Blood transcriptome differentiates clinical clusters for asthma.

Background: In previous studies, several asthma phenotypes were identified using clinical and demographic parameters. Transcriptional phenotypes were mainly identified using sputum and bronchial cells. Objective: We aimed to investigate asthma phenotypes via clustering analysis using clinical variables and compare the transcription levels among clusters using gene expression profiling of the blood. Methods: Clustering analysis was performed using 6 parameters: age of asthma onset, body mass index, pack-years of smoking, forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity, and blood eosinophil counts. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and RNA was extracted from selected PBMCs. Transcriptional profiles were generated (Illumina NovaSeq 6000) and analyzed using the reference genome and gene annotation files (hg19.refGene.gft). Pathway enrichment analysis was conducted using GO, KEGG, and REACTOME databases. Results: In total, 355 patients with asthma were included in the analysis, of whom 72 (20.3%) had severe asthma. Clustering of the 6 parameters revealed 4 distinct subtypes. Cluster 1 (n = 63) had lower predicted FEV1 % and higher pack-years of smoking and neutrophils in sputum. Cluster 2 (n = 43) had a higher proportion and number of eosinophils in sputum and blood, and severe airflow limitation. Cluster 3 (n = 110) consisted of younger subjects with atopic features. Cluster 4 (n = 139) included features of late-onset mild asthma. Differentially expressed genes between clusters 1 and 2 were related to inflammatory responses and cell activation. Th17 cell differentiation and interferon gamma-mediated signaling pathways were related to neutrophilic inflammation in asthma. Conclusion: Four clinical clusters were differentiated based on clinical parameters and blood eosinophils in adult patients with asthma form the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) cohort. Gene expression profiling and molecular pathways are novel means of classifying asthma phenotypes.

Mendelian randomization shows depression increases the risk of type 2 diabetes.

Introduction: Type 2 diabetes (T2D) is associated with severe mental illnesses (SMIs), such as schizophrenia, bipolar disorder, and depression. However, causal relationships between SMIs and T2D remain unclear owing to potential bias in observational studies. We aimed to characterize the causal effect of SMI liability on T2D using two-sample Mendelian randomization (MR). Methods: The causality between liability to SMI and T2D was investigated using the inverse-variance weighted (IVW), MREgger, MR-Egger with a simulation extrapolation, weighted median, and the MR pleiotropy residual sum and outlier method. Similarly, we performed additional MR which can detect the reverse causation effect by switching exposure and outcome for T2D liability for SMI. To further consider pleiotropic effects between SMIs, multivariable MR analysis was performed after accounting for the other traits. Results: In the univariable IVW method, depression showed a causal effect on T2D (odds ratio [OR]: 1.128, 95% confidence interval [CI]: 1.024-1.245, p = 0.014). Multinomial MR more strongly supported these results (IVW OR: 1.197, 95% CI: 1.069, 1.340, p = 0.002; MR-Egger OR: 1.198, 95% CI: 1.062, 1.349, p = 0.003). Bidirectional MR showed absence of reversecausality between depression and T2D. However, causal relationship of bipolar and schizophrenia on T2D was not detected. Discussion: Careful attention is needed for patients with depression regarding T2D prevention and treatment.

Genome-Wide Association Study on Longitudinal Change in Fasting Plasma Glucose in Korean Population.

BACKGROUND: Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time. METHODS: We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project. RESULTS: A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic ß-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level. CONCLUSION: We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.

Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians.

This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.

Identification of genetic variants associated with diabetic kidney disease in multiple Korean cohorts via a genome-wide association study mega-analysis.

BACKGROUND: The pathogenesis of diabetic kidney disease (DKD) is complex, involving metabolic and hemodynamic factors. Although DKD has been established as a heritable disorder and several genetic studies have been conducted, the identification of unique genetic variants for DKD is limited by its multiplex classification based on the phenotypes of diabetes mellitus (DM) and chronic kidney disease (CKD). Thus, we aimed to identify the genetic variants related to DKD that differentiate it from type 2 DM and CKD. METHODS: We conducted a large-scale genome-wide association study mega-analysis, combining Korean multi-cohorts using multinomial logistic regression. A total of 33,879 patients were classified into four groups-normal, DM without CKD, CKD without DM, and DKD-and were further analyzed to identify novel single-nucleotide polymorphisms (SNPs) associated with DKD. Additionally, fine-mapping analysis was conducted to investigate whether the variants of interest contribute to a trait. Conditional analyses adjusting for the effect of type 1 DM (T1D)-associated HLA variants were also performed to remove confounding factors of genetic association with T1D. Moreover, analysis of expression quantitative trait loci (eQTL) was performed using the Genotype-Tissue Expression project. Differentially expressed genes (DEGs) were analyzed using the Gene Expression Omnibus database (GSE30529). The significant eQTL DEGs were used to explore the predicted interaction networks using search tools for the retrieval of interacting genes and proteins. RESULTS: We identified three novel SNPs [rs3128852 (P = 8.21×10-25), rs117744700 (P = 8.28×10-10), and rs28366355 (P = 2.04×10-8)] associated with DKD. Moreover, the fine-mapping study validated the causal relationship between rs3128852 and DKD. rs3128852 is an eQTL for TRIM27 in whole blood tissues and HLA-A in adipose-subcutaneous tissues. rs28366355 is an eQTL for HLA-group genes present in most tissues. CONCLUSIONS: We successfully identified SNPs (rs3128852, rs117744700, and rs28366355) associated with DKD and verified the causal association between rs3128852 and DKD. According to the in silico analysis, TRIM27 and HLA-A can define DKD pathophysiology and are associated with immune response and autophagy. However, further research is necessary to understand the mechanism of immunity and autophagy in the pathophysiology of DKD and to prevent and treat DKD.

Laboratory information management system for COVID-19 non-clinical efficacy trial data.

BACKGROUND: As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. RESULTS: In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. CONCLUSIONS: This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.

missForest with feature selection using binary particle swarm optimization improves the imputation accuracy of continuous data.

BACKGROUND: Missing data are a common problem in large-scale datasets and its appropriate handling is crucial for data analyses. Missingness can be categorized as (1) missing completely at random (MCAR), (2) missing at random (MAR), and (3) missing not at random (MNAR). Different missingness mechanisms require different imputation strategies. Multiple imputation, an approach for averaging outcomes across multiple imputed data, is more suitable than single imputation for dealing with various missing mechanisms. missForest, a nonparametric missing value imputation strategy using random forest, is one of the most prevalent multiple imputation methods for missing-data because it can be applied to mixed-type data and does not require distributional assumptions. However, a recent study found that missForest can produce biased results for non-normal data. In addition, missForest is computationally expensive. OBJECTIVE: Therefore, we aimed to further develop the missForest algorithm by combining a binary particle swarm optimization (BPSO)-based feature-selection strategy. METHODS: The BPSO is an evolutionary algorithm that is well known for global optimization and computational efficiency. By using the BPSO-based feature selection step prior to imputing missing values with missForest, the imputation accuracy for continuous variables could be increased by pruning redundant variables. RESULTS: In this study, missForest with BPSO (BPSOmf) showed better imputation accuracy than missForest alone with respect to continuous variables by feature selection prior to the imputation step. CONCLUSIONS: BPSOmf is an appropriate and robust method when the imputation target data consist mainly of continuous variables.

Unveiling genetic variants for age-related sarcopenia by conducting a genome-wide association study on Korean cohorts.

Sarcopenia is an age-related disorder characterised by a progressive decrease in skeletal muscle mass. As the genetic biomarkers for sarcopenia are not yet well characterised, this study aimed to investigate the genetic variations related to sarcopenia in a relatively aged cohort, using genome-wide association study (GWAS) meta-analyses of lean body mass (LBM) in 6961 subjects. Two Korean cohorts were analysed, and subgroup GWAS was conducted for appendicular skeletal muscle mass (ASM) and skeletal muscle index. The effects of significant single nucleotide polymorphisms (SNPs) on gene expression were also investigated using multiple expression quantitative trait loci datasets, differentially expressed gene analysis, and gene ontology analyses. Novel genetic biomarkers were identified for LBM (rs1187118; rs3768582) and ASM (rs6772958). Their related genes, including RPS10, NUDT3, NCF2, SMG7, and ARPC5, were differently expressed in skeletal muscle tissue, while GPD1L was not. Furthermore, the 'mRNA destabilisation' biological process was enriched for sarcopenia. Our study identified RPS10, NUDT3, and GPD1L as significant genetic biomarkers for sarcopenia. These genetic loci were related to lipid and energy metabolism, suggesting that genes involved in metabolic dysregulation may lead to the pathogenesis of age-related sarcopenia.

Unveiling Genetic Variants Underlying Vitamin D Deficiency in Multiple Korean Cohorts by a Genome-Wide Association Study.

BACKGROUND: Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS). METHODS: We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed. RESULTS: rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles. CONCLUSION: The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations.

Association between socioeconomic position and diabetic foot ulcer outcomes: a population-based cohort study in South Korea.

BACKGROUND: Low socioeconomic position (SEP) is associated with a high incidence of diabetic foot ulcers (DFUs). However, reports on the association between SEP and DFU outcomes are limited. Therefore, in this study, we investigated this association and determined the prognostic factors of DFU outcomes. METHODS: The total cohort comprised 976,252 individuals. Using probability sampling, we randomly selected a sample of patients by reviewing the data from the Health Insurance Review and Assessment Service database of South Korea during 2011-2015. Residence, household income, and insurance type represented SEP. The primary outcome was amputation, and the secondary outcome was mortality. A multivariate model was applied to identify the predictive factors. Amputation-free survival and overall survival were calculated using the Kaplan-Meier method. RESULTS: Among 976,252 individuals in the cohort, 1362 had DFUs (mean age 62.9 ± 12.2 years; 42.9% were women). Overall amputation and mortality rates were 4.7 and 12.3%, respectively. Male sex (hazard ratio [HR], 2.41; p < 0.01), low SEP (HR 5.13, 5.13; p = 0.018), ophthalmopathy (HR, 1.89; p = 0.028), circulatory complications (HR, 2.14; p = 0.020), and institutional type (HR, 1.78; p = 0.044) were prognostic factors for amputation. Old age (HR, 1.06; p < 0.01), low SEP (HR, 2.65; p < 0.01), ophthalmopathy (HR, 1.74; p < 0.01), circulatory complications (HR, 1.71; p < 0.01), and institution type (HR 1.84; p < 0.01) were predictors of mortality. CONCLUSIONS: DFU patients with a low SEP are strongly associated with increased amputation and mortality rates. Along with age and comorbidities, SEP could provide the basis for risk assessment of adverse outcomes in DFU. Providing targeted care for this population considering SEP may improve the prognosis.

Association of Gap Healing With Angle of Correction After Opening-Wedge High Tibial Osteotomy Without Bone Grafting.

BACKGROUND: Studies have reported that opening wedge high tibial osteotomy (OWHTO) without bone grafting has outcomes that are similar to or even better than those of OWHTO with bone grafting, especially after use of a locking plate. However, a consensus on managing the gap after OWHTO has not been established. PURPOSE: To determine the degree of gap healing achieved without bone grafting, the factors associated with gap healing, and whether additional gap healing would be obtained after plate removal. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This retrospective study included 73 patients who underwent OWHTO without bone grafting between 2015 and 2018. Patients in the study were divided into 2 groups based on the correction angle: small correction group (<10°; SC group) and large correction group (≥10°; LC group). The locking plate used in OWHTO was removed at a mean of 13.5 months after surgery in 65 patients. Radiographic indexes were measured: gap filling height, gap vacancy ratio (GVR), and osteotomy filling index. The acceptable gap healing was defined as an osteotomy filling index ≥3. The factors related to gap healing around the osteotomy site were selected after multicollinearity analysis. RESULTS: Although both groups achieved acceptable gap healing regardless of the correction angle, the SC group showed higher and earlier gap healing than did the LC group (gap healing rate 81.4% in the SC group vs 41.7% in the LC group at 3 months postoperatively). The GVR was 8.6% in the SC group and 15.3% in the LC group at 12 months after surgery (P = .005). Both the amount of time that elapsed after surgery and the correction angle were associated with gap healing (P < .05). Additional gap healing was observed after plate removal, as the GVR decreased 2.7% more in the patients with plate removal than in patients who did not have plate removal (P = .012). CONCLUSION: All patients achieved acceptable gap healing without bone graft. The degree of gap healing was higher in the SC group and increased over time. Gap healing was promoted after plate removal. Considering the results of this study, a bone graft is not necessary in routine OWHTO in terms of gap healing.

Interleukin 10 level in the peritoneal cavity is a prognostic marker for peritoneal recurrence of T4 colorectal cancer.

Peritoneal recurrence (PR) is a major relapse pattern of colorectal cancer (CRC). We investigated whether peritoneal immune cytokines can predict PR. Cytokine concentrations of peritoneal fluid from CRC patients were measured. Patients were grouped according to peritoneal cancer burden (PCB): no tumor cells (≤ pT3), microscopic tumor cells (pT4), or gross tumors (M1c). Cytokine concentrations were compared among the three groups and the associations of those in pT4 patients with and without postoperative PR were assessed. Of the ten cytokines assayed, IL6, IL10, and TGFB1 increased with progression of PCB. Among these, IL10 was a marker of PR in pT4 (N = 61) patients based on ROC curve (p = 0.004). The IL10 cut-off value (14 pg/mL) divided patients into groups with a low (7%, 2 of 29 patients) or high (45%, 16 of 32 patients) 5-year PR (p < 0.001). Multivariable analysis identified high IL10 levels as the independent risk factor for PR. Separation of patients into training and test sets to evaluate the performance of IL10 cut-off model validated this cytokine as a risk factor for PR. Peritoneal IL10 is a prognostic marker of PR in pT4 CRC. Further research is necessary to identify immune response of intraperitoneal CRC growth.

Handgrip strength: Should repeated measurements be performed in both hands?

AIM: We aimed to determine whether both hands should be tested for handgrip strength and whether it is necessary to perform repeated measurements in each hand. METHODS: The data were obtained from the Korea National Health and Nutrition Examination Survey conducted from 2014 to 2018. The participants performed three trials of handgrip strength measurement for each hand alternately, with 60-s rest between the trials. From this pool of data, we included 23 901 participants aged ≥19 years who had completed surveys on the handgrip strength test, and obtained their medical history. RESULTS: The dominant hand had a significantly stronger handgrip strength than the non-dominant hand (32.75 ± 0.10 vs. 30.95 ± 0.09 kg, P < 0.001); however, 26.4% of the subjects had stronger handgrip strength in the non-dominant hand. During the three repeated measurements, the handgrip strength gradually increased; however, the mean difference between the trials (0.579 and 0.104 kg) was below the noninferiority threshold. In older adults, however, the mean difference in the handgrip strength between the first and the second trial was higher than the noninferiority threshold. CONCLUSIONS: While the handgrip strength gradually increased during three repeated measurements, the difference was clinically important only in older adults. Hence, we suggest that the handgrip strength should be measured in both hands and at least twice in older adults, whereas a single attempt provides a maximal value in younger adults. Geriatr Gerontol Int 2021; 21: 426-432.

Relationship Between Low Handgrip Strength and Chronic Kidney Disease: KNHANES 2014-2017.

OBJECTIVE: Accelerated loss of muscle mass is common in patients with chronic kidney disease (CKD). Various factors associated with CKD, such as nutritional deficiencies, metabolic acidosis, and chronic inflammation, contribute to muscle wasting. This study aimed to investigate the relationship between CKD and handgrip strength (HGS) in the Korean population. DESIGN AND METHODS: This is a population-based, cross-sectional study of a nationally representative sample of 18,765 patients aged ≥19 years from the Korea National Health and Nutrition Examination Survey in 2014-2017. We measured HGS using a digital hand dynamometer and determined the cutoff for low HGS by deriving -2 standard deviation values of sex-matched healthy young adults (19-39 years old). We defined CKD as eGFR <60 mL/min/1.73 m2 or the presence of CKD based on a self-reported questionnaire. RESULTS: The prevalence of CKD was 4.0% in the total population. The cutoff values for the low HGS were 29.5 kg for men and 16.8 kg for women. The prevalence of low HGS was 6.2% in patients without CKD, and 25.2% in patients with CKD. There was a significant correlation between HGS and eGFR in both men and women. In multivariate logistic regression adjusted by age group, diabetes, hypertension, and obesity, CKD showed an independent relationship with low HGS in both men (odds ratio [OR] 1.910, 95% confidence interval [CI] 1.468-2.485) and women (OR 1.570, 95% CI 1.202-2.052). CONCLUSIONS: The prevalence of low HGS was higher in patients with CKD. We suggest that the sarcopenia should be evaluated in patients with CKD.

Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas.

BACKGROUND: The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials. METHODS: We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines. RESULTS: PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. "Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8+/low tumor-infiltrating lymphocytes (TILs)," and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3+/low TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3+/high TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(-) cell lines. CONCLUSIONS: The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of "tumoral PD-L1/immune cell PD-L1/CD8+ TILs" may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8+/low TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.

Causal Evaluation of Laboratory Markers in Type 2 Diabetes on Cancer and Vascular Diseases Using Various Mendelian Randomization Tools.

Multiple studies have demonstrated the effects of type 2 diabetes (T2D) on various human diseases; however, most of these were observational epidemiological studies that suffered from many potential biases including reported confounding and reverse causations. In this article, we investigated whether cancer and vascular disease can be affected by T2D-related traits, including fasting plasma glucose (FPG), 2-h postprandial glucose (2h-PG), and glycated hemoglobin A1c (HbA1c) levels, by using Mendelian randomization (MR). The summary statistics for FPG, 2h-PG, and HbA1c level were obtained through meta-analyses of large-scale genome-wide association studies that included data from 133,010 nondiabetic individuals from collaborating Meta-analysis of Glucose and Insulin Related Traits Consortium studies. Thereafter, based on the statistical assumptions for MR analyses, the most reliable approaches including inverse-variance-weighted (IVW), MR-Egger, MR-Egger with a simulation extrapolation (SIMEX), weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods were applied to identify traits affected by FPG, 2h-PG, and HbAlc. We found that coronary artery disease is affected by FPG, as per the IVW [log odds ratio (logOR): 0.21; P = 0.012], MR-Egger (SIMEX) (logOR: 0.22; P = 0.014), MR-PRESSO (logOR: 0.18; P = 0.045), and weighted median (logOR: 0.29; P < 0.001) methods but not as per the MR-Egger (logOR: 0.13; P = 0.426) approach. Furthermore, low-density lipoprotein cholesterol levels are affected by HbA1c, as per the IVW [beta (B): 0.23; P = 0.015), MR-Egger (B: 0.45; P = 0.046), MR-Egger (SIMEX) (B: 0.27; P = 0.007), MR-PRESSO (B; 0.14; P = 0.010), and the weighted median (B: 0.15; P = 0.012] methods. Further studies of the associated biological mechanisms are required to validate and understand the disease-specific differences identified in the TD2-related causal effects of each trait.

The use of bisphosphonates after joint arthroplasty is associated with lower implant revision rate.

PURPOSE: This study hypothesized that the use of bisphosphonates (BPs) after total joint arthroplasty (TJA) is associated with a lower implant revision rate. This study aimed (1) to investigate the association between BP use and the revision rate of TJA and (2) to determine the relationship between the medication period and the revision rate of TJA. METHODS: National Health Insurance Service data on surgeries, medications, diagnoses, and screenings of 50 million Koreans were reviewed. People who underwent TJA in the period from 2002 to 2012 were identified and followed until 2016. During that period, 331,660 patients underwent total knee arthroplasty (TKA), and 56,043 patients underwent total hip arthroplasty (THA). Among them, 8447 knee patients (2.5%) and 2851 hip patients (5.0%) required revision surgery due to aseptic loosening. Demographic data, the duration of BP medication, and comorbidities were identified. The rate of revision surgery according to BP medication was investigated. The extended Cox proportional hazard model was used to evaluate the effect of the medication period. RESULTS: The rate of TKA revision was 1.4% for BP users and 2.9% for BP non-users (p < 0.001). The THA revision rate was 2.8% and 5.3% for BP users and non-users, respectively (p < 0.001). The hazard ratio (HR) of revision was significantly lower in patients who took BP medication for more than one year (TKA HR = 0.472, 95% CI [0.350-0.637]; THA HR = 0.490, 95% CI [0.247-0.972]) compared to that in short-term users (less than 1 year). CONCLUSIONS: The use of BPs after TJA was associated with a lower revision rate. The use of BPs for more than one year further reduced the risk of revision. Bisphosphonate use can be highly recommended to reduce the revision rate of TJA. LEVEL OF EVIDENCE: Retrospective cohort study, Level III.

Efficient Statistical Method for Association Analysis of X-Linked Variants.

BACKGROUND/AIMS: Unlike the gene-poor Y chromosome, the X chromosome contains over 1,000 genes that are essential for viability of cells. Females have 2 X chromosomes, and thus female X-linked gene expression would be expected to be twice that of males. To adjust this imbalance, one of the 2 X-linked genes is often inactivated, and this is known as X-chromosome inactivation (XCI). However, recent studies described that a gene can be nonrandomly selected for inactivation from 2 X-linked genes and that XCI is not observed in some X-linked genes. Since this complex biological process has prevented efficient statistical association analyses, we propose a new statistical method against this uncertain biological process. METHODS: The proposed method consists of 2 steps. First, p values for various biological processes are calculated and then combined into a single p value with the modified Fisher method and a minimum p value. RESULTS: Our simulation results show that the proposed method is generally the most statistically efficient and is not sensitive to the unknown biological model. CONCLUSION: Therefore, we can conclude that the proposed approaches are robust against the various XCI processes for testing the association of X-linked single nucleotide polymorphisms with the disease of interest and the proposed method is a practical solution.

Morphological and histological changes of rabbit vocal fold after steroid injection.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the morphological and histological change of vocal folds (VFs) after steroid injection in a rabbit model. STUDY DESIGN: Prospective animal study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: Twenty-four New Zealand white rabbits were used in this study. We randomly classified rabbits into the 3 groups and triamcinolone acetonide suspension was injected to the right VF with different concentrations. Left VF was injected with the same volume of phosphate-buffered saline as control. Endoscopic evaluation was performed to measure morphological changes. The larynges were collected for histological analysis, and the VFs were stained with hematoxylin-eosin for assessing inflammatory response, glandular atrophy, and muscular atrophy and with Masson's trichrome for assessing collagen deposition. RESULTS: In morphological assessment, there were no differences in VF mass reduction, mucosal atrophy, and granulation formation between both VFs. Histological assessments showed no significant difference in inflammatory response, glandular atrophy, and collagen deposition between both VFs. However, there was a difference in muscular atrophy and epithelial layer thinning in steroid injected right VFs. Muscular atrophy had been completely recovered over time, but mild epithelial thinning was continued until 12 weeks. The longer exposure time and larger dose did not increase the intensity of muscular atrophy or epithelial thinning. CONCLUSION: We demonstrated that the VF steroid injection resulted in no significant changes in morphology and histology of rabbit VF. However, steroid injection may induce several VF histological changes and these results are needed to be considered when treating humans.

Local steroid injection via the cricothyroid membrane in patients with a vocal nodule.

OBJECTIVE: To analyze the usefulness and safety of a steroid injection into vocal nodules via the cricothyroid membrane. Local administration of steroid directly into the larynx has been reported in many laryngeal diseases with different methods. DESIGN: Prospective case series at an academic tertiary care hospital. PATIENTS: Eighty patients with vocal nodules were enrolled between December 2008 and May 2010. INTERVENTIONS: Triamcinolone acetonide was injected through the cricothyroid membrane with a transnasal flexible laryngoscope to patients in a sitting position. MAIN OUTCOME MEASURES: Vocal nodules were evaluated before and 2 and 4 weeks after the injection; improvement was assessed both objectively and subjectively. RESULTS: The nodules disappeared in 35 patients by the fourth week after the injection (44%), and 39 patients showed improvement (49%). Jitter, shimmer, maximum phonation time, and mean voice handicap index also improved significantly after the steroid injection (P < .05 for all). Six patients with voice-related occupations showed improvement at the second week (8%), but the nodules had recurred after 4 weeks. Four patients experienced mild vocal fold atrophy, and 2 patients showed a white plaque formation on the vocal fold that resolved spontaneously 1 to 2 months after the injection. CONCLUSIONS: A local steroid injection via the cricothyroid membrane is a useful and safe treatment option for vocal nodules. However, vocal nodules are caused mainly by excessive voice use; therefore, nodules can recur unless the voice use pattern changes. Further study of this treatment technique, including long-term follow-up, is needed.