A persistent major mutation in canonical jasmonate signaling is embedded in an herbivory-elicited gene network.

When insect herbivores attack plants, elicitors from oral secretions and regurgitants (OS) enter wounds during feeding, eliciting defense responses. These generally require plant jasmonate (JA) signaling, specifically, a jasmonoyl-L-isoleucine (JA-Ile) burst, for their activation and are well studied in the native tobacco Nicotiana attenuata. We used intraspecific diversity captured in a 26-parent MAGIC population planted in nature and an updated genome assembly to impute natural variation in the OS-elicited JA-Ile burst linked to a mutation in the JA-Ile biosynthetic gene NaJAR4. Experiments revealed that NaJAR4 variants were associated with higher fitness in the absence of herbivores but compromised foliar defenses, with two NaJAR homologues (4 and 6) complementing each other spatially and temporally. From decade-long seed collections of natural populations, we uncovered enzymatically inactive variants occurring at variable frequencies, consistent with a balancing selection regime maintaining variants. Integrative analyses of OS-induced transcriptomes and metabolomes of natural accessions revealed that NaJAR4 is embedded in a nonlinear complex gene coexpression network orchestrating responses to OS, which we tested by silencing four hub genes in two connected coexpressed networks and examining their OS-elicited metabolic responses. Lines silenced in two hub genes (NaGLR and NaFB67) co-occurring in the NaJAR4/6 module showed responses proportional to JA-Ile accumulations; two from an adjacent module (NaERF and NaFB61) had constitutively expressed defenses with high resistance. We infer that mutations with large fitness consequences can persist in natural populations due to compensatory responses from gene networks, which allow for diversification in conserved signaling pathways and are generally consistent with predictions of an omnigene model.

Application of the ERS/ATS Spirometry Standards and Race-Neutral Equations in the COPDGene Study.

RATIONALE: The European Respiratory Society (ERS) and the American Thoracic Society (ATS) recommend using z-scores, and the ATS has recommended using Global Lung Initiative (GLI)- "Global" race-neutral reference equations for spirometry interpretation. However, these recommendations have been variably implemented and the impact has not been widely assessed, both in clinical and research settings. OBJECTIVES: We evaluated the ERS/ATS airflow obstruction severity classification. METHODS: In the COPDGene Study (n = 10,108), airflow obstruction has been defined as a forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio <0.70, with spirometry severity graded from class 1 to 4 based on race-specific percent predicted (pp) FEV1 cut-points as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We compared the GOLD approach, using NHANES III race-specific equations, to the application of GLI-Global equations using the ERS/ATS definition of airflow obstruction as FEV1/FVC ratio < lower limit of normal (LLN) and z-FEV1 cut-points of -1.645, -2.5, and -4 ("zGLI Global"). We tested the four-tier severity scheme for association with COPD outcomes. MEASUREMENTS AND MAIN RESULTS: The lowest agreement between ERS/ATS with zGLI Global and the GOLD classification was observed in individuals with milder disease (56.9% and 42.5% in GOLD 1 and 2) and race was a major determinant of redistribution. After adjustment for relevant covariates, zGLI Global distinguished all-cause mortality risk between normal spirometry and the first grade of COPD (Hazard Ratio 1.23, 95% CI 1.04-1.44, p=0.014), and showed a linear increase in exacerbation rates with increasing disease severity, in comparison to GOLD. CONCLUSIONS: The zGLI Global severity classification outperformed GOLD in the discrimination of survival, exacerbations, and imaging characteristics.

Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Merging Flow Synthesis and Enzymatic Maturation to Expand the Chemical Space of Lasso Peptides.

Many peptidic natural products, such as lasso peptides, cyclic peptides, and cyclotides, are conformationally constrained and show biological stability, making them attractive scaffolds for drug development. Although many peptides can be synthesized and modified through chemical methods, knot-like lasso peptides such as microcin J25 (MccJ25) and their analogues remain elusive. As the chemical space of MccJ25 analogues accessible through purely biological methods is also limited, we proposed a hybrid approach: flow-based chemical synthesis of non-natural precursor peptides, followed by in vitro transformation with recombinant maturation enzymes, to yield a more diverse array of lasso peptides. Herein, we established the rapid, flow-based synthesis of chemically modified MccJ25 precursor peptides (57 amino acids). Heterologous expression of enzymes McjB and McjC was extensively optimized to improve yields and facilitate the synthesis of multiple analogues of MccJ25, including the incorporation of non-canonical tyrosine and histidine derivatives into the lasso scaffold. Finally, using our chemoenzymatic strategy, we produced a biologically active analogue containing three d-amino acids in the loop region and incorporated backbone N-methylations. Our method provides rapid access to chemically modified lasso peptides that could be used to investigate structure-activity relationships, epitope grafting, and the improvement of therapeutic properties.

Anthropometric traits and risk of multiple myeloma: differences by race, sex and diagnostic clinical features.

BACKGROUND: Obesity is an established modifiable risk factor for multiple myeloma (MM). However, associations of obesity and MM risk in Black populations, for whom obesity and MM are more common, is less clear. METHODS: Using participants enrolled in the Integrative Molecular And Genetic Epidemiology study, we evaluated the association of anthropometric traits with MM risk overall, stratified by race and sex. Among cases, we assessed the association of BMI with the presence of myeloma-defining events. RESULTS: We observed an 18% increase in MM risk for every 5 kg/m2 increase in usual adult BMI. Participants with severe obesity (BMI ≥ 40 kg/m2) had the highest risk compared to those with a normal usual adult BMI (18.5-24.9 kg/m2; OR = 1.87, 95% CI 1.25-2.80), particularly among Black men (OR = 3.94, 95% CI 0.90-17.36). Furthermore, MM cases with overweight/obesity (BMI ≥ 25 kg/m2) were more likely to present at diagnosis with low renal function (OR = 1.62, 95% CI 1.09-2.40), deletion 13q (OR = 1.73, 95% CI 1.08-2.76) and lytic lesions or compression fractures (OR = 2.39, 95% CI 0.82-7.01) and less likely to present with severe diffuse osteopenia (OR = 0.51, 95% CI 0.31-0.81). CONCLUSIONS: Findings underscore the importance of obesity as a modifiable risk factor for MM, particularly in high-risk populations, and for the clinical presentation of disease.

Pulmonary sarcoidosis: differences in lung function change over time.

INTRODUCTION: Given the heterogeneity of sarcoidosis, predicting disease course of patients remains a challenge. Our aim was to determine whether the 3-year change in pulmonary function differed between pulmonary function phenotypes and whether there were differential longitudinal changes by race and sex. METHODS: We identified individuals seen between 2005 and 2015 with a confirmed diagnosis of sarcoidosis who had at least two pulmonary function test measurements within 3 years of entry into the cohort. For each individual, spirometry, diffusion capacity, Charlson Comorbidity Index, sarcoidosis organ involvement, diagnosis duration, tobacco use, race, sex, age and medications were recorded. We compared changes in pulmonary function by type of pulmonary function phenotype and for demographic groups. RESULTS: Of 291 individuals, 59% (173) were female and 54% (156) were black. Individuals with restrictive pulmonary function phenotype had significantly greater 3-year rate of decline of FVC% (forced vital capacity) predicted and FEV1% (forced expiratory volume in 1 s) predicted course when compared with normal phenotype. We identified a subset of individuals in the cohort, highest decliners, who had a median 3-year FVC decline of 156 mL. Black individuals had worse pulmonary function at entry into the cohort measured by FVC% predicted, FEV1% predicted and diffusing capacity for carbon monoxide % predicted compared with white individuals. Black individuals' pulmonary function remained stable or declined over time, whereas white individuals' pulmonary function improved over time. There were no sex differences in rate of change in any pulmonary function parameters. SUMMARY: We found significant differences in 3-year change in pulmonary function among pulmonary function phenotypes and races, but no difference between sexes.

FEV1Q: a race-neutral approach to assessing lung function.

BACKGROUND: Forced expiratory volume in 1 s quotient (FEV1Q) is a simple approach to spirometry interpretation that compares measured lung function to a lower boundary. This study evaluated how well FEV1Q predicts survival compared with current interpretation methods and whether race impacts FEV1Q. METHODS: White and Black adults with complete spirometry and mortality data from the National Health and Nutrition Examination Survey (NHANES) III and the United Network for Organ Sharing (UNOS) database for lung transplant referrals were included. FEV1Q was calculated as FEV1 divided by 0.4 L for females or 0.5 L for males. Cumulative distributions of FEV1 were compared across races. Cox proportional hazards models tested mortality risk from FEV1Q adjusting for age, sex, height, smoking, income and among UNOS individuals, referral diagnosis. Harrell's C-statistics were compared between absolute FEV1, FEV1Q, FEV1/height2, FEV1 z-scores and FEV1 % predicted. Analyses were stratified by race. RESULTS: Among 7182 individuals from NHANES III and 7149 from UNOS, 1907 (27%) and 991 (14%), respectively, were Black. The lower boundary FEV1 values did not differ between Black and White individuals in either population (FEV1 first percentile difference ≤0.01 L; p>0.05). Decreasing FEV1Q was associated with increasing hazard ratio (HR) for mortality (NHANES III HR 1.33 (95% CI 1.28-1.39) and UNOS HR 1.18 (95% CI 1.12-1.23)). The associations were not confounded nor modified by race. Discriminative power was highest for FEV1Q compared with alternative FEV1 approaches in both Black and White individuals. CONCLUSIONS: FEV1Q is an intuitive and simple race-neutral approach to interpreting FEV1 that predicts survival better than current alternative methods.

Ventilator Weaning and Terminal Extubation: Withdrawal of Life-Sustaining Therapy in Children. Secondary Analysis of the Death One Hour After Terminal Extubation Study.

OBJECTIVE: Terminal extubation (TE) and terminal weaning (TW) during withdrawal of life-sustaining therapies (WLSTs) have been described and defined in adults. The recent Death One Hour After Terminal Extubation study aimed to validate a model developed to predict whether a child would die within 1 hour after discontinuation of mechanical ventilation for WLST. Although TW has not been described in children, pre-extubation weaning has been known to occur before WLST, though to what extent is unknown. In this preplanned secondary analysis, we aim to describe/define TE and pre-extubation weaning (PW) in children and compare characteristics of patients who had ventilatory support decreased before WLST with those who did not. DESIGN: Secondary analysis of multicenter retrospective cohort study. SETTING: Ten PICUs in the United States between 2009 and 2021. PATIENTS: Nine hundred thirteen patients 0-21 years old who died after WLST. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 71.4% ( n = 652) had TE without decrease in ventilatory support in the 6 hours prior. TE without decrease in ventilatory support in the 6 hours prior = 71.4% ( n = 652) of our sample. Clinically relevant decrease in ventilatory support before WLST = 11% ( n = 100), and 17.6% ( n = 161) had likely incidental decrease in ventilatory support before WLST. Relevant ventilator parameters decreased were F io2 and/or ventilator set rates. There were no significant differences in any of the other evaluated patient characteristics between groups (weight, body mass index, unit type, primary diagnostic category, presence of coma, time to death after WLST, analgosedative requirements, postextubation respiratory support modality). CONCLUSIONS: Decreasing ventilatory support before WLST with extubation in children does occur. This practice was not associated with significant differences in palliative analgosedation doses or time to death after extubation.

Reproductive healthcare in adolescents with autism and other developmental disabilities.

BACKGROUND: Adults with developmental disabilities often have less access to reproductive health services than adults without these disabilities. However, little is known about how adolescents with developmental disabilities, including autism, access reproductive healthcare. OBJECTIVE: We aimed to characterize the use of reproductive healthcare services among adolescents with autism and those with other developmental disabilities in comparison with adolescents with typical development. STUDY DESIGN: We conducted a cohort study of a sample of adolescents who were continuously enrolled members of Kaiser Permanente Northern California, an integrated healthcare system, from ages 14 to 18 years. The final analytical sample included 700 adolescents with autism, 836 adolescents with other developmental disabilities, and 2187 typically developing adolescents who sought care between 2000 and 2017. Using the electronic health record, we obtained information on menstrual conditions, the use of obstetrical-gynecologic care, and prescriptions of hormonal contraception. We compared healthcare use between the groups using chi-square tests and covariate-adjusted risk ratios estimated using modified Poisson regression. RESULTS: Adolescents with autism and those with other developmental disabilities were significantly more likely to have diagnoses of menstrual disorders, polycystic ovary syndrome, and premenstrual syndrome than typically developing adolescents. These 2 groups also were less likely than typically developing peers to visit the obstetrician-gynecologist or to use any form of hormonal contraception, including oral contraception, hormonal implants, and intrauterine devices. Adolescents in all 3 groups accessed hormonal contraception most frequently through their primary care provider, followed by an obstetrician-gynecologist. CONCLUSION: Adolescents with autism and those with other developmental disabilities are less likely than their typically developing peers to visit the obstetrician-gynecologist and to use hormonal contraception, suggesting possible care disparities that may persist into adulthood. Efforts to improve access to reproductive healthcare in these populations should target care delivered in both the pediatric and obstetrics-gynecology settings.

Intrathecal chemotherapy for leptomeningeal disease in high-grade gliomas: a systematic review.

BACKGROUND: Leptomeningeal disease (LMD) secondary to high grade glioma (HGG), such as glioblastoma (GBM), are characterized by the spread of tumor cells to the leptomeninges which further complicates treatment approaches. Intrathecal (IT) chemotherapy has surfaced as a potential strategy to bypass the blood-brain barrier and address the challenges posed by disseminated disease. Here, we present a review of the safety and efficacy of IT chemotherapy in the treatment of LMD secondary to HGG. METHODS: A systematic review following PRISMA guidelines was conducted searching PubMed and Embase from January 1995 to September 2022 using specified terms related to IT chemotherapy for LMD. Included articles involved patients diagnosed with LMD from HGG, treated with intrathecal chemotherapy, and provided survival data. Data, including demographics, tumor characteristics, treatment, and survival information, were collected and independently extracted. RESULTS: A total of 68 patients across 10 clinical studies were diagnosed with LMD from HGG and included in the review. Among these patients, the average age at diagnosis was 44.2 years. GBM was the most common tumor type (n = 58, 85.3%). A majority of the patients presented with recurrent disease (n = 29, 60.4%). The review encompassed various IT chemotherapy regimens, including mafosfamide, thio-TEPA, 5-fluoro-2'-deoxyuridine (FdUrd), methotrexate (MTX), and cytarabine; however, dosages and frequencies were inconsistently reported. The mean progression-free survival (PFS) and overall survival (OS) for this cohort were 7.5 months and 11.7 months, respectively. Common side effects of IT chemotherapy included headaches, nausea, and vomiting, with more severe complications such as myelotoxicity, disseminated intravascular coagulopathy, meningitis, and gastrointestinal toxicity reported in some cases. CONCLUSION: LMD continues to be an uncommon complication associated with HGG with a poor prognosis. This article provides an overview of the presently available literature on IT chemotherapy for LMD secondary to HGG, and their respective treatment protocols with overall survival attributes. Additional research is warranted to ascertain how to maximize the potential efficacy of IT chemotherapy as a treatment option.

Improved glycaemic control induced by evening activity breaks does not persist overnight amongst healthy adults: A randomized crossover trial.

AIMS: To compare the effects of 4 hours of laboratory-based regular activity breaks (RABs) and prolonged sitting (SIT) on subsequent 48-h free-living interstitial glucose levels in a group of healthy adults. MATERIALS AND METHODS: In this randomized crossover trial, participants completed two 4-h laboratory-based interventions commencing at ~5:00 pm: (1) SIT and (2) SIT interrupted with 3 min of body weight resistance exercise activity breaks every 30 min (RABs). Continuous glucose monitoring was performed during the intervention and for 48-h after, during which time participants returned to a free-living setting. RESULTS: Twenty-eight adults (female n = 20, mean ± SD age 25.5 ± 5.6 years, body mass index 29.2 ± 6.9 kg/m2) provided data for this analysis. During the intervention period, RABs lowered mean interstitial glucose by 8.3% (-0.47 mmol/L/4 h, 95% confidence interval [CI] -0.74 to -0.20; p = 0.001) and area under the curve (AUC) by 8.9% (-2.01 mmol/L/4 h, 95% CI -3.05 to -0.97; p < 0.001) compared to SIT. Measures of glycaemic variability were not significantly different during the intervention. There were no significant differences in mean glucose and AUC between conditions during the first nocturnal period and 24-h post intervention. When compared to SIT, RABs increased continuous overall net action of glucose at 1 h and SD glucose by 22% (0.18 mmol/L, 95% CI 0.03 to 0.29; p = 0.018) and 26% (95% CI 4.9 to 42.7; p = 0.019) in the first nocturnal period and by 10% (0.09 mmol/L, 95% CI 0.01, 0.17; p = 0.025) and 15% (95% CI 6.6 to 22.4; p = 0.001) in the 24-h post intervention period, respectively. CONCLUSION: Performing activity breaks in the evening results in acute reductions in interstitial glucose concentrations; however, the magnitude of these changes is not maintained overnight or into the following 48 hours.

Surgical management of bladder outlet obstruction due to functional and anatomical etiologies in women.

INTRODUCTION: Bladder outlet obstruction (BOO) in women includes functional and anatomic etiologies. Primary bladder neck obstruction (PBNO), Fowler's syndrome (FS), and dysfunctional voiding (DV) are some examples of functional obstructions, whereas pelvic organ prolapse (POP), periurethral masses, and intragenic causes are some of the anatomic causes. METHODS: This literature review describes the etiologies of female BOO, unique aspects of the workup and diagnosis, and the data for the standard surgical treatments and newer surgical techniques to treat women. Urethral stenosis and sling-related obstruction are treated in the other articles of this series. Where possible the focus is the efficacy and outcomes. RESULTS: Treatment of PBNO using a transurethral incision of the bladder neck and injection of botulinum toxin in the bladder neck decreases the BOO. After the failure of conservative approaches, sacral neuromodulation (SNM) is effective for FS, while DV may benefit from SNM or botulinum toxin injections. Concerning POP, most surgeries have been reported to significantly improve a pre-existent BOO but the level of evidence is low. Benign urethral and periurethral masses may provoke BOO, and surgical excision usually resolves this condition. CONCLUSION: Although most surgical treatments of BOO for functional and benign anatomical etiologies in women seem to be effective, data are scarce even for more common conditions like POP. Further studies are required to give better advice on the choice of surgical technique for these patients.

Factors Associated With Abstinence Among Young Adult Smokers Enrolled in a Real-world Social Media Smoking Cessation Program.

OBJECTIVE: Social media platforms are promising to provide smoking cessation support. This study aimed to identify baseline factors associated with cigarette smoking abstinence among young adult smokers enrolled in a real-world social media-based smoking cessation program. AIMS AND METHODS: We analyzed data from young adult smokers (aged 18-30 years) participating in a publicly available Facebook-based smoking cessation program serving the San Francisco Bay Area. The analytic sample consisted of 248 participants who completed both the baseline and follow-up surveys at 3 months. Multivariable logistic regression analysis determined baseline factors significantly associated with self-reported 7-day cigarette smoking abstinence at 3 months. RESULTS: Participants were race/ethnically diverse, well-educated, and 47.6% reported LGB + sexual identity. Those who reported dual use of cigarettes and e-cigarettes in the past 30 days (vs. cigarette use only), current alcohol users (vs. non-users), and those aged 25-30 years (vs. 18-24 years) were significantly less likely to report 7-day abstinence at 3 months. Non-daily smokers (vs. daily smokers) and those with high desire to quit smoking (vs. low to moderate desire) were more likely to report abstinence. Results also showed reduction in the percentage of e-cigarette and other tobacco product use among participants. CONCLUSIONS: Social media interventions may be more effective for young adult non-daily smokers and those with high desire to quit smoking. Smoking cessation programs may help reduce use of other tobacco products among treatment-seeking smokers. Smoking cessation interventions for young adults need to explicitly address dual use of cigarettes and e-cigarettes and use of alcohol. IMPLICATIONS: Findings of this study highlight the need for future interventions to address dual use of cigarettes and e-cigarettes and use of alcohol to improve cigarette smoking abstinence outcomes. The reduction in the use of other tobacco products among program participants indicates that social media smoking cessation programs may exert a broader positive influence on overall tobacco consumption. The large number of LGB+ smokers participating in the program suggests social media is a promising cessation channel for this hard-to-reach group, warranting further study.

Indoor particulate matter concentrations and air cleaner intervention association with biomarkers in former smokers with COPD.

BACKGROUND: Indoor pollutants have been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Elevated biomarkers are associated with ambient pollution exposure, however the association with indoor pollution remains unclear. METHODS: Former smokers with spirometry-confirmed COPD were randomized to portable air cleaner or placebo. Indoor particulate matter (PM2.5, PM10, and ultrafine particles [UFP; PM<0.1]) and biomarkers were measured longitudinally at pre-specified intervals and course PM fraction (PM10-2.5) was calculated. Biomarkers were categorized based on associations with biologic mechanisms: inflammation (white blood cell count, interleukin [IL]-6, IL-8, IL-1ß, tumor necrosis factor-α, interferon-γ, serum amyloid A), platelet activation (P-selectin, CD40 ligand [CD40L], 11-dehdydro-thromboxane-B2 [11dTxB2]), endothelial dysfunction (Vascular Cell Adhesion Molecule [VCAM]-1, Intercellular Adhesion Molecule [ICAM]-1), and oxidative stress (thiobarbituric acid reactive substances [TBARS], 8-hydroxydeoxyguanosine, 8-isoprostane). Associations between PM concentrations and each biomarker were analyzed using multivariable linear mixed models. An intention-to-treat analysis was performed to evaluate the air cleaner intervention on the biomarker levels longitudinally. RESULTS: Fifty-eight participants were randomized to each group. Finer PM was more strongly associated with higher IL-8 (mean difference per doubling: UFP 13.9% [p = 0.02], PM2.5 6.8% [p = 0.002], PM10-2.5 5.0% [p = 0.02]) while interferon-γ was associated with UFP and IL-1ß with PM10-2.5. UFP and PM2.5 were associated with elevated levels of the oxidative stress biomarkers TBARS and 8-isoprostane respectively. For platelet activation markers, UFP was associated with higher 11dTxB2 while PM2.5 was associated with higher P-selectin and CD40L. Pollutants were not associated with biomarkers of endothelial dysfunction. In intention-to-treat analysis there was no association of the air cleaner intervention with any of the biomarkers. DISCUSSION: Among former smokers with COPD, elevated levels of indoor air pollutants, particularly ultrafine particles (PM<0.1), were associated with elevated biomarkers of inflammation, platelet activation, and oxidative stress. However, an air cleaner intervention that reduced PM did not significantly reduce biomarker levels.

Child Opportunity Index and Pediatric Intensive Care Outcomes: A Multicenter Retrospective Study in the United States.

OBJECTIVES: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS). DESIGN: Retrospective cohort study. SETTING: Fifteen PICUs in the United States. PATIENTS: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance. CONCLUSIONS: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood.

The Pediatric Data Science and Analytics Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators Network: Use of Supervised Machine Learning Applications in Pediatric Critical Care Medicine Research.

OBJECTIVE: Perform a scoping review of supervised machine learning in pediatric critical care to identify published applications, methodologies, and implementation frequency to inform best practices for the development, validation, and reporting of predictive models in pediatric critical care. DESIGN: Scoping review and expert opinion. SETTING: We queried CINAHL Plus with Full Text (EBSCO), Cochrane Library (Wiley), Embase (Elsevier), Ovid Medline, and PubMed for articles published between 2000 and 2022 related to machine learning concepts and pediatric critical illness. Articles were excluded if the majority of patients were adults or neonates, if unsupervised machine learning was the primary methodology, or if information related to the development, validation, and/or implementation of the model was not reported. Article selection and data extraction were performed using dual review in the Covidence tool, with discrepancies resolved by consensus. SUBJECTS: Articles reporting on the development, validation, or implementation of supervised machine learning models in the field of pediatric critical care medicine. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 5075 identified studies, 141 articles were included. Studies were primarily (57%) performed at a single site. The majority took place in the United States (70%). Most were retrospective observational cohort studies. More than three-quarters of the articles were published between 2018 and 2022. The most common algorithms included logistic regression and random forest. Predicted events were most commonly death, transfer to ICU, and sepsis. Only 14% of articles reported external validation, and only a single model was implemented at publication. Reporting of validation methods, performance assessments, and implementation varied widely. Follow-up with authors suggests that implementation remains uncommon after model publication. CONCLUSIONS: Publication of supervised machine learning models to address clinical challenges in pediatric critical care medicine has increased dramatically in the last 5 years. While these approaches have the potential to benefit children with critical illness, the literature demonstrates incomplete reporting, absence of external validation, and infrequent clinical implementation.

A Race-neutral Approach to the Interpretation of Lung Function Measurements.

Rationale: The use of self-reported race and ethnicity to interpret lung function measurements has historically assumed that the observed differences in lung function between racial and ethnic groups were because of thoracic cavity size differences relative to standing height. Very few studies have considered the influence of environmental and social determinants on pulmonary function. Consequently, the use of race and ethnicity-specific reference equations may further marginalize disadvantaged populations. Objectives: To develop a race-neutral reference equation for spirometry interpretation. Methods: National Health and Nutrition Examination Survey (NHANES) III data (n = 6,984) were reanalyzed with sitting height and the Cormic index to investigate whether body proportions were better predictors of lung function than race and ethnicity. Furthermore, the original GLI (Global Lung Function Initiative) data (n = 74,185) were reanalyzed with inverse-probability weights to create race-neutral GLI global (2022) equations. Measurements and Main Results: The inclusion of sitting height slightly improved the statistical precision of reference equations compared with using standing height alone but did not explain observed differences in spirometry between the NHANES III race and ethnic groups. GLI global (2022) equations, which do not require the selection of race and ethnicity, had a similar fit to the GLI 2012 "other" equations and wider limits of normal. Conclusions: The use of a single global spirometry equation reflects the wide range of lung function observed within and between populations. Given the inherent limitations of any reference equation, the use of GLI global equations to interpret spirometry requires careful consideration of an individual's symptoms and medical history when used to make clinical, employment, and insurance decisions.

Indoor Air Pollution and Impaired Cardiac Autonomic Function in Chronic Obstructive Pulmonary Disease.

Rationale: Indoor air pollution represents a modifiable risk factor for respiratory morbidity in chronic obstructive pulmonary disease (COPD). The effects of indoor air pollution, as well as the impact of interventions to improve indoor air quality, on cardiovascular morbidity in COPD remain unknown. Objectives: To determine the association between indoor particulate matter (PM) and heart rate variability (HRV), a measure of cardiac autonomic function tied to cardiovascular morbidity and mortality, as well as the impact of household air purifiers on HRV. Methods: Former smokers with moderate-severe COPD were recruited from a 6-month randomized controlled trial of a portable air cleaner intervention to undergo paired assessment of both in-home PM and HRV using 24-hour Holter monitoring at up to five time points. Primary outcomes were HRV measures tied to cardiovascular morbidity (standard deviation of normal-to-normal intervals [SDNN] and root mean square of successive differences between normal-to-normal intervals [RMSSD]). Measurements and Results: Eighty-five participants contributed 317 HRV measurements. A twofold increase in household PM ⩽2.5 µm in aerodynamic diameter was associated with decreases in SDNN (ß, -2.98% [95% confidence interval (CI), -5.12 to -0.78]) and RMSSD (ß, -4.57% [95% CI, -10.1 to -1.60]). The greatest effects were observed with ultrafine particles (<100 nm) (RMSSD; ß, -16.4% [95% CI, -22.3 to -10.1]) and among obese participants. Participants randomized to the active air cleaner saw improvements in RMSSD (ß, 25.2% [95% CI, 2.99 to 52.1]), but not SDNN (ß, 2.65% [95% CI, -10.8 to 18.1]), compared with the placebo group. Conclusions: This is the first U.S. study to describe the association between household PM and cardiac autonomic function among individuals with COPD, as well as the potential cardiovascular health benefits of household air cleaners.

Race and Ethnicity in Pulmonary Function Test Interpretation: An Official American Thoracic Society Statement.

Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.

The Associations Between Drinking Motives and Alcohol-Related Consequences in Graduate Students from Universities in the United States.

Many college students "mature out" of heavy drinking when they graduate. Yet, those who go onto graduate education report engaging in problematic drinking patterns. Drinking motives are one factor that uniquely predicts problematic drinking patterns in college students. Evidence suggests that these unique associations also generalize to individuals' post-college, specifically between drinking motives and specific alcohol-related consequences. However, no research to date has examined the association between drinking motives and alcohol-related consequences in graduate students. The current study aimed to examine the unique associations between drinking motives, and drinks per week and specific alcohol-related consequences. Participants included 330 graduate students from various universities in the United States, recruited through social media. The majority of participants were White (71.3%), 54.9% female identifying, with a mean age of 26. Results revealed that conformity motives were positively associated with drinks per week, self-control consequences, self-care consequences, risky consequences, academic/occupational consequences, and blackout consequences. Social motives were negatively associated with interpersonal consequences and academic/occupational consequences. Enhancement motives were negatively associated with drinks per week, and positively associated with academic/occupational consequences. However, coping motivation was not associated with any of the outcomes. These findings highlight the need to further understand how drinking motives influence specific types of alcohol-related consequences as these associations change post-college. Results can be used to better inform future prevention and interventions for this population.