A new insight on evaluation of the fertility and pregnancy outcome in patients with primary Sjögren syndrome: a propensity score matched study in multi-IVF centers.

BACKGROUND: Primary Sjögren syndrome (pSS) is often related to adverse neonatal outcomes. But it's currently controversial whether pSS has an adverse effect on female fertility and clinical pregnancy condition. More importantly, it's unclear regarding the role of pSS in oocyte and embryonic development. There is a lack of comprehensive understanding and evaluation of fertility in pSS patients. OBJECTIVE: This study aimed to investigate oocyte and embryonic development, ovarian reserve, and clinical pregnancy outcomes in Primary Sjögren syndrome (pSS) patients during in vitro fertilization (IVF) treatment from multi-IVF centers. METHODS: We performed a muti-central retrospective cohort study overall evaluating the baseline characteristics, ovarian reserve, IVF laboratory outcomes, and clinical pregnancy outcomes between the pSS patients and control patients who were matched by Propensity Score Matching. RESULTS: Following PSM matching, baseline characteristics generally coincided between the two groups. Ovarian reserve including anti-müllerian hormone (AMH) and antral follicle counting (AFC) were significantly lower in the pSS group vs comparison (0.8 vs. 2.9 ng/mL, P < 0.001; 6.0 vs. 10.0, P < 0.001, respectively). The pSS group performed significant reductions in numbers of large follicles, oocytes retrieved and MII oocytes. Additionally, pSS patients exhibited obviously deteriorate rates of oocyte maturation, 2PN cleavage, D3 good-quality embryo, and blastocyst formation compared to comparison. As for clinical pregnancy, notable decrease was found in implantation rate (37.9% vs. 54.9%, P = 0.022). The cumulative live birth rate (CLBR) following every embryo-transfer procedure was distinctly lower in the pSS group, and the conservative and optimal CLBRs following every complete cycle procedure were also significantly reduced in the pSS group. Lastly, the gestational weeks of the newborns in pSS group were distinctly early vs comparison. CONCLUSION: Patients with pSS exhibit worse conditions in terms of female fertility and clinical pregnancy, notably accompanied with deteriorate oocyte and embryo development. Individualized fertility evaluation and early fertility guidance are essential for these special patients.

Causal relationships between gut microbiota and polycystic ovarian syndrome: A bidirectional Mendelian randomization study.

INTRODUCTION: Previous studies have established a link between gut microbiota and polycystic ovary syndrome (PCOS), but little is known about their precise causal relationship. Therefore, this study aims to explore whether there are precise causal relationships between gut microbiota and PCOS. MATERIAL AND METHODS: We performed a bidirectional two-sample Mendelian randomization (MR) analysis. Datasets were from the largest published meta-analysis on gut microbiota composition and the FinnGen cohort of the IEU Open Genome-Wide Association Study Project database. Inverse variance weighted (IVW), MR-Egger, constrained maximum likelihood-based Mendelian randomization, weighted median, weighted mode, and simple mode were used. Cochran's Q and MR-Egger intercept tests were employed to measure the heterogeneity. RESULTS: A total of 211 gut microbiota taxa were identified in MR analysis. Nine taxa of bacteria, including Alphaproteobacteria (0.55, 0.30-0.99, p = 0.04), Bacilli (1.76, 1.07-2.91, p = 0.03), Bilophila (0.42, 0.23-0.77, p < 0.01), Blautia (0.16, 0.03-0.79, p = 0.02), Burkholderiales (2.37, 1.22-4.62, p = 0.01), Candidatus Soleaferrea (0.65, 0.43-0.98, p = 0.04), Cyanobacteria (0.51, 0.31-0.83, p = 0.01), Holdemania (0.53, 0.35-0.81, p < 0.01), and Lachnospiraceae (1.86, 1.04-3.35, p = 0.03), were found to be associated with PCOS in the above MR methods included at least IVW method. Cochran's Q statistics and MR-Egger intercept test suggested no significant heterogeneity. In addition, 69 taxa were shown significant for at least the IVW method in reverse MR analysis, of these, 25 had a positive correlation, and 37 had a negative correlation. Additionally, Alphaproteobacteria and Lachnospiraceae (0.95, 0.91-0.98, p < 0.01; 0.97, 0.94-0.99, p = 0.02, respectively) were shown a bidirected causally association with PCOS. CONCLUSIONS: Our study provides evidence of the bidirectional causal association between gut microbiota and PCOS from a genetic perspective.

An overview of CFTR mutation profiles and assisted reproductive technology outcomes in Chinese patients with congenital obstructive azoospermia.

PURPOSE: The cystic fibrosis transmembrane conductance regulator (CFTR) is the most common causative gene attributed to congenital obstructive azoospermia (OA). The aim of this study was to conduct an epidemiological survey of congenital OA patients, to screen for CFTR mutations, and to follow their pregnancy outcomes in assisted reproductive technology (ART). METHODS: This cohort study enrolled congenital OA patients undergoing ART and whole-exome sequencing from January 2018 to September 2023. Semen parameters, sex hormones, and seminal plasma biochemistry were evaluated. CFTR mutations identified in OA patients were analyzed. In addition, the laboratory outcomes, clinical outcomes, and neonatal outcomes were compared between OA patients carrying two CFTR mutations and the others after surgical sperm extraction-intracytoplasmic sperm injection (ICSI) treatment. RESULTS: A total of 76 patients with congenital OA were enrolled. CFTR mutations were identified in 35 (46.1%) congenital OA patients. A total of 60 CFTR mutation sites of 27 types were identified, and 10 of them were novel. The average frequency was 1.71 (60/35) per person. The most common mutation was c.1210-11T > G (25%, 15/60). After ICSI treatment, there were no statistically significant differences in laboratory outcomes, clinical outcomes, and neonatal outcomes between OA patients carrying two CFTR mutations (n = 25) and other OA patients (n = 51). CONCLUSION: Apart from the IVS9-5T mutation, the genetic mutation pattern of CFTR in Chinese OA patients is heterogeneous, which is significantly different from that of Caucasians. Although carrying two CFTR mutations or not had no effect on the pregnancy outcomes in OA patients after ICSI, genetic counseling is still recommended for such patients.

Medium-long term prognosis prediction for idiopathic pulmonary fibrosis patients based on quantitative analysis of fibrotic lung volume.

PURPOSE: To investigate the prognostic value of quantitative analysis of CT among patients with idiopathic pulmonary fibrosis (IPF) by quantifying the fibrosis extent and to attempt to provide precise medium-long term prognostic predictions for individual patients. METHODS: This was a retrospective cohort study that included 95 IPF patients in Zhongshan Hospital, Fudan University. 64 patients firstly diagnosed with IPF from 2009 to 2015 was included as the derivation cohort. Information regarding sex, age, the Gender-Age-Physiology (GAP) index, high-resolution computed tomography (HRCT) images, survival status, and pulmonary function parameters including forced vital capacity (FVC), FVC percent predicted (FVC%pred), diffusing capacity of carbon monoxide (DLCO), DLCO percent predicted (DLCO%pred), carbon monoxide transfer coefficient (KCO), KCO percent predicted (KCO%pred) were collected. 31 patients were included in the validation cohort. The Synapse 3D software was used to quantify the fibrotic lung volume (FLV) and total lung volume (TLV). The ratio of FLV to TLV was calculated and labeled CTFLV/TLV%, reflecting the extent of fibrosis. All the physiological variants and CTFLV/TLV% were analyzed for the dimension of survival through both univariate analysis and multivariate analysis. Formulas for predicting the probability of death based on the baseline CTFLV/TLV% were calculated by logistic regression, and validated by the validation cohort. RESULTS: The univariate analysis indicated that CTFLV/TLV% along with DLCO%pred, KCO%pred and GAP index were significantly correlated with survival. However, only CTFLV/TLV% was meaningful in the multivariate analysis for prognostic prediction (HR 1.114, 95% CI 1.047-1.184, P = 0.0006), and the best cutoff was 11%, based on receiver operating characteristic (ROC) curve analysis. The survival times for the CTFLV/TLV% ≤ 11% and CTFLV/TLV% > 11% groups were significantly different. Given the CTFLV/TLV% data, the death probability of a patient at 1 year, 3 years and 5 years could be calculated by using a particular formula. The formulas were tested by the validation cohort, showed high sensitivity (88.2%), specificity (92.8%) and accuracy (90.3%). CONCLUSION: Quantitative volume analysis of CT might be useful for evaluating the extent of fibrosis in the lung. The CTFLV/TLV% could be a valuable biomarker for precisely predicting the medium-long term prognosis of individual patients with IPF.

Pyrroloquinoline Quinone Administration Alleviates Allergic Airway Inflammation in Mice by Regulating the JAK-STAT Signaling Pathway.

The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma.

Preventative tracheal administration of interleukin-27 attenuates allergic asthma by improving the lung Th1 microenvironment.

BACKGROUND: Interleukin-27 (IL-27) modulates CD4+ T-cell differentiation and function. The aim of this study is to investigate the effect and molecular mechanisms of IL-27 on the development of asthma. METHODS: IL-27 was intranasally administered in an ovalbumin-induced asthma model, and lung mononuclear cells and different Th cell classes were detected by fluorescence-activated cell sorting. The effect and mechanisms of IL-27 on human bronchial epithelial (HBE) cells were investigated by measuring changes in chemotactic factors, cytokines, transcription factors, and signaling pathways. RESULTS: We found that intranasal administration of IL-27 could attenuate airway inflammation and hyperresponsiveness, upregulate the type 1 T helper (Th1)-T memory (Tm) cells and regulatory T (Treg) cells subgroups of lung tissue lymphocytes, and diminish the levels of type 2 T helper (Th2) cytokines. IL-27 upregulated the expression of C-C motif chemokine ligand 2 (CCL2), CCL3, and CCL4 in HBE cells and promoted the production of chemotactic factors to attract monocyte recruitment. Recruited monocytes secondarily secreted IL-27 to influence HBE cells in a positive feedback cycle. After IL-27 intervention, signal transducer and activator of transcription 1 (STAT1) phosphorylation increased, while STAT4 and STAT6 phosphorylation declined. CONCLUSIONS: Preventative intranasal administration of IL-27 can recruit more IL-27-secreted monocytes to the airway and change the different T-cell classes in lung. The improved Th1 environment helps to alleviate Th2-mediated allergic asthma by repairing the STAT1 pathway but not the STAT4 pathway.

The genetic relationship between systemic lupus erythematosus and risk of primary ovarian failure from a mendelian randomization study.

Previous studies investigating the relationship between systemic lupus erythematosus (SLE) and primary ovarian failure (POF) generated conflicting results. To data, no mendelian randomization study has been applied to examine this association. In this study, genetic instruments for exposure (SLE) were selected from a GWAS study with 5201 cases and 9066 noncases. Outcome data for POF and three reproductive traits (age at menarche, age at menopause, and age at first live birth) were obtained from other eligible GWASs. To estimate causal association, the inverse-variance weighted (IVW) method (the main analyse), MR Egger test, weighted median, simple mode, and weighted mode were applied. Moreover, sensitivity analyses were conducted to ensure the robustness of the results. Estimated by the IVW method, SLE was suggested to be causally related to the risk of POF (OR = 1.166, 95% CI 1.055-1.289, P = 0.003) and delayed age at first live birth (OR = 1.006, 95% CI 1.002-1.010, P = 0.007), with no evidence of a causal association between SLE and age at menopause or menarche. The estimates were robust according to sensitivity analysis. In conclusion, the two-sample MR study supported a causal association between SLE and POF from a genetic aspect.

A novel heterozygous missense variant of PANX1 causes human oocyte death and female infertility.

Pannexin1 (PANX1) is a highly glycosylated membrane channel-forming protein, which has been found to implicate in multiple physiological and pathophysiological functions. Variants in the PANX1 gene have been reported to be associated with oocyte death and recurrent in vitro fertilization failure. In this study, we identified a novel heterozygous PANX1 variant (NM_015368.4 c.410 C > T (p.Ser137Leu)) associated with the phenotype of oocyte death in a non-consanguineous family, followed by an autosomal dominant (AD) mode. We explored the molecular mechanism of the novel variant and the variant c.976_978del (p.Asn326del) that we reported previously. Both of the variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, affected ATP release and membrane electrophysiological properties, which resulted in mouse and human oocyte death in vitro. For the first time, we presented the direct evidence of the effect of the PANX1 variants on human oocyte development. Our findings expand the variant spectrum of PANX1 genes associated with oocyte death and provide new support for the genetic diagnosis of female infertility.

Serum Metabolomics Reveals Metabolomic Profile and Potential Biomarkers in Asthma.

PURPOSE: Asthma is a highly heterogeneous disease. Metabolomics plays a pivotal role in the pathogenesis and development of asthma. The main aims of our study were to explore the underlying mechanism of asthma and to identify novel biomarkers through metabolomics approach. METHODS: Serum samples from 102 asthmatic patients and 18 healthy controls were collected and analyzed using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) system. Multivariate analysis and weighted gene co-expression network analysis (WGCNA) were performed to explore asthma-associated metabolomics profile and metabolites. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Subsequently, 2 selected serum hub metabolites, myristoleic acid and dodecanoylcarnitine, were replicated in a validation cohort using ultra-high performance LC-MS/MS system (UHPLC-MS/MS). RESULTS: Distinct metabolomics profile of asthma was revealed by multivariate analysis. Then, 116 overlapped asthma-associated metabolites between multivariate analysis and WGCNA, including 12 hub metabolites, were identified. Clinical features-associated hub metabolites were also identified by WGCNA. Among 116 asthma-associated metabolites, Sphingolipid metabolism and valine, leucine and isoleucine biosynthesis were revealed by KEGG analysis. Furthermore, serum myristoleic acid and dodecanoylcarnitine were significantly higher in asthmatic patients than in healthy controls in validation cohort. Additionally, serum myristoleic acid and dodecanoylcarnitine demonstrated high sensitivities and specificities in predicting asthma. CONCLUSIONS: Collectively, asthmatic patients showed a unique serum metabolome. Sphingolipid metabolism and valine, leucine and isoleucine biosynthesis were involved in the pathogenesis of asthma. Furthermore, our results suggest the promising values of serum myristoleic acid and dodecanoylcarnitine for asthma diagnosis in adults.

Recryopreservation impairs blastocyst implantation potential via activated endoplasmic reticulum stress pathway and induced apoptosis.

Recryopreservation (recryo) is occasionally applied in clinical, while the underlying mechanism of impaired clinical outcomes after recryo remains unclear. In this study, frozen embryo transfer (FET) cycles of single blastocyst transfer in an academic reproductive medicine center were enrolled. According to the number of times blastocysts experienced cryopreservation, they were divided into the cryopreservation (Cryo) group and the Recryo group. Donated human blastocysts were collected and detected for mechanism exploration. It was found that recryo procedure resulted in impaired blastocyst developmental potential, including decreased implantation rate, reduced biochemical pregnancy rate, declined clinical pregnancy rate, higher early miscarriage rate, and lower live birth rate. Moreover, recryo led to impaired trophectoderm (TE) function, exhibiting lower human chorionic gonadotropin levels 12 days after FET. In addition, single-cell RNA sequencing showed that the expression of genes involved in cell adhesion and embryo development were altered. More specifically, activated endoplasmic reticulum (ER) pathway and induced apoptosis were further verified by immunofluorescence and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay involving in the recryo procedure. In conclusion, recryo could interfere with the process of blastocyst implantation by impairing TE function, affecting blastocyst adhesion, activating ER stress pathway and inducing apoptosis. It provides caution to embryologists about the potential risk of recryopreservation.

Decreased embryo developmental potential and lower cumulative pregnancy rate in men with multiple morphological abnormalities of the sperm flagella.

Objective: Multiple morphological abnormalities of the sperm flagella (MMAF) is characterized by abnormal flagellar phenotypes, which is a particular kind of asthenoteratozoospermia. Previous studies have reported a comparable intracytoplasmic sperm injection (ICSI) outcome in terms of fertilization rate and clinical pregnancy rate in patients with MMAF compared with those with no MMAF; however, others have conflicting opinions. Assisted reproductive technology (ART) outcomes in individuals with MMAF are still controversial and open to debate. Methods: A total of 38 patients with MMAF treated at an academic reproductive center between January 2014 and July 2022 were evaluated in the current retrospective cohort study and followed up until January 2023. Propensity score matching was used to adjust for the baseline clinical characteristics of the patients and to create a comparable control group. The genetic pathogenesis of MMAF was confirmed by whole exome sequencing. The main outcomes were the embryo developmental potential, the cumulative pregnancy rate (CLPR), and the cumulative live birth rate (CLBR). Results: Pathogenic variants in known genes of DNAH1, DNAH11, CFAP43, FSIP2, and SPEF2 were identified in patients with MMAF. Laboratory outcomes, including the fertilization rate, 2PN cleavage rate, blastocyst formation rate, and available blastocyst rate, followed a trend of decline in the MMAF group (p < 0.05). Moreover, according to the embryo transfer times and complete cycles, the CLPR in the cohort of MMAF was lower compared with the oligoasthenospermia pool (p = 0.033 and p = 0.020, respectively), while no statistical differences were observed in the neonatal outcomes. Conclusion: The current study presented decreased embryo developmental potential and compromised clinical outcomes in the MMAF cohort. These findings may provide clinicians with evidence to support genetic counseling and clinical guidance in specific patients with MMAF.

TRPA1-PI3K/Akt-OPA1-ferroptosis axis in ozone-induced bronchial epithelial cell and lung injury.

BACKGROUND: Transient receptor potential (TRP) ankyrin 1 (TRPA1) could mediate ozone-induced lung injury. Optic Atrophy 1 (OPA1) is one of the significant mitochondrial fusion proteins. Impaired mitochondrial fusion, resulting in mitochondrial dysfunction and ferroptosis, may drive the onset and progression of lung injury. In this study, we examined whether TRPA1 mediated ozone-induced bronchial epithelial cell and lung injury by activating PI3K/Akt with the involvement of OPA1, leading to ferroptosis. METHODS: Wild-type, TRPA1-knockout (KO) mice (C57BL/6 J background) and ferrostatin-1 (Fer-1)-pretreated mice were exposed to 2.5 ppm ozone for 3 h. Human bronchial epithelial (BEAS-2B) cells were treated with 1 ppm ozone for 3 h in the presence of TRPA1 inhibitor A967079 or TRPA1-knockdown (KD) as well as pharmacological modulators of PI3K/Akt-OPA1-ferroptosis. Transcriptome was used to screen and decipher the differential gene expressions and pathways. Oxidative stress, inflammation and ferroptosis were measured together with mitochondrial morphology, function and dynamics. RESULTS: Acute ozone exposure induced airway inflammation and airway hyperresponsiveness (AHR), reduced mitochondrial fusion, and enhanced ferroptosis in mice. Similarly, acute ozone exposure induced inflammatory responses, altered redox responses, abnormal mitochondrial structure and function, reduced mitochondrial fusion and enhanced ferroptosis in BEAS-2B cells. There were increased mitochondrial fusion, reduced inflammatory responses, decreased redox responses and ferroptosis in ozone-exposed TRPA1-KO mice and Fer-1-pretreated ozone-exposed mice. A967079 and TRPA1-KD enhanced OPA1 and prevented ferroptosis through the PI3K/Akt pathway in BEAS-2B cells. These in vitro results were further confirmed in pharmacological modulator experiments. CONCLUSION: Exposure to ozone induces mitochondrial dysfunction in human bronchial epithelial cells and mouse lungs by activating TRPA1, which results in ferroptosis mediated via a PI3K/Akt/OPA1 axis. This supports a potential role of TRPA1 blockade in preventing the deleterious effects of ozone.

The effect of recryopreservation on embryo viability and outcomes of in vitro fertilization: a systematic review and meta-analysis.

OBJECTIVE: To investigate the impact of recryopreservation on embryo viability and the outcomes of in vitro fertilization (IVF) by comparison with single cryopreservation. There is a lack of consensus and reliable evidence regarding the impact of recryopreservation techniques on human embryos, particularly with respect to embryo viability and IVF outcomes. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. INTERVENTION(S): Various databases such as PubMed, Embase, Cochrane Library, and Scopus were searched until October 10, 2022. All comparative studies comparing embryonic and IVF outcomes between repeated and single cryopreservation of embryos were included. The random-effect and fixed-effect meta-analysis models were used to pool the odds ratio (OR) and corresponding 95% confidence intervals (CIs). A subgroup analysis was performed based on different methods of cryopreservation and different times of embryo cryopreservation or transfer. MAIN OUTCOME MEASURE(S): Outcomes referring to embryo surviva l, IVF outcomes (including clinical pregnancy rate, embryo implantation rate, miscarriage rate, and live birth rate), and neonatal outcomes (including low birth weight rate and preterm birth rate) were evaluated. RESULT(S): Fourteen studies were eligible for the present meta-analysis, involving 4,525 embryo transfer cycles in total (3,270 cycles with single cryopreservation [control group] and 1,255 with recryopreservation [experimental group]). Decreased embryo survival (OR, 0.51; 95% CI, 0.27-0.96) and clinical pregnancy rates (OR, 0.47; 95% CI, 0.23-0.96) were found in embryos that were recryopreserved by slow freezing. The live birth rate of revitrified embryos was also notably affected (OR, 0.60; 95% CI, 0.38-0.94). Overall, recryopreservation resulted in a decreased live birth rate (OR, 0.67; 95% CI, 0.50-0.90) and an increased miscarriage rate (OR, 1.52; 95% CI, 1.16-1.98) compared with single cryopreservation. No significant difference was found in neonatal outcomes. When embryos were cryopreserved and transferred at the blastocyst stage, both the embryo implantation rate (OR, 0.59; 95% CI, 0.39-0.89) and live birth rate (OR, 0.60; 95% CI, 0.37-0.96) were significantly different between the 2 groups. CONCLUSION(S): The present meta-analysis suggested that recryopreservation, compared with single cryopreservation, can lead to impaired embryo viability and a lower rate of IVF success, with no affected neonatal outcomes. Clinicians and embryologists should retain a cautious attitude toward recryopreservation strategies. REGISTRATION NUMBER: CRD42022359456.

A new insight into the impact of systemic lupus erythematosus on oocyte and embryo development as well as female fertility.

Background: Systemic lupus erythematosus (SLE) is often associated with adverse reproductive outcomes. But it's currently unclear regarding the role of SLE in oocyte and embryonic development. Also, it's controversial whether SLE has an adverse effect on fertility. There is a lack of comprehensive understanding and assessment of fertility in patients with SLE. Objective: This study was aim to investigate oocyte and embryonic development as well as ovarian reserve, and clinical outcomes in SLE patients during in vitro fertilization (IVF) treatment. By combining data on embryonic and gamete development in SLE patients, we hope to provide new insights into a comprehensive assessment of fertility in SLE patients. Methods: In this study, we collected data from 34 SLE patients who were previously diagnosed and in remission for a total of 44 IVF cycles and matched 102 infertile women with a total of 148 IVF cycles by Propensity Score Matching (PSM) of 1:3 ratio. We then evaluated baseline characteristics, ovarian reserve, IVF laboratory outcomes, and clinical outcomes between the two groups. Results: After PSM matching, baseline characteristics including age, infertility types, and duration, as well as infertility causes overall coincided between the two groups. Anti-müllerian hormone (AMH) was significantly lower in the SLE group vs comparison (1.9 vs. 3.3 ng/mL, P=0.001). The SLE group performed a significant reduction in available embryo rate (76.6% vs. 86.0%, P=0.001), good-quality blastocyst formation rate (35.1% vs. 47.0%, P=0.003), and blastocyst formation rate (51.0% vs. 67.7%, P=0.001) compared to the comparison. As for clinical outcomes, the implantation rate in the SLE group was notably lower (37.9% vs. 54.9%, P=0.022). The CLBR following every embryo-transfer procedure was distinctly lower (41.2% vs 64.7%, P=0.016) in the SLE group vs comparison. Also, the conservative and optimal CLBRs following every complete cycle procedure were significantly reduced in the SLE group vs the comparison (P=0.001, both). Conclusion: Patients with SLE present worse outcomes in oocyte and embryonic development, thus yielding compromised female fertility and clinical pregnancy. Individualized fertility assessment and early fertility guidance are necessary for these special groups.

CC16 as an Inflammatory Biomarker in Induced Sputum Reflects Chronic Obstructive Pulmonary Disease (COPD) Severity.

Purpose: The progression of an abnormal inflammatory response plays a crucial role in the lung function decline of chronic obstructive pulmonary disease (COPD) patients. Compared to serum biomarkers, inflammatory biomarkers in induced sputum would be a more reliable reflection of inflammatory processes in the airways. Patients and Methods: A total of 102 COPD participants were divided into a mild-to-moderate group (FEV1%pred≥ 50%, n=57) and a severe-to-very-severe group (FEV1%pred<50%, n=45). We measured a series of inflammatory biomarkers in induced sputum and analyzed their association with lung function and SGRQ in COPD patients. To evaluate the relationship between inflammatory biomarkers and the inflammatory phenotype, we also analyzed the correlation between biomarkers and airway eosinophilic phenotype. Results: We found increased mRNA levels of MMP9, LTB4R, and A1AR and decreased levels of CC16 mRNA in induced sputum in the severe-to-very-severe group. After adjustment for age, sex and other biomarkers, CC16 mRNA expression was positively associated with FEV1%pred (r=0.516, p=0.004) and negatively correlated with SGRQ scores (r=-0.3538, p=0.043). As previously known, decreased CC16 was related to the migration and aggregation of eosinophils in airway. It was also found that CC16 had a moderate negative correlation with the eosinophilic inflammation in airway (r=-0.363, p=0.045) in our COPD patients. Conclusion: Low CC16 mRNA expression levels in induced sputum were associated with low FEV1%pred and a high SGRQ score in COPD patients. Sputum CC16 as a potential biomarker for predicting COPD severity in clinical practice might attribute to the involvement of CC16 in airway eosinophilic inflammation.

Peripheral neutrophils and oxidative stress-associated molecules for predicting the severity of asthma: a cross-sectional study based on multidimensional assessment.

Objectives: This study aims to explore the relationship between the severity of asthma and neutrophils and related oxidative stress-associated molecules in peripheral blood and induced sputum. Methods: A total of 67 subjects were included in this study, namely, 25 patients with severe asthma and 42 patients with non-severe asthma. Clinical data, induced sputum and peripheral blood were collected. Lung function and molecules related to oxidative stress in induced sputum and peripheral blood of asthma patients were detected. The relationship between neutrophils and asthma severity was analyzed. HDAC2 mRNA and protein expression levels and HDAC2 activity were also analyzed. Multivariate logistic regression was performed to select statistically significant variables. Results: The absolute value of neutrophils and percentage of neutrophils were higher in the severe asthma patients. These two values were used to predict the severity of asthma by ROC analysis, with the best cutoff values being 4.55 × 109/L (sensitivity 83.3%, specificity 64.0%) and 55.15% (sensitivity 54.8%, specificity 88.0%). The ROS concentration of neutrophils in the induced sputum samples and the 8-iso-PGF2α concentration in the peripheral blood samples were higher in the severe asthma group (P = 0.012; P = 0.044), whereas there was reduced HDAC2 protein activity in PBMCs (P < 0.001). A logistic equation and a nomogram were created to give a precise prediction of disease severity. Conclusion: Oxidative stress is increased in severe asthma patients. Peripheral blood neutrophils and 8-iso-PGF2α can be used as biomarkers to predict the severity of asthma. A prediction model was created for evaluating asthma severity.

Stable Chronic Obstructive Pulmonary Disease (COPD) Management Under a Tiered Medical System in China.

BACKGROUND: Early diagnosis and proper management of a large number of chronic obstructive pulmonary disease (COPD) patients are great challenges for the Chinese health care system. Although tiered medical services have been promoted by the Chinese government since 2015, they have not been ideally implemented for COPD diagnosis and management. PATIENTS AND METHODS: We designed a cross-sectional study. Eligible COPD patients (n = 648) and physicians (n = 161) were consecutively recruited from 8 hospitals in different tiers in China. COPD characteristics and treatments were compared among hospitals in different tiers. Multivariate logistic regression was performed to identify risk factors associated with airflow limitation, symptoms and acute exacerbation. RESULTS: The PFT rate at first diagnosis was 99%, 69.4% and 29.9% in teaching, second-tier and community hospitals (P < 0.001). Only approximately 10.9%, 1.7% and 9.6% and 21.8%, 6.9% and 32% of COPD patients received influenza or pneumococcal vaccines (P < 0.001). The proportion of patients who did not use inhaled drugs or had irregular inhalation was 2%, 24.6% and 78.8% (P < 0.001). Education level (RR-1 = -41.26%, P = 0.007), FEV1%pred (RR-1 = -2.76%, P < 0.001), and influenza vaccination in the last year (RR-1 = -64.53%, P = 0.006) were all negatively correlated with COPD acute exacerbation (AE). COPD duration (RR-1 = 131.73%, P = 0.009), AE (RR-1 = 151.39%, P < 0.001), and COPD Assessment Test (CAT) scores (RR-1 = 3.82%, P = 0.019) were all positively correlated with COPD airflow limitation severity. CONCLUSION: Differences exist in the diagnosis, treatment and management of COPD among different tiers of hospitals in China. Teaching hospitals can manage COPD patients relatively well. There are still some gaps compared with developed countries.

Lipopolysaccharide-Activated Bone Marrow-Derived Dendritic Cells Suppress Allergic Airway Inflammation by Ameliorating the Immune Microenvironment.

Background: Previous studies have shown that lipopolysaccharide (LPS)-activated bone marrow-derived dendritic cells (DClps) might induce tolerance in autoimmune and cancer models in vivo, whereas it remains unclear whether DClps could play a role in allergic disease model. Herein, we aimed to elucidate the potential effects of DClps on OVA-sensitized/challenged airway inflammation in a mouse model, which may help facilitate the application of specific tolerogenic dendritic cells (tolDC) in allergic asthma in the future. Methods: The phenotype and function of immature DC (DCia), DClps or IL-10-activated-DC (DC10) were determined. OVA-sensitized/challenged mice were treated with OVA-pulsed DCia or DClps or DC10. We assessed the changes of histopathology, serum total IgE level, pulmonary signal transducers and activators of transcription (STAT), pulmonary regulatory T cells (Tregs), and airway recall responses to OVA rechallenge, including proliferation and cytokine secretory function of pulmonary memory CD4+ T cells in the treated mice. Results: DClps exhibited low levels of CD80 and MHCII and increased levels of anti-inflammatory cytokines such as IL-10 and TGF-ß. Additionally, DClps treatment dramatically diminished infiltration of inflammatory cells, eosinophilia, serum IgE and STAT6 phosphorylation level, increased the number of pulmonary Tregs. In addition, DClps treatment decreased the proliferation of pulmonary memory CD4+ T cells, which further rendered the downregulation of Th2 cytokines in vitro. Conclusion: LPS stimulation may lead to a tolerogenic phenotype on DC, and thereby alleviated the Th2 immune response of asthmatic mice, possibly by secreting anti-inflammatory cytokines, inhibiting pulmonary memory CD4+ T cells, downregulating pulmonary STAT6 phosphorylation level and increasing pulmonary Tregs.

Evaluating carbon content in airway macrophages as a biomarker of personal exposure to fine particulate matter and its acute respiratory effects.

It remains unclear whether carbon content in airway macrophages (AM) can predict personal short-term exposure to fine particulate matter (PM2.5) air pollution and its respiratory health effects. We aimed to evaluate the pathway from personal PM2.5 exposure to adverse respiratory outcomes through AM carbon content. We designed a longitudinal panel study with 3 scheduled follow-ups among 113 non-smoking patients of chronic obstructive pulmonary disease in Shanghai, China, from April 2017 to January 2019. We quantified AM carbon content from induced sputum by image analysis, tested lung function and measured sputum levels of 4 pro-inflammatory cytokines and 2 anti-inflammatory cytokines. We applied the "meet in the middle" approach incorporating linear mixed-effect models to evaluate the associations from external PM2.5 exposure to respiratory outcomes through AM carbon content. Our results indicated that personal exposure to PM2.5 within 24 h was significantly associated with decreased forced expiratory volume in 1s and anti-inflammatory cytokines, as well as increased macrophages and pro-inflammatory cytokines. These changes were accompanied by increased areas of AM carbon and higher percentage of AM area occupied by carbon, both of which were associated with increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines. Exposure to ambient black carbon and organic carbon in PM2.5 within 2 days was significantly associated with increased AM carbon area and percentage of AM area occupied by carbon. Our findings reinforced the causality in respiratory health effects of PM2.5 in which increased AM carbon content might serve as a valid exposure biomarker.

Induced sputum metabolomic profiles and oxidative stress are associated with chronic obstructive pulmonary disease (COPD) severity: potential use for predictive, preventive, and personalized medicine.

Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous disease, and metabolomics plays a hub role in predictive, preventive, and personalized medicine (PPPM) related to COPD. This study thus aimed to reveal the role of induced sputum metabolomics in predicting COPD severity. In this pilot study, a total of 20 COPD patients were included. The induced sputum metabolites were assayed using a liquid chromatography-mass spectrometry (LC-MS/MS) system. Five oxidative stress products (myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione (GSH), neutrophil elastase (NE), and 8-iso-PGF2α) in induced sputum were measured by ELISA, and the metabolomic profiles were distinguished by principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA). The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis, and a significant difference in induced sputum metabolomics was observed between moderate and severe COPD. The KEGG analysis revealed that the glycerophospholipid metabolism pathway was downregulated in severe COPD. Due to the critical role of glycerophospholipid metabolism in oxidative stress, significant negative correlations were discovered between glycerophospholipid metabolites and three oxidative stress products (SOD, MPO, and 8-iso-PGF2α). The diagnostic values of SOD, MPO, and 8-iso-PGF2α in induced sputum were found to exhibit high sensitivities and specificities in the prediction of COPD severity. Collectively, this study provides the first identification of the association between induced sputum metabolomic profiles and COPD severity, indicating the potential value of metabolomics in PPPM for COPD management. The study also reveals the correlation between glycerophospholipid metabolites and oxidative stress products and their value for predicting COPD severity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-020-00227-w.