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Background: Parkinson’s disease is a neurodegenerative disease characterized by progressive dopaminergic (DAergic) neuronal loss. Motor deficits experienced by patients with Parkinson’s disease are well documented, but non-motor symptoms, including mood disorders associated with circadian disturbances, are also frequent features. One common phenomenon is “sundowning syndrome,” which is characterized by the occurrence of neuropsychiatric symptoms at a specific time (dusk), causing severe quality of life challenges. This study aimed to elucidate the underlying mechanisms of sundowning syndrome in Parkinson’s disease and their molecular links with the circadian clock.Methods: To induce the Parkinson’s disease mouse model, a single injection of 6-hydroxydopamine (6-OHDA) was administered into the left dorsal striatum. Five weeks post injection, mood-related behavioral tests were performed at the indicated time of day (circadian time 22-01 vs. 10-13). Local injection of a REV-ERBα antagonist, SR8278, into the ventral tegmental area, was performed 3 h before each behavioral test. To determine the molecular mechanism of behavioral deficits, fluorescent in situ hybridization, chromatin immunoprecipitation assay, western blot analysis, and ATAC-sequencing were performed.Results: Our study demonstrated that 6-OHDA-lesioned mice exhibited increased depression- and anxiety-like behaviors only at dawn. SR8278 treatment exerted antidepressant and anxiolytic effects in a circadian time-dependent manner in 6-OHDA-lesioned mice, restoring the circadian rhythm of mood-related behaviors. 6-OHDA-lesion altered DAergic-specific Rev-erbα and Nurr1 transcription, and atypical binding activities of REV-ERBα and NURR1, which are upstream nuclear receptors for the discrete tyrosine hydroxylase promoter region SR8278, restored the binding activities of REV-ERBα and NURR1 to the tyrosine hydroxylase promoter and the induction of enrichment of the R/N motif, recognized by REV-ERBα and NURR1 only at dawn, as revealed by ATAC-sequencing; therefore, tyrosine hydroxylase expression was elevated in the ventral tegmental area of 6-OHDA-injected mice, especially at dawn.Conclusions: These results indicate that REV-ERBα is a potential therapeutic target, and its antagonist, SR8278, is a potential drug for mood disorders related to circadian disturbances, namely sundowning syndrome, in Parkinson’s disease.

Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14–20 μg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.

Osteoarthritis is among the most prevalent of musculoskeletal disorders in the world that causes joint pain, deformity, and limited range of movement. The resulting osteochondral defect can significantly decrease the patient's quality of life, but current treatment options have not demonstrated the capacity to fully regenerate the entire osteochondral microenvironment. Structurally, the osteochondral unit is a composite system composed of three layers-articular cartilage, calcified cartilage, and subchondral bone. Collectively these distinct layers contribute to the distinct biomechanical properties that maintain the health and aid in load transfer during joint articulation. The purpose of this review was to examine the role of the osteochondral interface in tissue engineering. Topics of discussion include the biomechanics of the osteochondral unit and an overview of various strategies for osteochondral interface tissue engineering, with a specific focus on three-dimensional bioprinting. The goal of this review was to elucidate the importance of the osteochondral interface and overview some strategies of developing an interface layer within tissue engineered scaffolds. Impact Statement This review provides an overview of interface tissue engineering for osteochondral regeneration. It offers a detailed investigation into the biomechanics of the osteochondral unit as it relates to tissue engineering, and highlights the strategies that have been utilized to develop the osteochondral interface within tissue engineering scaffolds.

(a). PURPOSE. A central neuropeptide mediator of ocular immune privilege is α-MSH, which can be used to therapeutically suppress experimental autoimmune uveitis (EAU). A part of α-MSH-regulation of immune activity is through its melanocortin 5 receptor (MC5r). One of the mechanisms of ocular immune privilege mediated by α-MSH is RPE suppression of phagolysosome activation associated with antigen presenting cell (APC) processing of antigen. Therefore, we examined the possible role of MC5r-expression in the recovery of RPE suppression of macrophage phagolysosome activation following α-MSH-treatment of EAU. (b). METHODS. The conditioned media of cultured in situ RPE-eyecup from α-MSH-treated EAU wild-type and MC5r((−/−)) mice were used to treat macrophages phagocytizing opsonized-pHrodoRed-bacterial bioparticles to assay for phagolysosome activation. In addition, the phagocytic activity of macrophages from MC5r((−/−)) mice was assayed. (c). RESULTS. The RPE from MC5r((−/−)) mice that have recovered from EAU after α-MSH-therapy do suppress phagosome maturation in wildtype macrophages; but do not suppress phagosome maturation in MC5r((−/−)) macrophages. In addition, α-MSH does not suppress phagolysosome activation in MC5r((−/−)) macrophages, and the macrophages are highly enhanced in their phagocytic activity. Along with the enhanced macrophage activity was observed an increase in damage of the EAU MC5r((−/−)) retinas. (d). CONCLUSION. The results demonstrated that treatment of EAU with α-MSH mediated recovery of RPE suppression of phagolysosome activation in macrophages and protected the retina from inflammatory damage. This was dependent on the expression of MC5r. Moreover, through MC5r the neuropeptide α-MSH potentially acts as a homeostatic moderator of phagosome-maturation within macrophages.

Objective Lubricin, a glycoprotein encoded by the proteoglycan 4 (PRG4) gene, is an essential boundary lubricant that reduces friction between articular cartilage surfaces. The loss of lubricin subsequent to joint injury plays a role in the pathogenesis of post-traumatic osteoarthritis (PTOA). Here we describe the development and evaluation of an adeno-associated virus (AAV)-based PRG4 gene therapy intended to restore lubricin in injured joints. The green fluorescent protein (GFP) gene was inserted the PRG4 gene to facilitate tracing the distribution of the transgene product (AAV-PRG4-GFP) in vivo. Methods Transduction efficiency of AAV-PRG4-GFP was evaluated in joint cells, and the conditioned medium containing secreted PRG4-GFP was used for shear loading/friction and viability tests. In vivo transduction of joint tissues following intra-articular injection of AAV-PRG4-GFP was confirmed in the mouse stifle joint in a surgical model of destabilization of the medial meniscus (DMM), and chondroprotective activity was tested in a rabbit anterior cruciate ligament transection (ACLT) model. Results In vitro studies showed that PRG4-GFP has lubricin-like cartilage binding and anti-friction properties. Significant cytoprotective effects were seen when cartilage was soaked in PRG4-GFP prior to cyclic shear loading (n = 3). Polymerase chain reaction and confocal microscopy confirmed the presence of PRG4-GFP DNA and protein, respectively, in a mouse DMM (n = 3 per group). In the rabbit ACLT model, AAV-PRG4-GFP gene therapy enhanced lubricin expression (p = 0.001 versus AAV-GFP: n = 7-14) and protected the cartilage from degeneration (p = 0.014 versus AAV-GFP: n = 9-10) when treatments were administered immediately post-operation, but efficacy was lost when treatment was delayed for 2 weeks. Conclusion AAV-PRG4-GFP gene therapy protected cartilage from degeneration in a rabbit ACLT model; however, data from the ACLT model suggest that early intervention is essential for efficacy.

BACKGROUND Living liver donation is generally considered safe, but donors may experience short or long-term complications. The purpose of this study was to assess healthcare resource utilization after liver donation in living liver donors in comparison to the general population. METHODS Outpatient or emergency department visits and hospital admissions were compared between living liver donors who underwent hepatic resection for living liver donation between 2004 and 2018 and the matched general population. Healthcare resource utilization data for 5 years after liver donation were collected from the National Health Insurance Service (NHIS) database. For every living liver donor, 4 individually matched nondonors were selected from the NHIS database using age, sex, preexisting comorbidities, and previous healthcare utilization history. RESULTS A total of 1886 living liver donors and 7309 nondonors were included. In the first year after donation, living liver donors required more outpatient department visits (7 [4-13] vs. 3 [1-7], P < 0.001) and more emergency department visits (13.33% vs. 0.15%, P < 0.001) compared to matched nondonors. A similar trend persisted for 5 years after donation. The number of hospital admissions of living liver donors was higher for up to 2 years after donation with longer hospital length of stay (13.0 [10.5-16.0] vs. 5.0 [3.0-9.0] days, P < 0.0001). CONCLUSIONS Healthcare resource utilization in living liver donors for 5 years after donation were higher compared to matched nondonors. The higher healthcare resource demand may be related to postoperative complications or lowered threshold for healthcare resource utilization after donation.Supplemental Visual Abstract; http://links.lww.com/TP/C291.

Background/Aims: The preventive role of hydroxychloroquine (HCQ) on coronavirus disease 2019 (COVID-19) remains unclear. The aim of this study was to examine the effects of HCQ and other immunosuppressive drugs on the incidence of COVID-19.Methods: The data were collected from the South Korea National Health Insurance Sharing-COVID-19 database. All individuals who underwent nasopharyngeal and oropharyngeal swab tests for COVID-19 from January 2020 to May 2020 are included. The association between COVID-19 risk and HCQ use was examined in a propensity score-matched population. Factors associated with COVID-19 were identified using multiple logistic regression analysis.Results: Total 8,070 patients with COVID-19 and 121,050 negative controls were included from the database. Among all participants, 381 were HCQ users. In a propensity score-matched population, the incidence of COVID-19 was 7.1% in HCQ users and 6.8% in non-users. The odds ratio (OR) for HCQ use was 1.05 with a 95% confidence interval (CI) of 0.58 to 1.89. Among the subpopulation of patients with rheumatoid arthritis (RA), 33 were diagnosed with COVID-19 and 478 were not. Use of HCQ, glucocorticoids, or other immunosuppressive drugs was not associated with COVID-19 risk, whereas abatacept use was. Chronic lung disease was an independent risk factor for COVID-19 diagnosis in patients with RA (adjusted OR, 6.07; 95% CI, 1.10 to 33.59).Conclusions: The risk of COVID-19 did not differ between HCQ users and non-users. Glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs other than abatacept did not increase the risk of COVID-19.

Background: Deep learning has been heavily explored for pulmonary nodule detection on chest radiograph. Reticular opacity detection in interstitial lung disease (ILD) is challenging and may also be...

Rapid evolution of pulmonary complications associated with severe COVID-19 pneumonia often pose a management challenge to clinicians especially in the critical care setting. Serial chest imaging enable clinicians to better monitor disease progression and identify potential complications early which may decrease the mortality and morbidity associated with COVID-19. We report a case of severe COVID-19 pneumonia in a 69-year-old man that presented to University Malaya Medical Centre in March 2020 with multiple pulmonary complications including lung cavitation, bronchopleural fistula, pneumothorax, pneumomediastinum, subcutaneous emphysema and acute pulmonary embolism which we highlight through serial chest radiographs (CXR) and computed tomography (CT). The patient unfortunately succumbed to his disease one month after admission. COVID-19 patients may develop pulmonary complications due to a combination of direct viral lung damage, hypoxemia and high stress ventilation. Awareness of COVID-19 complications can prompt early diagnosis and timely management to reduce morbidity and mortality. Keywords: COVID-19 case report, lung cavitation, bronchopleural fistula, pneumothorax, pneumomediastinum.

Objective To evaluate factors contributing to positive surgical margins associated with reflector guidance for patients undergoing breast conserving therapy for malignancy. Materials and Methods A retrospective IRB-approved review of our institutional database was performed for malignant breast lesions preoperatively localized from January 1, 2018 to December 31, 2020. The following data was recorded using electronic medical records: lesion type and grade, lesion location, reflector and wire placement modality, use of intraoperative ultrasound, margin status, patient age, family history, BMI, and final pathology. Statistical analysis was performed with univariate summary statistics and logistic regression. P Results A total of 606 image-guided pre-surgical localizations were performed for lumpectomies of breast malignancies. A total of 352 of 606 (58%) wire localizations and 254 of 606 (42%) SCOUT reflector localizations were performed. Sixty out of 352 (17%) of wire-localized patients had positive surgical margins, whereas forty-eight out of 254 (19%) of reflector-localized patients had positive surgical margins. (OR = 1.12, P value: .59). For reflector guided cases, the use of intraoperative ultrasound (IOUS) was associated with decreased positive margin status (OR = 0 .28, 95% CI = [0.14, 0.58]) while in situ disease was associated with increased positive margin status (OR = 1.99, 95% CI = [1.05, 3.75]). No association between modality used for localization (mammography vs. ultrasound) and positive margin status was observed (OR = 0.63, 95% CI = [0.33, 1.19]). No association between positive margins and age, family history, tumor location and BMI was observed. Conclusion For reflector guided surgeries, the use of IOUS was associated with decreased positive margins, by contrast the presence of ductal carcinoma in situ was associated with increased positive margins. There was no statistically significant difference in surgical outcomes for reflector-guided localization compared to wire localizations of the breast.

OBJECTIVE To develop a machine learning algorithm that identifies detrusor overactivity (DO) in Urodynamic Studies (UDS) in the spina bifida population. UDS plays a key role in assessment of neurogenic bladder in patients with spina bifida. Due to significant variability in individual interpretations of UDS data, there is a need to standardize UDS interpretation. MATERIALS AND METHODS Patients who underwent UDS at a single pediatric urology clinic between May 2012 and September 2020 were included. UDS files were analyzed in both time and frequency domains, varying inclusion of vesical, abdominal, and detrusor pressure channels. A machine learning pipeline was constructed using data windowing, dimensionality reduction, and support vector machines. Models were designed to detect clinician identified detrusor overactivity. RESULTS Data were extracted from 805 UDS testing files from 546 unique patients. The generated models achieved good performance metrics in detecting DO agreement with the clinician, in both time- and frequency-based approaches. Incorporation of multiple channels and data windowing improved performance. The time-based model with all 3 channels had the highest area under the curve (AUC) (91.9 ± 1.3%; sensitivity: 84.2 ± 3.8%; specificity: 86.4 ± 1.3%). The 3-channel frequency-based model had the highest specificity (AUC: 90.5 ± 1.9%; sensitivity: 68.3 ± 5.3%; specificity: 92.9 ± 1.1%). CONCLUSION We developed a promising proof-of-concept machine learning pipeline that identifies DO in UDS. Machine-learning-based predictive modeling algorithms may be employed to standardize UDS interpretation and could potentially augment shared decision-making and improve patient care.

The independent effect of serum triglyceride levels on the development of ischemic cardiovascular disease (CVD) remains inconclusive, which might be due to heterogeneity among study populations.To evaluate the effect of triglyceride levels on ischemic CVD and mortality in Korean women, with stratification according to the menopausal status, diabetes mellitus, or low-density lipoprotein cholesterol levels (LDL-C).We retrospectively investigated Korean women aged 40-69 years who underwent health examination in 2009 and were followed up until 2018 using nationwide claim data. The subjects were divided according to triglyceride quartiles (Q): Q170 mg/dL, Q2 71-99 mg/dL, Q3 100-142 mg/dL, and Q4 ≥143 mg/dL. The primary outcome was the incidence of CVD defined as a composite of myocardial infarction and ischemic stroke.Among 2,208,347 women, primary outcome occurred in 62,255 (2.8%) subjects. As triglyceride levels increased, the event rate of primary outcome increased in both premenopausal and postmenopausal women in the fully adjusted model (hazard ratio [HR] per 1 Q, 1.10 [95% confidence interval (CI), 1.08-1.12] and 1.08 [95% CI, 1.07-1.09], respectively), which was maintained on further stratification according to diabetes or LDL-C (P0.05 in all). Higher triglyceride levels were more significantly associated with the primary outcome, MI, and stroke risk among women with optimal non-high-density lipoprotein cholesterol levels (non-HDL-C)130 mg/dL, but only weakly with stroke for women with non-optimal non-HDL-C.Triglyceride is an independent prognosticator in the development of ischemic CVD in Korean women aged 40-69 years.

Objectives Frail older adults with gastric cancer are at an increased risk of poor postoperative outcomes. We assessed whether geriatric frailty assessed using the Study of Osteoporotic Fractures (SOF) index could predict post-gastrectomy mortality. Materials and methods We retrospectively assessed older adults (age ≥ 65 years) who underwent gastrectomy for gastric cancer between April 2012 and September 2015. Frailty status was assessed using the SOF index (range, 0–3) and categorized as robust (0), pre-frail (1), and frail (2–3). The Kaplan–Meier method and log-rank tests were used to compare survival between frailty groups. Univariate and multivariate analyses were used to identify mortality-associated risk factors. Results Among 231 patients (the median age 72.04 years and 140 (60.6%) men), 138 (59.7%) were robust, 58 (25.1%) were pre-frail, and 35 (15.2%) were frail. The mortality rate was 14.5% among robust patients, 20.7% among pre-frail patients, and 20.0% among frail patients (log-rank test, P = 0.032). Frail patients had more than a 3-fold increased risk of mortality compared with robust patients (adjusted HR = 3.331; 95% CI, 1.161–9.559). Multivariate analysis revealed that the SOF index and TNM stage were associated with increased mortality. Conclusions SOF index predicted post-gastrectomy mortality among older patients independently of age, sex, TNM stage, type of approach, gastrectomy type, and extent of lymph node dissection. SOF index may be used with ease to assess frailty status among older patients with gastric cancer in busy clinics and subgroups that may benefit from targeted frailty interventions before cancer treatments.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Background and Purpose: The aim of this study was to examine whether sphingosine-1-phosphate (S1P) levels in patients with acute stroke are associated with stroke severity and outcome. Methods: In a prospective stroke cohort (MARK-STROKE), 374 patients with acute ischemic stroke or transient ischemic attack were enrolled (mean age: 67.9±13.0 years, sex: 64.7% male), and serum-S1P at admission was analyzed with tandem mass spectrometry. In addition to cross-sectional analyses, 79 adverse events (death, stroke, myocardial infarction, rehospitalization) were recorded in 270 patients during follow-up. Regression analyses were adjusted for age, sex, low-density lipoprotein cholesterol, and vascular risk factors. Results were validated in an independent stroke cohort with 219 patients with acute ischemic stroke (CIRCULAS). Results: Low serum-S1P was associated with higher National Institutes of Health Stroke Scale score at admission and with anterior circulation nonlacunar infarcts determined by multivariate regression analyses. During a follow-up of 294±170 days, patients with S1P in the lowest tertile (P =0.048 for trend). In adjusted Cox regression analysis, the lowest S1P tertile was associated with a worse outcome after stroke (hazard ratio, HR 0.51 [95% confidence interval 0.28–0.92]). Results were confirmed in an independent cohort, ie, low S1P levels were associated with higher National Institutes of Health Stroke Scale, larger infarct volumes and worse outcome after 90 days (β-coefficient: –0.03, P =0.026; β-coefficient: −0.099, P =0.009 and odds ratio 0.52 [0.28–0.96], respectively). Conclusions: Our findings imply a detrimental role of low S1P levels in acute stroke and therefore underpin the therapeutic potential of S1P-mimics.

Background Sarcopenia is defined as muscle wasting, characterized by a progressive loss of muscle mass and function due to ageing. Diagnosis of sarcopenia typically involves both muscle imaging and the physical performance of people exhibiting signs of muscle weakness. Despite its worldwide prevalence, a molecular method for accurately diagnosing sarcopenia has not been established. Methods We develop an artificial intelligence (AI) diagnosis model of sarcopenia using a published transcriptome dataset comprising patients from multiple ethnicities. For the AI model for sarcopenia diagnosis, we use a transcriptome database comprising 17 339 genes from 118 subjects. Among the 17 339 genes, we select 27 features as the model inputs. For feature selection, we use a random forest, extreme gradient boosting and adaptive boosting. Using the top 27 features, we propose a four‐layer deep neural network, named DSnet‐v1, for sarcopenia diagnosis. Results Among isolated testing datasets, DSnet‐v1 provides high sensitivity (100%), specificity (94.12%), accuracy (95.83%), balanced accuracy (97.06%) and area under receiver operating characteristics (0.99). To extend the number of patient data, we develop a web application (http://sarcopeniaAI.ml/), where the model can be accessed unrestrictedly to diagnose sarcopenia if the transcriptome is available. A focused analysis of the top 27 genes for their differential or co‐expression with other genes implied the potential existence of race‐specific factors for sarcopenia, suggesting the possibility of identifying causal factors of sarcopenia when a more extended dataset is provided. Conclusions Our new AI model, DSnet‐v1, accurately diagnoses sarcopenia and is currently available publicly to assist healthcare providers in diagnosing and treating sarcopenia.

Purpose: To report a case of late-onset bleb-associated endophthalmitis caused by streptococcus cristatus (S. cristatus) after trabeculectomy.Case summary: A 59-year-old woman presented with left ocular pain and visual disturbance. She had undergone trabeculectomy of the left eye 2 years ago. At the initial visit, she was only able to count fingers from the left eye. Whitish thin bleb, conjunctival injection, and inflammation were observed in the left anterior chamber, and the fundus could not be visualized. Despite administering topical and systemic antibiotics, the chamber reaction worsened, and hypopyon and inflammatory membrane were noticed the next day. Vitrectomy with phacoemulsification and intravitreal antibiotic injection was performed, and the intravitreal antibiotic injections were repeated over the next two days. Bacterial culture of vitreous fluid showed a growth of S. cristatus 5 days after the surgery, and inflammation improved after 7 days. One month later, she was still only able to count fingers from the left eye, but there were no signs of endophthalmitis.Conclusions: Postoperative endophthalmitis after glaucoma filtering surgeries caused by S. cristatus has not been reported previously from Korea. To the best of our knowledge, this is the first Korean case of late-onset bleb-associated endophthalmitis caused by S. cristatus. If gram-positive cocci are grown in samples from the patients with endophthalmitis after trabeculectomy, resident oral microflora such as S. cristatus should be considered as the causative pathogen.

Bone loss caused by primary hyperparathyroidism (PHPT) is an indication for parathyroidectomy (PTX). However, whether adding bisphosphonates would be superior to PTX alone to increase bone mass remains unclear. We thus aimed to compare the skeletal effects of the combination treatment of bisphosphonates and PTX with PTX alone. In this retrospective analysis, bone mineral density (BMD) changes after 1 year of combination treatment and PTX alone were compared. We also analyzed the correlation between changes in serum biochemical parameters and BMD after 1 year of treatment in both groups. The baseline characteristics of patients treated with PTX alone (n = 24) and combination treatment (n = 26) were comparable. BMD significantly increased after 1 year of treatment in both groups (all p

INTRODUCTION Reproductive endocrinologists recommend selective multifetal pregnancy reduction (MFPR) to save at least one or two babies, because triplet pregnancy is known to increase the risk of miscarriage and preterm delivery. However, recently improved obstetric and neonatal care may affect pregnancy outcomes differently in triplet pregnancies, which could alter practice. We compared the maternal, perinatal, and long-term outcomes of triplet pregnancies managed expectantly with those of pregnancies reduced to twins. MATERIAL AND METHODS In this retrospective cohort study, we reviewed the clinical records of 552 trichorionic triplet pregnancies for obstetric, perinatal, and neurodevelopmental outcomes, which consisted of the expectant management (EM) group (n = 225) and MFPR group (n = 327), in Seoul National University Hospital and CHA Bundang Medical Center from January 2006 to December 2018. Neuromotor development was evaluated using the Korean-Ages and Stages Questionnaire, Bayley-III tests, and/or Gross Motor Function Measure. The two groups were compared for the following outcomes: (1) nonviable pregnancy loss before 23 weeks, (2) preterm birth before 32 weeks of gestation, (3) fetal and neonatal survival and (4) long-term neurodevelopmental outcomes. RESULTS There were no differences in maternal age, body mass index, nulliparity or previous preterm birth between the two groups. The risk of nonviable pregnancy loss was lower in the EM group than that in the MFPR group (2 [0.9%] vs 21 [6.4%], p = 0.001). The risk of preterm delivery before 34 weeks of gestation was lower in the MFPR group (adjusted odds ratios [aOR] = 0.47, 95% confidence interval [CI] 0.30-0.73, p = 0.001). The survival rate of neonates until discharge (644 [95.4%] vs 572 [87.5], p < 0.001) and the rate of pregnancies with at least one survivor (220 [97.8%] vs 301 [92.0], p = 0.002) were higher in the EM group than those in the MFPR group. In the MFPR group, the risk of developmental delay (aOR = 2.89, 95% CI 1.38-6.02, p = 0.005) was higher. CONCLUSIONS In trichorionic triplet pregnancies, the possibility of EM to improve survival and reduce the risk of developmental delay has been shown.

Epithelial ovarian cancer is a gynecological cancer with the highest mortality rate, and it exhibits resistance to conventional drugs. Gold nanospheres have gained increasing attention over the years as photothermal therapeutic nanoparticles, owing to their excellent biocompatibility, chemical stability, and ease of synthesis; however, their practical application has been hampered by their low colloidal stability and photothermal effects. In the present study, we developed a yolk-shell-structured silica nanocapsule encapsulating aggregated gold nanospheres (aAuYSs) and examined the photothermal effects of aAuYSs on cell death in drug-resistant ovarian cancers both in vitro and in vivo. The aAuYSs were synthesized using stepwise silica seed synthesis, surface amino functionalization, gold nanosphere decoration, mesoporous organosilica coating, and selective etching of the silica template. Gold nanospheres were agglomerated in the confined silica interior of aAuYSs, resulting in the red-shifting of absorbance and enhancement of the photothermal effect under 808 nm laser irradiation. The efficiency of photothermal therapy was first evaluated by inducing aAuYS-mediated cell death in A2780 ovarian cancer cells, which were cultured in a two-dimensional culture and a three-dimensional spheroid culture. We observed that photothermal therapy using aAuYSs together with doxorubicin treatment synergistically induced the cell death of doxorubicin-resistant A2780 cancer cells in vitro. Furthermore, this type of combinatorial treatment with photothermal therapy and doxorubicin synergistically inhibited the in vivo tumor growth of doxorubicin-resistant A2780 cancer cells in a xenograft transplantation model. These results suggest that photothermal therapy using aAuYSs is highly effective in the treatment of drug-resistant cancers.

The incidence of invasive fungal infection (IFI) in patients with acute myeloid leukemia (AML) has decreased with the introduction of antimold prophylaxis. Although acute lymphoblastic leukemia (ALL) has a lower risk of IFI than does AML, the incidences of IFI in both AML and ALL in the era of antimold prophylaxis should be re-evaluated. We analyzed adults with AML or ALL who had undergone induction, re-induction, or consolidation chemotherapy from January 2017 to December 2019 at Seoul National University Hospital. Their clinical characteristics during each chemotherapy episode were reviewed, and cases with proven or probable diagnoses were regarded as positive for IFI. Of 552 episodes (393 in AML and 159 in ALL), 40 (7.2%) were IFI events. Of the IFI episodes, 8.1% (12/148) and 5.9% (13/220) (P = 0.856) occurred in cases of ALL without antimold prophylaxis and AML with antimold prophylaxis, respectively. After adjusting for clinical factors, a lack of antimold prophylaxis (adjusted odds ratio [aOR], 3.52; 95% confidence interval [CI], 1.35–9.22; P = 0.010) and a longer duration of neutropenia (per one day, aOR, 1.02; 95% CI, 1.01–1.04; P = 0.001) were independently associated with IFI. In conclusion, the incidence of IFI in ALL without antimold prophylaxis was not lower than that in AML. A lack of antimold prophylaxis and prolonged neutropenia were independent risk factors for IFI. Clinicians should be on guard for detecting IFI in patients with ALL, especially those with risk factors.

Atypical small acinar proliferation (ASAP) occurs in approximately 5% of prostate biopsies. Approximately 30–40% of patients with ASAP have biopsy detectable prostate cancer (PCa) within 5 years. Current guidelines recommend a repeat biopsy within 3–6 months after the initial diagnosis. The aim of the present study was to examine the association between ASAP and subsequent diagnosis of clinically significant PCa (csPCa). The need for immediate repeat biopsy was also evaluated. We identified 212 patients with an ASAP diagnosis on their first biopsy at our institution between February 2006 and March 2018. Of these patients, 102 (48.1%) had at least one follow-up biopsy. Clinicopathologic features including rates of subsequent PCa and csPCa were assessed. Thirty-five patients subsequently underwent radical prostatectomy (RP). Their pathologic results were reviewed. csPCa was defined as the presence of Gleason score (GS) ≥ 3 + 4 in ≥ 1 biopsy core. Adverse pathology (AP) was defined as high-grade (primary Gleason pattern ≥ 4) or non-organ-confined disease (pT3/N1) after RP. Of 102 patients, 87 (85.3%), 13 (12.7%), and 2 (2.0%) had one, two, and three follow-up biopsies, respectively. Median time from the initial ASAP diagnosis to the 2nd follow-up biopsy and the last follow-up biopsy were 21.9 months (range 1–129 months) and 27.7 months (range 1–129 months), respectively. Of these patients, 46 (45.1%) were subsequently diagnosed with PCa, including 20 (19.6%) with csPCa. Only 2 (2.0%) patients had GS ≥ 8 disease. Five (4.9%) patients had number of positive cores > 3. Of 35 patients who subsequently underwent RP, seven (20%) had AP after RP and 17 (48.6%) showed GS upgrading. Of these 17 patients, the vast majority (16/17, 94.1%) had GS upgrading from 3 + 3 to 3 + 4. 45.1% of patients with an initial diagnosis of ASAP who had repeat prostate biopsy were subsequently diagnosed with PCa and 19.6% were found to have csPCa. Our findings add further evidence that after a diagnosis of ASAP, a repeat biopsy is warranted and that the repeat biopsy should not be postponed.

Perianal fistulizing diseases, namely perianal fistulas and/or abscesses, are well-known complications of Crohn's disease (CD). These are known to develop more frequently in Asian children with CD, especially in the early stages of the disease course. Approximately half of the pediatric CD cases in Korea present with perianal fistulizing diseases at diagnosis. We report a rare case of a 12-year-old boy with CD with an incidental discovery of a perianal abscess on pelvic magnetic resonance imaging during CD diagnosis. No symptoms or signs of perianal fistulizing disease were identified. The early diagnosis of the perianal abscess enabled timely and effective treatment. Considering the high incidence of concomitant perianal CD in Korean children at diagnosis, perianal imaging may be useful and should be considered during diagnostic evaluation, even in patients with no subjective or objective findings indicating perianal CD.

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.

Background/Aims: This study was performed to clarify inf luences of anticentromere antibody (ACA) on clinical phenotypes of primary Sjögren’s syndrome (pSS) patients in Korea. Methods: We assessed 318 patients who met the 2016 American College of Rheumatology/ European League Against Rheumatism classification criteria for pSS. All patients were selected from the Korean Initiative of primary Sjögren’s Syndrome (KISS), a prospective cohort. Among them, 53 patients were positive for ACA, while another 265 patients were not. We compared various clinical data including demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values available from the KISS database between the two groups. Results: Patients in the ACA-positive pSS group were older (p = 0.042), and had higher xerostomia inventory scores (p = 0.040), whereas glandular dysfunction represented with Schirmer I test was more severe in the ACA-negative group. More frequent Raynaud’s phenomenon and liver involvement (both p < 0.001) and less articular involvement (p = 0.037) were observed among the EGMs in the ACA-positive group. Less frequency of leukopenia (p = 0.021), rheumatoid factor (p < 0.001), anti-Ro/SSA antibody positivity (p < 0.001), and hypergammaglobulinemia (p = 0.006), as well as higher positivity rates of anti-nuclear antibody and anti- topoisomerase antibody (p < 0.001 and p = 0.006, respectively) were found in the laboratory data in the ACA-positive pSS group. Conclusions: Considering distinct phenotypes in hematological and serological features and EGMs, we should monitor the occurrence of these clinical features among pSS patients with ACA in caution.

Context The upregulation of TRIB3 (Tribbles homolog 3), a stress-inducible gene encoding a pseudokinase, has been implicated in the development of insulin resistance in the skeletal muscle and liver of patients with obesity and type 2 diabetes. However, there is little information regarding TRIB3 expression in human adipose tissue. Objective To investigate whether TRIB3 expression is dysregulated in human adipose tissue in the context of obesity and type 2 diabetes and whether TRIB3 expression in adipose tissues is associated with insulin resistance. Methods We measured metabolic parameters and TRIB3 expression in abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Regulation of TRIB3 expression was studied in human adipocytes. Results TRIB3 expression in both fat depots was higher in patients with obesity and/or type 2 diabetes; in addition, the expression level was significantly associated with insulin resistance. Incubating adipocytes under conditions mimicking the microenvironment of obese adipose tissue, including increased endoplasmic reticulum (ER) stress, induced TRIB3 expression. In human adipocytes, the overexpression of TRIB3 impaired insulin-stimulated protein kinase B (AKT) phosphorylation and caused dysregulation of the transcription of genes encoding bioactive molecules released from adipocytes, such as proinflammatory cytokines, adiponectin, and leptin. Pioglitazone, an insulin-sensitizing agent, reduced both these effects of TRIB3 and the ER stressor–induced expression of TRB3. Conclusion Our data indicate that TRIB3 expression in adipose tissue is enhanced in patients with obesity and suggest that increased TRIB3 dysregulates adipocyte function, which may contribute to the development of insulin resistance.

Objective More attempts have been made recently to improve psychosocial functioning and quality of life in patients with schizophrenia, due to their crucial role in long-term outcomes. Previous studies on the effects of clozapine on psychosocial functioning have been limited in terms of generalizability and application to clinical practice. This study examined the relationship of clozapine use with psychosocial functioning and quality of life in patients with schizophrenia in a real-world setting.Methods Data were obtained from a survey targeting community-dwelling patients with schizophrenia. The Behavior and Symptom Identification Scale (BASIS) and Satisfaction with Life Scale (SWLS) were administered to evaluate psychosocial functioning and quality of life, and patients were classified into Clozapine and Non-clozapine groups. Group differences were assessed using ANCOVA, with additional sensitivity analyses for participants on atypical antipsychotic medications only.Results Of 292 patients, the Clozapine group (n=34) had significantly better psychosocial functioning and quality of life than the Nonclozapine group (n=258), as demonstrated by their low BASIS score (F=4.651, df=1, 290, p=0.032) and high SWLS score (F=14.637, df=1, 290, p

Crohn’s disease (CD) presenting as gastric outlet obstruction is rare but serious clinical presentation of CD causing severe morbidity. However, there have been few case reports concerning this disorder in East Asian children and adolescents. The current case report describes 2 pediatric patients with CD who had had gastric outlet obstruction as an initial symptom of CD. Two pediatric patients developed postprandial vomiting, bloating, and unintentional weight loss. The upper endoscopy result indicated that there was pyloric obstruction with mucosal edema, inflammation and ulcers. The serologic test and colonoscopy results suggested CD. These patients were treated with infliximab, and endoscopic balloon dilation without surgery and showed remarkable improvement in obstructing symptoms with maintaining clinical and biochemical remission. This case report elucidates the benefits of early intervention using infliximab and endoscopic balloon dilation to improve gastric outlet obstruction and achieve baseline recovery in patients with upper gastrointestinal B2 phenotype of CD.

OBJECTIVE Although anterior compression factors and cervical alignment affect neural decompression, cervical laminoplasty may be used to achieve indirect posterior decompression. The focal apex (FA) angle of the anterior compression factor of the spine represents the degree of anterior prominence toward the spinal cord. The authors investigated the mechanism underlying the influence of FA angle and cervical alignment on spinal cord alignment (SCA) after laminoplasty, including how high-intensity signal cord change (HISCC) on preoperative T2-weighted MRI (T2-MRI) may affect neurological improvement. METHODS We performed a retrospective study of patients who underwent laminoplasty for CSM or OPLL at two hospitals (Kanto Rosai Hospital, Kawasaki City, and Yokohama Minami Kyousai Hospital, Yokohama City, Japan) between April 2004 and March 2015. In total, 109 patients (mean age 67.3 years) with cervical compression myelopathy were included. FA angle was defined as the preoperative angle between the lines from the top of the prominence to the upper and lower adjacent vertebrae. Preoperative cervical alignment was measured between the C2 and C7 vertebrae (C2–7 angle). MRI was used to classify SCA as lordosis (type-L SCA), straight (type-S), local kyphosis (type-LK), or kyphosis (type-K). Preoperative HISCC was investigated by using T2-MRI. Neurological status was evaluated by using the Japanese Orthopaedic Association score. RESULTS The mean preoperative FA and C2–7 angles were 32.1° and 12.4°, respectively. Preoperative SCA was type-L or type-S in 53 patients. The neurological recovery rate (NRR) was significantly higher for patients with preoperative type-L and type-S SCA (51.4% for those with type-L and 45.0% for those with type-S) than for patients with other types (35.3% for those with type-LK and 31.7% for those with type-K). Among patients with preoperative type-L or type-S SCA, 87.3% maintained SCA; however, 5/12 (41.7%) patients with a preoperative average C2–7 angle < 12.4° and an average FA angle > 32.1° had postoperative type-LK or type-K SCA. SCA changed to type-L or type-S in 13.0% of patients with preoperative type-LK or type-K SCA. Moreover, in these patients, FA angle was significantly smaller and NRR was significantly higher than in other patients in whom postoperative SCA remained type-LK or type-K. Preoperative T2-MRI showed 73 patients with HISCC (43 with type-L and type-S, and 30 with type-LK and type-K SCA) and 36 without HISCC (20 with type-L and type-S, and 16 with type-LK and type-K SCA); the NRRs of these patients were 42.6% and 41.2%, respectively. No significant differences in SCA or NRR were observed between patients with and without HISCC. CONCLUSIONS NRR depends on preoperative SCA type; however, it is possible to change the type of SCA after laminoplasty. Preoperative FA and C2–7 angles influence change in SCA; therefore, they are important parameters for successful decompression with cervical laminoplasty.

Although patients with cirrhosis are known to be in a state of “rebalance” in that pro- and anticoagulant factors increase the risk for both bleeding and thrombosis, the prevalence of portal vein thrombosis (PVT) in patients with cirrhosis can be up to 26%. Therefore, physicians should consider anticoagulation for the prevention and management of PVT in patients with cirrhosis who are at high risk of PVT. Vitamin K antagonist or low molecular weight heparin is suggested as the standard treatment for PVT in cirrhosis. With the advent of new direct-acting oral anticoagulants (DOACs), there is a paradigm shift of switching to DOACs for the treatment of PVT in patients with cirrhosis. However, the safety and efficacy of DOACs in the treatment of PVT was not well-known in patients with cirrhosis. Therefore, this review focused on the current knowledge about the efficacy, safety concerns, and hepatic metabolism of DOACs in patients with cirrhosis and PVT.

The purpose of this study was to evaluate whether bicuspid anatomy affects the discrepancy between CT-derived annular size and intraoperative size. We retrospectively analyzed annular measurements in 667 patients who underwent surgical aortic valve replacement (AVR). Preoperative CT measurements of the aortic annulus were compared to surgically implanted valve sizes. To evaluate whether the bicuspid valve affects the differences between CT annulus diameter and surgical AVR size, patients with diameter larger by > 10% (CT-Lg group) on CT, compared to surgical AVR size, were compared with those having size difference p p p p

Background We aimed to investigate the effect of epidural polydeoxyribonucleotide (PDRN) on mechanical allodynia and motor dysfunction in a rat model of lumbar foraminal stenosis (LFS). Methods This study was conducted in two stages, using male Sprague-Dawley rats. The rats were randomly divided into eight groups. In the first stage, the groups were as follows: vehicle (V), sham (S), and epidural PDRN at 5 (P5), 8 (P8), and 10 (P10) mg/kg; and in the second stage, they were as follows: intraperitoneal PDRN 8 mg/kg, epidural 3,7-dimethyl-1-propargilxanthine (DMPX) (0.1 mg/kg), and DMPX (0.1 mg/kg). The LFS model was established, except for the S group. After an epidural injection of the test solutions, von Frey and treadmill tests were conducted for 3 weeks. Subsequently, histopathologic examinations were conducted in the V, S, P5, and P10 groups. Results A total of 65 rats were included. The P8 and P10 groups showed significant recovery from mechanical allodynia and motor dysfunction at all time points after drug administration compared to the V group. These effects were abolished by concomitant administration of DMPX. On histopathological examination, no epineurial inflammation or fibrosis was observed in the epidural PDRN groups. Conclusions Epidural injection of PDRN significantly improves mechanical allodynia and motor dysfunction in a rat model of LFS, which is mediated by the spinal adenosine A2A receptor. The present data support the need for further research to determine the role of epidural PDRN in spinal stenosis treatment.

Introduction Maintaining mineral homeostasis as well as the secretion and metabolism of mineralotropic hormones is important for healthy of periparturient dairy cows. To increase the activity of mineralotropic hormones, blood pH can be adjusted. The purpose of this study was to investigate changes in blood pH and the mechanism of action of this change in induced hypercalcaemic cows. Material and Methods Six non-lactating Holstein cows were used in a 2 × 2 crossover design. To induce hypercalcaemia, calcium borogluconate was administered subcutaneously to experimental cows and normal saline was administered subcutaneously to control cows. Blood and urine samples were collected serially after administration. Whole blood without any anticoagulant was processed with a portable blood gas analyser. Plasma concentration and urinary excretion of calcium were measured. Results In hypercalcaemic cows, both blood and urine calcium levels were significantly increased at 8 h compared to those at 0 h (P < 0.05), and a spontaneous increase in blood pH was also observed. The calcium concentration in plasma was highest at 2 h after administration (3.02 ± 0.27 mmol/L). The change in pH correlated with that in bicarbonate (r = 0.781, P < 0.001) rather than that in partial pressure of CO2 (r = 0.085, P = 0.424). Conclusion Hypercalcaemia induced a spontaneous change in blood pH through the bicarbonate buffer system and this system may be a maintainer of calcium homeostasis.

Background/Aims: Because hepatitis B virus (HBV) replication has been known to play an important role in cancer recurrence after curative treatment of HBV-related hepatocellular carcinoma (HCC), we examined whether treatment based on nucleos(t)ide analogues (NAs) might decrease the recurrence rate and improve patient survival. Methods: The retrospective cohort study enrolled 73 patients with chronic hepatitis B who were treated with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) with curative intent for HCC. Among those, 30 and 43 patients were treated with tenofovir disoproxil fumarate (TDF) and entecavir (ETV), respectively. Results: Of the 73 patients, 51 experienced HCC recurrence, and 14 patients were dead during a follow-up of 73±34 months. Multivariate analyses showed that tumor size (hazard ratio [HR], 1.590; 95% confidence-interval [CI], 1.106-2.285; P=0.012) and Child-Pugh class B (vs. class A/non cirrhosis; HR, 5.794; 95% CI, 2.311-14.523; P=0.001) was significantly associated with HCC recurrence, and Child-Pugh class B (HR, 7.357; 95% CI, 2.100-25.777; P=0.002) was an independent unfavorable prognostic factor for survival. During NAs therapy, TDF was superior to ETV for complete viral response at 1 year after the date of combination of TACE and RFA (P=0.016). However, the risks of HCC recurrence and survival were not significantly different between those treated with TDF versus ETV. Conclusions: TDF was superior to ETV for achieving complete viral response. However, the recurrence and mortality after TACE and RFA for HBV-related HCC were not significantly different between patients treated with TDF versus ETV. (J Liver Cancer 2021;21:155-162)

A 60-year-old man diagnosed with unresectable hepatocellular carcinoma (HCC) presented to the hospital with pain in the perineal region. He had been taking lenvatinib every day for 2 months after he was diagnosed with HCC with metastases to the lymph node, small bowel mesentery, and retroperitoneal space. Enhanced abdominal computed tomography revealed mild elevation in intensity in the perineal subcutaneous tissue with subcutaneous emphysema. The patient was diagnosed with Common Terminology Criteria for Adverse Events grade 3, skin ulceration of stage IV with full-thickness skin loss and tissue necrosis in the muscular layer. The patient was taken off the medication with prescription of antibiotics, and after 3 weeks, the skin has fully recovered. This is the first report of an HCC patient who presented with a skin ulceration of stage IV after lenvatinib treatment. We recommend stopping the medication immediately and changing to alternative treatments with appropriate supportive care.

Purpose: To investigate the limited response to aflibercept after switching to aflibercept in neovascular age-related macular degeneration (AMD). Methods: This retrospective study included 70 eyes with neovascular AMD that were initially treated with ranibizumab and then switched to aflibercept. The incidence and timing of the limited response to aflibercept were identified and visual outcome was compared between eyes with and without limited response. In addition, factors predictive of limited response were analyzed. Results: A limited response to aflibercept was noted in approximately 1/5 of the patients who underwent switching to aflibercept in neovascular AMD. Switching to aflibercept was performed at a mean of 16.2 ± 12.7 months after diagnosis. During the mean 34.7 months of follow-up after switching, limited response was noted in 15 eyes (21.4%) at a mean of 22.0 ± 13.9 months after switching. The degree of reduction in visual acuity was mean logMAR 0.34 ± 0.41 in eyes with limited response and mean 0.06 ± 0.20 in eyes without (p = 0.002). In addition, the duration between the diagnosis and the switching was shorter (p = 0.012), and the number of ranibizumab injections before switching was lower (p = 0.016) in eyes with limited response than in eyes without. Conclusions: Patients who showed limited response to aflibercept after switching to aflibercept showed a worse visual outcome. The probability of having a limited response is higher when the switching is performed earlier.

We present a case of rapidly growing disseminated Mycobacterium tuberculosis (MTB) that presented as an empyema necessitans (EN) in a 65-year-old woman with a single right lung transplant admitted for progressive dyspnea. While hospitalized, she had daily fevers and was found to have a right-sided chest wall abscess and pleural effusion. Acid-fast bacilli cultures from the abscess and pleural fluid grew MTB within 4 and 6 days, respectively. Blood cultures later grew MTB as well. Upon initiation of rifampin, isoniazid, pyrazinamide, and ethambutol, she developed hemorrhagic pancreatitis and distributive shock secondary to antituberculosis medications and disseminated MTB. Noteworthy features of this case include the rapid rate of MTB culture growth in less than a week, the development of a likely donor-derived MTB EN, and the clinical challenges of MTB screening and MTB infection management in a solid organ transplant recipient.

Doxorubicin is one of the most effective agents used to treat various cancers, including breast cancer, but its usage is limited by the risk of adverse effects, including cardiotoxicity. Melatonin, a natural hormone that functions as a major regulator of circadian rhythms, has been considered a supplemental component for doxorubicin due to its potential to improve its effectiveness. However, the mechanisms and biological targets of the combination of melatonin and doxorubicin with respect to cancer cell death are not well understood. In the present study, we found that melatonin synergized with doxorubicin to induce apoptosis of breast cancer cells by decreasing the expression of AMP-activated protein kinase α1 (AMPK α1), which acts as a critical survival factor for cancer cells. This cotreatment-induced reduction in AMPKα1 expression occurred at the transcriptional level via an autophagy-dependent mechanism. The synergistic effects of the combined treatment were evident in many other cancer cell lines, and melatonin was also highly effective in inducing cancer death when combined with other cancer drugs, including cisplatin, 5-fluorouracil, irinotecan, and sorafenib. AMPKα1 expression was decreased in all of these cases, suggesting that reducing AMPKα1 can be considered an effective method to increase the sensitivity of cancer cells to doxorubicin treatment., Breast cancer: Melatonin could boost efficacy of chemotherapy Combining the chemotherapy drug doxorubicin with the natural hormone melatonin reduces levels of a key enzyme and boosts treatment efficacy. Doxorubicin is a valuable treatment option for breast cancer but can have toxic side effects. Recent research suggests that taking melatonin in combination with chemotherapy drugs can increase treatment efficacy, but the underlying mechanisms are unclear. Joohun Ha at Kyung Hee University in Seoul, South Korea, and co-workers examined the effects of combining doxorubicin with melatonin on multiple breast cancer cell lines. They found that the synergistic activity of doxorubicin and melatonin reduced AMP-activated protein kinase (AMPK α1) levels in breast cancer cells. AMPKα1 is involved in cellular energy metabolism, and is known to promote cancer cell survival. By reducing AMPKα1 levels, the melatonin increased cancer cell sensitivity to doxorubicin, leading to cancer cell death.

Serum neurofilament light chain (NfL) levels are associated with disease severity in early Parkinson's disease (PD). We assessed the association of serum NfL with motor and cognitive function and decline in advanced PD patients.NfL concentrations were analyzed with single molecule array (Simoa) assay in serum of 289 PD patients with advanced disease from the single-center prospective observational biobank study Biomarkers in Parkinson's disease (MARK-PD). Motor and cognitive symptoms were assessed with MDS-UPDRS III, HoehnYahr stages and Montreal Cognitive Assessment (MoCA) at baseline and during 520 [364, 674] days of follow-up.Serum NfL concentrations were associated with HoehnYahr stages. During follow-up, baseline NfL levels were associated with time to cognitive decline in adjusted Cox regression models (hazard ratio: 3.23; 95% CI [1.16, 9.00], P 0.025). Serum NfL was associated with NT-proBNP in adjusted models linking neuronal and cardiac damage in advanced PD patients.In advanced PD patients, serum NfL concentrations are associated with motor function, cognitive decline and subclinical cardiac damage.

Objectives: To compare night-time muscle activity in children with cerebral palsy (CP) with that in typical developing peers. Methods: Polysomnography with electroencephalography (EEG), electrocardiogram, electromyography (EMG), respiration, and electrooculography movements recorded during one night were used to characterize sleep stages in a group of children with CP (Gross Motor Function Classification Scale I–III) and a group of typically developing (TD) children (aged 3–13 years). Periods of EMG activity for the tibialis anterior and soleus (SOL) muscles were identified, and the coherence between EEG and EMG was measured to assess corticomuscular drive during sleep. Results: There were no significant differences between the groups in total sleep time, average time spent awake, or rapid eye movement, N1, and N3 sleep. Children with CP spent significantly less time in N2 than their healthy peers (43% vs. 51%, p=0.03). There was only a significant difference between TD and CP in SOL muscle activity during the wake stage. Otherwise, there were no differences between groups in coherence in EEG and EMG signals for any sleep stage. Conclusion: Mildly affected children with CP do not show altered night sleep or muscle activity patterns as compared to TD peers. Abnormal muscle activity is unlikely to contribute to sleep disturbance, development of contractures, joint deformation, pain, or general discomfort in this group of children with CP.

Although the long-term use of topical glucocorticoids (TGC) may induce skin atrophy including striae distensae (SD), patients with atopic dermatitis (AD) appear to have lesser degree of skin atrophy than those with psoriasis (PSO). Periostin, encoded by POSTN, is involved in tissue remodelling processes of chronic AD lesions. This study was designed to investigate the difference in the occurrence of skin atrophy in patients with AD or PSO when treated with TGC and to elucidate the association between skin atrophy and periostin. Big data analysis using Korean Health Claims Database was performed to determine the prevalence of SD in AD and PSO patients. Blood and skin eosinophils count and dermal fibrosis between AD and PSO patients were compared, and immunohistochemistry for periostin and mRNA sequencing in the dermis were performed. Animal experiments using AD and PSO murine model were conducted. Big data analysis revealed that patients with AD have significantly lesser degree of SD than patients with PSO. The ratio of the dermal fibrous tissues and eosinophil counts were significantly higher in AD patients. In AD skin, periostin was more widely distributed in the entire dermis and POSTN mRNAs were significantly upregulated. Dermal thickness and fibrosis were significantly higher in AD mice even after TGC treatment. A significant positive correlation was observed between dermal fibrosis and tissue eosinophil counts. Lesser skin atrophy in AD patients even after long-term TGC application could be resulted from skin fibrosis caused by increased tissue eosinophils and periostin deposition.

Background: Giant lip hemangioma is a rare disease that may cause difficulty in preoxygenation and ventilation when using face masks and intubation during general anesthesia induction.Case: A laparoscopic cholecystectomy was planned for a 77-year-old woman. The patient had a giant lower lip hemangioma that was 12 x 5 x 5 cm, which made preoxygenation and ventilation through a face mask impossible and put her at risk of hemangioma rupture. We preoxygenated her through a high-flow nasal cannula (HFNC). Following propofol and succinylcholine administration, we intubated the patient with a video laryngoscope without desaturation, hemangioma rupture, or CO2 retention. Conclusions: HFNC is a useful tool when difficult intubation is expected in patients who have problems using conventional face masks.

Chronic starvation and refeeding have been associated with liver injury (LI). We present a patient with anorexia nervosa who exhibited both phenomena of malnutrition-related LI. At presentation, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were elevated at 154 and 136 U/L, respectively, and rose rapidly to peaks of 750 and 638 U/L, respectively, as nutrition was introduced. Mechanisms of starvation-related LI include impaired degradation and secretion of lipids, as well as starvation-induced autophagy. LI during refeeding may be related to rapid increase in glucose availability. These phenomena are crucial to consider in patients with chronic starvation undergoing refeeding.

Background Postoperative pain control after the minimally invasive repair of pectus excavatum (MIRPE) is essential, but there is a controversy about a better analgesic method between epidural and intravenous (IV) analgesia. This systematic review and meta-analysis aimed to compare the effect of epidural versus IV analgesia following MIRPE. Methods We searched PubMed, MEDLINE, EMBASE, Cochrane Central Register, and ClinicalTrials.gov for randomized control trials (RCTs) dated up to 31st May 2021. The primary outcome was the area under the curve (AUC) of the weighted mean visual analog scale (VAS) after MIRPE. The secondary outcomes were postoperative nausea, operation time, total operating room time, and postoperative length of hospital stay. Results Four RCTs involving 243 patients were finally included in this meta-analysis. The AUC of the weighted mean VAS was 343.62 in the epidural group and 375.24 in IV group. Epidural group showed lower VAS than IV group at 12 hours (mean difference -0.99 [95% CI: -1.52, -0.47], P = 0.001, I2 = 0%), at 24 hours (mean difference -0.65 [95% CI: -1.15, -0.16], P = 0.009, I2 = 0%), and 48 hours (mean difference -0.81 [95% CI: -1.61, -0.01], P = 0.046, I2 = 46%) after the surgery. Conclusion Epidural analgesia after the MIRPE had a better analgesic effect than IV analgesia from 12 hours to 48 hours after surgery, and AUC of VAS was lower in the epidural group. However, IV analgesia may also be a viable option, and physicians should wisely choose analgesic modalities after MIRPE.

Background/Aims Anti-drug antibodies (ADAs) can develop during treatment with anti-tumor necrosis factor (TNF) agents. We aimed to investigate the factors associated with immunogenicity of anti-TNF agents in pediatric patients with inflammatory bowel disease (IBD) and observe the clinical course of ADA-positive patients. Methods Pediatric IBD patients receiving maintenance treatment with anti-TNF agents who had been tested for ADAs against infliximab (IFX) or adalimumab (ADL) were included in this cross-sectional study. Factors associated with ADA positivity were investigated by analyzing clinicodemographic, laboratory, and treatment-related factors. Results A total of 76 patients (Crohn’s disease, 65; ulcerative colitis, 11) were included. Among these, 59 and 17 patients were receiving IFX and ADL, respectively. ADAs were found in 10 patients (13.2%), all of whom were receiving IFX. According to multivariable logistic regression analysis, the IFX trough level (TL) was associated with ADA positivity (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.51; p=0.002). According to the receiver operating characteristic analysis, the optimal cutoff of the IFX TLs for stratifying patients based on the presence of ADAs against IFX was 1.88 μg/mL (area under curve, 0.941; 95% CI, 0.873 to 1.000; sensitivity, 80.0%; specificity, 95.9%; p

Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Patients and Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2–40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8–6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

Aim: This study aimed to evaluate the 2-year outcomes from a clinical trial of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Patients & methods: Sixty-four patients with nontraumatic, precollapse and large ONFHs were percutaneously administered with 800 μg rhFGF-2 contained in gelatin hydrogel. Setting the end point of radiological collapse, we analyzed the joint preservation period of the historical control. Changes in two validated clinical scores, bone regeneration and safety were evaluated. Results: Radiological joint preservation time was significantly higher in the rhFGF-2 group than in the control group. The ONFHs tended to improve to smaller ONFHs. The postoperative clinical scores significantly improved. Thirteen serious adverse events showed recovery. Conclusion: rhFGF-2 treatment increases joint preservation time with clinical efficacy, radiological bone regeneration and safety.

While carpal tunnel syndrome (CTS) is the most common entrapment neuropathy affecting the wrist, resulting in substantial physical, psychological, and economic effects, there is no gold standard therapy for CTS. In this case series study, we aimed to report CTS patients treated with Carthami Semen Pharmacopuncture (CSP) and electroacupuncture (EA) showing improvements in their symptoms, and the combinatorial effects of CSP and EA. We collected medical records of CTS outpatients who received CSP and EA at Chuk-u Acupuncture & Moxibustion Korean Medicine Clinic from August 2017 to September 2018. The outcome measures were the visual analog scale (VAS) for pain, paresthesia, the Korean version of the Boston carpal tunnel questionnaire (K-BCTQ) score, and changes in nocturnal pain, Tinel sign, and Phalen’s test. We included patient satisfaction at the completion of all treatments. 17 patients were included for this case series study. After treatment, VAS for pain decreased significantly from 50.41 ± 16.19 to 9.59 ± 9.46, VAS for paresthesia also decreased significantly from 63.50 ± 11.49 to 14.75 ± 12.97, and K-BCTQ symptom severity scale decreased from 2.48 ± 0.68 to 1.89 ± 0.70 (all p < 0.001). Nocturnal pain, Tinel signs, and Phalen’s test showed improvements after all the treatments. All the patients reported favorable overall satisfaction with the treatments, and 69.23% wanted future pharmacopuncture treatments if CTS recurred. No complications were detected. The combination of CSP and EA could be an effective and safe option in treating CTS.