Specimen type validation and establishment of normal cytokine reference intervals in cerebrospinal fluid.

Cerebrospinal fluid (CSF) is a critical body fluid to examine in attempts to discover potential biomarkers for neuroinflammatory and other disorders of the central nervous system (CNS). Serum and/or plasma cytokine levels have been associated with a variety of inflammatory conditions, and some have been shown to be actionable therapeutic targets. Less is known, however, about cytokine levels in CSF. Serum and plasma cytokine testing is widely available in clinical and research laboratories, but cytokine testing in CSF is extremely limited and if performed, accompanied by a disclaimer that it is an unvalidated specimen type. In this study, we validate CSF as a suitable specimen type and determine normal reference intervals for multiple cytokines as well as a soluble cytokine receptor. CSF was validated as a specimen type for testing using a laboratory developed multiplexed cytokine assay previously validated to measure 13 cytokines/markers in serum and plasma. Performance parameters including specimen dilution, specimen interference, linearity and precision were examined. Reference intervals were established using 197 normal and control CSF specimens by non-parametric quantile-based methods. CSF cytokine analysis demonstrated within and between run precision of <10% and < 20% CV, respectively and linearity of ±15% for all analytes throughout the analytical measurement range of the assay. Reference intervals for the 13 cytokines/markers were established from 197 normal and control CSF specimens (78 Male; mean 44.8 y ± 21.7 SD, 119 Female; mean 42.8 y ± 20.3 SD). Cytokine concentrations in CSF from normal donors and controls were less than the lower limit of quantitation of our assay for 6 of the 13 measured cytokines/markers. The chemokine IL8 demonstrated the highest concentration of all analytes measured. CSF demonstrated acceptable performance as a specimen type in our multiplexed cytokine assay. By validating CSF as a specimen type and establishing normal reference intervals for cytokine concentrations in CSF, their potential as biomarkers for infectious, autoimmune and other inflammatory CNS disorders can be more appropriately investigated.

Preoperative prediction model for risk of readmission after total joint replacement surgery: a random forest approach leveraging NLP and unfairness mitigation for improved patient care and cost-effectiveness.

BACKGROUND: The Center for Medicare and Medicaid Services (CMS) imposes payment penalties for readmissions following total joint replacement surgeries. This study focuses on total hip, knee, and shoulder arthroplasty procedures as they account for most joint replacement surgeries. Apart from being a burden to healthcare systems, readmissions are also troublesome for patients. There are several studies which only utilized structured data from Electronic Health Records (EHR) without considering any gender and payor bias adjustments. METHODS: For this study, dataset of 38,581 total knee, hip, and shoulder replacement surgeries performed from 2015 to 2021 at Novant Health was gathered. This data was used to train a random forest machine learning model to predict the combined endpoint of emergency department (ED) visit or unplanned readmissions within 30 days of discharge or discharge to Skilled Nursing Facility (SNF) following the surgery. 98 features of laboratory results, diagnoses, vitals, medications, and utilization history were extracted. A natural language processing (NLP) model finetuned from Clinical BERT was used to generate an NLP risk score feature for each patient based on their clinical notes. To address societal biases, a feature bias analysis was performed in conjunction with propensity score matching. A threshold optimization algorithm from the Fairlearn toolkit was used to mitigate gender and payor biases to promote fairness in predictions. RESULTS: The model achieved an Area Under the Receiver Operating characteristic Curve (AUROC) of 0.738 (95% confidence interval, 0.724 to 0.754) and an Area Under the Precision-Recall Curve (AUPRC) of 0.406 (95% confidence interval, 0.384 to 0.433). Considering an outcome prevalence of 16%, these metrics indicate the model's ability to accurately discriminate between readmission and non-readmission cases within the context of total arthroplasty surgeries while adjusting patient scores in the model to mitigate bias based on patient gender and payor. CONCLUSION: This work culminated in a model that identifies the most predictive and protective features associated with the combined endpoint. This model serves as a tool to empower healthcare providers to proactively intervene based on these influential factors without introducing bias towards protected patient classes, effectively mitigating the risk of negative outcomes and ultimately improving quality of care regardless of socioeconomic factors.

Association of diet with per- and polyfluoroalkyl substances in plasma and human milk in the New Hampshire Birth Cohort Study.

Per- and polyfluoroalkyl substances (PFAS) are related to various adverse health outcomes, and food is a common source of PFAS exposure. Dietary sources of PFAS have not been adequately explored among U.S. pregnant individuals. We examined associations of dietary factors during pregnancy with PFAS concentrations in maternal plasma and human milk in the New Hampshire Birth Cohort Study. PFAS concentrations, including perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), and perfluorodecanoate (PFDA), were measured in maternal plasma collected at ~28 gestational weeks and human milk collected at ~6 postpartum weeks. Sociodemographic, lifestyle and reproductive factors were collected from prenatal questionnaires and diet from food frequency questionnaires at ~28 gestational weeks. We used adaptive elastic net (AENET) to identify important dietary variables for PFAS concentrations. We used multivariable linear regression to assess associations of dietary variables selected by AENET models with PFAS concentrations. Models were adjusted for sociodemographic, lifestyle, and reproductive factors, as well as gestational week of blood sample collection (plasma PFAS), postpartum week of milk sample collection (milk PFAS), and enrollment year. A higher intake of fish/seafood, eggs, coffee, or white rice during pregnancy was associated with higher plasma or milk PFAS concentrations. For example, every 1 standard deviation (SD) servings/day increase in egg intake during pregnancy was associated with 4.4 % (95 % CI: 0.6, 8.4), 3.3 % (0.1, 6.7), and 10.3 % (5.6, 15.2) higher plasma PFOS, PFOA, and PFDA concentrations respectively. Similarly, every 1 SD servings/day increase in white rice intake during pregnancy was associated with 7.5 % (95 % CI: -0.2, 15.8) and 12.4 % (4.8, 20.5) greater milk PFOS and PFOA concentrations, respectively. Our study suggests that certain dietary factors during pregnancy may contribute to higher PFAS concentrations in maternal plasma and human milk, which could inform interventions to reduce PFAS exposure for both birthing people and offspring.

An Update on the Formation in Tobacco, Toxicity, and Carcinogenicity of N'-Nitrosonornicotine and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered "carcinogenic to humans" by the International Agency for Research on Cancer (IARC) and are believed to be important in the carcinogenic effects of both smokeless tobacco and combusted tobacco products. This short review focuses on the results of recent studies on the formation of NNN and NNK in tobacco, and their carcinogenicity and toxicity in laboratory animals. New mechanistic insights are presented regarding the role of dissimilatory nitrate reductases in certain microorganisms involved in the conversion of nitrate to nitrite that leads to the formation of NNN and NNK during curing and processing of tobacco. Carcinogenicity studies of the enantiomers of the major NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the enantiomers of NNN are reviewed. Recent toxicity studies of inhaled NNK and co-administration studies of NNK with formaldehyde, acetaldehyde, acrolein, and CO2, all of which occur in high concentrations in cigarette smoke, are discussed.

Safety Assessment of Polysilicone-11 as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Polysilicone-11 as used in cosmetic formulations. This ingredient is reported to function as a film former. The Panel considered the available data and concluded that Polysilicone-11 is safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Safety Assessment of Palm-Derived Ingredients as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 8 palm tree (Euterpe edulis (juçara) and Euterpe oleracea (açaí))-derived ingredients as used in cosmetic products; these ingredients are reported to function mostly as skin conditioning agents. The Panel reviewed relevant data relating to the safety of these ingredients in cosmetic formulations. Industry should continue to use good manufacturing practices to limit impurities. The Panel concluded that palm tree (açaí and juçara)-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Safety Assessment of Capryloyl Salicylic Acid as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reassessed the safety of Capryloyl Salicylic Acid in cosmetic products; this ingredient is reported to function as a skin conditioning agent. The Panel reviewed relevant data relating to the safety of this ingredient in cosmetic formulations, and concluded that the available data are insufficient to make a determination that Capryloyl Salicylic Acid is safe under the intended conditions of use in cosmetic formulations.

Comparison of three methods for the detection of antibodies against muscle-specific kinase.

OBJECTIVES: To compare 3 different methods for the detection of antibodies against muscle-specific kinase (MuSK). METHODS: MuSK antibody testing was performed in 237 serum samples by enzyme-linked immunosorbent assay (ELISA) and fixed cell-based assay (f-CBA-IFA). One hundred and forty-eight (148) of the sera had previously been tested by RIA during clinical testing: 47 MuSK antibody positive and 101 MuSK antibody negative. Of the MuSK RIA negative antibodies, 46 tested positive for other neural antibodies. Additionally, 89 sera were subsequently tested by all three methods: 70 healthy controls and 19 sera positive for other neural antibodies. RESULTS: Qualitative inter-assay agreement based on tiered RIA values was 100% for results of 1.00 nmol/L or greater by both methods; 81% and 94% for results between 0.21 and 0.99 nmol/L by ELISA and f-CBA-IFA, respectively; and 0% for results of 0.04-0.20 nmol/L by both methods. Negative results showed 100% agreement between RIA and both ELISA and f-CBA-IFA (n = 55). None of the controls positive for other neural autoantibodies or healthy controls were positive in any assay. CONCLUSION: Overall, excellent agreement was observed between the 3 methods used to detect antibodies against MuSK. Both the f-CBA-IFA and ELISA performed comparably to RIA and exhibited excellent overall accuracy for MuSK IgG detection, with the f-CBA-IFA demonstrating higher agreement between positive samples with the RIA than the ELISA without identifying false positives in the control samples. Advantages of non-radioactive methods for the detection of MuSK antibodies include reduced handling and disposal of hazardous materials, potential for automation and the reagents having a longer shelf-life, reducing costs associated with both workflow and lot validations. Thus, commercially available ELISA and transfected cell-based assays are viable alternatives to the traditional radioactive assay used for serologic determination of MuSK IgG.

Safety Assessment of Soy-Derived Ingredients as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 28 soy-derived ingredients as used in cosmetic products. These ingredients are reported to primarily function as antioxidants, skin protectants, skin-conditioning agents, and hair-conditioning agents. The Panel considered the available data relating to the safety of these ingredients in cosmetic formulations, and concluded that 24 of the 28 soy-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment. The Panel also concluded that the available data are insufficient to make a determination that Glycine Max (Soybean) Callus Culture, Glycine Max (Soybean) Callus Culture Extract, Glycine Max (Soybean) Callus Extract, and Glycine Max (Soybean) Phytoplacenta Conditioned Media are safe under the intended conditions of use in cosmetic formulations.

Methacrylate Ester Monomers.

The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 2005, along with updated information regarding product types and concentrations of use, and confirmed that these 22 methacrylate ester monomers are safe as used in nail enhancement products in the practices of use and concentration as described in this report, when skin contact is avoided.

Sulfites.

The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1998, along with updated information regarding product types and concentrations of use, and confirmed that Sodium Sulfite, Potassium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite are safe as cosmetic ingredients in the practices of use and concentration as described in this report.

Influenza Antiviral Shortages Reported by State and Territorial Public Health Officials, 2022-2023.

This study provides survey results from state and territorial public health preparedness directors regarding antiviral shortages during the 2022-2023 respiratory viral season.

Isopropyl Lanolate.

The Expert Panel for Cosmetic Ingredient Safety reviewed updated information that has become available since their original assessment from 1980, along with updated information regarding product types, and frequency and concentrations of use, and reaffirmed their original conclusion that Isopropyl Lanolate is safe as a cosmetic ingredient in the practices of use and concentration as described in this report.

Quaternium-18 and Quaternium-18 Bentonite.

The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1982, along with updated information regarding product types and concentrations of use, and confirmed that Quaternium-18 and Quaternium-18 Bentonite are safe as cosmetic ingredients in the practices of use and concentration as described in this report.

High level of agreement in a fixed vs. live cell-based assay for antibodies to myelin oligodendrocyte glycoprotein in a real-world clinical laboratory setting.

Introduction: As recognition of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease becomes more widespread, the importance of appropriately ordering and interpreting diagnostic testing for this antibody increases. Several assays are commercially available for MOG testing, and based on a few small studies with very few discrepant results, some have suggested that live cell-based assays (CBA) are superior to fixed CBA for clinical MOG antibody testing. We aimed to determine the real-world agreement between a fixed and live CBA for MOG using two of the most commonly available commercial testing platforms. Methods: We compared paired clinical samples tested at two national clinical reference laboratories and determined the real-world agreement between the fixed CBA and live CBA. Results: Of 322 paired samples tested on both platforms, 53 were positive and 246 were negative by both methodologies (agreement 92.9%, Cohen's kappa 0.78, [0.69-0.86]). Spearman correlation coefficient was 0.80 (p < 0.0001). Of the discrepant results, only 1 of 14 results positive by the live CBA had a titer greater than 1:100, and only 1 of 9 results positive by the fixed CBA had a titer of greater than 1:80. Lower titers on the fixed CBA correlate to higher titers on the live CBA. Conclusion: Overall, there is excellent agreement between fixed and live CBA for MOG antibody testing in a real-world clinical laboratory setting. Clinicians should be aware of which method they use to assess any given patient, as titers are comparable, but not identical between the assays.

Safety Assessment of Cocos nucifera (Coconut)-Derived Ingredients as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 11 Cocos nucifera (coconut)-derived ingredients, most of which are reported to function as skin-conditioning agents in cosmetic products. The Panel reviewed the available data to determine the safety of these ingredients. The Panel concluded that 10 ingredients, derived from coconut flower, fruit, and liquid endosperm, are safe in cosmetics in the present practices of use and concentration described in this safety assessment, and that the available data are insufficient to make a determination of safety for Cocos Nucifera (Coconut) Shell Powder under the intended conditions of use in cosmetic formulations.

Clinical Significance of Anti-U1 Ribonucleoprotein Antibody Is Analyte Dependent: Implications for Laboratory Reporting, Interpretation, and Interassay Correlations.

CONTEXT.­: Antibodies to U1 ribonucleoprotein (U1RNP) were first described more than 50 years ago, and although clinically relevant for antinuclear antibody-associated connective tissue disease (ANA-CTD), test results are challenging to interpret. OBJECTIVE.­: To evaluate the impact of anti-U1RNP analyte diversity in the assessment of patients at risk for ANA-CTD. DESIGN.­: Two multiplex assays for U1RNP (Smith [Sm]/RNP and RNP68/A) were used to test serum specimens from consecutive patients (n = 498) under evaluation for CTD in a single academic center. Discrepant specimens were further tested for Sm/RNP antibody by enzyme-linked immunosorbent assay and the BioPlex multiplex assay. Data were evaluated for antibody positivity per analyte and their method of detection, correlations between analytes, and impact on clinical diagnoses through retrospective chart review. RESULTS.­: Of the 498 patients tested, 47 (9.4%) were positive in the RNP68/A (BioPlex) and 15 (3.0%) were positive in the Sm/RNP (Theradiag) immunoassays. U1RNP-CTD, other ANA-CTD, and no ANA-CTD were diagnosed in 34% (16 of 47), 12.8% (6 of 47), and 53.2% (25 of 47) of the cases, respectively. The prevalence of antibody by method in patients with U1RNP-CTD was 100.0% (16 of 16), 85.7% (12 of 14), 81.5% (13 of 16), and 87.5% (14 of 16) for RNP68/A, Sm/RNP BioPlex, Sm/RNP Theradiag, and Sm/RNP Inova, respectively. For other ANA-CTD and no ANA-CTD, the highest prevalence was observed with RNP68/A; all others had comparable performance. CONCLUSIONS.­: In this study, the overall performance characteristics of Sm/RNP antibody assays were comparable; however, the RNP68/A immunoassay was very sensitive but less specific. In the absence of harmonization, reporting the type of U1RNP analyte in clinical testing may be useful in guiding interpretation and interassay correlations.

Tobacco smoke exposure, the lower airways microbiome and outcomes of ventilated children.

BACKGROUND: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome. METHODS: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g. RESULTS: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality. CONCLUSION: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities. IMPACT: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children.

Early-life exposure to per- and polyfluoroalkyl substances and infant gut microbial composition.

Human milk is rich in essential nutrients and immune-activating compounds but is also a source of toxicants including per- and polyfluoroalkyl substances (PFAS). Evidence suggests that immune-related effects of PFAS may, in part, be due to alterations of the microbiome. We aimed to identify the association between milk PFAS exposure and the infant gut microbiome. Methods: PFAS [perfluorooctane sulfonic acid (PFOS) and perfluorooctanoate (PFOA)] were quantified in milk from ~6 weeks postpartum using high-performance liquid chromatography with tandem mass spectrometry. A molar sum (ΣPFAS) was calculated. Caregivers collected infant stool samples at 6 weeks (n = 116) and/or 1 year postpartum (n = 119). Stool DNA underwent metagenomic sequencing. We estimated the association of PFAS with diversity and relative abundances of species with linear regression. Single- and multi-PFAS models adjusted for potential confounders in complete case analyses and with imputed missing covariate data for 6-week and 1-year microbiomes separately. We assessed sensitive populations with stratification. Results: PFOS and PFOA were detected in 94% and 83% of milk samples, respectively. PFOS was associated with increased diversity at 6 weeks among infants fed exclusively human milk [ß = 0.24 per PFOS doubling, (95% CI = 0.03, 0.45), P = 0.03] and born to primiparous mothers [ß = 0.37 (0.06, 0.67), P = 0.02]. Estimates were strongest in multi-PFAS models and among complete cases. ΣPFAS was associated with Bacteroides vulgatus relative abundance at 1 year [(ß = -2.34% per doubling (-3.63, -1.05), FDR q = 0.099]. Conclusions: PFAS may increase infant gut microbiome diversity and alter the relative abundance of biologically relevant bacteria. Additional analyses may identify related health outcomes.