Hormonal stimulation reduces numbers and impairs function of human uterine natural killer cells during implantation.

STUDY QUESTION: How does an altered maternal hormonal environment, such as that seen during superovulation with gonadotropins in ART, impact human uterine immune cell distribution and function during the window of implantation? SUMMARY ANSWER: Hormonal stimulation with gonadotropins alters abundance of maternal immune cells including uterine natural killer (uNK) cells and reduces uNK cell ability to promote extravillous trophoblast (EVT) invasion. WHAT IS KNOWN ALREADY: An altered maternal hormonal environment, seen following ART, can lead to increased risk for adverse perinatal outcomes associated with disordered placentation. Maternal immune cells play an essential role in invasion of EVTs, a process required for proper establishment of the placenta, and adverse perinatal outcomes have been associated with altered immune cell populations. How ART impacts maternal immune cells and whether this can in turn affect implantation and placentation in humans remain unknown. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out between 2018 and 2021 on 51 subjects: 20 from natural cycles 8 days after LH surge; and 31 from stimulated IVF cycles 7 days after egg retrieval. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial biopsies and peripheral blood samples were collected during the window of implantation in subjects with regular menstrual cycles or undergoing superovulation. Serum estradiol and progesterone levels were measured by chemiluminescent competitive immunoassay. Immune cell populations in blood and endometrium were analyzed using flow cytometry. uNK cells were purified using fluorescence-activated cell sorting and were subjected to RNA sequencing (RNA-seq). Functional changes in uNK cells due to hormonal stimulation were evaluated using the implantation-on-a-chip (IOC) device, a novel bioengineered platform using human primary cells that mimics early processes that occur during pregnancy in a physiologically relevant manner. Unpaired t-tests, one-way ANOVA, and pairwise multiple comparison tests were used to statistically evaluate differences. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were comparable for both groups. As expected, serum estradiol levels on the day of biopsy were significantly higher in stimulated (superovulated) patients (P = 0.0005). In the setting of superovulation, we found an endometrium-specific reduction in the density of bulk CD56+ uNK cells (P < 0.05), as well as in the uNK3 subpopulation (P = 0.025) specifically (CD103+ NK cells). In stimulated samples, we also found that the proportion of endometrial B cells was increased (P < 0.0001). Our findings were specific to the endometrium and not seen in peripheral blood. On the IOC device, uNK cells from naturally cycling secretory endometrium promote EVT invasion (P = 0.03). However, uNK cells from hormonally stimulated endometrium were unable to significantly promote EVT invasion, as measured by area of invasion, depth of invasion, and number of invaded EVTs by area. Bulk RNA-seq of sorted uNK cells from stimulated and unstimulated endometrium revealed changes in signaling pathways associated with immune cell trafficking/movement and inflammation. LIMITATIONS, REASONS FOR CAUTION: Patient numbers utilized for the study were low but were enough to identify significant overall population differences in select immune cell types. With additional power and deeper immune phenotyping, we may detect additional differences in immune cell composition of blood and endometrium in the setting of hormonal stimulation. Flow cytometry was performed on targeted immune cell populations that have shown involvement in early pregnancy. A more unbiased approach might identify changes in novel maternal immune cells not investigated in this study. We performed RNA-seq only on uNK cells, which demonstrated differences in gene expression. Ovarian stimulation may also impact gene expression and function of other subsets of immune cells, as well as other cell types within the endometrium. Finally, the IOC device, while a major improvement over existing in vitro methods to study early pregnancy, does not include all possible maternal cells present during early pregnancy, which could impact functional effects seen. Immune cells other than uNK cells may impact invasion of EVTs in vitro and in vivo, though these remain to be tested. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate that hormonal stimulation affects the distribution of uNK cells during the implantation window and reduces the proinvasive effects of uNK cells during early pregnancy. Our results provide a potential mechanism by which fresh IVF cycles may increase risk of disorders of placentation, previously linked to adverse perinatal outcomes. STUDY FUNDING/COMPETING INTEREST(S): Research reported in this publication was supported by the University of Pennsylvania University Research Funding (to M.M.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD068157 to M.M., S.S., and S.M.), National Center for Advancing Translational Sciences of the National Institutes of Health (TL1TR001880 to J.K.), the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the Children's Hospital of Philadelphia Research Institute (to S.M.G.), and the National Institute of Allergy and Infectious Diseases (K08AI151265 to S.M.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Effect of pneumatic leg compression on post-induction hypotension in elderly patients undergoing robot-assisted laparoscopic prostatectomy: a double-blind randomised controlled trial.

Post-induction hypotension is common and associated with postoperative complications. We hypothesised that pneumatic leg compression reduces post-induction hypotension in elderly patients undergoing robot-assisted laparoscopic prostatectomy. In this double-blind randomised study, patients were allocated randomly to the pneumatic leg compression group (n = 50) or control (n = 50). In the intervention group, pneumatic leg compression was initiated before induction of anaesthesia. In the control group, pneumatic leg compression was initiated 20 min after anaesthesia induction. The primary outcome was the incidence of post-induction hypotension in these groups. Post-induction hypotension was defined as systolic blood pressure < 90 mmHg during the first 20 min after induction. Haemodynamic variables and area under the curve of post-induction systolic blood pressure over time were assessed. Complications associated with pneumatic leg compression were recorded, including: peripheral neuropathy; compartment syndrome; extensive bullae beneath the leg sleeves; and pulmonary thromboembolism. The incidence of post-induction hypotension decreased in the pneumatic leg compression group compared with that in the control group; 5 (10%) vs. 29 (58%), respectively, p < 0.001. In the pneumatic leg compression group, the lowest systolic, diastolic and mean blood pressures 20 min after induction of anaesthesia were significantly greater than the control group. Pneumatic leg compression resulted in an increased area under the curve of systolic blood pressure in the first 20 min after induction, p = 0.001. There were no pneumatic leg compression-related complications. Pneumatic leg compression reduced post-induction hypotension in elderly patients undergoing robot-assisted laparoscopic prostatectomy, suggesting that it is an effective and safe intervention to prevent post-induction hypotension among elderly patients undergoing general anaesthesia.

Health and job-related factors associated with work ability in older working populations of Korea.

BACKGROUND: Knowledge about determinants of workability is crucial for designing interventions to increase the participation of older employees in the workforce and maintain or increase their productivity levels at work. AIMS: This study explored the impact of health conditions and job characteristics on poor work ability. METHODS: This study used data from the Korean Longitudinal Study of Aging (KLoSA) from 2014 to 2020, which is a nationally representative population-based panel study of Korean citizens aged ≥45 years. The KLoSA survey assessed subjective work ability using work ability score. The participants were asked if they had been diagnosed with any underlying diseases by a physician. The job characteristics were assessed in terms of working conditions and satisfaction. Generalized estimating equations were used to calculate the odds ratios (ORs) and 95% confidence intervals for workers' health-related variables and job characteristics associated with poor work ability. RESULTS: The results showed that workers' health-related factors were associated with poor work ability; poor vision (OR = 1.52) and bad hearing ability (OR = 2.37); low gripping strength (OR = 2.29); poor self-rated health (OR = 3.77) and various diseases such as hypertension, diabetes, cancer, chronic lung disease, liver disease, heart disease, cerebrovascular disease, mental illness, arthritis, prostate disease, gastrointestinal disease and disc disease. Additionally, high physical work demands (OR = 1.51) and low job satisfaction (OR = 4.23) were highly correlated with poor work ability. CONCLUSIONS: The findings addressing poor work abilities caused by individuals' health- and job-related factors can help prioritize worker health management and the development of more effective human capital investment strategies at the workplace.

What does family involvement in care provision look like across hospital settings in Bangladesh, Indonesia, and South Korea?

BACKGROUND: Family members provide care whilst staying in the patient's room across a range of cultural settings, irrespective of resource availability in many Asian countries. This has been reported as a contributing factor to the spread of several outbreaks, including COVID-19. Despite these reports, very little is known about the risk of healthcare-associated infection (HAI) transmission related to the involvement of family and private carers in the clinical setting. As a starting point to understanding this issue, this study aimed to provide insights regarding the patient care activities undertaken by family and private carers and the guidance provided to these carers around infection control measures in hospitals located in Bangladesh, Indonesia, and South Korea. METHOD: A qualitative study involving 57 semi-structured interviews was undertaken in five tertiary level hospitals across the selected countries. Two groups of individuals were interviewed: (1) patients and their family carers and private carers; and (2) healthcare workers, including doctors, nurses, hospital managers and staff members. Drawing upon the principles of grounded theory, an inductive approach to data analysis using thematic analysis was adopted. RESULTS: Five main themes were generated from the analysis of the data: (1) expectation of family carers staying with a patient; (2) residing in the patient's environment: (3) caring activities undertaken by family carers; (4) supporting and educating family carers and (5) communication around healthcare-associated infection and infection prevention and control. CONCLUSION: Based on the types of activities being undertaken, coupled with the length of time family and private carers are residing within the clinical setting, coupled with an apparent lack of guidance being given around IPC, more needs to be done to ensure that these carers are not being inadvertently exposed to HAI's or other occupational risks.

Cell-free culture supernatant of Lactobacillus curvatus Wikim38 inhibits RANKL-induced osteoclast differentiation and ameliorates bone loss in ovariectomized mice.

This study was conducted to investigate the inhibitory effects of the cell-free culture supernatant of Lactobacillus curvatus Wikim 38 (LC38-CS) on RANKL-induced osteoclast differentiation and bone loss in a mice model of ovariectomy-induced post-menopausal osteoporosis. LC38-CS inhibited the RANKL-induced differentiation of bone marrow-derived macrophages (BMDMs) into osteoclasts in a dose-dependent manner. F-actin ring formation and bone resorption were also reduced by LC38-CS treatment of RANKL-treated BMDMs. In addition, LC38-CS decreased the RANKL-induced activation of the TRAF6/NF-κB/MAPKs axis at the early stage and the expression of osteoclastogenesis-related genes in BMDMs treated with RANKL. PRMT1 and ADMA levels, new biomarkers for osteoclastogenesis, were decreased by LC38-CS treatment. The administration of LC38-CS increased bone volume and bone mineral density in ovariectomized mice in µ-CT analysis. These findings suggest that LC38-CS inhibited RANKL-induced osteoclast differentiation by the downregulation of molecular mechanisms and exerted anti-osteoporotic effects.

The potential cytotoxic effects of urban particle matter on olfaction.

BACKGROUND: Urban particulate matter (UPM) in ambient air is implicated in a variety of human health issues worldwide, however, few studies exist on the effect of UPM on the olfactory system. This study aimed to identify the factors affecting the destruction of the olfactory system in a mouse model following UPM exposure. METHODS: Mice were divided into: control and four UPM-exposed groups (200 µg UPM at 1 and 2 weeks, and 400 µg UPM at 1 and 2 weeks [standard reference material 1649b; average particle diameter 10.5 µm]). The olfactory neuroepithelium was harvested for histologic examination, gene ontology, quantitative real-time polymerase chain reaction, and western blotting. RESULTS: Compared to the control group, olfactory marker protein, Olfr1507, ADCY3, and GNAL mRNA levels were lower, and S-100, CNPase, NGFRAP1, BDNF, and TACR3 mRNA levels were higher in the olfactory neuroepithelium of the UPM groups. Moderately positive correlation was present between the 1- and 2-week groups. After analyzing the 200 and 400 UPM groups separately, the strength of the association between the 200 UPM 1- and 2-week groups was moderately positive. No differences was present in the neuroepithelial inflammatory marker levels between the UPM and control groups. CONCLUSIONS: UPM could have cytotoxic effects on the olfactory epithelium. The exposure time and particular concentration of UPM exposure could affect the degree of destruction of the olfactory neuroepithelium. The olfactory regeneration mechanism could be related to the neurotrophic factors, olfactory ensheathing cell stimulation, and trigeminal nerve support.

The effect of low body mass index on the development of chronic obstructive pulmonary disease and mortality.

BACKGROUND: Sarcopenia may worsen disease progression and lead to poor outcomes in chronic obstructive pulmonary disease (COPD). OBJECTIVES: We aimed to determine the effect of BMI on the development of COPD and mortality. METHODS: We enrolled 437 584 participants registered in the physical health check-up cohort database of the Korean National Health Interview Survey from 2002 to 2003, and we defined COPD diagnosis based on the ICD-10 code and prescribed medication. BMI (kg m-2 ) classified them to five groups (low BMI < 18.5, normal BMI 18.5-23, overweight 23-25, obesity 25-30, severe obesity ≥30) at baseline. RESULTS: Participants in the low BMI group had a significantly higher rate of COPD development for 13 years (7.6%) than those in other groups (3.4-4.1%, P < 0.0001). Amongst never or light smokers, COPD development in the low BMI group (5.6-6.7%) was significantly higher than that in other groups (2.8-4.7%). Similarly, amongst participants with a smoking history of ≥30 years, COPD development in the low BMI group (20.1%) was higher than those in other groups (8.4-12.4%). On multivariable analysis, normal or higher than normal body weight was significantly protective against the development of COPD (hazard ratio [HR], 0.609-0.739,) compared to low BMI. COPD-free-survival (HR, 0.491-0.622) and overall survival (HR, 0.440-0.585) were also better in them compared to those with low BMI (all P < 0.0001). CONCLUSIONS: Low BMI is an important risk factor for COPD development and mortality. Maintaining adequate body weight may reduce the risk for COPD development and mortality.

Tunable broadband terahertz polarizer using graphene-metal hybrid metasurface.

We demonstrate an electrically tunable polarizer for terahertz (THz) frequency electromagnetic waves formed from a hybrid graphene-metal metasurface. Broadband (>3 THz) polarization-dependent modulation of THz transmission is demonstrated as a function of the graphene conductivity for various wire grid geometries, each tuned by gating using an overlaid ion gel. We show a strong enhancement of modulation (up to ∼17 times) compared to graphene wire grids in the frequency range of 0.2-2.5 THz upon introduction of the metallic elements. Theoretical calculations, considering both plasmonic coupling and Drude absorption, are in good agreement with our experimental findings.

Akt1-Mediated Phosphorylation of RBP-Jk Controls Notch1 Signaling.

The Notch1 signaling pathway plays a crucial role in determining cell fate, including cell growth and differentiation. In this study, we demonstrated that the antagonistic action of RTK (receptor tyrosine kinase) signaling pathway on the Notch1 signaling pathway is mediated via Ras-PI3K-Akt1. The PI3K-Akt1 signaling pathway was shown to inhibit Notch1 signaling via phosphorylation of RBP-Jk. We observed not only reduced association between Notch1 and RBP-Jk, but also suppression of the Notch1 transcriptional activity. Our results demonstrated that Akt1 functions as a natural inhibitor of the Notch1 signaling pathway via phosphorylation of RBP-Jk.

Evolution and persistence of resistance-associated substitutions of hepatitis C virus after direct-acting antiviral treatment failures.

Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all-oral direct-acting antiviral (DAA) therapy for the genotype 1b HCV-infected patients. In this study, we investigated how resistance-associated substitutions (RASs) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS5A and NS3 revealed typical RASs after treatment failures. Interestingly, the RASs of NS3 reverted to the wild-type amino acid within 1 year after treatment failures. However, the RASs of NS5A were stable and did not change. The effect of NS5A and NS3 RASs on viral RNA replication was assessed after mutagenic substitution in the genotype 1b HCV RNA. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS at NS5A Y93 affected both viral RNA replication and virus production. Finally, the effect of trans-complementation of NS5A was demonstrated in our co-transfection experiments and these results suggest that such a trans-complementation effect of NS5A may help maintain the NS5A RASs for a long time even after cessation of the DAA treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RASs.

Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance.

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy (TDF group) and TDF plus entecavir (ETV) combination-rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.

Folate and vitamin B12 concentrations are associated with plasma DHA and EPA fatty acids in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study.

This study aimed to examine the association between vitamin B6, folate and vitamin B12 biomarkers and plasma fatty acids in European adolescents. A subsample from the Healthy Lifestyle in Europe by Nutrition in Adolescence study with valid data on B-vitamins and fatty acid blood parameters, and all the other covariates used in the analyses such as BMI, Diet Quality Index, education of the mother and physical activity assessed by a questionnaire, was selected resulting in 674 cases (43 % males). B-vitamin biomarkers were measured by chromatography and immunoassay and fatty acids by enzymatic analyses. Linear mixed models elucidated the association between B-vitamins and fatty acid blood parameters (changes in fatty acid profiles according to change in 10 units of vitamin B biomarkers). DHA, EPA) and n-3 fatty acids showed positive associations with B-vitamin biomarkers, mainly with those corresponding to folate and vitamin B12. Contrarily, negative associations were found with n-6:n-3 ratio, trans-fatty acids and oleic:stearic ratio. With total homocysteine (tHcy), all the associations found with these parameters were opposite (for instance, an increase of 10 nmol/l in red blood cell folate or holotranscobalamin in females produces an increase of 15·85 µmol/l of EPA (P value <0·01), whereas an increase of 10 nmol/l of tHcy in males produces a decrease of 2·06 µmol/l of DHA (P value <0·05). Positive associations between B-vitamins and specific fatty acids might suggest underlying mechanisms between B-vitamins and CVD and it is worth the attention of public health policies.

Morphological characteristics of visual cells in the endemic Korean loach Kichulchoia multifasciata (Pisces; Cobitidae) by microscopy.

The visual cell of the retina in the Korean loach Kichulchoia multifasciata, a bottom-dwelling freshwater loach in shallow water, contains double cones and large rods. With light microscopy, the cones form a row mosaic pattern in which the partners of double cones are linearly oriented with a large rod. In a double cone or twin cone, the two members are unequal such that one cone may be longer than the other. An anatomical unit is apparent which consists of 5 rod cells and 15 double cone cells per 20 × 20 µm area. We found that the cone cells of outer segments are linked to the inner segment by so-called "calyceal process" using a scanning electron microscopy, unlike rod cells. In the transmission electron microscopy, the outer membrane shows piles of membrane discs surrounded by double membranes.

A randomized, double-blind, placebo-controlled trial of Schisandra chinensis for menopausal symptoms.

OBJECTIVES: The purpose of this clinical trial was to evaluate the effectiveness of a natural extract from Schisandra chinensis for relief of various menopausal symptoms. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from January 1, 2014 until January 13, 2015. We recruited women between the ages of 40 and 70 years who complained of menopausal symptoms measured by the Kupperman Index (KI). Patients were randomly assigned to treatment with either an extract from Schisandra chinensis (BMO-30) or placebo. They received the treatment for 6 weeks and were followed for 12 weeks. The primary endpoint was the mean interval change in KI score from baseline to week 12. Secondary measures included laboratory studies and the Menopause Rating Scale (MRS) score for sexual and bladder problems. RESULTS: Forty-one patients were considered eligible for enrolment, and 36 completed the study. After screening and randomization, patients were categorized into the placebo group (n = 18) and the BMO-30 group (n = 18). Total KI scores were significantly lower in the BMO-30 group than in the placebo group when evaluated with respect to group and time (p = 0.042). CONCLUSIONS: BMO-30 from Schisandra chinensis can be a safe and effective complementary medicine for menopausal symptoms, especially for hot flushes, sweating, and heart palpitations.

Efficacy and possible mechanisms of topical tranexamic acid in melasma.

BACKGROUND: Tranexamic acid (TA) has been suggested as an effective treatment for melasma. AIM: To investigate the effects and mechanism of action of topical TA in the treatment of melasma. METHODS: In this study, 23 participants with melasma applied a 2% TA formulation to the whole face for 12 weeks. Clinical effects were evaluated using the modified Melasma Area and Severity Index (mMASI) and a chromameter. Skin biopsies were obtained from 10 participants to evaluate pigmentation, vascularity and the expression levels of possible paracrine factors contributing to the effect of TA. RESULTS: Most of the participants had mild melasma, with mMASI of < 5. The mMASI scores significantly improved in 22 of 23 participants after application. The L* values were increased and the a* values were decreased in both lesional and perilesional normal skin. Fontana-Masson staining showed a significant decrease in melanin content in the epidermis. The number of CD31-positive vessels and the expression of the vascular endothelial growth factor both tended to decrease. Endothelin (ET)-1 was found to be downregulated with TA. CONCLUSIONS: Topical TA is effective for melasma. This immunohistochemical study found that suppression of ET-1 could be one of the mechanisms of action of TA on melasma.

In vivo time-sequential histological study focused on melanocytes: suggestion of golden time for intervention to prevent post-laser pigmentary changes.

BACKGROUND: Post-inflammatory pigmentary changes after laser treatments are challenging adverse effect. OBJECTIVE: To suggest an ideal time period with regard to intervention to prevent post-laser pigmentary changes, an in vivo time-sequential histological study focused on melanocytes was performed. METHODS: The back skin of four volunteers was irradiated with Q-switched alexandrite laser (QSAL). In one subject (subject 4), topical corticosteroid was applied onto the irradiated skin from the time of irradiation to day 28. In all subjects, time-sequential skin biopsies were performed at baseline, an immediate time after irradiation, day 2, day 7, and day 28. Histological and immunohistochemical analyses were conducted. RESULTS: Q-switched alexandrite laser led to the successful removal of pigments and most melanocytes from the epidermis in all subjects. At day 28, there was increased epidermal pigmentation in the skin of the subjects 1-3. It was noted that numerous activated melanocytes appeared on day 7, continued to be observed until day 28. However, in the subject 4, the melanocyte activation and post-laser pigmentary changes were not observed. CONCLUSION: In regard to intervene melanocyte activation, at least 1 week after laser treatment is suggested as a 'golden' time period to prevent pigmentary changes.

A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Efficacy and safety of teneligliptin, a dipeptidyl peptidase-4 inhibitor, combined with metformin in Korean patients with type 2 diabetes mellitus: a 16-week, randomized, double-blind, placebo-controlled phase III trial.

The aim of the present study was to assess the efficacy and safety of teneligliptin in combination with metformin in Korean patients with type 2 diabetes mellitus who were inadequately controlled with metformin monotherapy. Patients [glycated haemoglobin (HbA1c) 7.0-10.0%, on stable metformin ≥1000 mg/day] were randomized 2 : 1 to receive 20 mg teneligliptin plus metformin (n = 136) or placebo plus metformin (n = 68). The primary endpoint was the change in HbA1c levels from baseline to week 16. The mean baseline HbA1c was 7.9% in the teneligliptin group and 7.8% in the placebo group. The differences between the teneligliptin and placebo groups regarding changes in HbA1c and fasting plasma glucose levels were -0.78 % and -1.24 mmol/l (22.42 mg/dl), respectively, at week 16. The incidence of adverse events was similar between the groups. The addition of teneligliptin once daily to metformin was effective and generally well tolerated in Korean patients with type 2 diabetes.

Anagliptin and sitagliptin as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, active-controlled, phase III clinical trial with a 28-week extension.

We conducted a 24-week, multicentre, double-blind, randomized study with a 28-week extension to compare the efficacy and safety of anagliptin and sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients inadequately controlled on metformin were randomized to either anagliptin (100 mg twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. The mean changes in HbA1c were -0.85 ± 0.70% (p < 0.0001) for anagliptin and -0.83 ± 0.61% (p < 0.0001) for sitagliptin, with a mean difference of -0.02% (95% confidence interval of difference, -0.22 to 0.18%). In both groups, the fasting proinsulin : insulin ratio significantly decreased from baseline, with improved insulin secretion. Safety profiles were similar in each group. In conclusion, the non-inferiority of the efficacy of anagliptin to sitagliptin as an add-on therapy was established with regard to efficacy and safety.

Radiologic and laboratory differences in patients with tuberculous and parapneumonic pleural effusions showing non-lymphocytic predominance and high adenosine deaminase levels.

PURPOSE: Tuberculous pleural effusion (TPE) is characterized by lymphocytic predominance and high adenosine deaminase (ADA) levels. However, TPEs sometimes present non-lymphocytic predominance, and parapneumonic effusion (PPE) often exceeds the cutoff value of ADA for TPE. Thus, the differential diagnosis of cases with pleural fluid (PF) showing non-lymphocytic predominance and high ADA levels is challenging. However, limited data concerning the clinical differences in these patients are available. METHODS: A retrospective study was conducted on TPE and PPE patients with PF showing non-lymphocytic predominance and ADA levels ≥40 U/L in 2009-2013 in a South Korean tertiary referral hospital. The clinical, laboratory, and computed tomography (CT) findings between the groups were analyzed using multivariate logistic regression to develop a prediction model with independent factors for TPE. RESULTS: Among 353 patients with TPE, 24 (6.8 %) showed PF with non-lymphocytic predominance and ADA levels of ≥40 U/L. Twenty-eight PPE patients who presented PF findings comparable with those of TPE patients were included in the control group. In the final analysis, PF ADA levels >58 U/L and nodular lung lesions on CT were independent positive predictors, while loculated effusion was an independent negative predictor for TPE. Using the prediction model, a score ≥ +3 provided a sensitivity of 88 %, specificity of 93 %, positive predictive value of 91 %, and negative predictive value of 90 % for TPE. CONCLUSION: PF ADA levels, nodular lung lesions, and loculated pleural effusion may help differentiate TPE from PPE in patients with PF showing non-lymphocytic predominance and ADA levels ≥40 U/L.