees, and bonobos), with the aim of identifying if microbes have been potentially exchanged between humans and dogs as a result of domestication and cohabitation. We found little if any evidence for such exchanges. The significance of our research is in finding that the oral microbiota and/or the host limit the acquisition of exogenous microbes, which is important in the context of natural exclusion of potential novel pathogens. We provide a framework for expanded higher-resolution studies across domestic and wild animals to understand resistance/resilience.

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.

BACKGROUND: Genetic mitochondrial diseases impact over 1 in 4000 individuals, most often presenting in infancy or early childhood. Seizures are major clinical sequelae in some mitochondrial diseases including Leigh syndrome, the most common pediatric presentation of mitochondrial disease. Dietary ketosis has been used to manage seizures in mitochondrial disease patients. Mitochondrial disease patients often require surgical interventions, leading to anesthetic exposures. Anesthetics have been shown to be toxic in the setting of mitochondrial disease, but the impact of a ketogenic diet on anesthetic toxicities in this setting has not been studied. AIMS: Our aim in this study was to determine whether dietary ketosis impacts volatile anesthetic toxicities in the setting of genetic mitochondrial disease. METHODS: The impact of dietary ketosis on toxicities of volatile anesthetic exposure in mitochondrial disease was studied by exposing young Ndufs4(-/-) mice fed ketogenic or control diet to isoflurane anesthesia. Blood metabolites were measured before and at the end of exposures, and survival and weight were monitored. RESULTS: Compared to a regular diet, the ketogenic diet exacerbated hyperlactatemia resulting from isoflurane exposure (control vs. ketogenic diet in anesthesia mean difference 1.96 mM, Tukey's multiple comparison adjusted p = .0271) and was associated with a significant increase in mortality during and immediately after exposures (27% vs. 87.5% mortality in the control and ketogenic diet groups, respectively, during the exposure period, Fisher's exact test p = .0121). Our data indicate that dietary ketosis and volatile anesthesia interact negatively in the setting of mitochondrial disease. CONCLUSIONS: Our findings suggest that extra caution should be taken in the anesthetic management of mitochondrial disease patients in dietary ketosis.

Archaean continental crust formed from mafic cumulates.

Large swaths of juvenile crust with tonalite-trondhjemite-granodiorite (TTG) composition were added to the continental crust from about 3.5 billion years ago. Although TTG magmatism marked a pivotal step in early crustal growth and cratonisation, the petrogenetic processes, tectonic setting and sources of TTGs are not well known. Here, we investigate the composition and petrogenesis of Archaean TTGs using high field-strength-element systematics. The Nb concentrations and Ti anomalies of TTGs show the overwhelming effects of amphibole and plagioclase fractionation and permit constraints on the composition of primary TTG melts. These melts are relatively incompatible element-poor and characterised by variably high La/Sm, Sm/Yb and Sr/Y, and positive Eu anomalies. Differences in these parameters are not indicative of melting depth, but instead track differences in the degree of melting and fractional crystallisation. Primary TTGs formed by the melting of rutile- and garnet-bearing plagioclase-cumulate rocks that resided in proto-continental roots. The partial melting of these rocks is part of a causal chain that links TTG magmatism to the formation of sanukitoids and K-rich granites. Together, these processes explain the growth and differentiation of the continental crust during the Archaean without requiring external forcing such as meteorite impact or the start of global plate tectonics.

An exploration of the determinants of overweight and obesity and the capacity to intervene in North-West Tasmania: A stakeholder consultation.

ISSUE ADDRESSED: The capacity of communities to develop effective obesity prevention initiatives varies and should be a focus for obesity prevention intervention planning and investment. This research aimed at engaging and consulting local community stakeholders to identify determinants, needs, strategic priorities and capacity to act on overweight and obesity prevention in North-West (NW) Tasmania. METHODS: A series of semi-structured interviews and thematic analyses was implemented to explore the knowledge, insights, experiences and attitudes of stakeholders. RESULTS: Mental health and obesity were identified as major concerns and were often reported to share similar determinants. This study has identified health promotion capacity assets (existing partnerships, community capital, local leadership and some pockets of health promotion activity), and a range of capacity deficits (limited investment in health promotion, a small workforce, limited access to pertinent health information). CONCLUSIONS: This study has identified health promotion capacity assets (existing partnerships, community capital, local leadership and some pockets of health promotion activity), and a range of capacity deficits (limited investment in health promotion, a small workforce, limited access to pertinent health information). SO WHAT?: Broad upstream socio-economic, cultural and environmental determinants underpin the conditions by which the local community develops overweight/obesity and/or health and wellbeing outcomes. Including stakeholder consultations as a significant technique within a comprehensive plan of action aimed at achieving a sustainable, long-term strategy for obesity prevention and/or health promotion, should be considered in future programs.

Transcriptional and functional consequences of Oncostatin M signaling on young Dnmt3a-mutant hematopoietic stem cells.

Age-associated clonal hematopoiesis (CH) occurs due to somatic mutations accrued in hematopoietic stem cells (HSCs) that confer a selective growth advantage in the context of aging. The mechanisms by which CH-mutant HSCs gain this advantage with aging are not comprehensively understood. Using unbiased transcriptomic approaches, we identified Oncostatin M (OSM) signaling as a candidate contributor to age-related Dnmt3a-mutant CH. We found that Dnmt3a-mutant HSCs from young adult mice (3-6 months old) subjected to acute OSM stimulation do not demonstrate altered proliferation, apoptosis, hematopoietic engraftment, or myeloid differentiation. Dnmt3a-mutant HSCs from young mice do transcriptionally upregulate an inflammatory cytokine network in response to acute in vitro OSM stimulation as evidenced by significant upregulation of the genes encoding IL-6, IL-1ß, and TNFα. OSM-stimulated Dnmt3a-mutant HSCs also demonstrate upregulation of the anti-inflammatory genes Socs3, Atf3, and Nr4a1. In the context of an aged bone marrow (BM) microenvironment, Dnmt3a-mutant HSCs upregulate proinflammatory genes but not the anti-inflammatory genes Socs3, Atf3, and Nr4a1. The results from our studies suggest that aging may exhaust the regulatory mechanisms that HSCs employ to resolve inflammatory states in response to factors such as OSM.

Patterns of reproduction and autozygosity distinguish the breeding from non-breeding gray wolves of Yellowstone National Park.

For species of management concern, accurate estimates of inbreeding and associated consequences on reproduction are crucial for predicting their future viability. However, few studies have partitioned this aspect of genetic viability with respect to reproduction in a group-living social mammal. We investigated the contributions of foundation stock lineages, putative fitness consequences of inbreeding, and genetic diversity of the breeding versus non-reproductive segment of the Yellowstone National Park gray wolf population. Our dataset spans 25 years and seven generations since reintroduction, encompassing 152 nuclear families and 329 litters. We found over 87% of the pedigree foundation genomes persisted and report influxes of allelic diversity from two translocated wolves from a divergent source in Montana. As expected for group-living species, mean kinship significantly increased over time but with minimal loss of observed heterozygosity. Strikingly, the reproductive portion of the population carried a significantly lower genome-wide inbreeding coefficients, autozygosity, and more rapid decay for linkage disequilibrium relative to the non-breeding population. Breeding wolves had significantly longer lifespans and lower inbreeding coefficients than non-breeding wolves. Our model revealed that the number of litters was negatively significantly associated with heterozygosity (R=-0.11). Our findings highlight genetic contributions to fitness, and the importance of the reproductively active individuals in a population to counteract loss of genetic variation in a wild, free-ranging social carnivore. It is crucial for managers to mitigate factors that significantly reduce effective population size and genetic connectivity, which supports the dispersion of genetic variation that aids in rapid evolutionary responses to environmental challenges.

Habitual Diets Are More Expensive than Recommended Healthy Diets.

Understanding food prices and affordability is crucial for promoting healthy dietary habits and informing policy actions. We assessed changes in the cost and affordability of habitual and recommended healthy diets in Northwest Tasmania from 2021 to 2023. The recommended diet was 16-22% less expensive than the habitual diet during the period. Notably, 60% of the total cost of the habitual diet was spent on discretionary items. The cost of the habitual diet increased by 9% in this period, whereas the cost of the recommended diet increased by only 2%. The habitual diet was unaffordable for households with median gross, minimum wage disposable or welfare-dependent incomes. The recommended diet, however, was affordable for some groups but posed a risk of food stress for those with median gross and minimum wage disposable income and remained unaffordable for those who were welfare dependent. Our findings reveal that adhering to a healthy Australian Dietary Guidelines-recommended diet can be more cost-effective than following a habitual unhealthy diet. However, adopting a healthy diet can be challenging for low-income families. Interventions such as financial support, nutrition education, community gardens and food hubs, as well as price regulation and subsidies for farmers, can help address food insecurity in Northwest Tasmania.

Enhancing Food Literacy and Food Security through School Gardening in Rural and Regional Communities.

A qualitative case study approach with in-depth, semi-structured interviews of key school staff, and student feedback was used to assess a school kitchen and garden program in the regional area of North-West Tasmania, Australia. A detailed program description was produced to conduct a realist evaluation with a Context-Mechanism-Outcome configuration, followed by a program theory evaluation through the construction of a retrospective program logic model. Dedicated kitchen and garden spaces, knowledgeable teachers committed to the program, provision of sufficient materials and consumables, and support from the school and community were found to be the basic requirements to establish a program. Additionally, it is essential to integrate both the kitchen and garden teaching components into the school curriculum. The positive outcomes (e.g., engagement, participation, knowledge, skills, behavioral change) of the program were dependent on the underlying factors, including dedicated support of school leadership, teaching staff, and the parent body for effective student engagement in the teaching spaces and for wider engagement from families and the community. The students' feedback provided supporting evidence of increased food literacy with improvements in their understanding, abilities, and attitudes towards gardening, producing healthy food, and preparing food. This may further lead to enhanced food security for students' families and the broader community.

Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome.

BACKGROUND: Volatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic disorders. Anaesthesia hypersensitivity is well-documented in a subset of mitochondrial diseases, but whether volatile anaesthetics are toxic in this setting has not been explored. METHODS: We exposed Ndufs4(-/-) mice, a model of Leigh syndrome, to isoflurane (0.2-0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, and survival were assessed. We exposed post-symptom onset and pre-symptom onset animals and animals treated with the macrophage depleting drug PLX3397/pexidartinib to define the role of overt neuroinflammation in volatile anaesthetic toxicities. RESULTS: Isoflurane induced hyperlactataemia, weight loss, and mortality in a concentration- and duration-dependent manner from 0.2% to 0.6% compared with carrier gas (O2 100%) or mock (air) exposures (lifespan after 30-min exposures ∗P<0.05 for isoflurane 0.4% vs air or vs O2, ∗∗P<0.005 for isoflurane 0.6% vs air or O2; 60-min exposures ∗∗P<0.005 for isoflurane 0.2% vs air, ∗P<0.05 for isoflurane 0.2% vs O2). Isoflurane toxicity was significantly reduced in Ndufs4(-/-) exposed before CNS disease onset, and the macrophage depleting drug pexidartinib attenuated sequelae of isoflurane toxicity (survival ∗∗∗P=0.0008 isoflurane 0.4% vs pexidartinib plus isoflurane 0.4%). Finally, the laboratory animal standard of care of 100% O2 as a carrier gas contributed significantly to weight loss and reduced survival, but not to metabolic changes, and increased acute mortality. CONCLUSIONS: Isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. Toxic effects are dependent on the status of underlying neurologic disease, largely prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas.

Association between intracervical Foley balloon and clinical chorioamnionitis among patients with group B streptococcus colonization undergoing induction with standardized labor management.

BACKGROUND: Intracervical Foley balloons are commonly used for cervical ripening, but there has been a historical concern regarding an increased risk of clinical chorioamnionitis with Foley balloon use in patients with group B streptococcus. OBJECTIVE: This study aimed to determine whether intracervical Foley balloon use in patients with group B streptococcus is associated with an increased risk of clinical chorioamnionitis. STUDY DESIGN: This was a secondary analysis of a randomized controlled trial Mechanical and Pharmacologic Methods of Labor Induction: A Randomized Controlled Trial that compared cervical ripening agents within a standardized labor protocol. Foley balloon (alone, with oxytocin, or with misoprostol) was compared with misoprostol only to evaluate the primary outcome of clinical chorioamnionitis, defined based on the American College of Obstetricians and Gynecologists guidelines. Patients with a term, singleton pregnancy with intact membranes and an unfavorable cervix (Bishop score of ≤6 and dilation ≤2 cm) and a known group B streptococcus status were included. The secondary outcomes included a composite postpartum maternal infectious outcome consisting of any occurrence of endometritis, wound infection, postpartum urinary tract infection, or maternal sepsis; additional secondary outcomes included neonatal outcomes. Binomial regression with robust error variance was used to evaluate whether group B streptococcus status modified the relationship between Foley balloon use and clinical chorioamnionitis and to adjust for confounders. RESULTS: A total of 491 patients were enrolled in the original trial. Of these patients, 467 had a known group B streptococcus status and underwent cervical ripening: 182 (39.0%) had group B streptococcus, and 285 (61.0%) did not have group B streptococcus. Moreover, 73.0% of patients received a Foley balloon, and 27.0% of patients did not receive a Foley balloon. There was no difference in the demographic or clinical characteristics between groups. The overall rate of clinical chorioamnionitis was 12.2%, with no difference between those with and without a Foley balloon (12.6% vs 11.1%, respectively; P=.66). Group B streptococcus status did not modify the association between Foley balloon use and clinical chorioamnionitis (relative risk, 0.93; 95% confidence interval, 0.50-1.72). This remained unchanged after adjusting for gestational age (adjusted relative risk, 0.87; 95% confidence interval, 0.45-1.67). Furthermore, other maternal and neonatal outcomes were similar between groups. CONCLUSION: In this secondary analysis of a large randomized trial using a standardized labor protocol, there was no increased risk of infectious morbidity with Foley balloon use in patients overall and in patients with group B streptococcus. Our findings support that a Foley balloon can be safely used for cervical ripening in patients with group B streptococcus colonization.