Affective symptoms in pregnancy are associated with the vaginal microbiome.

BACKGROUND: Composition of the vaginal microbiome in pregnancy is associated with adverse maternal, obstetric, and child health outcomes. Therefore, identifying sources of individual differences in the vaginal microbiome is of considerable clinical and public health interest. The current study tested the hypothesis that vaginal microbiome composition during pregnancy is associated with an individual's experience of affective symptoms and stress exposure. METHODS: Data were based on a prospective longitudinal study of a medically healthy community sample of 275 mother-infant pairs. Affective symptoms and stress exposure and select measures of associated biomarkers (diurnal salivary cortisol, serum measures of sex hormones) were collected at each trimester; self-report, clinical, and medical records were used to collect detailed data on socio-demographic factors and health behavior, including diet and sleep. Vaginal microbiome samples were collected in the third trimester (34-40 weeks) and characterized by 16S rRNA sequencing. Identified taxa were clustered into three community clusters (CC1-3) based on dissimilarity of vaginal microbiota composition. RESULTS: Results indicate that depressive symptoms during pregnancy were reliably associated with individual taxa and CC3 in the third trimester. Prediction of functional potential from 16S taxonomy revealed a differential abundance of metabolic pathways in CC1-3 and individual taxa, including biosynthetic pathways for serotonin and dopamine. We did not find robust evidence linking symptom- and stress-related biomarkers and CCs. CONCLUSIONS: Our results provide further evidence of how prenatal psychological distress during pregnancy alters the maternal-fetal microbiome ecosystem that may be important for understanding maternal and child health outcomes.

Neighborhood Food Access in Early Life and Trajectories of Child Body Mass Index and Obesity.

Importance: Limited access to healthy foods, resulting from residence in neighborhoods with low food access, is a public health concern. The contribution of this exposure in early life to child obesity remains uncertain. Objective: To examine associations of neighborhood food access during pregnancy or early childhood with child body mass index (BMI) and obesity risk. Design, Setting, and Participants: Data from cohorts participating in the US nationwide Environmental Influences on Child Health Outcomes consortium between January 1, 1994, and March 31, 2023, were used. Participant inclusion required a geocoded residential address in pregnancy (mean 32.4 gestational weeks) or early childhood (mean 4.3 years) and information on child BMI. Exposures: Residence in low-income, low-food access neighborhoods, defined as low-income neighborhoods where the nearest supermarket is more than 0.5 miles for urban areas or more than 10 miles for rural areas. Main Outcomes and Measures: BMI z score, obesity (age- and sex-specific BMI ≥95th percentile), and severe obesity (age- and sex-specific BMI ≥120% of the 95th percentile) from age 0 to 15 years. Results: Of 28 359 children (55 cohorts; 14 657 [51.7%] male and 13 702 [48.3%] female; 590 [2.2%] American Indian, Alaska Native, Native Hawaiian, or Other Pacific Islander; 1430 [5.4%] Asian; 4034 [15.3%] Black; 17 730 [67.2%] White; and 2592 [9.8%] other [unspecified] or more than 1 race; 5754 [20.9%] Hispanic and 21 838 [79.1%] non-Hispanic) with neighborhood food access data, 23.2% resided in low-income, low-food access neighborhoods in pregnancy and 24.4% in early childhood. After adjusting for individual sociodemographic characteristics, residence in low-income, low-food access (vs non-low-income, low-food access) neighborhoods in pregnancy was associated with higher BMI z scores at ages 5 years (ß, 0.07; 95% CI, 0.03-0.11), 10 years (ß, 0.11; 95% CI, 0.06-0.17), and 15 years (ß, 0.16; 95% CI, 0.07-0.24); higher obesity risk at 5 years (risk ratio [RR], 1.37; 95% CI, 1.21-1.55), 10 years (RR, 1.71; 95% CI, 1.37-2.12), and 15 years (RR, 2.08; 95% CI, 1.53-2.83); and higher severe obesity risk at 5 years (RR, 1.21; 95% CI, 0.95-1.53), 10 years (RR, 1.54; 95% CI, 1.20-1.99), and 15 years (RR, 1.92; 95% CI, 1.32-2.80). Findings were similar for residence in low-income, low-food access neighborhoods in early childhood. These associations were robust to alternative definitions of low income and low food access and additional adjustment for prenatal characteristics associated with child obesity. Conclusions: Residence in low-income, low-food access neighborhoods in early life was associated with higher subsequent child BMI and higher risk of obesity and severe obesity. We encourage future studies to examine whether investments in neighborhood resources to improve food access in early life would prevent child obesity.

Evaluating the risk of SARS-CoV-2 reinfection with the Omicron or Delta variant in Wales, UK.

Recent studies suggest an increased risk of reinfection with the SARS-CoV-2 Omicron variant compared with previous variants, potentially due to an increased ability to escape immunity specific to older variants, high antigenic divergence of Omicron from earlier virus variants as well as its altered cell entry pathway. The present study sought to investigate epidemiological evidence for differential SARS-CoV-2 reinfection intervals and incidence rates for the Delta versus Omicron variants within Wales. Reinfections in Wales up to February 2022 were defined using genotyping and whole genome sequencing. The median inter-infection intervals for Delta and Omicron were 226 and 192 days, respectively. An incidence rate ratio of 2.17 for reinfection with Omicron compared to Delta was estimated using a conditional Poisson model, which accounted for several factors including sample collection date, age group, area of residence, vaccination and travel status. These findings are consistent with an increased risk of reinfection with the Omicron variant, and highlight the value of monitoring emerging variants that have the potential for causing further waves of cases.

Exposure to Low-Level Air Pollution and Hyperglycemia Markers during Pregnancy: A Repeated Measure Analysis.

Epidemiologic evidence has emerged showing an association between exposure to air pollution and increased risks of gestational diabetes mellitus (GDM). This study examines the effect of low-level air pollution exposure on a subclinical biomarker of hyperglycemia (i.e., HbA1c) in pregnant people without diabetes before conception. We measured HbA1c in 577 samples repeatedly collected from 224 pregnant people in Rochester, NY, and estimated residential concentrations of PM2.5 and NO2 using high-resolution spatiotemporal models. We observed a U-shaped trajectory of HbA1c during pregnancy with average HbA1c levels of 5.13 (±0.52), 4.97 (±0.54), and 5.43 (±0.40)% in early-, mid-, and late pregnancy, respectively. After adjustment for the U-shaped trajectory and classic GDM risk factors, each interquartile range increase in 10 week NO2 concentration (8.0 ppb) was associated with 0.09% (95% CI: 0.02 to 0.16%) and 0.18% (95% CI: 0.08 to 0.28%) increases in HbA1c over the entire pregnancy and in late pregnancy, respectively. These associations remained robust among participants without GDM. Using separate distributed lag models, we identified a period between 8th and 14th gestational weeks as critical windows responsible for increased levels of HbA1c measured at 14th, 22nd, and 30th gestational weeks. Our results suggest that low-level air pollution contributes to hyperglycemia in medically low-risk pregnant people.

Separable cell cycle arrest and immune response elicited through pharmacological CDK4/6 and MEK inhibition in RASmut disease models.

The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified a high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth. CRISPR-mediated RB1 depletion resulted in a decreased response to CDK4/6 and MEK inhibition, which was validated in both cell culture and xenograft models. Beyond its cell cycle inhibitory effects, pathway enrichment analysis revealed the robust activation of interferon pathways upon CDK4/6 and MEK inhibition. This induction of gene expression was associated with the upregulation of retroviral elements. The TBK1(TANK-binding kinase 1) inhibitor GSK8612 selectively blocked the induction of interferon-related genes induced by palbociclib and trametinib treatment, and highlighted the separable epigenetic responses elicited by combined CDK4/6 and MEK inhibition. Together, these findings provide key mechanistic insights into the therapeutic potential of CDK4/6 and MEK inhibition in soft tissue sarcoma.

An examination of process models and model risk frameworks for pharmaceutical manufacturing.

Process models are a growing tool for pharmaceutical manufacturing process design and control. The Industry 4.0 paradigm promises to increase the amount of data available to understand manufacturing processes. Tools such as Artificial Intelligence (AI) might accelerate process development and allow better predictions of process trajectories. Several examples of process improvements realized through the application of process models have been shown in lyophilization, chromatography, fluid bed drying, bioreactor control, continuous direct compression, and wet granulation. An important consideration of implementing a process model is determining the impact of the model on the quality of the product and the risks associated with model maintenance over the product lifecycle. Several regulatory documents address risk-based considerations for process models. This work discusses existing risk-based frameworks for model validation and lifecycle maintenance that could aid the adoption of process models in pharmaceutical manufacturing. Hypothetical case studies illustrate the implications of applying a model risk framework to facilitate model validation and lifecycle maintenance in the manufacture of pharmaceuticals and biological products.

Movement behavior in a dominant ungulate underlies successful adjustment to a rapidly changing landscape following megafire.

BACKGROUND: Movement plays a key role in allowing animal species to adapt to sudden environmental shifts. Anthropogenic climate and land use change have accelerated the frequency of some of these extreme disturbances, including megafire. These megafires dramatically alter ecosystems and challenge the capacity of several species to adjust to a rapidly changing landscape. Ungulates and their movement behaviors play a central role in the ecosystem functions of fire-prone ecosystems around the world. Previous work has shown behavioral plasticity is an important mechanism underlying whether large ungulates are able to adjust to recent changes in their environments effectively. Ungulates may respond to the immediate effects of megafire by adjusting their movement and behavior, but how these responses persist or change over time following disturbance is poorly understood. METHODS: We examined how an ecologically dominant ungulate with strong site fidelity, Columbian black-tailed deer (Odocoileus hemionus columbianus), adjusted its movement and behavior in response to an altered landscape following a megafire. To do so, we collected GPS data from 21 individual female deer over the course of a year to compare changes in home range size over time and used resource selection functions (RSFs) and hidden Markov movement models (HMMs) to assess changes in behavior and habitat selection. RESULTS: We found compelling evidence of adaptive capacity across individual deer in response to megafire. Deer avoided exposed and severely burned areas that lack forage and could be riskier for predation immediately following megafire, but they later altered these behaviors to select areas that burned at higher severities, potentially to take advantage of enhanced forage. CONCLUSIONS: These results suggest that despite their high site fidelity, deer can navigate altered landscapes to track rapid shifts in encounter risk with predators and resource availability. This successful adjustment of movement and behavior following extreme disturbance could help facilitate resilience at broader ecological scales.

Unified understanding of the impact of semiflexibility, concentration, and molecular weight on macromolecular-scale ring diffusion.

Conformationally fluctuating, globally compact macromolecules such as polymeric rings, single-chain nanoparticles, microgels, and many-arm stars display complex dynamic behaviors due to their rich topological structure and intermolecular organization. Synthetic rings are hybrid objects with conformations that display both ideal random walk and compact globular features, which can serve as models of genomic DNA. To date, emphasis has been placed on the effect of ring molecular weight on their unusual behaviors. Here, we combine simulations and a microscopic force-level theory to build a unified understanding for how key aspects of ring dynamics depend on different tunable molecular properties including backbone rigidity, monomer concentration, degree of traditional entanglement, and molecular weight. Our large-scale molecular dynamics simulations of ring melts with very different backbone stiffnesses reveal unanticipated behaviors which agree well with our generalized theory. This includes a universal master curve for center-of-mass diffusion constants as a function of molecular weight scaled by a chemistry and thermodynamic state-dependent critical molecular weight that generalizes the concept of an entanglement cross-over for linear chains. The key physics is how backbone rigidity and monomer concentration induced changes of the entanglement length, interring packing, degree of interpenetration, and liquid compressibility slow down space-time dynamic-force correlations on macromolecular scales. A power law decay of the center-of-mass diffusion constant with inverse molecular weight squared is the first consequence, followed by an ultraslow activated hopping transport regime. Our results set the stage to address slow dynamics and kinetic arrest in different families of compact synthetic and biological polymeric systems.

Intensity-based optoretinography reveals sub-clinical deficits in cone function in retinitis pigmentosa.

Introduction: Clinical tools have been widely used in the diagnosis, description, and monitoring the progression of retinitis pigmentosa (RP); however, many of these methods have inherently low sensitivity and specificity, and significant photoreceptor disruption can occur before RP progression has clinically manifest. Adaptive optics scanning light ophthalmoscopy (AOSLO) has shown promise as a powerful tool for assessing photoreceptor disruption both structurally and functionally due to its increased resolution. Methods: Here we assess photoreceptor structure and function at the cellular level through AOSLO by acquiring intensity based optoretinography (iORG) in 15 individuals with no reported retinal pathology and 7 individuals with a prior clinical diagnosis of RP. Photoreceptor structure was quantified by calculating cone nearest neighbor distance (NND) across different retinal eccentricities from the AOSLO images. Cone outer segment length was measured across different retinal eccentricities using optical coherence tomography (OCT) derived longitudinal reflectivity profiles (LRPs). Finally, iORG measures of photoreceptor function were compared to retinal sensitivity as measured using the macular integrity assessment (MAIA) microperimeter. Results: Broadly, participants with RP exhibited increasing cone nearest neighbor distances and decreasing cone outer segment length as a function of retinal eccentricity, consistent with prior reports for both controls and individuals with RP. Nearly all individuals with RP had reduced iORG amplitudes for all retinal eccentricities when compared to the control cohort, and the reduction was greater in eccentricities further from the fovea. Comparing iORG amplitudes to MAIA retinal sensitivity, we found that the iORG was more sensitive to early changes in photoreceptor function whereas MAIA was more sensitive to later stages of disease. Discussion: This highlights the utility of iORG as a method to detect sub-clinical deficits in cone function in all stages of disease progression and supports the future use of iORG for identifying cells that are candidates for cellular based therapies.

Association of maternal fish consumption and ω-3 supplement use during pregnancy with child autism-related outcomes: results from a cohort consortium analysis.

BACKGROUND: Prenatal fish intake is a key source of omega-3 (ω-3) polyunsaturated fatty acids needed for brain development, yet intake is generally low, and studies addressing associations with autism spectrum disorder (ASD) and related traits are lacking. OBJECTIVE: This study aimed to examine associations of prenatal fish intake and ω-3 supplement use with both autism diagnosis and broader autism-related traits. METHODS: Participants were drawn from 32 cohorts in the Environmental influences on Child Health Outcomes Cohort Consortium. Children were born between 1999 and 2019 and part of ongoing follow-up with data available for analysis by August 2022. Exposures included self-reported maternal fish intake and ω-3/fish oil supplement use during pregnancy. Outcome measures included parent report of clinician-diagnosed ASD and parent-reported autism-related traits measured by the Social Responsiveness Scale (SRS)-second edition (n = 3939 and v3609 for fish intake analyses, respectively; n = 4537 and n = 3925 for supplement intake analyses, respectively). RESULTS: In adjusted regression models, relative to no fish intake, fish intake during pregnancy was associated with reduced odds of autism diagnosis (odds ratio: 0.84; 95% confidence interval [CI]: 0.77, 0.92), and a modest reduction in raw total SRS scores (ß: -1.69; 95% CI: -3.3, -0.08). Estimates were similar across categories of fish consumption from "any" or "less than once per week" to "more than twice per week." For ω-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (ß: 1.98; 95% CI: 0.33, 3.64). CONCLUSIONS: These results extend previous work by suggesting that prenatal fish intake, but not ω-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low-fish intake in the United States general population and the rising autism prevalence, these findings suggest the need for better public health messaging regarding guidelines on fish intake for pregnant individuals.

Dietary Intake of Nutrients Involved in Serotonin and Melatonin Synthesis and Prenatal Maternal Sleep Quality and Affective Symptoms.

Poor sleep quality and psychological distress in pregnancy are important health concerns. Serotonin and melatonin levels may underlie variation in these adverse outcomes. In this study, we examined dietary nutrients involved in serotonin and melatonin synthesis in relation to maternal sleep quality and affective symptoms during pregnancy. Pregnant women at no greater than normal medical risk at enrollment completed 24-hour dietary recalls in mid-late pregnancy. Usual intakes of vitamin B6, vitamin D, eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), and tryptophan were estimated from dietary intake of foods and supplements using the National Cancer Institute (NCI) method. Sleep quality, depression, and anxiety were measured using validated questionnaires. Associations between nutrient intakes, sleep quality, and affective symptoms were estimated using generalized estimating equation models adjusting for potential confounding factors. In minimally adjusted models, EPA + DHA and tryptophan intakes were associated with a lower score indicating better sleep quality (b: -1.07, 95% CI: -2.09, -0.05) and (b: -12.40, 95% CI: -24.60, -0.21), respectively. EPA + DHA and tryptophan intakes were also associated with a lower odds of shorter sleep duration and sleep disturbances. In addition, tryptophan was associated with a lower odds of higher sleep latency. However, associations were attenuated and nonsignificant after adjustment for demographic and lifestyle factors. In conclusion, intakes of EPA + DHA and tryptophan were associated with improved sleep quality, but these associations were confounded by maternal demographic and lifestyle characteristics. This study highlights the need to consider dietary intake and pregnancy health in the context of demographic characteristics and lifestyle behaviors.

Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

Entanglement Kinetics in Polymer Melts Are Chemically Specific.

We investigate the universality of entanglement kinetics in polymer melts. We compare predictions of a recently developed constitutive equation for disentanglement to molecular dynamics simulations of both united-atom polyethylene and Kremer-Grest models for polymers in shear and extensional flow. We confirm that entanglements recover on the retraction time scale, rather than the reptation time scale. We find that the convective constraint release parameter ß is independent of molecular weight, but that it increases with the ratio of Kuhn length bK to packing length p as ß âˆ¼ (bK/p)α, with an exponent α = 1.9, which may suggest that disentanglement rate correlates with an increase in the tube diameter. These results may help shed light on which polymers are more likely to undergo shear banding.

Associations between mycoestrogen exposure and sex steroid hormone concentrations in maternal serum and cord blood in the UPSIDE pregnancy cohort.

Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet. Because the chemical structure of ZEN and metabolites closely resembles 17ß-estradiol (E2), they interact with estrogen receptors α/ß earning their designation as 'mycoestrogens'. In animal models, gestational exposure to mycoestrogens disrupts estrogen activity and impairs fetal growth. Here, our objective was to evaluate relationships between mycoestrogen exposure and sex steroid hormone concentrations in maternal circulation and cord blood for the first time in humans. In each trimester, pregnant participants in the UPSIDE study (n = 297) provided urine for mycoestrogen analysis and serum for hormone analysis. At birth, placental mycoestrogens and cord steroids were measured. We fitted longitudinal models examining log-transformed mycoestrogen concentrations in relation to log-transformed hormones, adjusting for covariates. Secondarily, multivariable linear models examined associations at each time point (1st, 2nd, 3rd trimesters, delivery). We additionally considered effect modification by fetal sex. ZEN and its metabolite, α-zearalenol (α-ZOL), were detected in >93% and >75% of urine samples; >80% of placentas had detectable mycoestrogens. Longitudinal models from the full cohort exhibited few significant associations. In sex-stratified analyses, in pregnancies with male fetuses, estrone (E1) and free testosterone (fT) were inversely associated with ZEN (E1 %Δ: -6.68 95%CI: -12.34, -0.65; fT %Δ: -3.22 95%CI: -5.68, -0.70); while α-ZOL was positively associated with E2 (%Δ: 5.61 95%CI: -1.54, 9.85) in pregnancies with female fetuses. In analysis with cord hormones, urinary mycoestrogens were inversely associated with androstenedione (%Δ: 9.15 95%CI: 14.64, -3.30) in both sexes, and placental mycoestrogens were positively associated with cord fT (%Δ: 37.13, 95%CI: 4.86, 79.34) amongst male offspring. Findings support the hypothesis that mycoestrogens act as endocrine disruptors in humans, as in animal models and livestock. Additional work is needed to understand impacts on maternal and child health.

Systemic oxidative stress levels during the course of pregnancy: Associations with exposure to air pollutants.

Increased systemic oxidative stress, implicated in adverse pregnancy outcomes for both mothers and fetuses, has been associated with gestational exposure to air pollutants such as polycyclic aromatic hydrocarbons (PAHs), fine particulate matter (PM2.5), and nitrogen dioxide (NO2). However, it is unclear whether exposure to pollutants at levels below the current air quality standards can increase oxidative stress in pregnant women. In a cohort of 305 pregnant persons residing in western New York, we examined the association between exposure to PM2.5, NO2, and PAHs (measured as urinary 1-hydroxypyrene) and urinary biomarkers of oxidative stress (malondialdehyde [MDA] and 8-hydroxy-2'-deoxyguanosine [8-OHdG]) measured in each trimester. After controlling for gestational stage, maternal age, lifestyles, and socioeconomic factors, each interquartile range (IQR) increase in 1-hydroxypyrene concentration (65.8 pg/ml) was associated with a 7.73% (95%CI: 3.18%,12.3%) higher in MDA levels throughout the pregnancy and in the first and second trimester. An IQR increase in PM2.5 concentration (3.20 µg/m3) was associated with increased MDA levels in the first trimester (8.19%, 95%CI: 0.28%,16.1%), but not the 2nd (-7.99%, 95% CI: 13.8%, -2.23%) or 3rd trimester (-2.81%, 95% CI: 10.0%, 4.38%). The average cumulative PM2.5 exposures in the 3-7 days before urine collection were associated with increased 8-OHdG levels during the second trimester, with the largest difference (22.6%; 95% CI: 3.46%, 41.7%) observed in relation to a one IQR increase in PM2.5 concentration in the previous 7 days. In contrast, neither oxidative stress biomarker was associated with NO2 exposure. Observed in pregnant women exposed to low-level air pollution, these findings expanded previously reported associations between systemic oxidative stress and high-level PM2.5 and PAH concentrations. Further, the first and second trimesters may be a susceptible window during pregnancy for oxidative stress responses to air pollution exposure.

Age of Juice Introduction and Cardiometabolic Outcomes in Middle Childhood.

BACKGROUND: The American Academy of Pediatrics recommends juice introduction after 12 months of age. Juice consumption has been linked to childhood obesity and cardiometabolic risk. OBJECTIVES: To examine the prospective relationship between the age of juice introduction and primary and secondary cardiometabolic outcomes in middle childhood. METHODS: Parents reported the age of juice introduction on Upstate KIDS questionnaires completed between 4 and 18 months. The quantity and type of juice introduced were not measured. Anthropometry, blood pressure (BP), and arterial stiffness by pulse wave velocity (PWV) were measured for 524 children (age, 8-10 y) at study visits (2017-2019). Age- and gender-adjusted z-scores were calculated using the Centers for Disease Control and Prevention reference for anthropometrics. Plasma lipids, hemoglobin A1c (HbA1c), and C-reactive protein (CRP) in a subset of children were also measured (n = 248). Associations between age at juice introduction (categorized as <6, 6 to <12, ≥12 months), and outcomes were estimated using mean differences and odds ratios, applying generalized estimating equations to account for correlations between twins. RESULTS: Approximately 18% of children were introduced to juice at <6 months, 52% between 6 and <12 months, and 30% ≥ 12 months of age. Children who were introduced to juice before 6 months had higher systolic BP (3.13 mmHg; 95% confidence interval [CI]: 0.52, 5.74), heart rate (4.46 bpm; 95% CI: 1.05, 7.87), and mean arterial pressure (2.08 mmHg; 95% CI: 0.15, 4.00) compared with those introduced ≥12 months after covariate adjustment including sociodemographic factors and maternal prepregnancy body mass index. No adjusted differences in anthropometry, lipids, HbA1c, and CRP levels were found. CONCLUSIONS: Early juice introduction during infancy was associated with higher systolic BP, heart rate, and mean arterial pressure in middle childhood. This trial was registered at clinicaltrials.gov as NCT03106493 (https://clinicaltrials.gov/study/NCT03106493?term=upstate%20KIDS&rank=1).

Characterizing the metabolome and microbiome at giant panda scent marking sites during the mating season.

Scent marking sites served as a primary means of chemical communication for giant pandas, enabling intraspecific communication. We integrated metabolomics and high-throughput sequencing techniques to examine the non-targeted metabolome and microbial community structure of scent marking sites and feces in the field. Integrative analysis revealed a more comprehensive array of chemical compounds compared to previous investigations, including ketones, acids, heterocycles, alcohols, and aldehydes. Notably, specific compounds such as 2-decenal, (E)-, octanal, decanal, L-α-terpineol, vanillin, and nonanal emerged as potential key players in scent signaling. Intriguingly, our study of the microbial domain identified dominant bacterial species from the Actinobacteria, Bacteroidetes, and Proteobacteria phyla, likely orchestrating metabolic processes at scent marking sites. Comparative analyses showed, for the first time, that feces do not share the same functions as scent markers, indicating distinct functional roles. This research deepens scientific understanding of chemical communication in wild pandas.

Combining developmental and sleep health measures for autism spectrum disorder screening: an ECHO study.

BACKGROUND: Sleep problems are reported for up to 80% of autistic individuals. We examined whether parsimonious sets of items derived from the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) and the Brief Infant Sleep Questionnaire (BISQ) are superior to the standard M-CHAT-R in predicting subsequent autism spectrum disorder (ASD) diagnoses. METHODS: Participants from 11 Environmental influences on Child Health Outcomes (ECHO) cohorts were included. We performed logistic LASSO regression models with 10-fold cross-validation to identify whether a combination of items derived from the M-CHAT-R and BISQ are superior to the standard M-CHAT-R in predicting ASD diagnoses. RESULTS: The final sample comprised 1552 children. The standard M-CHAT-R had a sensitivity of 44% (95% CI: 34, 55), specificity of 92% (95% CI: 91, 94), and AUROC of 0.726 (95% CI: 0.663, 0.790). A higher proportion of children with ASD had difficulty falling asleep or resisted bedtime during infancy/toddlerhood. However, LASSO models revealed parental reports of sleep problems did not improve the accuracy of the M-CHAT-R in predicting ASD diagnosis. CONCLUSION: While children with ASD had higher rates of sleep problems during infancy/toddlerhood, there was no improvement in ASD developmental screening through the incorporation of parent-report sleep metrics. IMPACT: Parental-reported sleep problems are common in autism spectrum disorder (ASD). We investigated whether the inclusion of parental-reports of infant/toddler sleep patterns enhanced the effectiveness of developmental screening for autism. We reported higher rates of difficulty falling asleep and resisting bedtime during infancy and toddlerhood among children later diagnosed with ASD; however, we did not find an improvement in ASD developmental screening through the incorporation of parent-report sleep metrics. In our sample, the standard M-CHAT-R had a sensitivity of 39% among children of mothers with government insurance compared with a sensitivity of 53% among children of mothers with employer-based insurance.

Real-World Experience among Elderly Metastatic Breast Cancer Patients Treated with CDK4/6 Inhibitor-Based Therapy.

The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration.

Host factors are associated with vaginal microbiome structure in pregnancy in the ECHO Cohort Consortium.

Using pooled vaginal microbiota data from pregnancy cohorts (N = 683 participants) in the Environmental influences on Child Health Outcomes (ECHO) Program, we analyzed 16S rRNA gene amplicon sequences to identify clinical and demographic host factors that associate with vaginal microbiota structure in pregnancy both within and across diverse cohorts. Using PERMANOVA models, we assessed factors associated with vaginal community structure in pregnancy, examined whether host factors were conserved across populations, and tested the independent and combined effects of host factors on vaginal community state types (CSTs) using multinomial logistic regression models. Demographic and social factors explained a larger amount of variation in the vaginal microbiome in pregnancy than clinical factors. After adjustment, lower education, rather than self-identified race, remained a robust predictor of L. iners dominant (CST III) and diverse (CST IV) (OR = 8.44, 95% CI = 4.06-17.6 and OR = 4.18, 95% CI = 1.88-9.26, respectively). In random forest models, we identified specific taxonomic features of host factors, particularly urogenital pathogens associated with pregnancy complications (Aerococcus christensenii and Gardnerella spp.) among other facultative anaerobes and key markers of community instability (L. iners). Sociodemographic factors were robustly associated with vaginal microbiota structure in pregnancy and should be considered as sources of variation in human microbiome studies.