PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-[18F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[18F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[18F]FETrp had a comparable tumor uptake with [18F]fluorodeoxyglucose (FDG). However, L-[18F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[18F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan-kynurenine pathway as a therapeutic target for treating NF1.

A Thy-1-negative immunofibroblast population emerges as a key determinant of fibrotic outcomes to biomaterials.

Fibrosis-associated fibroblasts have been identified across various fibrotic disorders, but not in the context of biomaterials, fibrotic encapsulation, and the foreign body response. In other fibrotic disorders, a fibroblast subpopulation defined by Thy-1 loss is strongly correlated with fibrosis yet we do not know what promotes Thy-1 loss. We have previously shown that Thy-1 is an integrin regulator enabling normal fibroblast mechanosensing, and here, leveraging nonfibrotic microporous annealed particle (MAP) hydrogels versus classical fibrotic bulk hydrogels, we demonstrate that Thy1-/- mice mount a fibrotic response to MAP gels that includes inflammatory signaling. We found that a distinct and cryptic α-smooth muscle actin-positive Thy-1- fibroblast population emerges in response to interleuklin-1ß (IL-1ß) and tumor necrosis factor-α (TNFα). Furthermore, IL-1ß/TNFα-induced Thy-1- fibroblasts consist of two distinct subpopulations that are strongly proinflammatory. These findings illustrate the emergence of a unique proinflammatory, profibrotic fibroblast subpopulation that is central to fibrotic encapsulation of biomaterials.

Effect of probiotic supplementation on the gut microbiota in very preterm infants: a systematic review.

OBJECTIVE: There is increasing evidence that probiotic supplementation in very preterm infants decreases the risk of necrotising enterocolitis (NEC), sepsis and mortality. The underlying mechanisms, including effects on the gut microbiota, are largely unknown. We aimed to systematically review the available literature on the effects of probiotic supplementation in very preterm infants on gut microbiota development. DESIGN: A systematic review in Medline, Embase, Cochrane Library, CINAHL and Web of Science. SETTING: Neonatal intensive care unit. PATIENTS: Premature infants. INTERVENTION: Probiotic supplementation. MAIN OUTCOME MEASURES: Gut microbiota. RESULTS: A total of 1046 articles were screened, of which 29 were included. There was a large heterogeneity in study design, dose and type of probiotic strains, timepoints of sample collection and analysing techniques. Bifidobacteria and lactobacilli were the most used probiotic strains. The effects of probiotics on alpha diversity were conflicting; however, beta diversity was significantly different between probiotic-supplemented infants and controls in the vast majority of studies. In most studies, probiotic supplementation led to increased relative abundance of the supplemented strains and decreased abundance of genera such as Clostridium, Streptococcus, Klebsiella and Escherichia. CONCLUSIONS: Probiotic supplementation to preterm infants seems to increase the relative abundance of the supplemented strains with a concurrent decrease of potentially pathogenic species. These probiotic-induced microbial alterations may contribute to the decreased risk of health complications such as NEC. Future trials, including omics technologies to analyse both microbiota composition and function linked to health outcomes, are warranted to identify the optimal mixture and dosing of probiotic strains. PROSPERO REGISTRATION NUMBER: CRD42023385204.

Design and Validation of a High-Throughput Reductive Catalytic Fractionation Method.

Reductive catalytic fractionation (RCF) is a promising method to extract and depolymerize lignin from biomass, and bench-scale studies have enabled considerable progress in the past decade. RCF experiments are typically conducted in pressurized batch reactors with volumes ranging between 50 and 1000 mL, limiting the throughput of these experiments to one to six reactions per day for an individual researcher. Here, we report a high-throughput RCF (HTP-RCF) method in which batch RCF reactions are conducted in 1 mL wells machined directly into Hastelloy reactor plates. The plate reactors can seal high pressures produced by organic solvents by vertically stacking multiple reactor plates, leading to a compact and modular system capable of performing 240 reactions per experiment. Using this setup, we screened solvent mixtures and catalyst loadings for hydrogen-free RCF using 50 mg poplar and 0.5 mL reaction solvent. The system of 1:1 isopropanol/methanol showed optimal monomer yields and selectivity to 4-propyl substituted monomers, and validation reactions using 75 mL batch reactors produced identical monomer yields. To accommodate the low material loadings, we then developed a workup procedure for parallel filtration, washing, and drying of samples and a 1H nuclear magnetic resonance spectroscopy method to measure the RCF oil yield without performing liquid-liquid extraction. As a demonstration of this experimental pipeline, 50 unique switchgrass samples were screened in RCF reactions in the HTP-RCF system, revealing a wide range of monomer yields (21-36%), S/G ratios (0.41-0.93), and oil yields (40-75%). These results were successfully validated by repeating RCF reactions in 75 mL batch reactors for a subset of samples. We anticipate that this approach can be used to rapidly screen substrates, catalysts, and reaction conditions in high-pressure batch reactions with higher throughput than standard batch reactors.

Influence of epinephrine reactivity to stress on meat quality in goats.

The magnitude of physiological responses to a stressor can vary among individual goats within a herd; however, whether these differences can differentially affect meat quality is not known. This study was conducted to determine the influence of the magnitude of epinephrine response (ER) to acute stress on muscle metabolome and meat quality in goats. Male Spanish goats (6 mo old) were transported for 180 min. (N = 75 goats; 25 goats/d) to impose stress. Blood samples were obtained after transport for analysis of physiological responses. Goats were slaughtered using humane procedures and samples were collected for muscle metabolomics and meat quality analyses. The data obtained from blood and muscle/meat analysis were then categorized based on epinephrine concentrations into low (LE), medium (ME), and high (HE) ER groups (n = 12/ER group). The physiological and meat quality variables were analyzed as a Completely Randomized Design in SAS, and metabolomics data were analyzed using R software. Plasma glucose concentrations were significantly high in the HE group, low in the LE group, and intermediate in the ME group (P < 0.05). However, leukocyte counts and cortisol, norepinephrine, blood urea nitrogen, and creatine concentrations were not different among the ER groups. Muscle (Longissimus dorsi) glycogen concentrations (15 min postmortem) were significantly higher (P < 0.05) in the ME and LE groups than in the HE group. However, postmortem Longissimus muscle pH and temperature (15 min and 24 h), 24 h calpastatin and desmin levels, and rib chop color (L*, a*, and b*), cooking loss, and Warner-Bratzler shear force values were unaffected by ER. Targeted metabolomics analysis of Longissimus muscle (15 min) revealed that diacyl phosphatidylcholines (C38:0; 40:6) and sphingomyelin (C20:2) were significantly different (P < 0.05) among the ER groups, with the concentrations of these metabolites being consistently high in the LE group. These differential muscle metabolite concentrations suggest that ER can influence biochemical pathways associated with cell membrane integrity and signaling. ER had a significant effect on dopamine concentrations, with the levels increasing with increasing levels of ER. The results indicate that differences in epinephrine reactivity can influence selected physiological responses and muscle metabolites; however, it does not significantly influence meat quality attributes.

From Bands to Bypasses: Navigating Safety of Band Conversions to Roux-en-Y Gastric Bypass and Single Anastomosis Duodenoileostomy Versus Sleeve Gastrectomy.

INTRODUCTION: Revisional bariatric surgery is associated with higher perioperative complications over primary procedures. Adjustable gastric bands (AGB) continue to be the most frequently converted bariatric configuration. This study examines trends in current clinical indication and safety profile of the most frequently pursued AGB conversions. MATERIALS AND METHODS: MBSAQIP data from 2020 to 2022 was retrospectively analyzed in a cohort study examining 30-day postoperative outcomes after AGB conversion to sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), or single anastomosis duodenoileostomy (SADI). Descriptive statistics were used, including multivariable and 2:1 nearest neighbor matching analysis. RESULTS: This study included 19,335 AGB conversions, of which most were to SG (n = 11,736) followed by RYGB (n = 7442) and SADI (n = 157). While a majority were completed for weight loss, there were differences in distribution of primary indication for each conversion cohort, such as higher proportion of RYGB conversion for gastroesophageal reflux disease (18.7%) compared to SG (7.92%) and SADI (5.10%). Multivariable analysis demonstrates conversion to RYGB has significantly higher odds of 30-day major complications (OR 1.75, p < 0.001), reoperation (OR 2.08; p = 0.001), readmission (OR 1.69; p = 0.001), and emergency department visits (OR 1.50; p = 0.001) over SG. These risks and odds of reintervention (OR 1.75; p < 0.001) remained significantly higher after conversion to RYGB versus SG on matched analysis. None of these risks is significantly different between conversions to SADI versus SG in either multivariable or matched analysis. CONCLUSIONS: Compared to AGB conversion to SG, single-stage conversion to RYGB had increased odds of perioperative complications while risks of conversion to SADI were not significantly different.

A phase II study of cabozantinib and pembrolizumab in advanced gastric/gastroesophageal adenocarcinomas resistant or refractory to immune checkpoint inhibitors.

BACKGROUND: Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA. METHODS: Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6). RESULTS: Twenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed. CONCLUSIONS: The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).

Wholegrain triticale sourdough: Effects of triticale:Wheat flour ratio and hydration level on bread quality.

Triticale (×Triticosecale) is a hybrid between wheat (Triticum spp.) and rye (Secale cereale), producing higher grain yields than wheat in challenging environments. Triticale grain is also highly nutritious. Thus, the potential of triticale grain for an expanded range of food applications should be explored. Sourdough bread has unique functional and nutritional properties, but understanding the effects of partial substitution of triticale for wheat flour and varying levels of dough moisture content on sourdough quality requires further research. The aim of this study was to evaluate the wholegrain flour of contrasting triticale cultivars in comparison to that of a common wheat cultivar in commercial sourdough breadmaking. Two triticale cultivars (Goanna and Hawkeye, selected from a panel of Australian genotypes) and one wheat cultivar (Scout) were grown in a field trial in northern NSW, Australia. Differences in quantitative texture and color parameters of the dough and sourdough bread resulting from (1) substitution of commercial wholemeal wheat flour with different proportions of wholegrain triticale or wholegrain wheat (Scout) flour (0%, 60%, 70%, 80%, and 90%) and (2) varying the amount of water included in the dough preparation (70%, 80%, 90%, and 100 g water/100 g flour) were determined. Replacement of wholemeal wheat flour with 60% wholegrain Goanna flour (protein content 12.76%; c.f. 11.50% for Hawkeye, 12.40% for Scout), and addition of 100 g water/100 g flour in the dough preparation gave the highest quality sourdough bread based on specific volume, texture, and color parameters and had similar properties to the control made from wheat alone.

Stereotactic radiosurgery for prostate cancer spine metastases: local control and fracture risk using a simultaneous integrated boost approach.

OBJECTIVE: Variation exists in approaches to delivery of spine stereotactic radiosurgery (SSRS). Here, the authors describe outcomes following single-fraction SSRS performed using a simultaneous integrated boost for the treatment of prostate cancer spine metastases. METHODS: Health records of patients with prostate cancer spine metastases treated with single-fraction SSRS at the authors' institution were reviewed. Treatment was uniform, with 16 Gy to the clinical tumor volume and 18 Gy to the gross tumor volume. The primary endpoint was local recurrence, with secondary endpoints including vertebral fracture and overall survival. Univariate and multivariate competing risk regression models made using the Fine and Gray method were used to identify factors predictive of local recurrence, considering death to be a competing event for local recurrence. RESULTS: A total of 87 targets involving 108 vertebrae in 68 patients were included, with a median follow-up of 22.5 months per treated target. The 1-, 2-, and 4-year cumulative incidence rates of local failure for all targets were 4.6%, 8.4%, and 19%, respectively. The presence of epidural disease (subdistribution hazard ratio [sHR] 5.43, p = 0.04) and SSRS as reirradiation (sHR 16.5, p = 0.02) emerged as significant predictors of local failure in a multivariate model. Hormone sensitivity did not predict local control. Vertebral fracture incidence rates leading to symptoms or requiring intervention at 1, 2, and 4 years were 1.1%, 3.7%, and 8.4%, respectively. In an exploratory analysis of patterns of failure, 3 (25%) failures occurred in the epidural space and only 1 (8%) occurred clearly in the clinical tumor volume. There were several lesions for which the precise location of failure with regard to target volumes was unclear. CONCLUSIONS: High rates of local control were observed, particularly for radiotherapy-naïve lesions without epidural disease. Hormone sensitivity was not predictive of local control in this cohort and fracture risk was low. Further research is needed to better predict which patients are at high risk of recurrence and who might benefit from treatment escalation.

Climate change impacts of bioenergy technologies: A comparative consequential LCA of sustainable fuels production with CCUS.

The use of sustainable biomass can be a cost-effective way of reducing the greenhouse gas emissions in the maritime and aviation sectors. Biomass, however, is a limited resource, and therefore, it is important to use the biomass where it creates the highest value, not only economically, but also in terms of GHG reductions. This study comprehensively evaluates the GHG reduction potential of utilising forestry residue in different bioenergy technologies using a consequential LCA approach. Unlike previous studies that assess GHG impacts per unit of fuel produced, this research takes a feedstock-centric approach which enables comparisons across systems that yield diverse products and by-products. Three technologies-combined heat and power plant with carbon capture, hydrothermal liquefaction, and gasification-are assessed, while considering both carbon capture and storage (CCS) or carbon capture and utilisation (CCU). Through scenario analysis, the study addresses uncertainty, and assumptions in the LCA modelling. It explores the impact of energy systems, fuel substitution efficiency, renewable energy expansion, and the up/down stream supply chain. All technology pathways showed a potential for net emissions savings when including avoided emissions from substitution of products, with results varying from -111 to -1742 kgCO2eq per tonne residue. When combining the bioenergy technologies with CCU the dependency on the energy system in which they are operated was a significantly higher compared to CCS. The breakpoint was found to be 44 kg CO2eq/kWh electricity meaning that the marginal electricity mix has to be below this point for CCU to obtain lower GHG emissions. Furthermore, it is evident that the environmental performance of CCU technologies is highly sensitive to how it will affect the ongoing expansion of renewable electricity capacity.

Decomposition analysis of racial and ethnic differences in receipt of immediate postpartum, long-acting, reversible, and permanent contraception.

OBJECTIVES: This study aimed to determine the factors contributing to racial and ethnic disparities in the use of immediate postpartum, long-acting reversible contraception (IPP LARC) and permanent contraception among Medicaid recipients. STUDY DESIGN: We conducted a cross-sectional study using 3 years of national Medicaid claims data to examine the rates of IPP LARC use alone and a composite measure of postpartum permanent contraception and IPP LARC within 7 days of delivery by race and ethnicity. We used a Blinder-Oaxaca model to quantify the extent to which medical complexity, age, rurality, mode of delivery, and year explained differences in outcomes among different minoritized groups in comparison to non-Hispanic White women. RESULTS: Our study sample contained 1,729,663 deliveries occurring from 2016 through 2018 among 1,605,199 people living in 16 states. IPP LARC use rates were highest among Black (2.2%), followed by American Indian and Alaska Native at 2.1% and Hawaiian/Pacific Islander beneficiaries at 1.9%, Hispanic (all races) at 1.2%, and Asian at 1.0%. IPP LARC was lowest among White beneficiaries (0.8%). Medical complexity, age, rurality, year, and mode of delivery explained only 12.3% of the difference in IPP LARC rates between Black and White beneficiaries. Postpartum permanent contraception was highest among White (7.6%), Hispanic (7.2%), and American Indian and Alaska Native (6.8%), followed by Black (6.3%), Hawaiian/Pacific Islander (5.1%) and lowest among Asian women (4.1%). When we examined the use of IPP LARC or postpartum permanent contraception together, these same factors explained 94.4% of the differences between Black and White beneficiaries. CONCLUSIONS: While differences in the use of IPP LARC by race and ethnicity were identified, our findings suggest that overall use of inpatient highly effective contraception are similar across racial and ethnic groups. IMPLICATIONS: When IPP LARC and postpartum permanent contraception are examined jointly, their use is similar across racial and ethnic groups.

Stratifying Risk for Postpartum Depression at Time of Hospital Discharge.

Objective: Postpartum depression (PPD) represents a major contributor to postpartum morbidity and mortality. Beyond efforts at routine screening, risk stratification models could enable more targeted interventions in settings with limited resources. Thus, we aimed to develop and estimate the performance of a generalizable risk stratification model for PPD in patients without a history of depression using information collected as part of routine clinical care. Methods: We performed a retrospective cohort study of all individuals who delivered between 2017 and 2022 in one of two large academic medical centers and six community hospitals. An elastic net model was constructed and externally validated to predict PPD using sociodemographic factors, medical history, and prenatal depression screening information, all of which was known before discharge from the delivery hospitalization. Results: The cohort included 29,168 individuals; 2,703 (9.3%) met at least one criterion for postpartum depression in the 6 months following delivery. In the external validation data, the model had good discrimination and remained well-calibrated: area under the receiver operating characteristic curve 0.721 (95% CI: 0.707-0.734), Brier calibration score 0.088 (95% CI: 0.084 - 0.092). At a specificity of 90%, the positive predictive value was 28.0% (95% CI: 26.0-30.1%), and the negative predictive value was 92.2% (95% CI: 91.8-92.7%). Conclusions: These findings demonstrate that a simple machine-learning model can be used to stratify the risk for PPD before delivery hospitalization discharge. This tool could help identify patients within a practice at the highest risk and facilitate individualized postpartum care planning regarding the prevention of, screening for, and management of PPD at the start of the postpartum period and potentially the onset of symptoms.

Can juvenile supply predict future abundance of large-bodied reef fishes?

The extent to which juvenile abundance can predict future populations of lethrinids at Ningaloo Reef was assessed using size frequency data collected over 13 consecutive years. Annual abundance of juvenile lethrinids (<5 cm TL) was highest in northern Ningaloo during La Niña years, when seawater is warmer and oceanic currents stronger. Juvenile lethrinid abundance explained 35% of the variance in 1-2 year-old Lethrinus nebulosus abundance the following year, a steeper relationship in the north suggesting greater survival of juveniles. Juvenile lethrinid abundance was also positively correlated to abundance of 1-2 year-old L. atkinsoni in the southern region of Ningaloo. Abundance of juvenile lethrinids were however poor predictors of L. nebulosus and L. atkinsoni older than 2 years of age. Post settlement processes likely weaken the link between juvenile supply and abundance of lethrinids >2 years old making it difficult to accurately quantify the overall size of future lethrinid populations.

Patterns of cognitive domain abnormalities enhance discrimination of dementia risk prediction: The ARIC study.

INTRODUCTION: The contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated. METHODS: We analyzed neuropsychological testing results in dementia-free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain-specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models. RESULTS: Among 5296 initially dementia-free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow-up of 7.9 years, the covariate-adjusted hazard ratio varied substantially depending on the pattern of domain-specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk). DISCUSSION: By identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age-sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression. HIGHLIGHTS: Domain-specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single-domain non-amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain-specific risks are similar by sex and race.

Transformations at the Dawn of Verbal Language.

In this essay the author describes some of the transformations that occur as one moves from preverbal functioning to verbally symbolic language. In preverbal experience, there is a direct connection between the sign and what is signified. An infant or child signifies displeasure by throwing his food or other objects to the floor. Much of the emotional tie between mother and infant and patient and analyst is communicated in this way. When a transformation occurs from preverbal to verbally symbolic language, as occurs in early development and as one interprets a dream, meaning is not merely translated, meaning is created. On acquiring verbally symbolic language, a "space" mediated by an interpreting subject opens between the symbol (for instance, the word guilt) and the symbolized (the experience of guilt) and a new subjectivity is created. On entry into verbally symbolic language, one becomes able to experience oneself in a qualitatively different way; one becomes both subject and object, I and me; one becomes able to experience a far broader range of feelings and types of thinking. Helen Keller's account of her experience of acquiring verbally symbolic language is drawn upon.

Lignin-derivable alternatives to bisphenol A with potentially undetectable estrogenic activity and minimal developmental toxicity.

Lignin-derivable bisguaiacols/bissyringols are viable alternatives to commercial bisphenols; however, many bisguaiacols/bissyringols (e.g., bisguaiacol F [BGF]) have unsubstituted bridging carbons between the aromatic rings, making them more structurally similar to bisphenol F (BPF) than bisphenol A (BPA) - both of which are suspected endocrine disruptors. Herein, we investigated the estrogenic activity (EA) and developmental toxicity of dimethyl-substituted bridging carbon-based lignin-derivable bisphenols (bisguaiacol A [BGA] and bissyringol A [BSA]). Notably, BSA showed undetectable EA at seven test concentrations (from 10-12 M to 10-6 M) in the MCF-7 cell proliferation assay, whereas BPA had detectable EA at five concentrations (from 10-10 M to 10-6 M). In silico results indicated that BSA had the lowest binding affinity with estrogen receptors. Moreover, in vivo chicken embryonic assay results revealed that lignin-derivable monomers had minimal developmental toxicity vs. BPA at environmentally relevant test concentrations (8.7-116 µg/kg). Additionally, all lignin-derivable compounds showed significantly lower expression fold changes (from ∼1.81 to ∼4.41) in chicken fetal liver tests for an estrogen-response gene (apolipoprotein II) in comparison to BPA (fold change of ∼11.51), which was indicative of significantly reduced estrogenic response. Altogether, the methoxy substituents on lignin-derivable bisphenols appeared to be a positive factor in reducing the EA of BPA alternatives.

Medicaid Policy Change and Immediate Postpartum Long-Acting Reversible Contraception.

Importance: Improving access to the choice of postpartum contraceptive methods is a national public health priority, and the need is particularly acute within the Medicaid population. One strategy to ensure individuals have access to the full range of contraceptive methods is the provision of a method prior to hospital discharge following a birth episode. Beginning in 2016, some states changed their Medicaid billing policy, allowing separate reimbursement for intrauterine devices and contraceptive implants to increase the provision of long-acting reversible contraceptive (LARC) methods immediately postpartum (IPP). Objective: To assess the association of a change in Medicaid billing policy with use of IPP LARC. Design, Setting, and Participants: The cohort study of postpartum Medicaid recipients in 9 treatment and 6 comparison states was conducted from January 2016 to October 2019. Data were analyzed from August 2023 to January 2024. Main Outcomes and Measures: The primary outcome was use of IPP LARC. Results: The final sample included 1 378 885 delivery encounters for 1 197 287 Medicaid enrollees occurring in 15 states. Mean age of beneficiaries at delivery was 27 years. The IPP LARC billing policy was associated with a mean increase of 0.74 percentage points (95% CI, 0.30-1.18 percentage points) in the immediate receipt of IPP LARC, with a prepolicy baseline rate of 0.54%. The IPP LARC billing policy was also associated with an overall increase of 1.48 percentage points (95% CI, 0.43-2.73 percentage points) in LARC use by 60 days post partum. Conclusions and Relevance: In this cohort study, changing Medicaid billing policy to allow for separate reimbursement of LARC devices from the global fee was associated with increased use of IPP LARC, suggesting that this may be a strategy to improve access to the full range of postpartum contraceptive methods.

Genetic barrier to resistance: a critical parameter for efficacy of neutralizing monoclonal antibodies against SARS-CoV-2 in a nonhuman primate model.

The potency of antibody neutralization in cell culture has been used as the key criterion for selection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for clinical development. As other aspects may also influence the degree of protection in vivo, we compared the efficacy of two neutralizing monoclonal antibodies (TRES6 and 4C12) targeting different epitopes of the receptor binding domain (RBD) of SARS-CoV-2 in a prophylactic setting in rhesus monkeys. All four animals treated with TRES6 had reduced viral loads in the upper respiratory tract 2 days after naso-oropharyngeal challenge with the Alpha SARS-CoV-2 variant. Starting 2 days after challenge, mutations conferring resistance to TRES6 were dominant in two of the rhesus monkeys, with both animals failing to maintain reduced viral loads. Consistent with its lower serum neutralization titer at the day of challenge, prophylaxis with 4C12 tended to suppress viral load at day 2 less efficiently than TRES6. However, a week after challenge, mean viral loads in the lower respiratory tract in 4C12-treated animals were lower than in the TRES6 group and no mutations conferring resistance to 4C12 could be detected in viral isolates from nasal or throat swabs. Thus, genetic barrier to resistance seems to be a critical parameter for the efficacy of prophylaxis with monoclonal antibodies against SARS-CoV-2. Furthermore, comparison of antibody concentrations in respiratory secretions to those in serum shows reduced distribution of the 4C12 antibody into respiratory secretions and a delay in the appearance of antibodies in bronchoalveolar lavage fluid compared to their appearance in secretions of the upper respiratory tract.IMPORTANCEMonoclonal antibodies are a powerful tool for the prophylaxis and treatment of acute viral infections. Hence, they were one of the first therapeutic agents licensed for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oftentimes, the main criterion for the selection of antibodies for clinical development is their potency of neutralization in cell culture. By comparing two antibodies targeting the Spike protein of SARS-CoV-2, we now observed that the antibody that neutralized SARS-CoV-2 more efficiently in cell culture suppressed viral load in challenged rhesus monkeys to a lesser extent. Extraordinary rapid emergence of mutants of the challenge virus, which had lost their sensitivity to the antibody, was identified as the major reason for the reduced efficacy of the antibody in rhesus monkeys. Therefore, the viral genetic barrier to resistance to antibodies also affects their efficacy.

Lung Function and Brain MRI Outcomes in the Atherosclerosis Risk in Communities Neurocognitive Study.

Background: Brain imaging studies may provide etiologic insight into observed links between lung function and dementia and stroke. Objective: We evaluated associations of lung function measures with brain MRI markers of vascular and neurodegenerative disease in the ARIC Neurocognitive Study, as few studies have examined the associations. Methods: Lung function was measured at participants' midlife in 1990-1992 (mean age = 56±5 years) and later-life in 2011-2013 (mean age = 76±5 years), and brain MRI was performed in 2011-2013. Linear regression models were used to examine the associations of lung function with brain and white matter hyperintensity (WMH) volumes, and logistic regression models were used for cerebral infarcts and microbleeds, adjusting for potential confounders. Results: In cross-sectional analysis (i.e., examining later-life lung function and MRI markers, n = 1,223), higher forced-expiratory volume in one second (FEV1) and forced vital capacity (FVC) were associated with larger brain and lower WMH volumes [e.g., 8.62 (95% CI:2.54-14.71) cm3 greater total brain volume per one-liter higher FEV1]. No association was seen with microbleeds in the overall sample, but higher FVC was associated with lower odds of microbleeds in never-smokers and higher odds in ever-smokers. In the cross-temporal analysis (i.e., associations with midlife lung function, n = 1,787), higher FVC levels were significantly associated with lower later-life brain volumes. Conclusions: Our results support modest associations of better lung function with less neurodegenerative and cerebrovascular pathology, although findings for microbleeds were unexpected in ever-smokers.