Urinary eicosanoid levels in early life and risk of atopic disease in childhood.

BACKGROUND: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.

Nucleotide, Phospholipid, and Kynurenine Metabolites Are Robustly Associated with COVID-19 Severity and Time of Plasma Sample Collection in a Prospective Cohort Study.

Understanding the molecular underpinnings of disease severity and progression in human studies is necessary to develop metabolism-related preventative strategies for severe COVID-19. Metabolites and metabolic pathways that predispose individuals to severe disease are not well understood. In this study, we generated comprehensive plasma metabolomic profiles in >550 patients from the Longitudinal EMR and Omics COVID-19 Cohort. Samples were collected before (n = 441), during (n = 86), and after (n = 82) COVID-19 diagnosis, representing 555 distinct patients, most of which had single timepoints. Regression models adjusted for demographics, risk factors, and comorbidities, were used to determine metabolites associated with predisposition to and/or persistent effects of COVID-19 severity, and metabolite changes that were transient/lingering over the disease course. Sphingolipids/phospholipids were negatively associated with severity and exhibited lingering elevations after disease, while modified nucleotides were positively associated with severity and had lingering decreases after disease. Cytidine and uridine metabolites, which were positively and negatively associated with COVID-19 severity, respectively, were acutely elevated, reflecting the particular importance of pyrimidine metabolism in active COVID-19. This is the first large metabolomics study using COVID-19 plasma samples before, during, and/or after disease. Our results lay the groundwork for identifying putative biomarkers and preventive strategies for severe COVID-19.

Assessing patient perception and preferences for outcomes in lung cancer resection surgery: a cross-sectional study.

Background: Surgical resection is the primary treatment for early-stage lung cancer, but little is known about the outcomes that truly matter to patients. This aim of our study was to identify the aspects of postoperative outcomes that matter most to patients undergoing lung cancer surgery and explore the influence of clinical and demographic factors on their importance ratings. Methods: We performed a cross-sectional study of patients undergoing lung resection for non-small cell lung cancer at our institution from November 2021 to May 2022. Patients were surveyed using a self-developed questionnaire and the European Organisation for Research and Treatment of Cancer core health-related quality of life questionnaire (EORTC QLQ-C30) prior to surgery. Ordinal logistic regression was performed to determine associations between individual patient factors and outcome importance ratings. Results: Forty patients completed the survey during the study period. Patients prioritized oncologic outcomes, with 95% rating R0 resection and cancer recurrence as "very important". Other important factors included overall survival (90%), postoperative complications (e.g., myocardial infarction: 92.5%, infection: 87.5%), and the need for reoperation (82.5%). Health-related quality of life factors, such as chronic pain (77.5%) and the ability to return to normal physical and exercise levels (75%), were also highly valued. Certain patient clinical and demographic factors demonstrated significant associations with importance placed on certain outcomes. Preoperative health-related quality of life scores did not influence outcome importance ratings. Conclusions: This study provides insights into the outcomes that matter most to patients undergoing lung cancer surgery. Oncologic outcomes and postoperative complications were prioritized, while scar-related factors were less important. Patient preferences varied based on demographic and clinical factors. Understanding these preferences can enhance shared decision-making and improve patient-centered care in thoracic surgical oncology.

Network Analysis Reveals Protein Modules Associated with Childhood Respiratory Diseases.

Background: The first year of life is a period of rapid immune development that can impact health trajectories and the risk of developing respiratory-related diseases, such as asthma, recurrent infections, and eczema. However, the biology underlying subsequent disease development remains unknown. Methods: Using weighted gene correlation network analysis (WGCNA), we derived modules of highly correlated immune-related proteins in plasma samples from children at age 1 year (N=294) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We applied regression analyses to assess relationships between protein modules and development of childhood respiratory diseases up to age 6 years. We then characterized genomic, environmental, and metabolomic factors associated with modules. Results: WGCNA identified four protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (Padj range: 0.02-0.03), respiratory infections (Padj range: 6.3×10-9-2.9×10-6), and eczema (Padj=0.01) by age 6 years; three modules were associated with at least one environmental exposure (Padj range: 2.8×10-10-0.03) and disrupted metabolomic pathway(s) (Padj range: 2.8×10-6-0.04). No genome-wide SNPs were identified as significant genetic risk factors for any protein module. Relationships between protein modules with clinical, environmental, and 'omic factors were temporally sensitive and could not be recapitulated in protein profiles at age 6 years. Conclusion: These findings suggested protein profiles as early as age 1 year predicted development of respiratory-related diseases through age 6 and were associated with changes in pathways related to amino acid and energy metabolism. These may inform new strategies to identify vulnerable individuals based on immune protein profiling.

Pregnancy complications and birth outcomes following low-level exposure to per- and polyfluoroalkyl substances in the vitamin D antenatal asthma reduction trial.

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic, highly fluorinated aliphatic compounds, commonly utilised in a wide variety of consumer products with diverse applications. Since the genesis of these compounds, a growing body of evidence has demonstrated adverse health effects associated with PFAS exposure. In a racially diverse cohort of 459 pregnant mothers, demographically weighted towards minority representation (black 44.4%, white 38.4%, other 17.2%), across three major populous cities of the US, PFAS profiling was performed. Nine distinct PFAS species were quantified using mass spectrometry in plasma samples collected during the third trimester. Multivariable logistic and linear regression analyses were conducted to interrogate the associations of PFAS with gestational and birth outcomes: gestational diabetes, preeclampsia, gestational age at delivery, low birth weight, birth weight-, birth length- and head circumference-for-gestational-age. Detectable levels for eight out of nine profiled PFAS species were found in the plasma of pregnant mothers with a median range of 0.1-2.70 ng ml-1. Using a mixtures approach, we observe that increased quantile-based g-computation (Qg-comp) "total" PFAS levels were associated with increased newborn birth-weight-for-gestational-age (ß 1.28; 95% CI 1.07-1.52; FDR p 0.006). In study centre-stratified analyses, we observed a similar trend in Boston pregnant mothers, with Qg-comp total PFAS associated with higher newborn birth-weight-for-gestational-age (ß 1.39; 95% CI 1.01-1.92, FDR p 0.05). We additionally found elevated PFUA concentrations were associated with longer gestational terms in San Diego pregnant mothers (ß 0.60; 95% CI 0.18-1.02, FDR p 0.05). In this multi-city study, we detected lower levels of PFAS than in many previous US environmental studies, concordant with current US trends indicating environmental PFAS levels are falling, and we note geographical variation in the associations between PFAS levels and birth outcomes.

Outcomes of single- versus multi-port video-assisted thoracoscopic surgery: Data from a multicenter randomized controlled trial of video-assisted thoracoscopic surgery versus thoracotomy for lung cancer.

Objectives: Surgery through a single port may be less painful because access is supplied by 1 intercostal nerve or more painful because multiple instruments are used in 1 port. We analyzed data collected from the video-assisted thoracoscopic surgery group of a randomized controlled trial to compare differences in pain up to 1 year. Methods: Groups were compared in a prespecified exploratory analysis using direct (regression) and indirect comparison (difference with respect to thoracotomy). In-hospital visual analogue scale pain scores were used, and analgesic ratios were calculated. After discharge, pain was evaluated using European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core 30 scores up to 1 year. Results: From July 2015 to February 2019, we randomized 503 participants. After excluding 50 participants who did not receive lobectomy, surgery was performed using a single port in 42 participants (predominately by a single surgeon), multiple ports in 166 participants, and thoracotomy in 245 participants. No differences were observed in-hospital between single- and multiple-port video-assisted thoracoscopic surgery when modeled using a direct comparison, mean difference of -0.24 (95% CI, -1.06 to 0.58) or indirect comparison, mean difference of -0.33 (-1.16 to 0.51). Mean analgesic ratio (single/multiple port) was 0.75 (0.64 to 0.87) for direct comparison and 0.90 (0.64 to 1.25) for indirect comparison. After discharge, pain for single-port video-assisted thoracoscopic surgery was lower than for multiple-port video-assisted thoracoscopic surgery (first 3 months), and corresponding physical function was higher up to 12 months. Conclusions: There were no consistent differences for in-hospital pain when lobectomy was undertaken using 1 or multiple ports. However, better pain scores and physical function were observed for single-port surgery after discharge.

Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma.

BACKGROUND: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. METHODS: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. FINDINGS: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10-5), SLC8A1 (P-value = 3.9 × 10-5); and TENM4 (P-value = 4.9 × 10-5). INTERPRETATION: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. FUNDING: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

Determining the optimal time to report mortality after lobectomy for lung cancer: An analysis of the time-varying risk of death.

Objective: Surgical mortality has traditionally been assessed at arbitrary intervals out to 1 year, without an agreed optimum time point. The aim of our study was to investigate the time-varying risk of death after lobectomy to determine the optimum period to evaluate surgical mortality rate after lobectomy for lung cancer. Methods: We performed a retrospective study of patients undergoing lobectomy for lung cancer at our institution from 2015 to 2022. Parametric survival models were assessed and compared with a nonparametric kernel estimate. The hazard function was plotted over time according to the best-fit statistical distribution. The time points at which instantaneous hazard rate peaked and stabilized in the 1-year period after surgery were then determined. Results: During the study period, 2284 patients underwent lobectomy for lung cancer. Cumulative mortality at 30, 90, and 180 days was 1.3%, 2.9%, and 4.9%, respectively. Log-logistic distribution showed the best fit compared with other statistical distribution, indicated by the lowest Akaike information criteria value. The instantaneous hazard rate was greatest during the immediate postoperative period (0.129; 95% confidence interval, 0.087-0.183) and diminishes rapidly within the first 30 days after surgery. Instantaneous hazard rate continued to decrease past 90 days and stabilized only at approximately 180 days. Conclusions: In-hospital mortality is the optimal follow-up period that captures the early-phase hazard during the immediate postoperative period after lobectomy. Thirty-day mortality is not synonymous to "early mortality," as instantaneous hazard rate remains elevated well past the 90-day time point and only stabilizes at approximately 180 days after lobectomy.