Improvement in Health-Related Quality of Life Following Antibiotic Treatment in Nontuberculous Mycobacterial Pulmonary Disease: Initial Analysis of the NTM-KOREA Cohort.

BACKGROUND: Improving health-related quality of life (HRQOL) has emerged as a priority in the management of nontuberculous mycobacterial pulmonary disease (NTM-PD). We aimed to evaluate HRQOL and its changes after 6 months' treatment in patients with NTM-PD. METHODS: The NTM-KOREA is a nationwide prospective cohort enrolling patients initiating treatment for NTM-PD in 8 institutions across South Korea. We conducted the Quality of Life-Bronchiectasis (QOL-B) at 6-month intervals and evaluated baseline scores (higher scores indicate better quality of life) and changes after 6 months' treatment. Multivariate logistic regression was performed to identify factors associated with improvement in the QOL-B physical functioning and respiratory symptoms domains. RESULTS: Between February 2022 and August 2023, 411 patients were included in the analysis. Baseline scores (95% confidence interval [CI]) for physical functioning and respiratory symptoms were 66.7 (46.7-86.7) and 81.5 (70.4-92.6), respectively. Among 228 patients who completed the QOL-B after 6 months' treatment, improvements in physical functioning and respiratory symptoms were observed in 61 (26.8%) and 71 (31.1%) patients, respectively. A lower score (adjusted odds ratio; 95% CI) for physical functioning (0.93; 0.91-0.96) and respiratory symptoms (0.92; 0.89-0.95) at treatment initiation was associated with a greater likelihood of physical functioning and respiratory symptom improvement, respectively; achieving culture conversion was not associated with improvement in physical functioning (0.62; 0.28-1.39) or respiratory symptoms (1.30; 0.62-2.74). CONCLUSIONS: After 6 months of antibiotic treatment for NTM-PD, HRQOL improved in almost one-third, especially in patients with severe initial symptoms, regardless of culture conversion. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT03934034.

Rare deep vein thrombosis in pregnancy and puerperium 3 case series; upper extremities vein thrombosis, ovarian vein thrombosis, portal and superior mesenteric vein thrombosis.

Pregnancy induces a hypercoagulable state, elevating thrombosis risk by 5-6 times compared to non-pregnant conditions. Predominantly affecting the left lower extremity due to anatomical and hematological factors, deep vein thrombosis can escalate into pulmonary embolism, impacting mortality. The authors aim to report rare incidents of thrombosis beyond the norm, including upper extremity vein thrombosis, right ovarian vein thrombosis, and portal vein and superior mesenteric vein thrombosis, highlighting their significance. Obstetricians should be mindful that thrombosis can occur not only in the lower extremities but also in other areas. Especially when symptoms such as fever unresponsive to antibiotics, atypical pain, and an abnormally high C-reactive protein level are present. Considering the possibility of a rare thrombosis is crucial. Understanding these less common thrombotic events during pregnancy and the postpartum period can contribute to the improvement of timely diagnosis and management strategies.

Discovery of Pathogenic Variants Associated with Idiopathic Recurrent Pregnancy Loss Using Whole-Exome Sequencing.

Idiopathic recurrent pregnancy loss (RPL) is defined as at least two pregnancy losses before 20 weeks of gestation. Approximately 5% of pregnant couples experience idiopathic RPL, which is a heterogeneous disease with various causes including hormonal, chromosomal, and intrauterine abnormalities. Although how pregnancy loss occurs is still unknown, numerous biological factors are associated with the incidence of pregnancy loss, including genetic variants. Whole-exome sequencing (WES) was conducted on blood samples from 56 Korean patients with RPL and 40 healthy controls. The WES data were aligned by means of bioinformatic analysis, and the detected variants were annotated using machine learning tools to predict the pathogenicity of protein alterations. Each indicated variant was confirmed using Sanger sequencing. A replication study was also conducted in 112 patients and 114 controls. The Variant Effect Scoring Tool, Combined Annotation Dependent Depletion tool, Sorting Intolerant from Tolerant annotation tool, and various databases detected 10 potential variants previously associated with spontaneous abortion genes in patients by means of a bioinformatic analysis of WES data. Several variants were detected in more than one patient. Interestingly, several of the detected genes were functionally clustered, including some with a secretory function (mucin 4; MUC4; rs200737893 G>A and hyaluronan-binding protein 2; HABP2; rs542838125 G>T), in which growth arrest-specific 2 Like 2 (GAS2L2; rs140842796 C>T) and dynamin 2 (DNM2; rs763894364 G>A) are functionally associated with cell protrusion and the cytoskeleton. ATP Binding Cassette Subfamily C Member 6 (ABCC6) was the only gene with two variants. HABP2 (rs542838125 G>T), MUC4 (rs200737893 G>A), and GAS2L2 (rs140842796 C>T) were detected in only the patient group in the replication study. The combination of WES and machine learning tools is a useful method to detect potential variants associated with RPL. Using bioinformatic tools, we found 10 potential variants in 9 genes. WES data from patients are needed to better understand the causes of RPL.

9 months of delamanid, linezolid, levofloxacin, and pyrazinamide versus conventional therapy for treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-END): a multicentre, randomised, open-label phase 2/3 non-inferiority trial in South Korea.

BACKGROUND: With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We aimed to investigate whether a new all-oral regimen was non-inferior to the conventional regimen including second-line anti-tuberculosis drugs for 20-24 months in the treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis. METHODS: In this multicentre, randomised, open-label phase 2/3 non-inferiority trial, we enrolled men and women aged 19-85 years with multidrug-resistant tuberculosis confirmed by phenotypic or genotypic drug susceptibility tests or rifampicin-resistant tuberculosis by genotypic tests at 12 participating hospitals throughout South Korea. Participants with fluoroquinolone-resistant multidrug-resistant tuberculosis were excluded. Participants were randomly assigned (1:1) to two groups using a block randomisation, stratified by the presence of diabetes and cavitation on baseline chest radiographs. The investigational group received delamanid, linezolid, levofloxacin, and pyrazinamide for 9 months, and the control group received a conventional 20-24-month regimen, according to the 2014 WHO guidelines. The primary outcome was the treatment success rate at 24 months after treatment initiation in the modified intention-to-treat population and the per-protocol population. Participants who were "cured" and "treatment completed" were defined as treatment success following the 2014 WHO guidelines. Non-inferiority was confirmed if the lower limit of a 97·5% one-sided CI of the difference between the groups was greater than -10%. Safety data were collected for 24 months in participants who received a predefined regimen at least once. This study is registered with ClinicalTrials.gov, NCT02619994. FINDINGS: Between March 4, 2016, and Sept 14, 2019, 214 participants were enrolled, 168 (78·5%) of whom were included in the modified intention-to-treat population. At 24 months after treatment initiation, 60 (70·6%) of 85 participants in the control group had treatment success, as did 54 (75·0%) of 72 participants in the shorter-regimen group (between-group difference 4·4% [97·5% one-sided CI -9·5% to ∞]), satisfying the predefined non-inferiority margin. No difference in safety outcomes was identified between the control group and the shorter-regimen group. INTERPRETATION: 9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis. FUNDING: Korea Disease Control and Prevention Agency, South Korea.

Uterine artery embolization for postpartum hemorrhage with placenta accreta spectrum.

BACKGROUND: The reported success rate of uterine artery embolization (UAE) for postpartum hemorrhage (PPH) differs by the cause of bleeding; in some reports, UAE shows less successful results in patients with placenta accreta spectrum (PAS). PURPOSE: To evaluate the outcome of UAE for treating PPH associated with PAS. MATERIAL AND METHODS: From September 2011 to September 2021, 227 patients (mean age = 34.67±4.06 years; age range = 19-47 years) underwent UAE for managing intractable PPH. Patients were divided into two groups: those with PAS (n = 46) and those without PAS (n = 181). Delivery details, embolization details, and procedure-related outcomes were compared between the two groups. P values <0.05 were considered statistically significant. RESULTS: The technical success rate was 96.9% (n = 222) and the clinical success rate was 93.8% (n = 215). There were no significant differences in outcome of UAE between the two patient groups. The technical success rate was 95.7% (n = 44) in patients with PAS and 98.3% (n = 178) in patients without PAS (P = 0.267). The clinical success rate was 91.3% (n = 42) in patients with PAS and 95.6% (n = 173) in patients without PAS (P = 0.269). There were 24 cases of immediate complications, including pelvic pain (n = 20), urticaria (n = 3), and puncture site hematoma (n = 1). No major complication was reported. CONCLUSION: UAE is a safe and effective method to control intractable PPH for patients with or without PAS.

Increased IGFBP2 Levels by Placenta-Derived Mesenchymal Stem Cells Enhance Glucose Metabolism in a TAA-Injured Rat Model via AMPK Signaling Pathway.

The insulin resistance caused by impaired glucose metabolism induces ovarian dysfunction due to the central importance of glucose as a source of energy. However, the research on glucose metabolism in the ovaries is still lacking. The objectives of this study were to analyze the effect of PD-MSCs on glucose metabolism through IGFBP2-AMPK signaling and to investigate the correlation between glucose metabolism and ovarian function. Thioacetamide (TAA) was used to construct a rat injury model. PD-MSCs were transplanted into the tail vein (2 × 106) 8 weeks after the experiment started. The expression of the IGFBP2 gene and glucose metabolism factors (e.g., AMPK, GLUT4) was significantly increased in the PD-MSC group compared to the nontransplantation (NTx) group (* p < 0.05). The levels of follicular development markers and the sex hormones AMH, FSH, and E2 were also higher than those in the TAA group. Using ex vivo cocultivation, the mRNA and protein expression of IGFBP2, AMPK, and GLUT4 were significantly increased in the cocultivation with the PD-MSCs group and the recombinant protein-treated group (* p < 0.05). These findings suggest that the increased IGFBP2 levels by PD-MSCs play an important role in glucose metabolism and ovarian function through the IGFBP2-AMPK signaling pathway.

Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population.

The growing prevalence of in vitro fertilization-embryo transfer procedures has resulted in an increased incidence of recurrent implantation failure (RIF), necessitating focused research in this area. STAT3, a key factor in maternal endometrial remodeling and stromal proliferation, is crucial for successful embryo implantation. While the relationship between STAT3 and RIF has been studied, the impact of single nucleotide polymorphisms (SNPs) in miRNAs, well-characterized gene expression modulators, on STAT3 in RIF cases remains uncharacterized. Here, we investigated 161 RIF patients and 268 healthy control subjects in the Korean population, analyzing the statistical association between miRNA genetic variants and RIF risk. We aimed to determine whether SNPs in specific miRNAs, namely miR-218-2 rs11134527 G>A, miR-34a rs2666433 G>A, miR-34a rs6577555 C>A, and miR-130a rs731384 G>A, were significantly associated with RIF risk. We identified a significant association between miR-34a rs6577555 C>A and RIF prevalence (implantation failure [IF] ≥ 2: adjusted odds ratio [AOR] = 2.264, 95% CI = 1.007-5.092, p = 0.048). These findings suggest that miR-34a rs6577555 C>A may contribute to an increased susceptibility to RIF. However, further investigations are necessary to elucidate the precise mechanisms underlying the role of miR-34a rs6577555 C>A in RIF. This study sheds light on the genetic and molecular factors underlying RIF, offering new avenues for research and potential advancements in the diagnosis and treatment of this complex condition.

Clinical features at the time of non-hysteroscopic myomectomy before pregnancy, which affect adverse pregnancy outcomes: a retrospective cohort study.

BACKGROUND: To investigate the association of clinical characteristics at the time of non-hysteroscopic myomectomy before pregnancy and adverse obstetric outcomes in the next pregnancy. METHODS: In this retrospective cohort study, we identified 248 women who underwent abdominal or laparoscopic myomectomy for intramural (IM) and/or subserosal (SS) uterine myomas in Bundang CHA Medical Center before pregnancy and delivered at the same hospital between 2010 and 2020. The association between clinical characteristics at the time of myomectomy and subsequent obstetric outcomes was analyzed using the Chi-square test, the Student t-test or one-way ANOVA, and multivariable analysis. RESULTS: There was one case of uterine rupture. The gestational age at delivery was 37.7 ± 2.4 weeks. There were 2 (0.8%) cases of fetal loss before 23 weeks, but there were no cases of perinatal death. The risk of transfusion during or after delivery was higher in the group in which multiple myomas were removed compared to the group in which only one was removed (aOR = 2.41, 95% CI [1.20-4.86], p = 0.014). The risk of neonatal composite morbidity was higher in the group in which myomas including the IM type were removed, than in the group in which only SS myomas were removed (aOR = 14.29, 95% CI [1.82-99.57], p = 0.012). Although not statistically significant, the group in which the sum of the diameters of the three largest myomas was greater than 15 cm showed a higher frequency of preterm birth (19.3% vs. 10.1%, p = 0.001) and lower birth weight (2901 ± 625 g vs. 3063 ± 576 g, p = 0.001) compared to the group with diameters less than 15 cm. Placenta accreta/increta (7.9% vs. 3.8%, p = 0.043) and lower placental weight (646 ± 170 g vs. 750 ± 232 g, p = 0.034) were more common in patients with an interval between myomectomy and pregnancy of less than 12 months compared to more than 12 months. CONCLUSIONS: To our knowledge, this is the first study to investigate the association between clinical features at the time of myomectomy before pregnancy and various adverse obstetric and perinatal outcomes. If the removed myomas are multiple, IM, large, or the interval between myomectomy and pregnancy is short, the risk of obstetric and neonatal complications may increase.

Actinoflavosides B-D, Flavonoid Type Glycosides from Tidal Mudflat-Derived Actinomyces.

Three new secondary metabolites, actinoflavosides B-D (1-3), were discovered in the culture broth of two actinomycete strains (JML48 and JMS33) that were isolated from tidal mudflat sediment in Muan, Republic of Korea. The planar structures of the actinoflavosides were elucidated by MS, UV, and NMR analyses. The stereochemistry of an aminosugar, 2,3,6-trideoxy-3-amino-ribopyranoside in the actinoflavosides was determined by J-based configuration analysis using values obtained from DQF-COSY experiments and modified Mosher's method. Actinoflavosides B-D (1-3) displayed antibacterial activity against Pseudomonas aeruginosa, and actinoflavoside D (3) significantly increased IL-2 production in mouse splenocytes.

The association of maternal serum biomarkers and birth weight in twin pregnancy: a retrospective cohort study.

We retrospectively reviewed the medical records of 524 women with twin pregnancies who underwent antenatal care and gave birth in the past 12 years. Birth weight (BW) data were classified into three groups. We analysed the association between maternal serum biomarkers and BW in twin pregnancies using multiple logistic regression analysis. There were significant differences in the MoM values of pregnancy-associated plasma protein-A (PAPP-A), unconjugated oestriol (uE3) and inhibin A between low BW and healthy newborns. The inhibin A value was significantly higher in women with small-for-gestational-age (SGA) foetuses and the PAPP-A, and uE3 values were lower in the SGA group than in the other groups using the generalised linear mixed model (hierarchical modelling considering cluster effects for twins). Maternal serum biomarkers, including PAPP-A, uE3, and inhibin A, may be associated with SGA in twin pregnancy. Our results might provide useful information for SGA prediction during prenatal period in twin pregnancy. IMPACT STATEMENTWhat is already known on this subject? The SGA is more frequent in twin pregnancies than in singleton, but there is no clearly identification of the aetiology of SGA. Further, most studies have been conducted in singleton pregnancies.What do the results of this study add? The association of each maternal serum marker with SGA was assessed in the current study, and it is demonstrated that the levels of PAPP-A and uE3 in maternal serum of SGA foetuses were significantly lower than those in the other groups. In contrast, the levels of inhibin A were significantly increased in the SGA.What are the implications of these findings for clinical practice and/or further research? The maternal serum biomarker of inhibin A was a more valuable predictive factor for SGA prediction in twins. The results of this study can be used in counselling prenatal screening. Further prospective research is needed to combine with ultrasound growth parameters, which can be generalised for the prediction of SGA in twins.

Transcatheter Arterial Embolization in the Management of Postpartum Hemorrhage due to Genital Tract Injury after Vaginal Delivery.

PURPOSE: To evaluate efficacy and safety of transcatheter arterial embolization (TAE) in managing postpartum hemorrhage (PPH) due to genital tract injury after vaginal delivery and to investigate factors associated with outcome of TAE. MATERIALS AND METHODS: A retrospective review of 43 women (mean age, 32.6 years) who underwent TAE to manage PPH secondary to genital tract injury after vaginal delivery was performed at a single institution between January 2007 and December 2018. Clinical data and outcomes were obtained. Patients were classified into clinical success (n = 39) and failure (n = 4) groups, and comparisons between the groups were performed. RESULTS: The clinical success rate of TAE for PPH due to genital tract injury was 90.7%. In the clinical failure group, transfusion volumes were higher (failure vs success: packed red blood cells, 14 pt ± 3.37 vs 6.26 pt ± 4.52, P = .003; platelets, 10.33 pt ± 4.04 vs 2.92 pt ± 6.15, P = .036); hemoglobin levels before the procedure were lower (failure vs success: 7.3 g/dL vs 10.7, P = .016). Periprocedural complications included pulmonary edema (25.6%), fever (23.3%), and pain (9.3%). Twenty-four patients were either followed for > 6 months or answered a telephone survey; 23 (95.8%) recovered regular menstruation, and pregnancy was confirmed in 11 (45.8%). Regarding fertility desires, 7 women attempted to conceive, 6 of whom (85.7%) became pregnant. CONCLUSIONS: TAE is an effective and safe method for managing PPH due to genital tract injury after vaginal delivery. Lower hemoglobin levels before the procedure and higher transfusion volumes were associated with clinical failure of TAE.

Anti-allergic Inflammatory Components from the Leaves of Piper crocatum Ruiz & Pav.

Piper crocatum Ruiz & Pav. (P. crocatum), a traditional medicinal plant, has been shown to possess various pharmacological activities, including anticancer activity, antioxidant activity, antibacterial activity, anti-hyperglycemic activity, anti-allergic inflammatory activity and others. To identify the potential anti-allergic inflammatory effective constituents of P. crocatum, 13 single compounds were isolated from the methanol extract of P. crocatum leaves, and their structures were identified by contrasting their NMR spectroscopic data and previously published papers. First, the anti-allergic inflammatory activities of these single compounds were examined by accessing immune function related biomarkers such as nitric oxide (NO) and ß-hexosaminidase. We found that the methanol extract and catechaldehyde (compound 1) potently suppressed NO production. Additionally, Western blot analysis showed that P. crocatum methanol extract and compound 1 suppressed the production of NO by reducing inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Consistent with these observations, P. crocatum methanol extract and compound 1 remarkably decreased ß-hexosaminidase release from RBL-2H3 cells stimulated with 2,4-dinitrophenylated bovine serum albumin (DNP-BSA)-specific immunoglobulin E (IgE) antibodies. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay indicated that P. crocatum methanol extract and compound 1 exhibited no cytotoxicity to RAW264.7 and RBL-2H3 cells. Based on these findings, compound 1 is suggested as an active anti-allergic inflammatory component of P. crocatum.

Effect of Endogenic and Exogenic Oxidative Stress Triggers on Adverse Pregnancy Outcomes: Preeclampsia, Fetal Growth Restriction, Gestational Diabetes Mellitus and Preterm Birth.

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify them. During a normal pregnancy, oxidative stress increases the normal systemic inflammatory response and is usually well-controlled by the balanced body mechanism of the detoxification of anti-oxidative products. However, pregnancy is also a condition in which this adaptation and balance can be easily disrupted. Excessive ROS is detrimental and associated with many pregnancy complications, such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB), by damaging placentation. The placenta is a tissue rich in mitochondria that produces the majority of ROS, so it is important to maintain normal placental function and properly develop its vascular network to ensure a safe and healthy pregnancy. Antioxidants may ameliorate these diseases, and related research is progressing. This review aimed to determine the association between oxidative stress and adverse pregnancy outcomes, especially PE, FGR, GDM, and PTB, and explore how to overcome this oxidative stress in these unfavorable conditions.

Association between HOX Transcript Antisense RNA Single-Nucleotide Variants and Recurrent Implantation Failure.

Recurrent implantation failure (RIF) refers to the occurrence of more than two failed in vitro fertilization-embryo transfers (IVF-ETs) in the same individual. RIF can occur for many reasons, including embryo characteristics, immunological factors, and coagulation factors. Genetics can also contribute to RIF, with some single-nucleotide variants (SNVs) reported to be associated with RIF occurrence. We examined SNVs in a long non-coding RNA, homeobox (HOX) transcript antisense RNA (HOTAIR), which is known to affect cancer development. HOTAIR regulates epigenetic outcomes through histone modifications and chromatin remodeling. We recruited 155 female RIF patients and 330 healthy controls, and genotyped HOTAIR SNVs, including rs4759314, rs920778, rs7958904, and rs1899663, in all participants. Differences in these SNVs were compared between the patient and control groups. We identified significant differences in the occurrence of heterozygous genotypes and the dominant expression model for the rs1899663 and rs7958904 SNVs between RIF patients and control subjects. These HOTAIR variants were associated with serum hemoglobin (Hgb), luteinizing hormone (LH), total cholesterol (T. chol), and blood urea nitrogen (BUN) levels, as assessed by analysis of variance (ANOVA). We analyzed the four HOTAIR SNVs and found significant differences in haplotype patterns between RIF patients and healthy controls. The results of this study showed that HOTAIR is not only associated with the development of cancer but also with pregnancy-associated diseases. This study represents the first report showing that HOTAIR is correlated with RIF.

miR-373-3p Regulates Invasion and Migration Abilities of Trophoblast Cells via Targeted CD44 and Radixin.

Preterm labor (PTL) is one of the obstetric complications, and is known to be associated with abnormal maternal inflammatory response and intrauterine inflammation and/or infection. However, the expression of specific miRNAs associated with PTL is not clear. In this study, we performed combination analysis of miRNA array and gene array, and then selected one miRNA (miR-373-3p) and its putative target genes (CD44 and RDX) that exhibited large expression differences in term and PTL placentas with or without inflammation. Using qRT-PCR and luciferase assays, we confirmed that miR-373-3p directly targeted CD44 and RDX. Overexpression of miR-373-3p reduced the migration and invasion of trophoblast cells, while inhibition of miR-373-3p restored the migration and invasion abilities of trophoblast cells. Finally, we validated the expression of miR-373-3p and its target genes in clinical patients' blood. miR-373-3p was increased in PTL patients' blood, and was the most expressed in PTL patients' blood with inflammation. In addition, by targeting the miR-373-3p, CD44 and RDX was decreased in PTL patients' blood, and their expression were the lowest in PTL patients' blood with inflammation. Taken together, these findings suggest that miR-373-3p and its target genes can be potential biomarkers for diagnosis of PTL.

Genetic Polymorphisms in miR-604A>G, miR-938G>A, miR-1302-3C>T and the Risk of Idiopathic Recurrent Pregnancy Loss.

The purpose of this study was to investigate whether polymorphisms in five microRNAs (miRNAs), miR-604A>G, miR-608C>G, 631I/D, miR-938G>A, and miR-1302-3C>T, are associated with the risk of idiopathic recurrent pregnancy loss (RPL). Blood samples were collected from 388 patients with idiopathic RPL (at least two consecutive spontaneous abortions) and 227 control participants. We found the miR-604 AG and AG + GG genotypes of miR-604, the miR-938 GA and GA + AA genotypes of miR-938, and the miR-1302-3CT and CT + TT genotypes of miR-1302-3 are less frequent than the wild-type (WT) genotypes, miR-604AA, miR-938GG, and miR-1302-3CC, respectively, in RPL patients. Using allele-combination multifactor dimensionality reduction (MDR) analysis, we found that eight haplotypes conferred by the miR-604/miR-608/miR-631/miR-938/miR-1302-3 allele combination, A-C-I-G-T, A-C-I-A-C, G-C-I-G-C, G-C-I-G-T, G-G-I-G-C, G-G-I-G-T, G-G-I-A-C, G-G-D-G-C, three from the miR-604/miR-631/miR-938/miR-1302-3 allele combination, A-I-G-T, G-I-G-C, G-I-A-T, one from the miR-604/miR-631/miR-1302-3 allele combination, G-I-C, and two from the miR-604/miR-1302-3 allele combination, G-C and G-T, were less frequent in RPL patients, suggesting protective effects (all p < 0.05). We also identified the miR-604A>G and miR-938G>A polymorphisms within the seed sequence of the mature miRNAs and aligned the seed sequences with the 3'UTR of putative target genes, methylenetetrahydrofolate reductase (MTHFR) and gonadotropin-releasing hormone receptor (GnRHR), respectively. We further found that the binding affinities between miR-604/miR-938 and the 3'UTR of their respective target genes (MTHFR, GnRHR) were significantly different for the common (miR-604A, miR-938G) and variant alleles (miR-604G, miR-938A). These results reveal a significant association between the miR-604A>G and miR-938G>A polymorphisms and idiopathic RPL and suggest that miRNAs can affect RPL in Korean women.

Associations between microRNA (miR-25, miR-32, miR-125, and miR-222) polymorphisms and recurrent implantation failure in Korean women.

BACKGROUND: Recurrent implantation failure (RIF) is the failure of embryos to implant more than two times in a given individual. There is debate about a precise definition for RIF, but we consider more than two implantation failures for individuals who undergo in vitro fertilization-embryo transfer (IVF-ET) to constitute RIF. There are many potential reasons for RIF, including embryonic factors, immunological factors, uterine factors, coagulate factors, and genetic factors. Genetic variation has been suggested as one of the contributing factors leading to RIF, and a number of single-nucleotide polymorphisms (SNPs) have been reported to be associated with RIF. The recent elucidation of miRNA functions has provided new insight into the regulation of gene expression. METHODS: We investigated associations between polymorphisms in four miRNAs and RIF in 346 Korean women: 118 patients with RIF and 228 controls. We determined the genotypes of the miRNAs in the study participants by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis. We analyzed the effects of genotypes, allele combinations, and environmental and clinical factors on the risk of RIF. RESULTS: The miR-25 T/miR-125aT/miR-222G (odds ratio (OR), 0.528; 95% confidence interval (CI), 0.282-0.990; P = 0.044) and miR-25 T/miR-125aT allele combinations were associated with a reduced risk of RIF. The miR-25 T/miR-32C/miR-125aC/miR-222 T allele combination was associated with an increased risk of RIF. The miR-222GT+TT genotypes interacted with high prothrombin time (≥ 12 s) to increase the risk of RIF. CONCLUSIONS: MicroRNA polymorphisms are significantly different between patients that experience RIF and healthy controls. Combinations of microRNA polymorphisms were associated with the risk of RIF. Interactions between environmental factors and genotypes increased the risk of RIF in Korean women.

Per- and poly-fluoroalkyl substances (PFASs) in follicular fluid from women experiencing infertility in Australia.

Per- and poly-fluoroalkyl substances (PFASs) have been widely used and detected in human matrices. Evidence that PFAS exposure may be associated with adverse human reproductive health effects exists, however, data is limited. The use of a human matrix such as follicular fluid to determine chemical exposure, along with reproductive data will be used to investigate if there is a relationship between PFAS exposure and human fertility. OBJECTIVE: This study aims to: (1) assess if associations exist between PFAS concentrations and/or age and fertilisation rate (as determined in follicular fluid of women in Australia who received assisted reproductive treatment (ART)); and (2) assess if associations exist between PFAS concentrations and infertility aetiology. METHODS: Follicular fluids were originally collected from participants who underwent fully stimulated ART treatment cycles at an in vitro fertilisation (IVF) clinic in the period 2006-2009 and 2010-11 in Queensland, Australia. The samples were available for analysis of 32 PFASs including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA) using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). 97 samples were matched with limited demographic data (age and fertilisation rate) and five infertility factors (three known female factors): 1) endometriosis, 2) polycystic ovarian syndrome (PCOS), and 3) genital tract infections - tubal/pelvic inflammation disease; as well as 4) male factor, and 5) idiopathic or unknown from either males or females. SPSS was used for linear regression analysis. RESULTS: PFASs were detected in all follicular fluid samples with the mean concentrations of PFOS and PFOA, 4.9, and 2.4 ng/ml, respectively. A lower fertilisation rate was observed at higher age when age was added as a covariate, but there was no relationship between PFAS concentrations and fertilisation rate. There were few statistically significant associations between PFAS concentrations in follicular fluid and infertility factors. Log-transformed PFHxS concentrations were lower in females with endometriosis (factor 1) than in women who had reported 'male factors' as a reason of infertility, while PFHpA was higher in women who had infertile due to female factors (factor 1-3) compared to those who had infertile due to male factor. CONCLUSION: PFASs were detected in follicular fluid of Australian women who had been treated at an IVF clinic. PFAS exposure found in follicular fluids is linked to increased risk of some infertility factors, and increased age was associated with decreased fertilisation rate in our data. But there was no relationship between PFAS and ferlitisation rate. Further large-scale investigations of PFAS and health effects including infertility are warranted.

Medical Help-Seeking Strategies for Perinatal Women With Obstetric and Mental Health Problems and Changes in Medical Decision Making Based on Online Health Information: Path Analysis.

BACKGROUND: Previous studies have revealed that most pregnant women rarely discuss informal information found on the internet with health professionals and have frequently expressed concerns for medical experts' reactions to the online information they shared, as well as the lack of time to consult the medical experts in general. To date, little information is available on the effect of individual differences in utilizing medical help-seeking strategies on their medical decisions during the perinatal period. OBJECTIVE: The objectives of this study were (1) to determine associations among perinatal women's medical help-seeking strategies, changes in medical decision making, and online health information utilization with a focus on the mediating effect of self-efficacy in perinatal health literacy on the intent to consult health professionals, and (2) to clarify these associations in perinatal women with two different medical problems: obstetric and mental health. METHODS: A total of 164 perinatal women aged 24 to 47 years (mean 34.64, SD 3.80) repeatedly completed the Problem Solving in Medicine and Online Health Information Utilization questionnaires to examine the moderating effect of two types of medical problems on their decision-making processes. To validate the hypothesized relationships in the proposed conceptual model encompassing obstetric and mental health problem-solving models, path analyses were performed. RESULTS: This study found that some perinatal women, who use an online informal medical help-seeking (OIMH) strategy, would be more likely to change their medical decisions based only on internet-based information without consulting health professionals (P<.001), compared to other women using different medical help-seeking strategies. Particularly, this concern is significantly prevalent when encountering obstetric problems during the perinatal period (obstetric problem-solving: P<.001; mental health problem-solving: P=.02). Furthermore, perinatal women with mental health issues using the OIMH strategy showed a significant difference in intent to consult health professionals based on online health information when the medical problem they had to solve was different (obstetric problem-solving: P=.94; mental health problem-solving: P=.003). CONCLUSIONS: Despite the positive mediating effects of perinatal women's enhanced health literacy on the intent to discuss personal medical issues with health professionals based on online health information, the strategy used is of fundamental importance for understanding their help-seeking and decision-making processes during the perinatal period. Beyond a short consultation to steer patients quickly and authoritatively towards an obstetric doctor's choice of action, it is recommended in this study that obstetricians attempt to provide their patients with needed context for the information found online. To fully explain this information with an open mind, they should actively develop or support information and communications technology (ICT)-based health information services.

Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo.

Previously, we demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-uRCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-uRCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-uRCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-uRCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-uRCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.