The Effect of the COVID-19 Pandemic on Early Adolescent Fractures in the Republic of Korea.

Background and Objectives: Restrictions on daily activities to slow down the propagation of COVID-19 have changed the epidemiological pattern of pediatric fractures in many countries. However, the effect of the pandemic on pediatric fractures has not been fully studied. In this study, we investigated the impact of COVID-19 on early adolescent fractures in Korea. Materials and methods: We conducted a retrospective follow-up on a nationwide cohort of Korean early adolescents born between 2006 and 2009. The prevalence and incidence of pediatric fractures and the frequency of surgical treatment were compared between two different eras. Results: The prevalence and incidence of fractures during the pandemic have both shown a significant decrease: prevalence reduced from 34,626 to 24,789 (p < 0.001), while incidence decreased from 29,804 to 18,898 (p < 0.001). Considering sex, the shift in fracture prevalence was statistically significant (p = 0.020), whereas the incidence was not (p = 0.862). The decline in both fracture prevalence and incidence exhibited significant variation across birth year groups (prevalence, p < 0.001; incidence, p < 0.001), with a more pronounced reduction observed in the older age groups. While the proportion of patients who required surgeries has increased, the mean frequency of surgical treatment per patient remained at a similar level (by prevalence, p = 0.181; by incidence, p = 0.735). The decline in both fracture prevalence and incidence has shown significant variation in relation to fracture sites (prevalence, p < 0.001; incidence, p < 0.001), with a decrease in distal limb fractures and an increase in forearm and axial body fractures. Conclusions: The pediatric fracture pattern in Korea has been notably influenced by the COVID-19 pandemic, warranting further investigation into causal factors. Our findings should help predict epidemiology in the post-pandemic period and thus aid policymaking and patient management.

Comparison of whole trunk muscle mass between healthy and lumbar herniated nucleus pulposus patients using abdominal pelvic computed tomography.

Background: Paraspinal muscle asymmetry is associated with low back pain (LBP) problems. This study aimed to analyze skeletal muscle areas around the lumbar vertebra and compare the ratio of anterior and posterior muscles between patients with lumbar herniated nucleus pulposus (HNP) and healthy individuals using abdominal pelvic computed tomography (APCT). Methods: After propensity score matching, 122 HNP patients and 122 non-HNP individuals were finally used for analyses. In APCT, axial cut images were collected at the level of the third lumbar vertebra lower end plate and only the muscle structure was obtained. After obtaining the muscular portion of their image, we measured the skeletal muscle area (SMA). Second, for analysis relation of sarcopenia and HNP, the status of low skeletal muscle mass was determined using a previously reported criteria based on APCT scans in the Republic of Korea. Results: From the analysis of the anterior-posterior muscles, the ratio of anterior SMA was statistically significantly larger in the HNP group than in the non-HNP group. Regarding the anatomical classification of trunk muscles, a statistically significant left-right imbalance to peripheral muscle in HNP men was observed. Regarding the status of low skeletal muscle mass, no statistical difference in prevalence between the two groups were observed. Moreover, no statistical difference in the prevalence of low skeletal muscle mass obesity was observed. Conclusion: The lumbar flexor muscle was larger in HNP than others, showing trunk muscle imbalance. However, low skeletal muscle mass is not associated with HNP.

Network analysis of osteoporosis provides a global view of associated comorbidities and their temporal relationships.

We performed comorbidity-network analysis to obtain global view of comorbidity related with osteoporosis. We selected 10000-patients with osteoporosis registered in the National-Health-Insurance Service cohort-database. We found 45-significant disease-clusters. Of these, 14-disease-clusters were related to fra, while 10 were related to musculoskeletal diseases. Our findings will serve as basic data for further studies. PURPOSE: Osteoporosis causes devastating fractures; however, its exact etiology remains unknown. Elucidating associated comorbidities and their temporal relationships could provide better insights into its pathogenesis. Comorbidity-network analysis was performed to obtain global view of these associations. METHODS: We randomly selected 10000-patients with osteoporosis registered in the National-Health-Insurance Service cohort-database. These patients were identified using ICD-10 codes M81-M82, which represent osteoporosis without pathological fractures. Control group was created through propensity score matching. The comorbidities in each group were grouped into similar classifications to form "disease cluster"; 126 such clusters were identified. To create a comorbidity network, we selected disease clusters with high associations (i.e., odds ratios and relative risks ranked in the upper 50th percentile). To identify the temporal relationships between these clusters and osteoporosis, trajectories of directions were identified. RESULTS: Finally, we found 45 significant disease clusters. Of these, 14 disease clusters were related to fractures or injuries, while 10 were related to musculoskeletal diseases. Temporal analysis revealed that 15 disease clusters preceded osteoporosis; these included the following three with the strongest associations: "other fracture", "disorders of bone density and structure (M83-M85)", and "sequelae of injuries of neck and trunk (T91)". Thirty disease clusters followed osteoporosis; these included the following three with the strongest associations: "spine fracture," "spondylopathies (M45-M49)", and "pelvic region and thigh fracture,". CONCLUSION: We obtained a global view of the osteoporosis comorbidity network, which is otherwise difficult to achieve through study of individual diseases. Our findings will serve as the basic data for further studies.

Reliability of the TT-TG Index Versus TT-TG Distance on MRI: Morphometric Analyses in Asian Children and Adolescents.

Background: The tibial tuberosity-trochlear groove (TT-TG) distance measured on magnetic resonance imaging (MRI) is commonly used to decide the treatment for patellar instability; however, the patient's joint size is not considered in this measurement. The TT-TG index has been proposed as a knee size-adjusted measurement for tibial tuberosity location. Purpose: To evaluate the reliability of the TT-TG index compared with the TT-TG distance by analyzing variations in measurement according to age and sex in a pediatric Asian population. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A total of 698 knee MRI scans were collected in patients between 4 and 18 years of age who did not have any patellofemoral problems. Patient age, sex, height, and weight were recorded. The scans were divided into 5 groups according to patient age (4-6 years, 46 scans; 7-9 years, 56 scans; 10-12 years, 122 scans; 13-15 years, 185 scans; and 16-18 years, 289 scans); MRI scans were also divided by sex (497 male, 201 female). Three independent observers measured the TT-TG distance and TT-TG index on each scan, and age- and sex-based differences in the measurements were evaluated after adjusting for body mass index (BMI). The reliability of the measurements was calculated with the intraclass correlation coefficient (ICC). Results: Good to excellent inter- and intraobserver agreement was found for TT-TG distance (ICC, 0.74) and TT-TG index (ICC, 0.88). The TT-TG distance was significantly different among the groups and increased with age, while variations in the TT-TG index were minimal between age groups and sexes. This finding was also consistent after compensating for the effect of BMI. Conclusion: The TT-TG distance changed with age, while the TT-TG index was relatively constant. Therefore, the TT-TG index may be more reliable and effective for diagnosing and planning treatment, especially in children and adolescents.

Serious Clinical Outcomes of COVID-19 Related to Acetaminophen or NSAIDs from a Nationwide Population-Based Cohort Study.

Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed to infected patients; however, the safety of them has not been investigated in patients with serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to evaluate the association between the previous use of acetaminophen or NSAIDs and the clinical outcomes of SARS-CoV-2 infection. A nationwide population-based cohort study was conducted using the Korean Health Insurance Review and Assessment Database through propensity score matching (PSM). A total of 25,739 patients aged 20 years and older who tested for SARS-CoV-2 were included from 1 January 2015 to 15 May 2020. The primary endpoint was a positive result for a SARS-CoV-2 test, and the secondary endpoint was serious clinical outcomes of SARS-CoV-2 infection, such as conventional oxygen therapy, admission to the intensive care unit, need for invasive ventilation care, or death. Of 1058 patients, after propensity score matching, 176 acetaminophen users and 162 NSAIDs users were diagnosed with coronavirus disease 2019. After PSM, 162 paired data sets were generated, and the clinical outcomes of the acetaminophen group were not significantly different from those of the NSAIDs group. This suggests that acetaminophen and NSAIDs can be used safely to control symptoms in patients suspected of having SARS-CoV-2.

The Association of Low Skeletal Muscle Mass with Complex Distal Radius Fracture.

Objectives: Sarcopenia is a skeletal muscle loss disease with adverse outcomes, including falls, mortality, and cardiovascular disease (CVD) in older patients. Distal radius fractures (DRF), common in older people, are strongly related to falls. We aimed to investigate the correlation between DRF and low skeletal muscle mass, which strongly correlated to sarcopenia. Methods: We performed a retrospective review of data from patients diagnosed with or without DRF in our institute between 2015 and 2020. Finally, after propensity score matching, data from 115 patients with and 115 patients without DRF were used for analyses. Multivariate logistic regression analysis was performed for sex, body mass index (BMI), the presence of low skeletal muscle mass, bone quality measured by dual-energy X-ray absorptiometry (DXA), and comorbidities (diabetes mellitus, CVD). Results: We found that female sex (odds ratio = 3.435, p = 0.015), CVD (odds ratio = 5.431, p < 0.001) and low skeletal muscle mass (odds ratio = 8.062, p = 0.001) were significant predictors for DRF. BMI and osteoporosis were not statistically significantly related to DRF. Conclusions: Women with low skeletal muscle mass and CVD may be more responsible for DRF than osteoporosis.

Genome-Wide Association Study Identifies Genetic Variants Associated with Rotator Cuff Tear-A Pilot Study.

A rotator cuff is a muscle and tendon surrounding the shoulder joint, and a rotator cuff tear can be caused by overuse or injury, which leads to great pain in affected individuals. However, rotator cuff tear is a multifactorial process whose underlying mechanism is still unclear. Many previous studies have suggested an important role of genetic predisposition, such as single-nucleotide polymorphisms (SNPs), in explaining the genesis of tendinopathy. This study aimed to identify specific genes or genetic variants associated with rotator cuff tears by performing a genome-wide association study (GWAS) using an independent case of rotator cuff tears. GWAS was performed using data from CHA Bundang Medical Center with 20 cases of rotator cuff tears, and 20 cases of healthy controls genotyped on the Illumina HiSeq 2500. Tests of association were performed using the Burrows−Wheeler Aligner (BWA) software at 284,246 SNPs. Data were filtered based on sequence ontology, minor allele frequency, and Hardy−Weinberg equilibrium values, and SNPs were considered significant if the p-value was <0.05. The tests of association revealed more than 20 significantly associated SNPs. SNPs showing the highest significance occurred in candidate genes, including LAIR2 (rs2287828, OR 9.116, p-value 5.49 × 10−4) on chromosome 19 and CRIPAK (rs9328733, OR 6, p-value 1.11 × 10−3) and REST (rs2228991, OR 8.222, p-value 1.20 × 10−3) on chromosome 4. This study attempted to identify genetic variants influencing rotator cuff tears through a genome-wide association study using a dense set of SNPs. More than 20 SNPs were significantly associated with rotator cuff tears. The major limitation of this study is that it was conducted on a small study group and requires further validation. Nevertheless, the identification of potential genetic variants related to rotator cuff injury would aid in the early detection of individuals at risk for the development of tendinopathy and will provide insight into future gene therapies.

Hair methylmercury levels are inversely correlated with arterial stiffness.

BACKGROUND AND AIMS: Cardiovascular diseases (CVD), including coronary heart disease, are the leading cause of death worldwide. Several studies investigating the relationship between fish intake, methylmercury exposure, and CVDs in adults have reported inconsistent results. This study aimed to determine the association between hair methylmercury levels and arterial stiffness using brachial-ankle pulse wave velocity (baPWV). METHODS: This cross-sectional study included 891 seemingly healthy Korean adults (418 men and 473 women). The anthropometric and biochemical profiles, including methylmercury levels in the hair, were measured. Arterial stiffness was measured using baPWV, wherein high baPWV was defined as >1375 cm/s (>75th percentile). The odds ratios for high baPWVs were examined using multivariable logistic regression analysis after adjusting for potential confounders across the quintiles of hair methylmercury levels (Q1 = ≤0.6, Q2 = 0.6-0.8, Q3 = 0.8-1.1, Q4 = 1.1-1.5, and Q5=>1.5 µg/g). RESULTS: After adjusting for multiple confounders-age, sex, height, body weight, smoking status, weekly alcohol consumption, total metabolic equivalent of task, mean arterial blood pressure, resting heart rate, triglycerides, low density lipoprotein cholesterol, fasting plasma glucose, uric acid and white blood cell count-the odds ratios (95% confidence intervals) for high baPWVs in each quintile of hair methylmercury levels were 1.00, 0.36 (0.17-0.76), 0.38 (0.20-0.76), 0.28 (0.13-0.61), and 0.49 (0.24-0.99), respectively. CONCLUSIONS: Within non-toxic low levels, higher hair methylmercury levels are independently associated with lower arterial stiffness in seemingly healthy Korean adults regardless of classical cardiovascular risk factors.

Epidemiology of pediatric fractures before versus during the coronavirus disease 2019 pandemic.

Several studies have reported changes in the prevalence of childhood fractures between the prepandemic and coronavirus disease 2019 pandemic periods considering the overall decrease in activity during the latter. This review aimed to organize and summarize the global trends in pediatric fracture incidence. Our findings should help predict fracture patterns in the postpandemic period by identifying changes in the past and present, thus aiding patient management.

Carpal tunnel release can be a risk factor for trigger finger: National Health Insurance data analysis.

PURPOSE: We aimed to compare trigger finger (TF) development between patients with carpal tunnel syndrome (CTS) treated with carpal tunnel release (CTR) and those treated conservatively, using the National Health Insurance Services data of Korea. We also aimed to investigate risk factors for post-CTR TF development. METHODS: We selected CTS patients with or without CTR (3543 patients in each group) between 2002 and 2015. Sex, age, follow-up duration after CTS diagnosis, and comorbidities associated with TF-development were matched using propensity score. We compared the rates of TF diagnosis and subsequent TF operations between groups. Thereafter, we selected patients with CTS undergoing CTR, for whom minimum follow-up exceeded five years. We compared sex, age, height, weight, and comorbidities associated with TF risk factors between the TF-occurrence and non-TF-occurrence groups. RESULTS: On comparing CTR-treated patients with those treated conservatively for CTS, CTR-treated patients presented with significantly higher rates of TF diagnosis (12.2%) and TF operations (4.7%) than patients without CTR (6.2% and 1.2%, respectively). Among 433 TF-diagnosed patients and 166 TF-operated patients after CTR, most were identified < 5 years after CTR, with 379 diagnosed (87.5%) and 147 operated (88.5%) patients. A total of 240 patients presented with newly developed TF over a five year period. Patients with subsequent TF exhibited a higher female sex rate and shorter height. None of the variables was significant risk factors for TF development in logistic regression analysis. CONCLUSION: We confirmed high incidences of post-CTR TF diagnosis and operations. TF develops most frequently in the first postoperative year.

Incidence and Survival Rates of Cutaneous Melanoma in South Korea Using Nationwide Health Insurance Claims Data.

PURPOSE: Melanoma incidence is rising worldwide along with the associated personal and socioeconomic health expenditures. We investigated the incidence and survival-rate patterns of melanoma in South Korea using nationwide data. MATERIALS AND METHODS: This retrospective cohort study included patients with melanoma between 2004 and 2017, based on National Health Insurance (NHI) claims data in South Korea. The incidence, prevalence, and survival rate were analyzed along with baseline demographic characteristics. We collected solar irradiation dose (SID) and healthcare ranking score (HRS) according to the administrative district from the Korea Meteorological Administration and Korea Health Promotion Institute. The incidence and survival rates were assessed using Pearson's correlation, the Kaplan-Meier estimation, multiple linear regression, and multiple logistic regression methods. RESULTS: Twenty-five thousand, five hundred ninety-one patients with melanoma were diagnosed during the study period. The age-standardized incidence of melanoma steadily increased from 2004 to 2017 from 2.6 to 3.0/100,000/yr. The incidence of melanoma increased with significantly higher income (p < 0.05). The prevalence followed a similar pattern as the incidence. According to multivariate analysis, HRS significantly influenced the incidence of melanoma in high sun-exposed sites (p < 0.001). There was no significant change in annual mortality. Women had a higher 5-year survival rate than men (78.4% vs. 72.8%). Mortality by the administrative district was highly correlated with HRS. CONCLUSION: The incidence of melanoma is increasing in South Korea. A low HRS is associated with both higher incidence and mortality. The findings of this study could be utilized as a guideline for treating melanoma patients.

Recapitulation of First Pass Metabolism Using 3D Printed Microfluidic Chip and Organoid.

The low bioavailability of oral drugs due to first pass metabolism is a major obstacle in drug development. With significant developments in the field of in vitro organ modeling and microfluidic chip three-dimensional (3D) printing, the challenge is to apply these for the production and evaluation of new drug candidates. This study aimed to produce a microfluidic chip to recapitulate and assess the feasibility of the first pass metabolism. The infill condition of the polycarbonate transparent filament and layer height was optimized to visualize and maintain the organoid or spheroid on the chip. Next, the chip was fabricated using a 3D printer after a computer-aided design (CAD). The chip consisted of three wells of different heights. The small intestinal (SI) organoid and colorectal adenocarcinoma spheroids were placed on the second and third wells, respectively. No additional equipment was assembled, and the tilted tunnel was connected to each well to transport the material by gradient force. The chip was fabricated using 50% and 0.1 um thickness. Among the three different prototypes of chip (chips 1, 2, and 3), the highest distribution of plasmids in the Matrigel of the second well was observed in Chip 2 at 48 h. The effect of first pass metabolism was analyzed using docetaxel. In the chip without an SI organoid, there was a marked decrease in the viability of colorectal adenocarcinoma spheroids due to drug efficacy. However, in the chip with the SI organoid, no significant change in viability was observed because of first pass metabolism. In conclusion, we presented a simple, fast, and low-cost microfluidic chip to analyze the efficacy change of candidate drug by the first pass metabolism.

Association Between Overweight Sarcopenic Population and Acute Vertebral Osteoporotic Compression Fractures in Females: Retrospective, Cross-Sectional Study.

Background: This study aimed to determine whether the prevalence of acute vertebral osteoporotic compression fractures (VOCF) in the elderly population is related to the distribution of muscles and fat in the human body. Methods: Data of acute VOCF and non-VOCF patients presenting at our institution between January 2018 and May 2020 were analyzed. Patients aged 65 years and older, who underwent body composition test and dual-energy X-ray absorptiometry at the same time were enrolled. After applying exclusion criteria, patients were divided into four groups: normal, sarcopenia without obesity, obesity without sarcopenia, and sarcopenic obesity. Body mass index ≥25 kg/m2 was considered obesity, and sarcopenia was defined as skeletal muscle index lower than 7.0 kg/m2 in males and 5.4 kg/m2 in females. The VOCF rate was analyzed between the groups. Discussion: A total of 461 patients were included, of whom 103 were males. Among them, 163 (35.36%) had normal body composition, 151 (32.75%) had sarcopenia without obesity, 110 (23.86%) had obesity without sarcopenia, and 37 (8.03%) had sarcopenic obesity. The sarcopenic obesity group had the highest rate of acute VOCF (37.8%), which was statistically significant. Specifically, females with sarcopenic obesity and sarcopenia without obesity had significantly higher acute VOCF rates compared to those with normal body compositions. Multivariate analysis showed that sarcopenic obesity was significantly associated with acute VOCF rate overall, as well as in females. Conclusion: Sarcopenic obesity is strongly associated with acute VOCF, especially in females, and it could be an essential criterion for the prevention of acute VOCF.

Effect of Dosing Interval on Compliance of Osteoporosis Patients on Bisphosphonate Therapy: Observational Study Using Nationwide Insurance Claims Data.

Only a few studies are available on the effect of the dosing interval of bisphosphonate on drug compliance. We analyzed the data of patients who were newly prescribed bisphosphonate using a national insurance claims database. Drug compliance was assessed by calculating medication possession ratio (MPR) over a minimum of a 1-year follow-up. This analysis included 281,996 new bisphosphonate users with a mean age of 68.9 years (92% women). The patients were divided into daily, weekly, monthly, 3-monthly, and switch groups (who changed the drug to other dosing intervals). The average MPR was the highest in the switch group (66%), and the longer the dosing interval, the higher the compliance (3-monthly, 56% vs. daily, 37%). "Non-compliant" was defined as an MPR under 80%. Various factors which were possibly associated with "non-compliant" MPR were investigated using multiple regression analysis. Multivariate analysis showed that male patients were more likely to be non-compliant with pharmacotherapy than female patients, with as odds ratio of 1.389. Younger patients had a significantly lower likelihood of being non-compliant than older patients for age 60-69 vs. age 80+. Long dosing intervals were recommended to improve compliance and special attention was given to older and male patients.

Aspirin Is Related to Worse Clinical Outcomes of COVID-19.

Backgroundand Objectives: Aspirin is used globally to reduce pain and inflammation; however, its effect in patients with coronavirus disease (COVID-19) is not fully investigated and remains controversial. We evaluated the association between aspirin and COVID-19 outcomes using nationwide data from the Korean National Health Insurance System. Materials and Methods: This was a retrospective observational cohort study that included 22,660 eligible patients who underwent COVID-19 testing in South Korea between 1 January-31 July 2020. We identified all aspirin users prescribed aspirin within two weeks before or after the index date. The primary outcome was positivity for the COVID-19 test, and secondary outcomes included conventional oxygen therapy, intensive care unit, mechanical ventilation, or death. We applied the propensity score matching method to reduce the possible bias originating from the differences in patients' baseline characteristics. Results: Of those eligible, 662 patients were prescribed aspirin. Among them, 136 patients were on aspirin within two weeks before diagnosis and 526 patients were on aspirin after diagnosis. The COVID-19 test positivity rate was not significantly different according to aspirin use. Aspirin use before COVID-19 was related to an increased death rate and aspirin use after COVID-19 was related to a higher risk of the conventional oxygen therapy. Conclusion: Aspirin use was associated with adverse effects in COVID-19 patients. Further studies for mechanisms are needed.

Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing.

Inadequate vessel maintenance or growth causes ischemia in diseases such as myocardial infarction, stroke, and neurodegenerative disorders. Therefore, developing an effective strategy to salvage ischemic tissues using a novel compound is urgent. Drug repurposing has become a widely used method that can make drug discovery more efficient and less expensive. Additionally, computational virtual screening tools make drug discovery faster and more accurate. This study found a novel drug candidate for pro-angiogenesis by in silico virtual screening. Using Gene Expression Omnibus (GEO) microarray datasets related to angiogenesis studies, differentially expressed genes were identified and characteristic direction signatures extracted from GEO2EnrichR were used as input data on L1000CDS2 to screen pro-angiogenic molecules. After a thorough review of the candidates, a list of compounds structurally similar to TWS-119 was generated using ChemMine Tools and its clustering toolbox. ChemMine Tools and ChemminR structural similarity search tools for small-molecule analysis and clustering were used for second screening. A molecular docking simulation was conducted using AutoDock v.4 to evaluate the physicochemical effect of secondary-screened chemicals. A cell viability or toxicity test was performed to determine the proper dose of the final candidate, ellipticine. As a result, we found ellipticine, which has pro-angiogenic effects, using virtual computational methods. The noncytotoxic concentration of ellipticine was 156.25 nM. The phosphorylation of glycogen synthase kinase-3ß was decreased, whereas the ß-catenin expression was increased in human endothelial cells treated with ellipticine. We concluded that ellipticine at sublethal dosage could be successfully repositioned as a pro-angiogenic substance by in silico virtual screening.