Lung-Gut Microbiota and Tryptophan Metabolites Changes in Neonatal Acute Respiratory Distress Syndrome.

Purpose: Neonatal Acute Respiratory Distress Syndrome (NARDS) is a severe respiratory crisis threatening neonatal life. We aim to identify changes in the lung-gut microbiota and lung-plasma tryptophan metabolites in NARDS neonates to provide a differentiated tool and aid in finding potential therapeutic targets. Patients and Methods: Lower respiratory secretions, faeces and plasma were collected from 50 neonates including 25 NARDS patients (10 patients with mild NARDS in the NARDS_M group and 15 patients with moderate-to-severe NARDS in the NARDS_S group) and 25 control patients screened based on gestational age, postnatal age and birth weight. Lower airway secretions and feces underwent 16S rRNA gene sequencing to understand the microbial communities in the lung and gut, while lower airway secretions and plasma underwent LC-MS analysis to understand tryptophan metabolites in the lung and blood. Correlation analyses were performed by comparing differences in microbiota and tryptophan metabolites between NARDS and control, NARDS_S and NARDS_M groups. Results: Significant changes in lung and gut microbiota as well as lung and plasma tryptophan metabolites were observed in NARDS neonates compared to controls. Proteobacteria and Bacteroidota were increased in the lungs of NARDS neonates, whereas Firmicutes, Streptococcus, and Rothia were reduced. Lactobacillus in the lungs decreased in NARDS_S neonates. Indole-3-carboxaldehyde decreased in the lungs of NARDS neonates, whereas levels of 3-hydroxykynurenine, indoleacetic acid, indolelactic acid, 3-indole propionic acid, indoxyl sulfate, kynurenine, and tryptophan decreased in the lungs of the NARDS_S neonates. Altered microbiota was significantly related to tryptophan metabolites, with changes in lung microbiota and tryptophan metabolites having better differentiated ability for NARDS diagnosis and grading compared to gut and plasma. Conclusion: Significant changes occurred in the lung-gut microbiota and lung-plasma tryptophan metabolites of NARDS neonates. Alterations in lung microbiota and tryptophan metabolites were better discriminatory for the diagnosis and grading of NARDS.

Maternal smoking around birth and its influence on offspring allergic diseases: A mendelian randomization study.

Objective: The influence of maternal smoking around birth (MSAB) on offspring allergic diseases, specifically childhood asthma (CA), allergic rhinitis (AR), allergic conjunctivitis (AC), and atopic dermatitis (AD) remains incompletely understood. We performed a rigorous mendelian randomization (MR) study to obtain the unconfounded association between MSAB and allergic diseases in offspring with and without adjustment for the effect of breastfeeding. Methods: Utilizing publicly available information of MSAB, breastfeeding, CA, AR, AC, and AD from large-scale genome-wide association studies (GWAS), we performed a two-sample mendelian randomization (TSMR) analysis to assess the respective causal relationship of MSAB and breastfeeding to allergic diseases in offspring. To get a reliable conclusion, MR Egger regression, weighted median, and inverse variance weighted (IVW) were employed to estimate the causality, with IVW as the primary analysis. Multivariate MR (MVMR) analysis was used to assess the effect of MSAB on allergic diseases after adjusting for breastfeeding's impact. Sensitivity analysis was conducted using the Cochran Q test, MR-Egger, and leave-one-out approaches to ensure the reliability and stability of results. Results: The TSMR analysis demonstrated MSAB increased the risks of CA (PIVW = 0.013, OR: 1.018, 95%CI: 1.004 to 1.033) and AD (PIVW = 0.006, OR: 8.293, 95%CI: 1.815 to 37.884) in offspring. Conversely, breastfeeding decreased the risk of CA (PIVW <0.001, OR: 0.946, 95%CI: 0.918 to 0.974). MSAB still increased the risks of CA (P = 0.0497, OR: 1.013, 95%CI: 1.000017 to 1.026) and AD (P = 0.003, OR: 13.800, 95%CI: 2.490 to 269.246) after adjusting for breastfeeding. We observed no strong indication of a negative causality between MSAB and AC and AR. Conclusion: Our findings provided robust evidence of the adverse effects of MSAB on offspring. We emphasized the urgency of smoking cessation around birth and the importance of breastfeeding even in smoking mothers.

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease.

Background: Homozygous and compound heterozygous mutations in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, heterozygous pathogenic variants in HTRA1 were described in patients with autosomal dominant cerebral small vessel disease (CSVD). Here, we investigated the genetic variants in a cohort of Chinese patients with CSVD. Methods: A total of 95 Chinese index patients with typical characteristics of CSVD were collected. Whole exome sequencing was performed in the probands, followed by Sanger sequencing. Pathogenicity prediction software was applied to evaluate the pathogenicity of the identified variants. Results: We detected five heterozygous HTRA1 pathogenic variants in five index patients. These pathogenic variants included four known variants (c.543delT, c.854C>T, c.889G>A, and c.824C>T) and one novel variant (c.472 + 1G>A). Among them, c.854C>T, c.824C>T, and c.472 + 1G>A have never been reported in China and c.889G>A was once reported in homozygous but never in heterozygous. Three of them were distributed in exon 4, one in exon 2, and another splicing variant in intron 1. Four out of five probands presented typical features of CARASIL but less severe. The common clinical features included lacunar infarction, cognitive decline, alopecia, and spondylosis. All of them showed leukoencephalopathy, and the main involved cerebral area include periventricular and frontal area, centrum semiovale, thalamus, and corpus callosum. Anterior temporal lobes and external capsule involvement were also observed. Three probands had intracranial microbleeds. Conclusion: Our study expanded the mutation spectrum of HTRA1, especially in Chinese populations, and provided further evidence for "hot regions" in exon 1-4, especially in exon 4, in heterozygous HTRA1 pathogenic variants. Our work further supported that patients with heterozygous HTRA1 pathogenic variants presented with similar but less-severe features than CARASIL but in an autosomal dominantly inherited pattern.

Clinical Characteristics and Outcomes Until 2 Years of Age in Preterm Infants With Typical Chest Imaging Findings of Bronchopulmonary Dysplasia: A Propensity Score Analysis.

Objective: The goal of the current study was to assess the associations of typical chest imaging findings of bronchopulmonary dysplasia (BPD) in preterm infants with clinical characteristics and outcomes until 2 years of age. Method: This retrospective cohort study enrolled 256 preterm infants with BPD who were admitted between 2014 and 2018. A propensity score analysis was used to adjust for confounding factors. The primary outcomes were the severity of BPD, home oxygen therapy (HOT) at discharge and mortality between 28 days after birth and 2 years of age. A multivariate logistic regression analysis was performed to identify related variables of mortality. Results: Seventy-eight patients with typical chest imaging findings were enrolled, of which 50 (64.1%) were first found by CXR, while 28 (35.9%) were first found by CT. In addition, 85.9% (67/78) were discovered before 36 weeks postmenstrual age (PMA) (gestational age [GA] < 32 weeks) or before 56 days after birth (GA > 32 weeks). After propensity score matching, the matched groups consisted of 58 pairs of patients. Those with typical imaging findings had a remarkably higher mortality rate (29.3 vs. 12.1%, p = 0.022, OR 3.021), higher proportion of severe BPD (32.8 vs. 12.1%, p = 0.003, OR 4.669) and higher rate of HOT at discharge (74.1 vs. 46.6%, p = 0.002, OR 3.291) than those without typical imaging findings. The multivariate logistic regression analysis showed that typical imaging findings ≤ 7 days and typical typical imaging findings >7 days were independent risk factors for mortality in preterm infants with BPD (OR 7.794, p = 0.004; OR 4.533, p = 0.001). Conclusions: More attention should be given to chest imaging findings of BPD, especially in the early stage (within 7 days). Early recognition of the development of BPD helps early individualized treatment of BPD. Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04163822.

Grade-lymph node ratio predicts the survival of breast cancer in different molecular types: A surveillance, epidemiology, and end results population-based analysis.

The prognostic value and conflicting results of metastatic lymph node ratio (mLNR) on breast cancer have aroused an increasing concern. We aimed to evaluate the imperative of mLNR classification and prognostic factors in breast cancer with molecular subtypes.This study uses the database of surveillance, epidemiology, and end results (SEER) to investigate the imperative for reliable mLNR classification and critical prognostic factors in breast cancer with different molecular subtypes.The prognostic characteristics for disease-specific survival (DSS) of breast cancer were investigated in the SEER cohort (n = 3651). mLNR (P = .017) and histology grade (P < .001) were independent factors. A novel grade-lymph node ratio (G-R) staging system was proposed for breast cancer prognosis. The receiver operating characteristic curves revealed that the G-R staging system had an accurate 1-, 3-, and 5-year DSS prediction. Further stratification analysis with molecular subtypes of breast cancer (Luminal and TNBC) first proved robust prognostic values of the G-R staging system among molecular subtypes.The current population-based cohort demonstrated the capacity of mLNR serving as a critical prognostic factor. Also, G-R staging system has the potential to be regarded as reliable classification for breast cancer patients with different molecular subtypes.