Falls, fracture and frailty risk in multiple sclerosis: a Mendelian Randomization study to identify shared genetics.

INTRODUCTION: Patients with multiple sclerosis (MS) commonly present musculoskeletal disorders characterized by lower bone mineral density (BMD) and muscle weakness. However, the underlying etiology remains unclear. Our objective is to identify shared pleiotropic genetic effects and estimate the causal relationship between MS and musculoskeletal disorders. MATERIALS AND METHODS: We conducted linkage disequilibrium score regression (LDSR), colocalization, and Mendelian randomization (MR) analyses using summary statistics from recent large-scale genome-wide association studies (GWAS), encompassing MS, falls, fractures, and frailty. Additional MR analyses explored the causal relationship with musculoskeletal risk factors, such as BMD, lean mass, grip strength, and vitamin D. RESULTS: We observed a moderate genetic correlation between MS and falls (RG = 0.10, P-value = 0.01) but not between MS with fracture or frailty in the LDSR analyses. MR revealed MS had no causal association with fracture and frailty but a moderate association with falls (OR: 1.004, FDR q-value = 0.018). We further performed colocalization analyses using nine SNPs that exhibited significant associations with both MS and falls in MR. Two SNPs (rs7731626 on ANKRD55 and rs701006 on OS9 gene) showed higher posterior probability of colocalization (PP.H4 = 0.927), suggesting potential pleiotropic effects between MS and falls. The nine genes are associated with central nervous system development and inflammation signaling pathways. CONCLUSION: We found potential pleiotropic genetic effects between MS and falls. However, our analysis did not reveal a causal relationship between MS and increased risks of falls, fractures, or frailty. This suggests that the musculoskeletal disorders frequently reported in MS patients in clinical studies are more likely attributed to secondary factors associated with disease progression and treatment, rather than being directly caused by MS itself.

Microbiome signatures associated with clinical stages of gastric Cancer: whole metagenome shotgun sequencing study.

BACKGROUND: Gastric cancer is one of the global health concerns. A series of studies on the stomach have confirmed the role of the microbiome in shaping gastrointestinal diseases. Delineation of microbiome signatures to distinguish chronic gastritis from gastric cancer will provide a non-invasive preventative and treatment strategy. In this study, we performed whole metagenome shotgun sequencing of fecal samples to enhance the detection of rare bacterial species and increase genome sequence coverage. Additionally, we employed multiple bioinformatics approaches to investigate the potential targets of the microbiome as an indicator of differentiating gastric cancer from chronic gastritis. RESULTS: A total of 65 patients were enrolled, comprising 33 individuals with chronic gastritis and 32 with gastric cancer. Within each group, the chronic gastritis group was sub-grouped into intestinal metaplasia (n = 15) and non-intestinal metaplasia (n = 18); the gastric cancer group, early stage (stages 1 and 2, n = 13) and late stage (stages 3 and 4, n = 19) cancer. No significant differences in alpha and beta diversities were detected among the patient groups. However, in a two-group univariate comparison, higher Fusobacteria abundance was identified in phylum; Fusobacteria presented higher abundance in gastric cancer (LDA scored 4.27, q = 0.041 in LEfSe). Age and sex-adjusted MaAsLin and Random Forest variable of importance (VIMP) analysis in species provided meaningful features; Bacteria_caccae was the most contributing species toward gastric cancer and late-stage cancer (beta:2.43, se:0.891, p:0.008, VIMP score:2.543). In contrast, Bifidobacterium_longum significantly contributed to chronic gastritis (beta:-1.8, se:0.699, p:0.009, VIMP score:1.988). Age, sex, and BMI-adjusted MasAsLin on metabolic pathway analysis showed that GLCMANNANAUT-PWY degradation was higher in gastric cancer and one of the contributing species was Fusobacterium_varium. CONCLUSION: Microbiomes belonging to the pathogenic phylum Fusobacteria and species Bacteroides_caccae and Streptococcus_anginosus can be significant targets for monitoring the progression of gastric cancer. Whereas Bifidobacterium_longum and Lachnospiraceae_bacterium_5_1_63FAA might be protection biomarkers against gastric cancer.

Claims-Based Frailty Index and Its Relationship With Commonly Used Clinical Frailty Measures.

BACKGROUND: The relationship of claims-based frailty index (CFI), a validated measure to identify frail individuals using Medicare data, and frailty measures used in clinical practice has not yet been fully explored. METHODS: We identified community-dwelling participants of the 2015 National Health and Aging Trends Study (NHATS) whose CFI scores could be calculated using linked Medicare claims. We calculated 9 commonly used clinical frailty measures from their NHATS in-person examination: Study of Osteoporotic Fracture Index (SOF), FRAIL Scale, Frailty Phenotype, Clinical Frailty Scale (CFS), Vulnerable Elder Survey-13 (VES-13), Tilburg Frailty Indicator (TFI), Groningen Frailty Indicator (GFI), Edmonton Frail Scale (EFS), and 40-item Frailty Index (FI). Using equipercentile method, CFI scores were linked to clinical frailty measures. C-statistics and test characteristics of CFI to identify frailty as defined by each clinical frailty measure were calculated. RESULTS: Of the 3 963 older adults, 44.5% were ≥75 years, 59.4% were female, and 82.3% were non-Hispanic White. A CFI of 0.25 was equipercentile to the following clinical frailty measure scores: SOF 1.4, FRAIL 1.8, Phenotype 1.8, CFS 5.4, VES-13 5.7, TFI 4.6, GFI 5.0, EFS 6.0, and FI 0.26. The C-statistics of using CFI to identify frailty as defined by each clinical measure were ≥0.70, except for CFS and VES-13. The optimal CFI cutpoints to identify frailty per clinical frailty measure ranged from 0.212 to 0.242, with sensitivity and specificity of 0.37-0.83 and 0.66-0.84, respectively. CONCLUSIONS: Understanding the relationship of CFI and commonly used clinical frailty measures can enhance the interpretability and potential utility of CFI.

Translating GWAS Findings to Inform Drug Repositioning Strategies for COVID-19 Treatment.

We developed a computational framework that integrates Genome-Wide Association Studies (GWAS) and post-GWAS analyses, designed to facilitate drug repurposing for COVID-19 treatment. The comprehensive approach combines transcriptomic-wide associations, polygenic priority scoring, 3D genomics, viral-host protein-protein interactions, and small-molecule docking. Through GWAS, we identified nine druggable host genes associated with COVID-19 severity and SARS-CoV-2 infection, all of which show differential expression in COVID-19 patients. These genes include IFNAR1, IFNAR2, TYK2, IL10RB, CXCR6, CCR9, and OAS1. We performed an extensive molecular docking analysis of these targets using 553 small molecules derived from five therapeutically enriched categories, namely antibacterials, antivirals, antineoplastics, immunosuppressants, and anti-inflammatories. This analysis, which comprised over 20,000 individual docking analyses, enabled the identification of several promising drug candidates. All results are available via the DockCoV2 database (https://dockcov2.org/drugs/). The computational framework ultimately identified nine potential drug candidates: Peginterferon alfa-2b, Interferon alfa-2b, Interferon beta-1b, Ruxolitinib, Dactinomycin, Rolitetracycline, Irinotecan, Vinblastine, and Oritavancin. While its current focus is on COVID-19, our proposed computational framework can be applied more broadly to assist in drug repurposing efforts for a variety of diseases. Overall, this study underscores the potential of human genetic studies and the utility of a computational framework for drug repurposing in the context of COVID-19 treatment, providing a valuable resource for researchers in this field.

Prognostic microRNA signature for estimating survival in patients with hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the leading cancer types with increasing annual incidence and high mortality in the USA. MicroRNAs (miRNAs) have emerged as valuable prognostic indicators in cancer patients. To identify a miRNA signature predictive of survival in patients with HCC, we developed a machine learning-based HCC survival estimation method, HCCse, using the miRNA expression profiles of 122 patients with HCC. METHODS: The HCCse method was designed using an optimal feature selection algorithm incorporated with support vector regression. RESULTS: HCCse identified a robust miRNA signature consisting of 32 miRNAs and obtained a mean correlation coefficient (R) and mean absolute error (MAE) of 0.87 ±â€…0.02 and 0.73 years between the actual and estimated survival times of patients with HCC; and the jackknife test achieved an R and MAE of 0.73 and 0.97 years between actual and estimated survival times, respectively. The identified signature has seven prognostic miRNAs (hsa-miR-146a-3p, hsa-miR-200a-3p, hsa-miR-652-3p, hsa-miR-34a-3p, hsa-miR-132-5p, hsa-miR-1301-3p and hsa-miR-374b-3p) and four diagnostic miRNAs (hsa-miR-1301-3p, hsa-miR-17-5p, hsa-miR-34a-3p and hsa-miR-200a-3p). Notably, three of these miRNAs, hsa-miR-200a-3p, hsa-miR-1301-3p and hsa-miR-17-5p, also displayed association with tumor stage, further emphasizing their clinical relevance. Furthermore, we performed pathway enrichment analysis and found that the target genes of the identified miRNA signature were significantly enriched in the hepatitis B pathway, suggesting its potential involvement in HCC pathogenesis. CONCLUSIONS: Our study developed HCCse, a machine learning-based method, to predict survival in HCC patients using miRNA expression profiles. We identified a robust miRNA signature of 32 miRNAs with prognostic and diagnostic value, highlighting their clinical relevance in HCC management and potential involvement in HCC pathogenesis.

Pleiotropic Genetic Effects between Multiple Sclerosis and Musculoskeletal Traits.

Background: Musculoskeletal disorders were commonly reported in patients with multiple sclerosis. However, the underlying etiology linking Multiple Sclerosis (MS) and musculoskeletal disorders is not well studied. With large-scale Genome-Wide Association Studies (GWAS) publicly available, we conducted genetic correlation analysis to identify shared pleiotropic genetic effects between MS and musculoskeletal traits. We also conducted Mendelian Randomization (MR) to estimate the causal relation between MS and increased risks of musculoskeletal disorders. Methods: Linkage Disequilibrium Score Regression (LDSR) analysis was performed to estimate heritability and genetic correlation. Univariable, multivariable, and bidirectional MR analyses were conducted to estimate the causal relation. These analyses were done by utilizing the recent GWAS summary statistics of MS, fracture, frailty, falls, and several musculoskeletal risk factors, including bone mineral density, lean mass, grip strengths, and vitamin D. Results: LDSR analysis showed a moderate genetic correlation of MS with falls (RG=0.10, p=0.01) but not with fracture and frailty. Genetic variants (rs13191659) in LINC00240 gene which is associated with iron status biomarkers was found to be associated with both MS and falls. In MR analyses after excluding outlier SNPs with potential pleiotropic effects and correcting for multiple testing, MS presented no causal association with fracture and frailty but a minimal association with falls. Falls showed causally increased risks of fracture and frailty. Conclusion: Our study suggests a potential genetic correlation with shared pleiotropic genetic effects between MS and falls. However, we didn't find evidence to support the causal relation between MS and increased risks of falls, fracture, and frailty.

Hospitalization and emergency department visits associated with potentially inappropriate medication in older adults: self-controlled case series analysis.

Introduction: Potentially inappropriate medications (PIM) and resulting adverse health outcomes in older adults are a common occurrence. However, PIM prescriptions are still frequent for vulnerable older adults. Here, we sought to estimate the risk of hospitalization and emergency department (ED) visits associated with PIM prescriptions over different exposure periods and PIM drug categories. Methods: We used the National Health Insurance Service-Elderly Cohort Database (NHIS-ECDB) to construct the cohort and implemented a Self-Controlled Case Series (SCCS) method. Hospitalization or ED visits during the exposure and post-exposure periods were compared to those during the non-exposure period, and six PIM drug categories were evaluated. A conditional Poisson regression model was applied, and the risk of outcomes was presented as the incidence rate ratio (IRR). All potential time-varying covariates were adjusted by year. A total of 43,942 older adults aged ≥65 y who had at least one PIM prescription and the events of either hospitalization or ED visits between Jan 2016 and Dec 2019 were selected.. Results: Mean days of each exposure period was 46 d (±123); risk was highest in exposure1 (1-7 d, 37.8%), whereas it was similar during exposure2 (15-28 d), and exposure3 (29-56 d) (16.6%). The mean number of total PIM drugs administered during the study period was 7.34 (±4.60). Both hospitalization and ED visits were significantly higher in both exposure (adjusted IRR 2.14, 95% Confidence Interval (CI):2.11-2.17) and post-exposure periods (adjusted IRR 1.41, 95% CI:1.38-1.44) in comparison to non-exposure period. The risk of adverse health outcomes was highest during the first exposure period (1-14 d), but decreased gradually over time. Among the PIM categories, pain medication was used the most, followed by anticholinergics. All PIM categories significantly increased the risk of hospitalization and ED visits, ranging from 1.18 (other PIM) to 2.85 (pain medication). Sensitivity analyses using the first incidence of PIM exposure demonstrated similar results. All PIM categories significantly increased the risk of hospitalization and ED visits, with the initial period of PIM prescriptions showing the highest risk. In subgroup analysis stratified by the number of medications, PIM effects on the risk of hospitalization and ED visits remained significant but gradually attenuated by the increased number of medications. Discussion: Therefore, the development of deprescribing strategies to control PIM and polypharmacy collectively is urgent and essential.

A crosswalk of commonly used frailty scales.

BACKGROUND: Several validated scales have been developed to measure frailty, yet the direct relationship between these measures and their scores remains unknown. To bridge this gap, we created a crosswalk of the most commonly used frailty scales. METHODS: We used data from 7070 community-dwelling older adults who participated in National Health and Aging Trends Study (NHATS) Round 5 to construct a crosswalk among frailty scales. We operationalized the Study of Osteoporotic Fracture Index (SOF), FRAIL Scale, Frailty Phenotype, Clinical Frailty Scale (CFS), Vulnerable Elder Survey-13 (VES-13), Tilburg Frailty Indictor (TFI), Groningen Frailty Indicator (GFI), Edmonton Frailty Scale (EFS), and 40-item Frailty Index (FI). A crosswalk between FI and the frailty scales was created using the equipercentile linking method, a statistical procedure that produces equivalent scoring between scales according to percentile distributions. To demonstrate its validity, we determined the 4-year mortality risk across all scales for low-risk (equivalent to FI <0.20), moderate-risk (FI 0.20 to <0.40), and high-risk (FI ≥0.40) categories. RESULTS: Using NHATS, the feasibility of calculating frailty scores was at least 90% for all nine scales, with the FI having the highest number of calculable scores. Participants considered frail on FI (cutpoint of 0.25) corresponded to the following scores on each frailty measure: SOF 1.3, FRAIL 1.7, Phenotype 1.7, CFS 5.3, VES-13 5.5, TFI 4.4, GFI 4.8, and EFS 5.8. Conversely, individuals considered frail according to the cutpoint of each frailty measure corresponded to the following FI scores: 0.37 for SOF, 0.40 for FRAIL, 0.42 for Phenotype, 0.21 for CFS, 0.16 for VES-13, 0.28 for TFI, 0.21 for GFI, and 0.37 for EFS. Across frailty scales, the 4-year mortality risks between the same categories were similar in magnitude. CONCLUSION: Our results provide clinicians and researchers with a useful tool to directly compare and interpret frailty scores across scales.

Roles of AIM2 Gene and AIM2 Inflammasome in the Pathogenesis and Treatment of Psoriasis.

Psoriasis is an immune-mediated chronic inflammatory skin disease caused by a combination of environmental incentives, polygenic genetic control, and immune regulation. The inflammation-related gene absent in melanoma 2 (AIM2) was identified as a susceptibility gene for psoriasis. AIM2 inflammasome formed from the combination of AIM2, PYD-linked apoptosis-associated speck-like protein (ASC) and Caspase-1 promotes the maturation and release of inflammatory cytokines such as IL-1ß and IL-18, and triggers an inflammatory response. Studies showed the genetic and epigenetic associations between AIM2 gene and psoriasis. AIM2 gene has an essential role in the occurrence and development of psoriasis, and the inhibitors of AIM2 inflammasome will be new therapeutic targets for psoriasis. In this review, we summarized the roles of the AIM2 gene and AIM2 inflammasome in pathogenesis and treatment of psoriasis, hopefully providing a better understanding and new insight into the roles of AIM2 gene and AIM2 inflammasome in psoriasis.

Cognitive Function Associated with Gut Microbial Abundance in Sucrose and S-Adenosyl-L-Methionine (SAMe) Metabolic Pathways.

BACKGROUND: Differential abundance of gut microbiota has found to be associated with Alzheimer's disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied. OBJECTIVE: We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI. METHODS: Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches. RESULTS: We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes), Anaerotruncus colihominis (Firmicutes), and Gordonibacter pamelaeae (Actinobacteria). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways was more enriched in AD with MCI than AD with dementia and significantly associated with higher cognitive function scores. CONCLUSION: Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline.

Impact of COVID-19 Pandemic Declaration on New Oncology Trial Commencements: An Interrupted Time Series with Segmented Regression Analysis.

This study aimed to assess the trend in oncology trial commencements registered on ClinicalTrials.gov and to evaluate the contributing factors by comparing the trends in the pre- and post-COVID-19 pandemic era. The ClinicalTrials.gov database was searched to identify oncology study trials starting from 1 January 2018 to 28 February 2021. Data on the variables of start/complete date, phase, status, funding source, center, country and study type were extracted. According to the time point of the COVID-19 pandemic declaration by the World Health Organization (WHO), March 2020, we analyzed the extracted data, including interrupted time series (ITS) analysis and multivariable regression analysis. We identified 18,561 new oncology trials during the study period. A total of 5678 oncology trials in the prepandemic period and 6134 in the postpandemic period were included in the comparative analysis. The year 2020 had the most newly launched trials (32.3%), and the majority of trials were planned to be conducted for longer than two years (70.3%). The results of ITS show the trend in the commencement of oncology trials was significantly increased after the pandemic declaration (coefficient = 27.99; 95% CI = 19.27 to 36.71). Drug intervention trials were the largest contributor to the increased trial number compared to different interventions, such as trials of devices or procedures (OR = 1.14; 95% CI = 1.03 to 1.26, OR = 1.09; 95% CI = 0.91 to 1.29, and OR = 1.12; 95% CI = 0.96 to 1.31, respectively), whereas the United Kingdom was the highest contributor to the number of decreased trials (OR = 0.67; 95% CI = 0.51 to 0.89 p = 0.01) in the postpandemic era. The interruption in oncology trial initiation was diminished shortly after the COVID-19 pandemic declaration, which was influenced by several factors, such as interventions or national responses. Based on the current outcomes, appropriate strategies for developing oncology trials can be planned to mitigate the impact of future crises on oncology trials.

Survival, Prognosis, and Clinical Feature of Refractory Myasthenia Gravis: a 15-year Nationwide Cohort Study.

BACKGROUND: Myasthenia gravis (MG) is a rare classic autoimmune disease where immunosuppressant therapies have been successful to reduce MG attributable mortality fairly well. However, patients with refractory MG (rMG) among the actively treated MG (aMG) are nonresponsive to conventional therapy and display high disease severity, which calls for further research. We aimed to determine survival, prognosis, and clinical feature of patients with rMG compared to non-rMG. METHODS: Retrospective nationwide cohort study using Korea's healthcare database between 2002 and 2017 was conducted. Patients with rMG (n = 47) and non-rMG (n = 4,251) who were aged > 18 years, followed-up for ≥ 1 year, and prescribed immunosuppressants within 2 years after incident MG diagnosis were included. Patients with rMG were defined as administered plasma exchange or intravenous immunoglobulin at least 3 times per year after receiving ≥ 2 immunosuppressants. All-cause mortality, myasthenic crisis, hospitalization, pneumonia/sepsis, and emergency department (ED) visits were measured using Cox proportional hazard models and pharmacotherapy patterns for rMG were assessed. RESULTS: The rMG cohort included a preponderance of younger patients and women. The adjusted hazard ratio was 2.49 (95% confidence interval, 1.26-4.94) for mortality, 3.14 (2.25-4.38) for myasthenic crisis, 1.54 (1.15-2.06) for hospitalization, 2.69 (1.74-4.15) for pneumonia/sepsis, and 1.81 (1.28-2.56) for ED visits for rMG versus non-rMG. The immunosuppressant prescriptions were more prevalent in patients with rMG, while the difference was more remarkable before rMG onset rather than after rMG onset. CONCLUSION: Despite the severe prognosis of rMG, the strategies for pharmacotherapeutic regimens were similar in those two groups, suggesting that intensive monitoring and introduction of timely treatment options in the early phase of MG are required.

Patient- and Prescriber-Related Factors Associated with Potentially Inappropriate Medications and Drug-Drug Interactions in Older Adults.

We aimed to evaluate the prevalence of potentially inappropriate medication (PIM) use and drug-drug interactions (DDIs) in older adults and their associated factors. This cross-sectional study used National Health Insurance data of older adults in South Korea. The 2015 AGS Beers Criteria were used to classify PIM use and DDIs. The associations of PIM use and DDIs with patient- and prescriber-related factors were evaluated using multiple logistic regression. Of the older adults who received at least one outpatient prescription (N = 1,277,289), 73.0% and 13.3% received one or more prescriptions associated with PIM use or DDIs, respectively. Chlorphenamine was most commonly associated with PIM, followed by diazepam. Co-prescriptions of corticosteroids and NSAIDs accounted for 82.8% of DDIs. Polypharmacy and mainly visiting surgeons or neurologists/psychiatrists were associated with a higher likelihood of prescriptions associated with PIM use or DDIs. Older age, high continuity of care (COC), and mainly visiting a hospital were associated with a lower likelihood of PIM use or DDIs. Prescriptions associated with PIM use and DDIS were more frequent for low COC patients or those who mainly visited clinics; therefore, patients with these characteristics are preferred intervention targets for reducing prescriptions associated with PIM use and DDIs.

Effectiveness of Clinical Pharmacist Service on Drug-Related Problems and Patient Outcomes for Hospitalized Patients with Chronic Kidney Disease: A Randomized Controlled Trial.

(1) Background: The study aimed to analyze the effectiveness of clinical pharmacist services on drug-related problems (DRPs) and patient outcomes in inpatients with chronic kidney disease (CKD). (2) Methods: In a randomized controlled trial, the participants in the intervention group received pharmacist services, including medication reconciliation, medication evaluation and management, and discharge pharmaceutical care transition services. Participants in the control group received usual care. The primary outcome was the number of DRPs per patient at discharge. (3) Results: The baseline characteristics of 100 participants included the following: mean age, 52.5 years; median eGFR, 9.2 mL/min/1.73 m2. The number of DRPs in the intervention group during hospitalization increased significantly with decreasing eGFR (PR, 0.970; 95% CI, 0.951-0.989) and an increasing number of unintentional medication discrepancies at admission (PR, 1.294; 95% CI, 1.034-1.620). At discharge, the number of DRPs per patient was 0.94 ± 1.03 and 1.96 ± 1.25 in the intervention and control groups, respectively (p < 0.001). The service had a significant effect on the reduction of the unintentional discrepancies at discharge (p < 0.001). (4) Conclusion: Hospital pharmacists play an important role in the prevention of DRPs at discharge and unintentional medication discrepancies in inpatients with CKD.

Drug-induced Parkinsonism: A strong predictor of idiopathic Parkinson's disease.

BACKGROUND: Although Idiopathic Parkinson's disease (IPD) develops in considerable patients with drug-induced Parkinsonism (DIP), the association hasn't been well defined. We aimed to evaluate the underlying association and risk factors of DIP and IPD. METHODS: A retrospective cohort study using National Health Insurance Claims data in 2011-2016 was conducted. New-onset DIP patients in 2012 were selected and matched with active controls having diabetes mellitus at a 1:4 ratio by age, sex, and Charlson's Comorbidity Index score. Comorbidity, causative drugs, and prescription days were evaluated as covariates. RESULTS: A total of 441 DIP were selected. During the 4-year follow up, 14 IPD events in the DM group but 62 events in the DIP group were observed (adjusted hazard ratio, HR: 18.88, 95% CI, 9.09-39.22, adjusting for comorbidities and causative drugs). IPD diagnosis in DIP was observed high in males compared to females (15.58/13.24%). The event was the most within the 1st year follow-up, mean days 453 (SD 413.36). Subgroup analysis in DIP showed calcium channel blocker (verapamil, diltiazem, and flunarizine) was significantly associated with increased IPD risk (HR: 2.24, 95% CI, 1.27-3.93). CONCLUSION: Increased IPD in DIP patients might not be from the causal toxicity of antidopaminergic effects but from a trigger by the causative drugs on the DIP patients who already had subclinical IPD pathology. DIP can serve as a strong proxy for IPD incidence. Subjects who develop DIP should be monitored carefully for potential IPD incidence.

Impact of a nationwide prospective drug utilization review program to improve prescribing safety of potentially inappropriate medications in older adults: An interrupted time series with segmented regression analysis.

PURPOSE: A nationwide prospective drug utilization review (DUR) for potentially inappropriate medications (PIMs) in older adults was implemented in October 2015 in South Korea. We aimed to evaluate the effects of the DUR on reducing PIMs, in comparison with the PIMs defined using the Beers criteria that were not included in the DUR. METHODS: We divided the study period into a pre- and post-DUR period. The monthly percentage of patients or prescriptions with at least one PIM in the DUR or defined by the Beers criteria was calculated using national health insurance data. We evaluated the effect of the DUR on the prevalence of PIM use in older adults using an interrupted time series with segmented regression analysis. RESULTS: The prevalence of older adults prescribed PIMs in the DUR decreased by 0.49% (95% confidence interval (CI) [-0.60, -0.37]) based on patient-based measures and, by 0.41% (95% CI [-0.58, -0.23]) based on prescription-based measure, immediately after DUR implementation. However, there were no statistically significant changes in trend. Further, the prevalence of PIMs based on the Beers criteria had no statistically significant changes in terms of either level or trend. After 12 months of DUR, there was a reduction of 11.5% (95% CI [2.6 20.4]) relative to the PIMs in Beers. CONCLUSIONS: The implementation of a nationwide prospective DUR lowered the prescription of PIMs for older adults. On the other hand, PIMs that were not included were unchanged. Thus, it is worth considering expanding the DUR list to improve prescribing safety.

Risk Factors and the Usual Source of Care on Non-Adherence to Antihypertensive Drugs in Immigrants with Hypertension.

BACKGROUND: Immigrants are vulnerable to suboptimal health care utilization including non-adherence of medication use. Thus, we aimed to identify the potential risk factors of non-adherence and evaluate whether utilizing a usual source of care was associated with medication adherence in immigrants. METHODS: We utilized the Korea National Health Insurance Claims Database between 2012 and 2015. Cases were immigrants who had antihypertensive prescriptions at the time of hypertension diagnosis in 2012. Controls were native-born Koreans with hypertension who were 1:1 matched to immigrants by age, sex, and Charlson comorbidity index. We used the medication possession ratio for three years to assess the adherence to antihypertensive drugs. The likelihood of non-adherence was evaluated between cases and controls by multivariate linear regression models stratified by age, sex, and number of clinic visits. We assessed the potential risk factors of non-adherence in immigrants by multivariate linear regression and logistic regression models, respectively. RESULTS: In total, 4114 immigrants and 4114 matched native-born Koreans with hypertension were included. The mean MPR was significantly lower in immigrants (56% vs 70%, p<0.0001). Immigrants showed almost two times the level of non-adherence as native-born Koreans (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.83-2.21). Stratified analyses on non-adherence presented the highest non-adherence (2.28 times) in immigrants in the younger group (30-49 years old) and the lowest non-adherence in immigrants in 65 and old group where the risk was 1.69 times higher than native Korean with the same age. The absence of a usual source of care significantly increased medication non-adherence by 1.31 to 1.58 times among immigrants. CONCLUSION: When the number of visited clinics increased, the degree of non-adherence increased consistently. Therefore, the systematization of registering with primary care (a usual source of care) might be a modifiable health care strategy to improve health care outcomes in immigrants.

Increased risk of death with codeine use in the elderly over 85 years old and patients with respiratory disease: A case-control study using retrospective insurance claims database.

To investigate the risk of mortality associated with exposure to codeine, considering various risk groups, using population-based national insurance claims data.National sample cohort data from the National Health Insurance Service of South Korea (2002-2013) was used in this case-control study. Cases were defined as patients with a death record between January 1, 2002 and December 31, 2013. Each case was matched to 10 controls based on age, sex, baseline comorbidities, and year of death. Definition of exposure was codeine prescription in 30 days prior to death and sensitivity analyses were performed for 15 and 60-day exposures. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated using conditional logistic regression adjusting for benzodiazepine, other opioids, anesthetics, hypnotics, CYP2D6 inducer, CYP3A4 inducer, and the Charlson comorbidity index.A total of 19,341 cases and 185,700 matched controls were included. The overall risk associated with codeine use and mortality risk was not significant (aOR 1.08, 95% CI 1.00-1.16). Sensitivity analyses with different exposure time window also presented similar insignificant results. However, in the subgroup analyses, codeine use was associated with an increased risk of mortality in the >85-year-old age group (aOR 2.38, 95% CI 1.26-4.48) and patients with respiratory disease (aOR 1.29, 95% CI 1.17-1.42).Although no statistically significant association was found in codeine exposure and mortality risk between cases and controls, we demonstrated that the elderly over 85 years old and patients with respiratory disease are associated with a higher risk with codeine exposure. Therefore, a more cautious practice of codeine prescription in these groups might be needed.

Effects of maternal influenza vaccination on adverse birth outcomes: A systematic review and Bayesian meta-analysis.

BACKGROUND: Although pregnant women are a priority group for influenza vaccination, its effect on birth outcomes has long been debated. Numerous observational studies and a few randomized controlled studies have been conducted, with inconsistent results. OBJECTIVES: To evaluate the association of influenza vaccination in pregnancy with adverse birth outcomes. DATA SOURCE: The Cochrane Library, PubMed, EMBASE, Web of Science, and Scopus were searched. STUDY ELIGIBILITY CRITERIA: This analysis included randomized placebo-controlled studies, cohort studies, and case-control studies, in which inactivated influenza vaccination was given during pregnancy and fetal adverse birth outcomes were assessed. PARTICIPANTS & INTERVENTION: Women who received inactivated influenza vaccine during pregnancy and their offspring. STUDY APPRAISAL AND SYNTHESIS: Two independent reviewers and a third reviewer collaborated in study selection and data extraction. A Bayesian 3-level random-effects model was utilized to assess the impact of maternal influenza vaccination on birth outcomes, which were presented as odds ratios (ORs) with 95% credible interval (CrIs). Bayesian outcome probabilities (P) of an OR<1 were calculated, and values of at least 90% (0.9) were deemed to indicate a significant result. RESULTS: Among the 6,249 identified publications, 48 studies were eligible for the meta-analysis, including 2 randomized controlled trials, 41 cohort studies, and 5 case-control studies. The risk of none of the following adverse birth outcomes decreased significantly: preterm birth (OR = 0.945, 95% CrI: 0.736-1.345, P = 73.3%), low birth weight (OR = 0.928, 95% CrI: 0.432-2.112, P = 76.7%), small for gestational age (OR = 0.971, 95% CrI: 0.249-4.217,P = 63.3%), congenital malformation (OR = 1.026, 95% CrI: 0.687-1.600, P = 38.0%), and fetal death (OR = 0.942, 95% CrI: 0.560-1.954, P = 61.6%). Summary estimates including only cohort studies showed significantly decreased risks for preterm birth, small for gestational age and fetal death. However, after adjusting for season at the time of vaccination and countries' income level, only fetal death remained significant. CONCLUSION: This Bayesian meta-analysis did not find a protective effect of maternal influenza vaccination against adverse birth outcomes, as reported in previous studies. In fact, our results showed evidence of null associations between maternal influenza vaccination and adverse birth outcomes.

Socioeconomic determinants affecting the access and utilization of depression care services in immigrants: A population-based study.

BACKGROUND: It is imperative to address the health problems faced by immigrants in their destination countries in light of the current magnitude of migration processes worldwide. We aimed to evaluate the socioeconomic determinants of healthcare utilization in immigrants with depression. METHOD: A population-based cohort comprising all immigrants who were eligible for National Health Insurance coverage (permanent residents, marriage immigrants, and naturalized citizens) using the National Health Insurance Claims Database in 2011-2013 was established. Cases were defined as immigrants with new-onset depression. Controls were new-onset Korean patients with depression matched by age, sex, and Charlson comorbidity index in a 1:2 ratio. Appropriateness of care (AOC) was defined as visiting a clinic for depression management at least 3 times in the first 12 weeks and 4 times thereafter until 12 months post-cohort entry. RESULTS: A total of 2,378 immigrants and 4,756 matched Korean patients were identified. Of the immigrants, 30.0% achieved AOC, in contrast to 38.7% of Koreans (p < .0001). Adjusting for possible covariates, AOC was less likely for immigrants (adjusted OR (aOR), 0.760; 95% CI: 0.670-0.863). Medical Aid (aOR, 2.309; 95% CI, 1.479-3.610), rural residence (aOR, 1.536; 95% CI, 1.054-2.237), the presence of a psychiatric comorbidity (aOR, 1.912; 95% CI, 1.484-2.463), and visiting a psychiatrist (aOR, 2.387; 95% CI, 1.821-3.125) were associated with an increased likelihood of AOC in immigrants. CONCLUSION: Socioeconomic determinants included insurance type (Medical Aid and National Health Insurance), place of residence, psychiatric comorbid status, doctor specialty, easy access to medical services (clinic-based), and a SSRI-based treatment regimen. Those predictors should be taken into account when developing healthcare strategies for immigrants.