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Background: Thiazolidinediones (TZDs) have been associated with various safety concerns including weight gain, bladder cancer, and congestive heart failure (CHF). This study evaluated the efficacy and safety of lobeglitazone, a novel TZD in patients with type 2 diabetes mellitus (T2DM) in real practice.Methods: In this non-interventional, multi-center, retrospective, and observational study conducted at 15 tertiary or secondary referral hospitals in Korea, a total of 2,228 patients with T2DM who received lobeglitazone 0.5 mg for more than 1 year were enrolled.Results: Overall adverse events (AEs) occurred in 381 patients (17.10%) including edema in 1.97% (n=44). Cerebrovascular and cardiovascular diseases were identified in 0.81% (n=18) and 0.81% (n=18), respectively. One case of CHF was reported as an AE. Edema occurred in 1.97% (n=44) of patients. Hypoglycemia occurred in 2.47% (n=55) of patients. Fracture occurred in 1.17% (n=26) of all patients. Lobeglitazone significantly decreased HbA1c level, resulting in a mean treatment difference of -1.05%± 1.35% (P

Musculoskeletal conditions are common in patients with diabetes. Several musculoskeletal disorders are viewed as chronic complications of diabetes because epidemiological studies have revealed high correlations between such complications and diabetes, but the pathophysiological links with diabetes remains unclear. Genetic predispositions, shared risk factors, microvascular impairments, progressive accumulation of advanced glycation end-products, and diabetic neuropathy may underlie the development of musculoskeletal disorders. Musculoskeletal complications of diabetics have received less attention than life-threatening microvascular or macrovascular complications. Here, we review several diabetic musculoskeletal complications with a focus on the clinical importance of early recognition and management, which would improve quality of life and physical function.

Invasive group B Streptococcus (GBS) infections are increasing among adults with underlying health conditions; however, clinical manifestations and serotype distribution remain unclear. This study investigated the molecular characteristics and antimicrobial resistance of invasive GBS in Korean adults. GBS isolates from patients with invasive diseases during 2006-2015 were investigated for capsular serotype, multilocus sequence type (ST), antimicrobial susceptibility, and resistance genes. Among the 74 isolates analyzed, the most common serotype was Ib (31.1%), followed by III (21.6%), V (20.3%), Ia (12.2%), and VI (12.2%). Thirteen STs were detected, with ST1, ST10, ST19, and ST23 as the most prevalent. The dominant capsular serotype exhibited by ST1 was V, and those expressed by ST10, ST19, and ST23 were Ib, III, and Ia, respectively. Erythromycin and levofloxacin resistance were observed in 33.8% and 31.1% of the isolates, respectively. ST10-Ib (n = 11/11, 100%) and ST654-Ib (n = 3/3, 100%) were dominant levofloxacin-resistant strains. Serotypes Ib, III, and V were most common among adults, which is inconsistent with recent reports in Korea where III, V, and Ia were predominant in infants. The difference in the serotype distribution between adults and children may be associated with the selective pressure imparted by antibiotics.

This study examined the psychometric properties of the Korean version of the child sexual behavior inventory (CSBI) for children under 10 years of age. Participants comprised a community sample (CS) of 652 children aged three to nine years and 226 sexually abused (SA) children in the same age range. Parents rated the CSBI, the child behavior checklist (CBCL), and the traumatic symptom checklist for young children (TSCYC). We examined internal consistency as a measure of reliability and conducted ANOVA for discriminant and Pearson's correlations for convergent and divergent validity. The reliability coefficient indicated internal consistency (α = .59-.97). There was a significant correlation between sexual behaviors and internalizing and externalizing behavior problems in both samples (r = 0.30-0.48, p .001). The correlation between post-traumatic stress disorder symptoms and sexual concern in the SA sample was very high (r = 0.56-0.66, p .001). There was a significant difference in sexual behavior between the CS and SA. These findings demonstrate the reliability and validity of the Korean version of the CSBI and its usefulness in identifying children suspected of sexual abuse. However, the research identified cultural differences in the sexual behavior of the CS.

Osteoporosis is a well-known risk factor of screw loosening. Classically, dual-energy x-ray absorptiometry (DEXA) scan is an easy and cost-effective method of detecting bone mineral density (BMD). However, T-score on DEXA scan can be overestimated in patients with degenerative changes of the spine. Our objective was to identify correlation between Hounsfield unit (HU) measured by 3-dimensional computed tomography (3D-CT) and screw loosening.A total of 113 patients treated with lumbosacral spinal fusion were reviewed and categorized into a screw loosening group and a normal group to compare their average values of preoperative CT HU. Screw loosening was defined as radiolucent area around screw that was thicker than 1 mm with a "double halo sign".There were statistically significant differences in patient age and steroid use between screw loosening and non-loosening groups. There was no significant difference in BMD or T-score between the 2 groups. However, HU values measured in axial, coronal, and sagittal images were significantly different between the 2 groups. In the receiver operating characteristic for HU values measured in CT images, the greatest area under the curve was 0.774 and that was in case of Hounsfield unit measured by axial CT images from L1 to L4.Preoperative CT HU is associated with screw loosening. It can be a better predictor of screw loosening than DEXA scan. The best predictor of screw loosening in this study is the average value of HU from L1 to L4 in axial cut.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

This study investigated whether a new sustained-release (SR) pregabalin formulation is noninferior to immediate-release (IR) pregabalin in alleviating peripheral neuropathic pain in Korean patients.This was a randomized, double-blind, active-controlled phase 3 study of patients with diabetic peripheral neuropathy or postherpetic neuralgia from 41 sites in South Korea in 2017-2018. Eligible patients were randomized (1:1) to receive once-daily SR pregabalin or twice-daily IR pregabalin (150 to 600 mg/d) in a double-dummy manner for 12 weeks according to a stratified permuted block randomization scheme. The primary endpoint was the Daily Pain Rating Scale score at the end of treatment, averaged from the last 7 available scores.A total of 319 of 371 (86.0%) randomized patients completed the 12-week treatment (SR pregabalin: n=154; IR pregabalin: n=165; per-protocol set: n=296). The least square mean difference between both groups for the primary endpoint was 0.06 (SE 0.19); (95% confidence interval -0.31 to 0.42), with the lower limit of the confidence interval above the pre-specified margin (-0.78; Pnoninferiority0.0001). Drug-related treatment-emergent adverse events (TEAEs) were comparable between both groups. The incidence of drug-related TEAEs leading to treatment discontinuation was low (SR pregabalin: 2.7%; IR pregabalin: 1.1%). No serious drug-related TEAEs or deaths occurred.The results demonstrate that the new once-daily SR pregabalin formulation is noninferior to twice-daily IR pregabalin in reducing peripheral neuropathic pain and is well tolerated in Korean patients with diabetic peripheral neuropathy or postherpetic neuralgia after 12 weeks of treatment.

Upadacitinib, a Janus kinase inhibitor, has been shown to be effective in patients with ankylosing spondylitis. We aimed to assess the efficacy and safety of upadacitinib in non-radiographic axial spondyloarthritis.The SELECT-AXIS 2 non-radiographic axial spondyloarthritis study was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 113 sites across 23 countries (Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, Israel, Japan, Mexico, Poland, Russia, Slovakia, South Korea, Spain, Taiwan, Turkey, Ukraine, and the USA). Eligible adults had active non-radiographic axial spondyloarthritis, with objective signs of inflammation based on MRI or elevated C-reactive protein and an inadequate response to non-steroidal anti-inflammatory drugs. Patients were randomly assigned (1:1) to receive oral upadacitinib 15 mg once daily or placebo using interactive response technology. Random treatment assignment was stratified by MRI inflammation in the sacroiliac joints and screening high-sensitivity C-reactive protein status (MRI-positive and C-reactive protein-positive, MRI-positive and C-reactive protein-negative, and MRI-negative and C-reactive protein-positive) and previous exposure to biologic disease-modifying antirheumatic drugs (yes vs no). Treatment assignment was masked from patients, investigators, study site personnel, and the study sponsor. The primary endpoint was the proportion of patients with an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Analyses were performed on the full analysis set of patients, who underwent random allocation and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04169373.Between Nov 26, 2019, and May 20, 2021, 314 patients with active non-radiographic axial spondyloarthritis were enrolled into the study, and 313 received study drug (156 in the upadacitinib group and 157 in the placebo group); 295 (94%) patients (145 in the upadacitinib group and 150 in the placebo group) received treatment for the full 14 weeks. A significantly higher ASAS40 response rate was achieved with upadacitinib compared with placebo at week 14 (70 [45%] of 156 patients vs 35 [23%] of 157 patients; p0·0001; treatment difference 22%, 95% CI 12-32). The rate of adverse events up to week 14 was similar in the upadacitinib group (75 [48%] of 156 patients) and placebo group (72 [46%] of 157 patients). Serious adverse events and adverse events leading to discontinuation of study drug occurred in four (3%) of 156 patients in the upadacitinib group and two (1%) of 157 patients in the placebo group. Few patients had serious infections or herpes zoster in either treatment group (each event occurred in two [1%] of 156 patients in the upadacitinib group and one [1%] of 157 patients in the placebo group). Five (3%) of 156 patients in the upadacitinib group had neutropenia; no events of neutropenia occurred in the placebo group. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, or deaths were reported with upadacitinib treatment.Upadacitinib significantly improved the signs and symptoms of non-radiographic axial spondyloarthritis compared with placebo at week 14. These findings support the potential of upadacitinib as a new therapeutic option in patients with active non-radiographic axial spondyloarthritis.AbbVie.

Intensive local treatment comprising total mesorectal excision (TME) with selective lateral pelvic lymph node dissection (LPND) after neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) has received attention among clinicians treating rectal cancer. It remains unclear whether adjuvant chemotherapy (ACT) after intensive local treatment is beneficial for these patients. We evaluated the oncologic benefit of ACT for patients with LARC who received intensive local treatment.This international multicentre retrospective cohort study included 737 patients treated in Japan and Korea between 2010 and 2017. The effectiveness of ACT on recurrence-free survival (RFS) was evaluated using univariable and multivariable Cox proportional hazards models, with subgroup analyses to identify subpopulations potentially benefiting from ACT.The median follow-up was 49 months; the 5-year RFS and local recurrence rates for the entire cohort were 72.1% and 4.9%, respectively; 514 patients (69.7%) received adjuvant chemotherapy, without an oncologic benefit (hazard ratio, 1.14; 95% confidence interval [CI]: 0.79-1.68) demonstrated in the multivariable Cox regression analysis. In subgroup analyses, the distributions of the 95% CI in patients aged ≥70 years and those with ypStage 0 tended to place a disproportionate emphasis that favoured the non-ACT treatment strategy.Despite achieving good local control with intensive local treatment strategy, the effectiveness of ACT for the LARC patients with CRT followed by TME with selective LPND was not proved. Elderly patients and those with ypStage0 may not receive benefit from ACT after CRT and TME ± LPND.

There have been occasional reports on varicella infection among healthcare workers (HCWs) despite varicella-zoster virus (VZV) seropositivity. We compared the levels of humoral and cellular immunity to VZV in seropositive HCWs who had acquired immunity by natural infection or vaccination.Seropositive healthy HCWs with an apparent history of varicella or VZV vaccination once or twice were recruited. Their samples were assessed for anti-VZV IgG levels, the relative avidity index (RAI), and the frequencies of VZV-specific cytokine-producing or polyfunctional CD4A total of 75 seropositive HCWs (29 with a history of varicella, 25 vaccinated once, and 21 vaccinated twice) were assessed for humoral immunity. Cellular responses could be analyzed in 59 (28, 21, and 10 in the respective groups). The anti-VZV IgG level, RAI, and memory CD4Seropositive HCWs without a varicella history, especially those who received the vaccine only once, had significantly lower levels of immune responses to VZV. Such HCWs might need to comply with airborne precautions.

Carbohydrate-restricted diets and intermittent fasting (IF) have been rapidly gaining interest among the general population and patients with cardiometabolic disease, such as overweight or obesity, diabetes, and hypertension. However, there are limited expert recommendations for these dietary regimens. This study aimed to evaluate the level of scientific evidence on the benefits and harms of carbohydrate-restricted diets and IF to make responsible recommendations. A meta-analysis and systematic literature review of 66 articles on 50 randomized controlled trials (RCTs) of carbohydrate-restricted diets and 10 articles on eight RCTs of IF was performed. Based on the analysis, the following recommendations are suggested. In adults with overweight or obesity, a moderately-low carbohydrate or low carbohydrate diet (mLCD) can be considered as a dietary regimen for weight reduction. In adults with type 2 diabetes mellitus, mLCD can be considered as a dietary regimen for improving glycemic control and reducing body weight. In contrast, a very-low carbohydrate diet (VLCD) and IF are recommended against in patients with diabetes. Furthermore, no recommendations are suggested for VLCD and IF in adults with overweight or obesity, and carbohydrate-restricted diets and IF in patients with hypertension. Here, we describe the results of our analysis and the evidence for these recommendations.

Antimicrobial resistance is one of the most urgent global health threats. The need for the qualitative evaluation of antibiotic use at the national level is increasing. To identify areas for improvement, we aimed to assess the prevalence and appropriateness of antibiotic prescriptions during hospitalization and ambulatory care in Korea.The prevalence and appropriateness of antibiotic prescriptions on 29 August 2018 were assessed for 20 hospitals in Korea. Infectious disease specialists determined appropriateness. Except for antiviral and anti-tuberculosis agents, all antibacterial or antifungal agent prescriptions during hospitalization or ambulatory care were evaluated.The prevalence of antibiotic prescription was 14.1% (8,400/59 216 patients) on the study date. Antibiotics were prescribed for 50.8% of inpatients (6557/12 902), with two or more antibiotics prescribed for 27.4% (1798/6557) of patients. A total of 10 948 prescriptions (7999 therapeutic, 2105 surgical prophylaxes, and 844 medical prophylaxes) were included in the final analysis, and 27.7% of these were inappropriate. Surgical prophylaxis was inadequately prescribed most frequently (54.4%), followed by medical prophylaxis (29.5%) and therapeutic antibiotics (20.5%). The most common indications for therapeutic antibiotics were respiratory (29.1%, n=2332), gastrointestinal (22.4%, n=1791), and urinary tract infections (13.1%, n=1050). The most frequently prescribed antibiotics were cephalosporins (52.0%, n=5490), followed by beta lactam/beta lactamase inhibitors (13.7%, n=1373), fluoroquinolones (9.1%, n=957), and metronidazole (6.6%, n=699).This was the first nationwide qualitative antibiotic prescription adequacy evaluation in Korea. A significant proportion of antibiotic prescriptions were inappropriate. Therefore, interventions for high-frequency infections and prescription antibiotics are needed.

ABO-incompatible kidney transplantation (KTP) is effective for avoiding transplantation-related issues. It is a viable alternative to ABO-compatible KTP, as both techniques have similar patient and graft survival rates. However, anti-A/B antibody-mediated rejection (AMR) can occur, resulting in poor long-term graft survival.A 45-year-old man with end-stage renal disease presented with a serum creatinine level of 10.2 mg/dL. We decided to perform KTP with spousal donation. He had panel-reactive antibody class I and II and cross matching test negativity, a 3/6 mismatch on human leukocyte antigen typing, an ABO antibody titer of 1:256, and no donor-specific antibodies. The patient and donor blood types were O+ and A+, respectively. The anti-A/B antibody titer was reduced preoperatively with rituximab (200 mg/body), plasmapheresis, and intravenous immunoglobulin (0.2 mg/kg). Basiliximab and methylprednisolone were used for induction immunosuppression, and tacrolimus, mycophenolate mofetil, and prednisolone were used for maintenance immunosuppression. KTP was successful, and graft function was initially normal. On postoperative day (POD) 5, the serum creatinine level and anti-A/B antibody titer increased from 0.9 mg/dL to 1.9 mg/dL and 1:16 to 1:64, respectively. Graft biopsy revealed acute AMR and tubular injury. We started steroid pulse therapy, plasmapheresis, and subcutaneous bortezomib (2.6 mg, twice a day, every 3 days) with no side effects. The serum creatinine level decreased from 5.7 mg/dL to 1.5 mg/dL on POD 28. Graft biopsy showed no rejection, and normal function was maintained for 40 months.Acute, early anti-A/B AMR was successfully treated with plasmapheresis and bortezomib.

Hyperuricemia is a common condition in patients with chronic kidney disease and end-stage kidney disease. It occurs even after kidney transplant because of the use of calcineurin inhibitors and transplanted kidney failure. We describe the case of a patient with end-stage kidney disease who had multiple gouty arthritis with tophi formation despite receiving appropriate treatment but was successfully cured after kidney transplant.A 36-year-old male patient undergoing hemodialysis treatment was treated with febuxostat for multiple gouty arthritis and underwent tophi removal twice. He received a deceased donor kidney transplant 10 years after dialysis treatment. He received immunosuppressants (basiliximab, tacrolimus, mycophenolate mofetil) and steroids. Results of renal biopsy performed on days 7 and 21 postoperation showed no specific findings and normal renal function. The uric acid level before transplant was 3.1 mg/dL, and when renal function was normal, it reached 6-7 mg/dL and remained stable. Although hyperuricemia was still present, the tophi disappeared 3 months after transplant. It is presumed that the high-dose steroids interfered with the activation of inflammatory responses during tophi formation, which may have caused the tophi to disappear. It is also presumed that the patient adhered to the diet well after transplant, which suppressed tophi formation.Our findings suggest that disappearance of multiple tophi and arthritis in patients undergoing hemodialysis can be achieved with kidney transplant, especially when uric acid-lowering drugs are not effective.

OBJECTIVES To examine concurrent validity and discrimination of modified minimal disease activity (mMDA) criteria in peripheral spondyloarthritis (pSpA) following OMERACT filter principles and determine predictors of mMDA response. METHODS Four mMDA versions were derived in the ABILITY-2 study using the SPondyloArthritis Research Consortium of Canada (SPARCC) or Leeds Enthesitis Index (LEI) but excluding psoriasis. To assess concurrent validity, mMDA versions were correlated with Peripheral SpondyloArthritis Response Criteria (PSpARC) remission, Ankylosing Spondylitis Disease Activity Score for inactive disease (ASDAS ID), and physician global. Treatment discrimination was assessed between adalimumab and placebo at week 12. Multiple logistic regression was used to determine baseline predictors of long-term mMDA responses and sustained mMDA. RESULTS The four mMDA versions showed a stronger positive correlation with PSpARC remission (rtet >0.95) versus ASDAS ID (rtet >0.75) at week 12 and years 1-3 and were able to show discrimination (p

Background: Identifying the risk factors for falls among the elderly population is arguably one of the most imperative public health issues in the current aging society. Objectives: This study aimed to determine the associations between depressive symptoms, subjective cognitive decline (SCD), and poor subjective sleep quality and the risk of slips/falls in a Korean older population. Methods: This cross-sectional study involved 228,340 elderly individuals living in Korea. Measurements included self-reported depressive symptoms, SCD, and self-reported sleep quality. The risk of slips/falls was dichotomized depending on whether slips/falls had occurred during the past year, and the associations between different risk factors and slips/falls were explored. Multiple logistic regression was used to obtain the odds ratios (ORs) and 95% confidence intervals (CIs). Complex sampling methods were used to estimate the weighted value of each participant. Results: The risk of slips/falls was significantly associated with high levels of depressive symptoms (adjusted OR 1.06, 95% CI: 1.05–1.07) and SCD (adjusted OR 1.33, 95% CI: 1.19–1.50). Regarding each sleep quality component, the adjusted ORs for slips/falls were 1.85 for very poor sleep quality, 1.49 for long sleep latency, 1.04 for Conclusions: Our results demonstrated that depressive symptoms, SCD, and poor subjective sleep quality are independent factors affecting the occurrence of slips/falls. Thus, efforts to manage depressive symptoms and cognitive decline early and to improve sleep quality can be an alternative strategy to decrease the likelihood of falls.

Alzheimer’s disease (AD), a chronic neurodegenerative disease, is the most common form of dementia that causes cognitive function impairment, including memory, thinking, and behavioral changes that ultimately lead to death. The overactivation of GSK-3, an enzyme from the proline/serine Ki NS family, has been associated with hyper-phosphorylation of tau proteins. The self- -assembly of hyper-phosphorylated tau proteins to form tangles of straight and helical filaments is known to be involved in AD. Therefore, GSK-3 has been considered a potential target of novel drug discovery for AD treatment. Research on the development of GSK-3 inhibitors has received enormous attention from the vast scientific community because they are targeted for AD and other diseases, including type 2 diabetes, cancers, stroke, Parkinson’s disease and bipolar disorder. Various drugs of both synthetic and natural origins have been designed to inhibit GSK-3 activity. However, there is a need to develop novel drug candidates that can selectively inhibit GSK-3. Hence, this review summarizes the potential of GSK-3 inhibitors for AD therapy and discusses the structure- activity relationship of current drug molecules and the potential problems associated with them.

To evaluate the serial changes in the joint space width (JSW) of the medial and lateral compartments after medial open-wedge high tibial osteotomy (MOWHTO) and its associated factors.The medial and lateral weight-bearing JSWs were measured on serial radiographs and analyzed preoperatively and postoperatively within 2 weeks, as well as at 3 months, 6 months, 1 year, and 2 years. Associations between the medial and lateral JSWs and age, body mass index, mechanical axis, correction angle, lateral distal femoral angle, medial proximal tibial angle, joint line convergence angle (JLCA), JLCA on stress radiographs, and arthroscopic cartilage status were examined. Clinical outcome was measured according to the Knee Society objective and functional scores.Seventy-one patients who underwent MOWHTO with locking-plate fixation were analyzed. The respective mean medial and lateral JSWs on serial radiographs were as follows: 3.08 mm and 5.14 mm preoperatively, 3.10 mm and 4.63 mm postoperatively, 3.37 mm and 4.57 mm at 3 months, 3.40 mm and 4.59 mm at 6 months, 3.44 mm and 4.57 mm at 1 year, and 3.42 mm and 4.64 mm at 2 years. At 3 months, the medial JSW increased (P.001), whereas the lateral JSW decreased immediately (P.001). JSW showed no significant differences at other time points. Preoperative and postoperative JLCAs and medial femoral and tibial cartilage grades were associated with medial JSW changes (P = .021). However, no significant parameters were associated with decreases in the lateral JSW (P.05). The postoperative Knee Society objective and functional scores improved and were maintained.After MOWHTO, the medial JSW increased at 3 months postoperatively and the lateral JSW decreased immediately. The preoperative and postoperative JLCAs and the medial femoral and tibial cartilage grades were associated with the change in the medial JSW. However, no significant parameters were associated with the decrease in the lateral JSW.Level IV, case series of therapeutic study.

Background/Aims: This study aimed to assess the association between local and systemic reactogenicity and humoral immunogenicity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.Methods: Adverse events were prospectively evaluated using an electronic diary in 135 healthy adults who received a SARS-CoV-2 vaccine (AZD1222, AstraZeneca/Oxford, n = 42; or BNT162b2, Pfizer/BioNTech, n = 93). We semi-quantitatively measured anti-S1 immunoglobulin G (IgG) using an enzyme-linked immunosorbent assay at baseline, 3 weeks after the first dose of AZD1222 or BNT162b2, and 2 weeks after the second dose of BNT162b2. We evaluated the association between the maximum grade of local or systemic adverse events and the anti-S1 IgG optical density using multivariate linear regression with adjustment for age, sex, and use of antipyretics.Results: The median age of the 135 vaccinees was 30 years (36 years in the AZD1222 group and 29 years in the BNT162b2 group) and 25.9% were male (9.5% in the AZD1222 group and 33.3% in the BNT162b2 group). Local and systemic adverse events were generally comparable after the first dose of AZD1222 and the second dose of BNT162b2. The grades of local and systemic adverse events were not significantly associated with anti-S1 IgG levels in the AZD1222 or BNT162b2 group.Conclusions: Local and systemic reactogenicity may not be associated with humoral immunogenicity after SARS-CoV-2 vaccination.

Purpose To verify whether lateral hinge fracture (LHF) affects correction accuracy in open-wedge high tibial osteotomy (OWHTO) and to identify the fracture characteristics responsible for inaccurate correction, including LHF type and hinge location. Methods Patients undergoing OWHTO with locking plate fixation between 2010 and 2016 were retrospectively reviewed. Patients who did not have a minimum 2-year of follow-up or postoperative long-standing hip-to-ankle radiographs were excluded. Correction accuracy was assessed using the weight-bearing line ratio: 57% to 67%, planned correction; 50% to 70%, acceptable correction; otherwise, inappropriate correction. The association between LHF and correction accuracy was assessed using the χ2 test. To identify the fracture characteristics responsible for inaccurate correction, LHF type (stable type 1 and unstable types 2 and 3) and hinge location (shallow osteotomy, deep osteotomy, and occult complete osteotomy) were analyzed using ordinal logistic regression analysis, taking other related demographic and radiologic factors into account. Clinical outcomes according to LHF type were evaluated using the Hospital for Special Surgery scores. Results A total of 148 cases were included; 41 (27.7%) showed LHF: type 1, 32 cases; type 2, 7 cases; and type 3, 2 cases. Planned, acceptable, and inappropriate corrections were noted in 63 (42.6%), 36 (24.3%), and 48 (32.4%) cases, respectively. LHF had a significant association with correction accuracy (P = .010). Regarding fracture characteristics, unstable LHF and occult complete osteotomy were significant risk factors (P = .016 and P = .004, respectively). Specifically in cases of stable LHF, occult complete osteotomy adversely affected correction accuracy (P = .025). No difference was found in the final Hospital for Special Surgery scores according to LHF type (P = .816). Conclusions LHF affected the accuracy of coronal alignment correction in OWHTO. Unstable LHF or occult complete osteotomy were risk factors for inaccurate correction. Even among stable LHFs, those with occult complete osteotomy could lead to inaccurate correction. Level of Evidence Level III, retrospective cohort study.

This study analyzes the large number of lateral meniscal allograft transplantation (LMAT) procedures conducted by a single surgeon over 23 years to determine whether the absolute amount of graft subluxation and the incidence of extrusion are different at the present time compared to the early MAT era.We reviewed 320 cases of LMAT performed by a single surgeon between 1996 and 2019. This cohort was chronologically divided into 8 groups (of 40 subjects). The absolute amount of subluxation was measured by the coronal sections of magnetic resonance images taken 1 year after operation. Subluxation by more than 3 mm was considered as extrusion. The graft extrusion learning curve was plotted in each series using the learning curve cumulative summation test (LC-CUSUM).Extrusion incidence was 41.6%, and the mean absolute amount of graft subluxation was 3.4 ± 2.2 mm for all subjects. There were significant between-group differences in extrusion incidence and absolute amount of graft subluxation (extrusion incidence, P.001; absolute amount of graft subluxation, P.001), and the extension incidence and graft subluxation decreased from Group I (72.5%, 4.6 ± 1.7) to Group VIII (27.5%, 2.5 ± 2.1). LC-CUSUM analysis signaled that the surgeon had achieved predefined acceptable outcomes in avoiding extrusion after 128 cases.The incidence of extrusion and absolute amount of graft subluxation decreased significantly over a period of 23 years, and the surgeon achieved a certain level of proficiency after 128 cases.Level IV, Case series.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies., This research was funded by National Institute of Mental Health (NIMH) grant R01MH092293 (to GAH and JAT) and NJCTS (New Jersey Center for Tourette Syndrome and Associated Disorders; to GAH and JAT). This work was also supported by grants from the Judah Foundation, the Tourette Association of America, National Institute of Health (NIH) Grants NS40024, NS016648, MH079489, MH073250, the American Recovery and Re-investment Act (ARRA) Grants NS040024-07S1; NS16648-29S1; NS040024-09S1; MH092289; MH092290; MH092291; MH092292; R01MH092293; MH092513; MH092516; MH092520; MH071507; MH079489; MH079487; MH079488; and MH079494. Dr. Mir has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation. Dr. Morer has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. Dr. Münchau has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1 and FOR 2698). This study was also supported by a Grant from the National Institute for Environmental Health Science (R01 ES021462).

Spondyloarthritis (SpA) comprises a group of chronic inflammatory diseases with overlapping clinical, genetic and pathophysiological features including back pain, peripheral arthritis, psoriasis, enthesitis and dactylitis. Several cytokines are involved in the pathogenesis of SpA, variously contributing to each clinical manifestation. Many SpA-associated cytokines, including IL-23, IL-17, IL-6, type I/II interferon and tumour necrosis factor signal directly or indirectly via the Janus kinase (JAK)–signal transducer and activator of transcription pathway. JAK signalling also regulates development and maturation of cells of the innate and adaptive immune systems. Accordingly, disruption of this signalling pathway by small molecule oral JAK inhibitors can inhibit signalling implicated in SpA pathogenesis. Herein we discuss the role of JAK signalling in the pathogenesis of SpA and summarize the safety and efficacy of JAK inhibition by reference to relevant SpA clinical trials.

Purpose The incidence of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) has increased, and staging and optimal therapeutic approaches are challenging. A questionnaire survey was conducted to investigate the controversial treatment policy of stage T2 OPC according to the N category and determine the opinions of multidisciplinary experts in Korea.Materials and Methods Five OPC scenarios were developed by the Subcommittee on Oropharyngeal Treatment Guidelines of the Korean Society for Head and Neck Oncology and distributed to experts of multidisciplinary treatment hospitals.Results Sixty-five experts from 45 institutions responded. For the HPV-positive T2N0M0 scenario, 67.7% of respondents selected surgery followed by definitive concurrent chemoradiotherapy (CCRT) or radiotherapy alone. For the T2N1M0 HPV-positive scenario, there was a notable difference in the selection of primary treatment by expert specialty; 53.9% of respondents selected surgery and 39.8% selected definitive CCRT as the primary treatment. For the T2N3M0 advanced HPV-positive scenario, 50.0% of respondents selected CCRT and 33.3% considered induction chemotherapy (IC) as the primary treatment. CCRT and IC were significantly more frequently selected for the HPV-related OPC cases (p=0.010). The interdepartmental variability showed that the head and neck surgeons and medical oncologists favored surgery, whereas the radiation oncologists preferably selected definitive CCRT (p < 0.001).Conclusion In this study, surgery was preferred for lymph node-negative OPC, and as lymph node metastasis progressed, CCRT tended to be preferred, and IC was administered. Clinical practice patterns by stage and HPV status showed differences according to expert specialty. Multidisciplinary consensus guidelines will be essential in the future.

BackgroundThe aim of this study was to investigate the nutritional intakes and treatment regimens of Korean patients with type 2 diabetes who were aware of their condition.MethodsParticipants (n = 16582) aged ≥ 19 years from the 2016–18 National Health and Nutrition Survey were divided into diabetes-aware and unaware groups and the variables were compared.ResultsAmong 1,906 (11.5%) diabetic adults, 1,433 (75.2%) were aware of their condition; 130 (9.1%) had nutrition education, and 1,340 (93.5%) were in the diabetes-aware treatment group. The diabetes-aware group had higher average age (P < 0.0001) and lower average BMI (P = 0.0015) than the unaware group. Intake of total fat (P = 0.0034), saturated fatty acids (P = 0.0021), riboflavin (P = 0.0035) and niacin (P = 0.0228) was significantly higher in the unaware group than in the diabetes-aware group, after adjusting energy intake for age and sex. Current smoking (P = 0.0046) and heavy drinking (P < 0.0001) rates were higher in the unaware group, whereas fiber intake (P = 0.0054) was lower in the unaware group. Higher levels of glycated hemoglobin were found in the group treated for diabetes (7.2%) than in the no-treatment (6.8%) group (P = 0.0048). Diabetes control was significantly better in the high income group.ConclusionsThere is a need to strengthen nutritional education to prevent diabetes and improve the health status of diabetic patients in Korea.

Background: Previous studies regarding tranexamic acid (TXA) in total knee arthroplasty (TKA) investigated only symptomatic deep vein thrombosis (DVT) or did not include high risk patients. The incidence of DVT including both symptomatic and asymptomatic complications after applying topical TXA has not been evaluated using ultrasonography. Methods: Medical records of 510 patients who underwent primary unilateral TKA between July 2014 and December 2017 were retrospectively reviewed. Because TXA was routinely applied through the topical route, those who had history of venous thromboembolism, myocardial infarction, or cerebral vascular occlusive disease were not excluded. Regardless of symptom manifestation, DVT was examined at 1 week postoperatively for all patients using ultrasonography, and postoperative transfusion rate was investigated. The study population was divided according to the use of topical TXA. After the two groups were matched based on the propensity scores, the incidence of DVT and the transfusion rate were compared between the groups. Results: Of the 510 patients comprising 298 patients in the TXA group and 212 patients in the control group, DVT was noted in 22 (4.3%) patients. Two patients had DVT proximal to the popliteal vein. After propensity score matching (PSM), 168 patients were allocated to each group. 11 patients in the TXA group and 7 patients in the control group were diagnosed with DVT, which did not show a significant difference (p=0.721). However, the two groups differ significantly in the transfusion rate (pConclusion: The incidence of DVT, whether symptomatic or asymptomatic, was not affected by the use of topical TXA. Postoperative transfusion rate was reduced in the TXA group. Topical TXA could be applied safely even in patients who had been known to be at high risk.

IntroductionDespite vaccine development, the COVID-19 pandemic is ongoing due to immunity-escaping variants of concern (VOCs). Estimations of vaccine-induced protective immunity against VOCs are essential for setting proper COVID-19 vaccination policy.MethodsWe performed plaque-reduction neutralizing tests (PRNTs) using sera from healthcare workers (HCWs) collected from baseline to six months after COVID-19 vaccination and from convalescent COVID-19 patients. The 20.2% of the mean PRNT titer of convalescent sera was used as 50% protective value, and the percentage of HCWs with protective immunity for each week (percent-week) was compared among vaccination groups. A correlation equation was deduced between a PRNT 50% neutralizing dose (ND50) against wild type (WT) SARS-CoV-2 and that of the Delta variant.ResultsWe conducted PRNTs on 1,287 serum samples from 297 HCWs (99 HCWs who received homologous ChAdOx1 vaccination (ChAd), 99 from HCWs who received homologous BNT162b2 (BNT), and 99 from HCWs who received heterologous ChAd followed by BNT (ChAd-BNT)). Using 365 serum samples from 116 convalescent COVID-19 patients, PRNT ND50 of 118.25 was derived as 50% protective value. The 6-month cumulative percentage of HCWs with protective immunity against WT SARS-CoV-2 was highest in the BNT group (2297.0 percent-week), followed by the ChAd-BNT (1576.8) and ChAd (1403.0) groups. In the inter-group comparison, protective percentage of the BNT group (median 96.0%, IQR 91.2–99.2%) was comparable to the ChAd-BNT group (median 85.4%, IQR 15.7–100%; P =0.117) and significantly higher than the ChAd group (median 60.1%, IQR 20.0–87.1%; P <0.001). When Delta PRNT was estimated using the correlation equation, protective immunity at the 6-month waning point was markedly decreased (28.3% for ChAd group, 52.5% for BNT, and 66.7% for ChAd-BNT).ConclusionDecreased vaccine-induced protective immunity at the 6-month waning point and lesser response against the Delta variant may explain the Delta-dominated outbreak of late 2021. Follow-up studies for newly-emerging VOCs would also be needed.

Antoine Shako Hiango Omokanda Djunga was the pioneer of neurosurgery in the Democratic Republic of Congo (DRC), a country located in Central Africa. He was born in 1938 in Sankuru, a province of the DRC. He graduated from the Free University of Brussels medical school and later trained there in neurosurgery. Thereafter, he completed a fellowship at Bellevue Hospital in New York. As a neurosurgeon, he worked at the Kinshasa University Clinic of Lovanium School of Medicine in the DRC, where he introduced neurosurgery and advocated for the construction of the first dedicated neurosurgical operating room. His leadership helped ensure sustainability in the field in the DRC. He died at the age of 48, leaving a void in neurosurgery and an unfulfilled mission of advocating for the construction of an independent neurosurgery hospital in the DRC.

Donor evaluation is important to ensure that life threatening diseases like cancer can be prevented from getting passed on to the recipient. The donor patient described in our report showed normal parameters in blood and urine biochemistry analysis. Additionally, kidney ultrasonography and renal artery CT showed no indications of any abnormalities. However, endoscopic analysis performed later turned out to be valuable in detection of a protruding mass of 22 to 25 cm in size at the anal verge, and positron emission tomography revealed liver metastasis. Thus, our study highlights that endoscopic techniques can be really valuable in cancer detection and medical centers must consider including these tests in their donor evaluation diagnostic procedures.

Background Anemia, which is a condition with reduced healthy red blood cells, is reported to be closely related to the development of infectious diseases. We aimed to investigate the association between history of anemia and 12-year mortality rate due to infections, and compare it with that among non-anemic individuals. Methods Data from the National Health Insurance Service Health Screening Cohort were used in this population-based cohort study. Adults who underwent standardized medical examination between and 2002–2003 were included, and the mortality rate due to infection between 2004 and 2015 was analyzed. Individuals were considered to have a history of anemia if the serum hemoglobin level in 2002–2003 was hemoglobin ≥11 g/dL in women and 13 g/dL > hemoglobin ≥11 g/dL in men), moderate (hemoglobin 8–10.9 g/dL), or severe (hemoglobin Results Overall, 512,905 individuals were included in this study. The mean age of the participants was 54.5 years old (range: 40–98), and 49,042 (9.6%) individuals were classified in the anemic group, which comprised of 36,383 (7.1%), 11,787 (2.3%), and 872 (0.2%) participants in the mild, moderate, and severe sub-groups, respectively. After PS matching, 49,039 individuals in each group were included in the analysis. The risk of mortality due to infection in the anemic group was 1.77-fold higher (hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.52–2.60; P P P P = 0.448). Conclusions History of anemia was associated with increased mortality rate due to infection at 12-year follow-up.

Background Valganciclovir is used to prevent posttransplant cytomegalovirus (CMV) infection among patients undergoing kidney transplant. However, the optimal dose remains controversial because continuous use decreases kidney function and can induce leukopenia. The purpose of this study was to identify the appropriate dose of valganciclovir for preventing CMV using network meta-analysis. Methods We searched the Cochrane Central Register, Ovid MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health, and Web of Science databases for studies published through April 15, 2017, evaluating 900-mg and 450-mg valganciclovir. We performed direct and indirect network meta-analysis using Bayesian models and generated rankings of different doses of valganciclovir by generating a mixed-treatment comparison. Results Twenty-three studies involving 3478 participants were included. Compared with the control group, there was no difference in the incidence of CMV infection between the low-dose (450 mg) (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.50-1.40) and high-dose (900 mg) (OR, 1.0; 95% CI, 0.61-1.60) groups. Low-dose valganciclovir had the best probability (71.1%) for decreasing CMV infection. Leukopenia was significantly more common in the high-dose group than in the control group (OR, 4.3; 95% CI, 2.69-7.10) and in the low-dose group (OR, 2.9; 95% CI, 1.88-4.67), but there was no significant difference in the incidence of leukopenia between the low-dose and control groups (OR, 1.5; 95% CI, 0.99-2.20). Conclusions The incidence of CMV was not different based on the dose of valganciclovir, although the tendency for CMV infection was decreased at 450 mg. However, the low dose of valganciclovir significantly reduced the incidence of leukopenia

BACKGROUND/AIM There are no clinically significant cutoff values of serum vitamin D levels and time points to predict the prognosis of colon cancer, particularly in patients who underwent curative surgical resection. PATIENTS AND METHODS We retrospectively analyzed serum vitamin D levels in 795 patients with stages I to III colon cancer who underwent curative surgical resection. RESULTS Patients with vitamin D levels below 12 ng/ml at one year after surgical resection demonstrated a significantly reduced disease-free survival (DFS) than those who did not have vitamin D deficiency (p=0.01). In the multivariate analysis, an age of 70 years or older [hazard ratio (HR)=1.992; p=0.001], pathologic stage (HR=3.739; p

The objective of the study was to develop and validate a prediction model that identifies COVID-19 patients at risk of requiring oxygen support based on five parameters: C-reactive protein (CRP), hypertension, age, and neutrophil and lymphocyte counts (CHANeL). This retrospective cohort study included 221 consecutive COVID-19 patients and the patients were randomly assigned randomly to a training set and a test set in a ratio of 1:1. Logistic regression, logistic LASSO regression, Random Forest, Support Vector Machine, and XGBoost analyses were performed based on age, hypertension status, serial CRP, and neutrophil and lymphocyte counts during the first 3 days of hospitalization. The ability of the model to predict oxygen requirement during hospitalization was tested. During hospitalization, 45 (41.8%) patients in the training set (n = 110) and 41 (36.9%) in the test set (n = 111) required supplementary oxygen support. The logistic LASSO regression model exhibited the highest AUC for the test set, with a sensitivity of 0.927 and a specificity of 0.814. An online risk calculator for oxygen requirement using CHANeL predictors was developed. “CHANeL” prediction models based on serial CRP, neutrophil, and lymphocyte counts during the first 3 days of hospitalization, along with age and hypertension status, provide a reliable estimate of the risk of supplement oxygen requirement among patients hospitalized with COVID-19.

Background Recent studies regarding deep vein thrombosis (DVT) after anterior cruciate ligament (ACL) reconstruction investigated only symptomatic complications. The purpose of this study was to assess the true incidence of DVT after ACL reconstruction, regardless of symptom manifestation. Materials and methods Medical records of 260 patients who underwent isolated ACL reconstruction between January 2014 and December 2019 were retrospectively reviewed. Regardless of symptom manifestation, DVT was examined for all patients at 1 week postoperatively using ultrasonography. Demographics, injury mechanism (high energy direct injury and low energy indirect injury), soft tissue injury, preoperative anterior laxity, tourniquet time, and surgical technique (transtibial, anteromedial portal, and outside-in techniques) were investigated. Soft tissue injury was evaluated on magnetic resonance imaging (MRI) scans, based on the Tscherne classification. Risk factors for proximal DVT were identified using logistic regression analyses. Results A total of 21 (8.1%) patients showed DVT. 5 (1.9%) patients had thrombosis at the popliteal vein; however, none of them exhibited symptoms. The other 16 patients had thrombosis at the distal veins: 1 patient at the anterior tibial vein, 5 patients at the posterior tibial vein, 3 patients at the peroneal vein, 6 patients at the soleal vein, and 1 patient at the muscular branch vein. The risk factors for proximal DVT included high energy direct injury (p = 0.013, odds ratio = 10.62) and grade 2 soft tissue injury (p = 0.039, odds ratio = 6.78). Conclusions The true incidence of DVT, including symptomatic and asymptomatic complications, were 8.1% after ACL reconstruction. This rate is higher than the previously known incidence which has been investigated only for symptomatic patients. Injury mechanism and soft tissue injury should be assessed when considering thromboprophylaxis.

Background Clonorchis sinensis requires bile acid transporters as this fluke inhabits bile juice-filled biliary ducts, which provide an extreme environment. Clonorchis sinensis sodium-bile acid co-transporter (CsSBAT) is indispensable for the fluke’s survival in the final host, as it circulates taurocholate and prevents bile toxicity in the fluke; hence, it is recognized as a useful drug target. Methodology and principal findings In the present study, using structure-based virtual screening approach, we presented inhibitor candidates targeting a bile acid-binding pocket of CsSBAT. CsSBAT models were built using tertiary structure modeling based on a bile acid transporter template (PDB ID: 3zuy and 4n7x) and were applied into AutoDock Vina for competitive docking simulation. First, potential compounds were identified from PubChem (holding more than 100,000 compounds) by applying three criteria: i) interacting more favorably with CsSBAT than with a human homolog, ii) intimate interaction to the inward- and outward-facing conformational states, iii) binding with CsSBAT preferably to natural bile acids. Second, two compounds were identified following the Lipinski’s rule of five. Third, other two compounds of molecular weight higher than 500 Da (Mr > 500 Da) were presumed to efficiently block the transporter via a feasible rational screening strategy. Of these candidates, compound 9806452 exhibited the least hepatotoxicity that may enhance drug-likeness properties. Conclusions It is proposed that compound 9806452 act as a potential inhibitor toward CsSBAT and further studies are warranted for drug development process against clonorchiasis.

To optimize antibiotic use, the US CDC has outlined core elements of antimicrobial stewardship programs (ASP). However, they are difficult to implement in limited-resource settings. We report on the successful implementation of a series of ASP with insufficient number of infectious diseases specialists. We retrospectively collected data regarding antibiotic administration and culture results of all patients admitted to a tertiary care teaching hospital, Seoul National University Bundang Hospital (SNUBH), from January 2010 to December 2019. Trends of antibiotic use and antibiotic resistance rates were compared with those from Korean national data. Trend analyses were performed using nonparametric, two-sided, correlated seasonal Mann-Kendall tests. Total antibiotic agent usage has significantly decreased with ASP implementation at SNUBH since 2010. National claim data from tertiary care hospitals have revealed an increase in the use of all broad-spectrum antibiotics except for third-generation cephalosporins (3GC). In contrast, at SNUBH, glycopeptide and fluoroquinolone use gradually decreased, and 3GC and carbapenem use did not significantly change. Furthermore, the rate of colonization with methicillin-resistant Staphylococcus aureus showed a consistently decreasing trend, while that with 3GC- and fluoroquinolone-resistant Escherichia coli significantly increased. Unlike the national rate, the rate of colonization with antibiotic resistant-Klebsiella pneumoniae did not increase and that of 3GC- and fluoroquinolone-resistant Pseudomonas aeruginosa significantly decreased. Stepwise implementation of core ASP elements was effective in reducing antibiotic use despite a lack of sufficient manpower. Long-term multidisciplinary teamwork is necessary for successful and sustainable ASP implementation.

This retrospective study aimed to clarify the interspecies differences in the clinical characteristics and risk factors of bloodstream infection (BSI) due to third-generation cephalosporin-resistant (3GC-R) Escherichia coli (EC) and Klebsiella pneumoniae (KP) in patients with liver cirrhosis (LC). KP BSI had more comorbidities and higher treatment failure rate than EC BSI. Non-alcoholic LC was a risk factor for treatment failure in EC, whereas it was not associated with KP. Risk factors for BSI due to 3GC-R strain were nosocomial infection in EC, and β-lactam/fluoroquinolone treatment ≤ 30 days in KP. These results could help predict outcomes of BSI and improve clinical practice.

Purpose Colorectal cancer (CRC) is increasing in South Korea due to westernized eating habits and regular health check-ups. The Korean Health Insurance Review and Assessment Service (HIRA) has conducted a national quality assessment of the treatment of CRC. This study examined the quality assessment report of the Korean HIRA and analyzed the status of practice pattern and the epidemiology of CRC in South Korea.Materials and Methods The number of subjects was determined based on the number of surgical procedures in each institution during 2012-2017. The institution types were classified according to the number of beds and the composition of oncologic specialists. Twenty-one indicators for diagnosis, chemotherapy, radiotherapy, surgery, pathology, and mortality were analyzed and the interinstitutional variation for each indicator was calculated.Results Among 21 evaluation indices, indicators related to medical records, receipt of chemotherapy with a high coefficient of variation of ≥ 0.1% were improved over 6 years until the survey in 2017. In the analysis of indices affecting surgical mortality, the regional lymph node resection and examination rate (p=0.022) showed a negative correlation with surgical mortality. Hospitalization stay (p < 0.001) and hospitalization cost (p=0.002) were positively correlated with surgical mortality.Conclusion This study showed that the treatment quality and examination status for CRC in South Korea were appropriate for improving relevant medical records, receipt of chemotherapy, maintaining the quality of treatment, and mortality. These analyses could be the basis for developing an improved quality assessment program worldwide.

We designed a postmarketing surveillance study of linagliptin for patients with type 2 diabetes (T2D) in Korea. This prospective, observational, multicentre study investigated the safety and glycaemic effectiveness of linagliptin as monotherapy or combination therapy with other antidiabetic drugs in routine clinical practice. Endpoints were the incidence of adverse drug reactions (ADRs) and the change in HbA1c. Overall, 3119 and 2171 patients were included in the safety and effectiveness analysis sets, respectively. A total of 56 patients (1.8%) experienced ADRs. The most common ADR was gastrointestinal disorders (0.7%), followed by metabolism and nutrition disorders (0.5%). ADRs of special interest, including pancreatic diseases, cardiac diseases and hypoglycaemia, occurred in 12 patients, 11 of whom had hypoglycaemia, while one had a skin lesion. Mean HbA1c change during the study period was -0.8%. Lower body mass index, shorter diabetes duration and higher baseline HbA1c were independently associated with a better effectiveness, while the presence of diabetic complications, dyslipidaemia and the use of sulphonylureas were associated with a poor response. In conclusion, linagliptin showed an excellent safety profile and glycaemic effectiveness in Korean patients with T2D.

Purpose: We analyzed the safety and feasibility of preoperative short-course radiotherapy (SCRT) followed by consolidation chemotherapy for patients with locally advanced rectal cancer (LARC).Methods: From April 2018 to May 2019, 19 patients with LACR were treated with SCRT followed by three cycles of consolidation chemotherapy with leucovorin, fluorouracil, and oxaliplatin (FOLFOX6) before surgery. Adjuvant chemotherapy relied on oxaliplatin. Tumor response, patient compliance, and toxicities were analyzed.Results: The median age was 60 years (range 44–71), and 16 of the patients were male. The median tumor height was 5 cm (range 0–9) from anal verge. All patients received a total dose of 25 Gy in five fractions. The number of cycles of FOLFOX6 before surgery was three in 17, four in one, five in one. Five patients required dose reductions in consolidation chemotherapy. The median interval between initiation of SCRT and surgery was 10.6 weeks (range 8.6–16.4). A pathologic complete response was seen in two patients (11%). Grade III toxicities to the preoperative treatment were seen in five patients (26%): diarrhea in two, a decreased white blood cell count in one, and anemia in two. Postoperative complications arising within 30 days developed in five patients (26%). During the median follow-up period of 20.4 months, there was no tumor recurrence. Conclusion: Preoperative SCRT followed by oxaliplatin-based consolidation chemotherapy showed acceptable toxicity and feasibility in patients with LARC. Prospective randomized trials are warranted to verify the efficacy and safety of this treatment strategy compared with conventional long-course concurrent chemoradiotherapy.

Recently, the number of patients with coronavirus disease 2019 (COVID-19) who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), via the reverse transcription polymerase chain reaction (RT-PCR) test, after recovery has increased; this has caused a dilemma regarding the medical measures and policies. We evaluated the dynamics of viral load and anti-SARS-CoV-2 antibodies in four patients with positive RT-PCR results after recovery. In all patients, the highest levels of immunoglobulin G (IgG) and IgM antibodies were reached after about a month of the onset of the initial symptoms. Then, the IgG titers plateaued, and the IgM titers decreased, regardless of RT-PCR results. The IgG and IgM levels did not increase after the post-negative positive RT-PCR results in any of the patients. Our results reinforced that the post-negative posi tive RT-PCR results may be due to the detection of RNA particles rather than re infection in individuals who have recovered from COVID-19.

DA-9801, a plant-based drug used for the treatment of diabetic neuropathy, is known to improve angiotensin II (Ang II)-induced vascular endothelial cell dysfunction. However, the underlying mechanism is not fully understood. We aimed to determine whether the protective effect of DA-9801 against Ang II-induced endothelial cell dysfunction was mediated via inhibition of endothelial cell inflammation and apoptosis. Ang II-induced oxidative stress was attenuated by pretreatment of human dermal microvascular endothelial cells (HDMECs) with DA-9801. This prevented the Ang II-induced upregulation of NAD(P)H oxidase (the NOX4 and p22phox subunits) and reactive oxygen species. Further, pretreatment of HDMECs with DA-9801 ameliorated Ang II-mediated nuclear factor kappa B activity via prevention of the upregulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. It also decreased the Ang II-stimulated increase in inducible nitric oxide synthase (NOS) and decreased endothelial NOS protein expression. DA-9801 decreased Ang II-induced upregulation of intercellular adhesion molecule 1, vascular adhesion molecule, and E-selectin in HDMECs. Moreover, TUNEL and annexin V-FITC fluorescence staining for apoptosis and the activities of caspases 9, 7, and 3 decreased in HDMECs pretreated with DA-9801, indicating that the drug enhanced anti-apoptotic pathways. Thus, DA-9801 modulated Ang II-induced endothelial cell dysfunction via inflammatory and apoptotic pathways.

Purpose To compare the differences with respect to clinical and graft survivorship and patient-reported outcomes (PROs) between lateral (LMAT) and medial (MMAT) meniscus allograft transplantation. Methods Patients having a primary MAT between 1998 and 2016 were enrolled. The inclusion criteria were (1) patients who had a minimum 2-year follow-up and (2) patients who had magnetic resonance imaging (MRI) >2 years after surgery. Knees with localized grade 4 articular cartilage lesions >3 cm2 at the time of MAT were excluded. Clinical failure was defined as follows: modified Lysholm score 50% of the graft, meniscectomy to the meniscocapsular junction zone, conversion to revision MAT, or realignment osteotomy or arthroplasty. Graft failure was defined as follows: tears involving >50% of the graft or unhealed peripheral rim observed on MRI. Kaplan–Meier survival analysis with log-rank test was used to compare survivorship between LMAT and MMAT. Patient-reported outcomes were compared based on the Hospital for Special Surgery, modified Lysholm, and International Knee Documentation Committee subjective scores collected preoperatively and at the final follow-up. Results A total of 299 knees (249 LMAT, 50 MMAT, mean age 33.0 ± 9.8 years) were included. Twenty clinical [2 MMAT (4.0%), 18 LMAT (7.2%)] and 24 graft [2 MMAT (4.0%), 22 LMAT (8.8%)] failures were identified. The mean clinical follow-up period was 63.1 ± 43.1 months (range 2 to 248), and MRI follow-up period was 62.6 ± 43.8 months (range 2 to 248). No significant differences in clinical and graft survivorship were found between the LMAT and MMAT groups (P = .481, P = .271, respectively). PROs preoperatively and at last follow-up also showed no significant difference between the groups. Conclusion No significant differences in clinical survivorship, graft survivorship, and PROs were found between the LMAT and MMAT groups. Level of evidence Level III, retrospective comparative study.

The clinical features of coronavirus disease 2019 (COVID-19) patients in the COVID-19 vaccination era need to be clarified because breakthrough infection after vaccination is not uncommon.We retrospectively analyzed hospitalized COVID-19 patients during a delta variant-dominant period 6 months after the national COVID-19 vaccination rollout. The clinical characteristics and risk factors for severe progression were assessed and subclassified according to vaccination status.A total of 438 COVID-19 patients were included; the numbers of patients in the unvaccinated, partially vaccinated and fully vaccinated groups were 188 (42.9%), 117 (26.7%) and 133 (30.4%), respectively. The vaccinated group was older, less symptomatic and had a higher Charlson comorbidity index at presentation. The proportions of patients who experienced severe progression in the unvaccinated and fully vaccinated groups were 20.3% (31/153) and 10.8% (13/120), respectively. Older age, diabetes mellitus, solid cancer, elevated levels of lactate dehydrogenase and chest X-ray abnormalities were associated with severe progression, and the vaccination at least once was the only protective factor for severe progression. Chest X-ray abnormalities at presentation were the only predictor for severe progression among fully vaccinated patients.In the hospitalized setting, vaccinated and unvaccinated COVID-19 patients showed different clinical features and risk of oxygen demand despite a relatively high proportion of patients in the two groups. Vaccination needs to be assessed as an initial checkpoint, and chest X-ray may be helpful for predicting severe progression in vaccinated patients.

Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG+ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.

Background Spinal anesthesia and autonomic neuropathy (caused by diabetes) prolong the QTc interval. Changes in the duration of the QTc interval following subarachnoid blockade in patients with diabetes have not been evaluated. We hypothesized that after subarachnoid blockade, QTc interval prolongation would be greater in patients with diabetes than in those without. Accordingly, we compared the QTc interval, T wave peak-to-end interval (Tp-e interval), blood pressure, heart rate, and heart rate variability before and after spinal anesthesia in patients with and without diabetes. Methods This prospective observational study (Clinical Research Information Service identifier: KCT0004897) was conducted in a tertiary university hospital and included 24 patients with diabetes mellitus (DM group) and 24 patients without it (control group) who were scheduled for spinal anesthesia. The QTc interval, Tp-e interval, heart rate variability, blood pressure, and heart rate were measured before (T1) and 1 (T2), 5 (T3), and 10 min (T4) following subarachnoid blockade. Results Ten minutes following subarachnoid blockade, the QTc intervals of patients in the DM group were significantly longer than the baseline values, whereas the change in the QTc interval in the control group was not significant (p p = 0.06). Conclusion Spinal anesthesia caused a more significant prolongation of the QTc interval in patients with diabetes than in those without.

Osteoporosis affects millions of people worldwide. As such, this study assessed the macrophage-dependent in vitro anti-osteoporosis, phytochemical profile and hepatotoxicity effects in zebrafish larvae of the stem bark extracts of P. africana. Mouse bone marrow macrophages (BMM) cells were plated in 96-well plates and treated with P. africana methanolic bark extracts at concentrations of 0, 6.25, 12.5, 25, and 50 µg/ml for 24 h. The osteoclast tartrate-resistant acid phosphatase (TRAP) activity and cell viability were measured. Lipopolysaccharides (LPS) induced Nitrite (NO) and interleukin-6 (IL-6) production inhibitory effects of P. africana bark extracts (Methanolic, 150 µg/ml) and β-sitosterol (100 µM) were conducted using RAW 264.7 cells. Additionally, inhibition of IL-1β secretion and TRAP activity were determined for chlorogenic acid, catechin, naringenin and β-sitosterol. For toxicity study, zebrafish larvae were exposed to different concentrations of 25, 50, 100, and 200 µg/ml P. africana methanolic, ethanolic and water bark extracts. Dimethyl sulfoxide (0.05%) was used as a negative control and tamoxifen (5 µM) and dexamethasone (40 µM or 80 µM) were positive controls. The methanolic P. africana extracts significantly inhibited (p p P. africana methanolic extract (p P. africana methanolic extract significantly inhibited RANKL-induced TRAP activity. The phytochemical study of P. africana stem bark revealed a number of chemical compounds with anti-osteoporosis activity. There was no observed hepatocyte apoptosis in the liver of zebrafish larvae. In conclusion, the stem bark of P. africana is non-toxic to the liver and its inhibition of TRAP activity makes it an important source for future anti-osteoporosis drug development.

We aimed to evaluate the mycobacterial culture positivity rates according to biopsy methods and sites in patients with tuberculous spondylitis (TS) and identify which tissues are the best sites for the diagnosis of TS.We retrospectively identified and reviewed medical records of all patients with TS in three university-affiliated hospitals in the Republic of Korea from January 2003 to December 2020. TS was diagnosed by culture or histopathologic examination of vertebral bodies or paraspinal tissues and characteristic clinical and radiologic features. Patients with TS who received a needle biopsy or underwent surgical biopsy were investigated. The sites of needle biopsy were classified as vertebral bodies or paraspinal tissues.During the study period, 206 tissues from 200 patients with TS were included in the analysis. The culture positivity rates of vertebral bodies obtained by needle biopsy, paraspinal tissues obtained by needle biopsy, and tissues obtained by surgery were 69.0%, 85.3%, and 83.2%, respectively. Multivariate logistic regression identified that paraspinal tissues as biopsy sites were independently associated with mycobacterial culture positivity in TS undergoing needle biopsy (adjusted odds ratio, 3.68; 95% confidence interval: 1.13-11.99, P = 0.030).We demonstrated that the positivity rates of mycobacterial culture in TS were 69.0-85.3%. Paraspinal tissues as biopsy sites were significantly associated with culture positivity in needle biopsy, suggesting that targeting paraspinal tissues during needle biopsy may be the best method for diagnosing TS.

ObjectivesTo evaluate efficacy and safety of immediate switch from upadacitinib to adalimumab, or vice versa, in patients with rheumatoid arthritis with non-response or incomplete-response to the initial therapy.MethodsSELECT-COMPARE randomised patients to upadacitinib 15 mg once daily (n=651), placebo (n=651) or adalimumab 40 mg every other week (n=327). A treat-to-target study design was implemented, with blinded rescue occurring prior to week 26 for patients who did not achieve at least 20% improvement in both tender and swollen joint counts (‘non-responders’) and at week 26 based on Clinical Disease Activity Index (CDAI) >10 (‘incomplete-responders’) without washout.ResultsA total of 39% (252/651) and 49% (159/327) of patients originally randomised to upadacitinib and adalimumab were rescued to the alternate therapy. In both switch groups (adalimumab to upadacitinib and vice versa) and in non-responders and incomplete-responders, improvements in disease activity were observed at 3 and 6 months following rescue. CDAI low disease activity was achieved by 36% and 47% of non-responders and 45% and 58% of incomplete-responders switched to adalimumab and upadacitinib, respectively, 6 months following switch. Overall, approximately 5% of rescued patients experienced worsening in disease activity at 6 months postswitch. The frequency of adverse events was similar between switch groups.ConclusionsThese observations support a treat-to-target strategy, in which patients who fail to respond initially (or do not achieve sufficient response) are switched to a therapy with an alternate mechanism of action and experience improved outcomes. No new safety findings were observed despite immediate switch without washout.

Background Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. Methods Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (≤5 d, 6–9 d, 10–13 d, 14–19 d, and ≥ 20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. Results TLR2 levels varied among 59 SAB patients. On days 2–5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p = 0.040) and slightly but not significantly higher than non-survivors (p = 0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P = 0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2–5 post-bacteremia (P = 0.010 and P = 0.021, respectively), and those dying within 7 d of SAB (n = 3) displayed significantly higher IL-10/TNF-α ratios than the survivors did (P = 0.007). Conclusion TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.