Excessively Delayed Radiation Changes After Proton Beam Therapy for Brain Tumors: Report of Two Cases.

Delayed cerebral necrosis is a well-known complication of radiation therapy (RT). Because of its irreversible nature, it should be avoided if possible, but avoidance occurs at the expense of potentially compromised tumor control, despite the use of the modern advanced technique of conformal RT that minimizes radiation to normal brain tissue. Risk factors for radiation-induced cerebral necrosis include a higher dose per fraction, larger treatment volume, higher cumulative dose, and shorter time interval (for re-irradiation). The same principle can be applied to proton beam therapy (PBT) to avoid delayed cerebral necrosis. However, conversion of PBT radiation energy into conventional RT is still short of clinical support, compared to conventional RT. Herein, we describe two patients with excessively delayed cerebral necrosis after PBT, in whom follow-up MRI showed no RT-induced changes prior to 3 years after treatment. One patient developed radiation necrosis at 4 years after PBT to the resection cavity of an astroblastoma, and the other developed brainstem necrosis that became symptomatic 6 months after its first appearance on the 3-year follow-up brain MRI. We also discuss possible differences between radiation changes after PBT versus conventional RT.

Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells.

Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood. Here, we confirm, in 36 patients with NSCLC-LM, that elevated miR-21 expression prior to treatment correlates with poor prognosis. MiR-21 overexpression or sponging results in a corresponding increase or decrease in MTX resistance, demonstrating that cellular miR-21 expression correlates with drug resistance. MiR-21-monitoring sensor and fluorescent extracellular vesicle (EV) staining revealed that EV-mediated delivery of miR-21 could modulate MTX resistance. Moreover, EVs isolated from the CSF of LM patients containing miR-21 could enhance the cell proliferation and MTX resistance of recipient cells. These results indicate that miR-21 can be transferred from cell-to-cell via EVs and potentially modulate MTX sensitivity, suggesting that miR-21 in CSF EVs may be a prognostic and therapeutic target for overcoming MTX resistance in patients with NSCLC-LM.

Spontaneous Regression of Glioma-Mimicking Brainstem Lesion in a Child: A Case Report.

Differential diagnosis of focal brainstem lesions detected on MRI is challenging, especially in young children. Formerly, brainstem gliomas were classified mainly based on MRI features and location. However, since 2016, the World Health Organization's brainstem lesion classification requires tissue biopsy to reveal molecular characteristics. Although modern techniques of stereotactic or navigation-guided biopsy ensure accurate biopsy of the lesion with safety, biopsy of brainstem lesions is still generally not performed. Here, we report a focal brainstem lesion mimicking brainstem glioma in a 9-year-old girl. Initial MRI, MR spectroscopy, and 11C-methionine positron emission tomography (PET) features suggested low-grade glioma or diffuse intrinsic pontine glioma. However, repeated MR spectroscopy, perfusion MRI, and 18fluorodeoxyglucose PET findings suggested that it was more likely a non-tumorous lesion. As the patient presented not with a neurological manifestation but with precocious puberty, the attending oncologist chose to observe with regular follow-up MRI. The pontine lesion with high signal intensity on T2-weighted MRI regressed from the 6-month follow-up and became invisible on the 1.5-year follow-up MRI. We reviewed brainstem glioma-mimicking lesions in the literature and discussed the key points of differential diagnosis.

The efficacy of slow-rate ventriculolumbar perfusion chemotherapy for leptomeningeal carcinomatosis: a phase II study.

PURPOSE: This study aimed to evaluate the symptomatic response and side effects of ventriculolumbar perfusion (VLP) methotrexate chemotherapy with a low perfusion rate in patients with leptomeningeal metastasis. METHODS: Patients in a single-arm, two-stage phase II trial based on Simon's minimax design received VLP with a reduced (15 cc/h) perfusion rate with the purpose of decreasing constitutional side effects such as nausea/vomiting, insomnia, and confusion. The primary outcome was control of increased intracranial pressure (ICP). The secondary outcome was an occurrence of side effects. The results were compared with those of a previous trial of VLP with a 20-cc/h perfusion rate. RESULTS: Total 90 patients were enrolled. Out of 65 patients with increased ICP, 32 achieved normalized ICP after VLP chemotherapy (bias-adjusted response rate = 51%). The incidence of moderate-to-severe nausea/vomiting was reduced to 46% from 64% in the previous study, and that of sleep disturbance was increased to 13% from 9%, but both failed to reach statistical significance. The incidence of moderate-to-severe confusion was significantly reduced to 12% from 23% in the previous study (p = 0.04). Median overall survival was better among patients with controlled ICP than among those who remained with increased ICP (193 days vs. 94 days, p = 0.013). CONCLUSION: Compared with a higher perfusion rate, the low perfusion rate failed to provide non-inferior ICP control or improved side effects, except for confusion. The relationship between VLP perfusion rate and ICP control needs to be evaluated in future trials adjusting for bias from uncompleted protocol due to poor general condition.

Disseminating Necrotizing Leukoencephalopathy Associated With Intra-CSF Methotrexate Chemotherapy: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVES: Leptomeningeal metastases (LMs) are neoplasms that proliferate to membranes lining the brain and spinal cord. Intra-CSF methotrexate (MTX) chemotherapy is a prevalent treatment option. However, resultant long-term neurotoxicity can lead to irreversible disseminated necrotizing leukoencephalopathy (DNL). This study aims to determine the incidence, characteristics, risk factors, and outcomes of DNL following intra-CSF MTX chemotherapy for LM. METHODS: We retrospectively reviewed patients with LM who received intra-CSF MTX between 2001 and 2021 at the National Cancer Center of Korea. Patients with a follow-up duration of <3 months and those without follow-up MRI after MTX administration were excluded. The primary outcome was the development of DNL, evaluated based on the clinical and radiologic definitions of DNL. Logistic and Cox proportional regression models were used to assess the risk of DNL in patients with LM receiving intra-CSF MTX chemotherapy. RESULTS: Of the 577 patients included in the DNL investigation, 13 (2.3%) were identified to have irreversible DNL. The MRI features of DNL typically include necrotic changes in the bilateral anterior temporal region, extensive white matter, and/or brainstem lesions. All patients with DNL experienced fatal clinical course despite MTX cessation. Logistic regression analysis revealed that a cumulative dose of MTX significantly affected DNL occurrence. Multivariable analysis showed that the factor of ≥10 MTX rounds was significant for DNL development after adjusting for route of MTX administration and prior brain radiotherapy (odds ratio 7.32, 95% CI 1.42-37.77 at MTX rounds ≥10 vs < 10). In the Cox proportional hazards model considering time to occurrence of DNL, ≥10 rounds of MTX were identified as an independent predictor of DNL (hazard ratio 12.57, 95% CI 1.62-97.28, p = 0.015), even after adjusting for the synergistic effect of brain radiotherapy. DISCUSSION: DNL is a rare but fatal complication of intra-CSF MTX chemotherapy, and its progression cannot be prevented despite early recognition. The cumulative dose of intra-CSF MTX was an independent risk factor for DNL occurrence. Thus, intra-CSF MTX treatment for patients with LM should be administered with caution considering the possibility of the cumulative irreversible neurotoxicity.

Integrated proteogenomic characterization of glioblastoma evolution.

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.

Presenteeism and social interaction in the "new normal" in Japan: a longitudinal questionnaire study

BACKGROUND@#Although social interaction and social support during the "new normal" due to coronavirus disease 2019 (COVID-19) may be related to presenteeism, the effect between these factors has not been clear for Japanese workers. The aim of this study was to describe the presenteeism of Japanese workers with reference to social interaction and social support following the lifestyle changes due to COVID-19 and to assess whether social interaction and social support affected their presenteeism.@*METHODS@#The data were obtained from internet panel surveys from October 2020. Descriptive statistics were calculated, and multiple linear regression was conducted using the data from the first, fourth and fifth surveys, which were conducted during October to November 2020, July to August 2021, and September to October 2021, respectively. To measure presenteeism, questions from "absenteeism and presenteeism questions of the World Health Organization's Heath and Work Performance Questionnaire", short version in Japanese was utilized. Multiple linear regressions were conducted to investigate the effects of social interaction and social support-related factors on presenteeism.@*RESULTS@#A total of 3,407 participants were included in the analysis. The mean score of absolute presenteeism from the fifth survey was 58.07 (SD = 19.71). More time spent talking with family, a larger number of social supporters and a higher satisfaction level for social support were associated with a higher absolute presenteeism score.@*CONCLUSIONS@#Our results suggested that social support reduced the presenteeism of the Japanese workers during the "new normal" due to the COVID-19 pandemic. Social interaction with family also relieved presenteeism.

Clinical Safety and Efficiency of the H-Port for Treatment of Leptomeningeal Metastasis.

Objective: To evaluate the usefulness of a cranial implantable chemoport, the H-port, as an alternative to the Ommaya reservoir for intraventricular chemotherapy/cerebrospinal fluid (CSF) access in patients with leptomeningeal metastasis (LM). Methods: One hundred fifty-two consecutive patients with a diagnosis of LM and who underwent H-port installation between 2015 and 2021 were evaluated. Adverse events associated with installation and intraventricular chemotherapy, and the rate of increased intracranial pressure (ICP) control via the port were evaluated for safety and efficacy. These indices were compared with published data of Ommaya (n=89), from our institution. Results: Time-to-install and installation-related complications of intracranial hemorrhage (n=2) and catheter malposition (n=5) were not significantly different between the two groups. Intraventricular chemotherapy-related complications of CSF leakage occurred more frequently in the Ommaya than in the H-port group (13/89 vs. 3/152, respectively, p<0.001). Intracranial hemorrhage during chemotherapy occurred only in the Ommaya group (n=4). The CSF infection rate was not statistically different between groups (14/152 vs. 12/89, respectively). The ICP control rate according to reservoir type revealed a significantly higher ICP control rate with the H-port (40/67), compared with the Ommaya result (12/58, p<0.001). Analyzing the ICP control rate based on the CSF drainage method, continuous extraventricular drainage (implemented only with the H-port), found a significantly higher ICP control rate than with intermittent CSF drainage (33/40 vs. 6/56, respectively, p<0.0001). Conclusion: The H-port for intraventricular chemotherapy in patients with LM was superior for ICP control; it had equal or lower complication rates than the Ommaya reservoir.

Cross-talk between PARN and EGFR-STAT3 Signaling Facilitates Self-Renewal and Proliferation of Glioblastoma Stem Cells.

Glioblastoma is the most common type of malignant primary brain tumor and displays highly aggressive and heterogeneous phenotypes. The transcription factor STAT3 has been reported to play a key role in glioblastoma malignancy. Thus, discovering targets and functional downstream networks regulated by STAT3 that govern glioblastoma pathogenesis may lead to improved treatment strategies. In this study, we identified that poly(A)-specific ribonuclease (PARN), a key modulator of RNA metabolism, activates EGFR-STAT3 signaling to support glioblastoma stem cells (GSC). Functional integrative analysis of STAT3 found PARN as the top-scoring transcriptional target involved in RNA processing in patients with glioblastoma, and PARN expression was strongly correlated with poor patient survival and elevated malignancy. PARN positively regulated self-renewal and proliferation of GSCs through its 3'-5' exoribonuclease activity. EGFR was identified as a clinically relevant target of PARN in GSCs. PARN positively modulated EGFR by negatively regulating the EGFR-targeting miRNA miR-7, and increased EGFR expression created a positive feedback loop to increase STAT3 activation. PARN depletion in GSCs reduced infiltration and prolonged survival in orthotopic brain tumor xenografts; similar results were observed using siRNA nanocapsule-mediated PARN targeting. Pharmacological targeting of STAT3 also confirmed PARN regulation by STAT3 signaling. In sum, these results suggest that a STAT3-PARN regulatory network plays a pivotal role in tumor progression and thus may represent a target for glioblastoma therapeutics. SIGNIFICANCE: A positive feedback loop comprising PARN and EGFR-STAT3 signaling supports self-renewal and proliferation of glioblastoma stem cells to drive tumor progression and can be targeted in glioblastoma therapeutics.

A Miniaturized Tri-Band Implantable Antenna for ISM/WMTS/Lower UWB/Wi-Fi Frequencies.

This study aims to design a compact antenna structure suitable for implantable devices, with a broad frequency range covering various bands such as the Industrial Scientific and Medical band (868-868.6 MHz, 902-928 MHz, 5.725-5.875 GHz), the Wireless Medical Telemetry Service (WMTS) band, a subset of the unlicensed 3.5-4.5 GHz ultra-wideband (UWB) that is free of interference, and various Wi-Fi spectra (3.6 GHz, 4.9 GHz, 5 GHz, 5.9 GHz, 6 GHz). The antenna supports both low and high frequencies for efficient data transfer and is compatible with various communication technologies. The antenna features an asynchronous-meandered radiator, a parasitic patch, and an open-ended square ring-shaped ground plane. The antenna is deployed deep inside the muscle layer of a rectangular phantom below the skin and fat layer at a depth of 7 mm for numerical simulation. Furthermore, the antenna is deployed in a cylindrical phantom and bent to check the suitability for different organs. A prototype of the antenna is created, and its reflection coefficient and radiation patterns are measured in fresh pork tissue. The proposed antenna is considered a suitable candidate for implantable technology compared to other designs reported in the literature. It can be observed that the proposed antenna in this study has the smallest volume (75 mm3) and widest bandwidth (181.8% for 0.86 GHz, 9.58% for 1.43 GHz, and 285.7% for the UWB subset and Wi-Fi). It also has the highest gain (-26 dBi for ISM, -14 dBi for WMTS, and -14.2 dBi for UWB subset and Wi-Fi) compared to other antennas in the literature. In addition, the SAR values for the proposed antenna are well below the safety limits prescribed by IEEE Std C95.1-1999, with SAR values of 0.409 W/Kg for 0.8 GHz, 0.534 W/Kg for 1.43 GHz, 0.529 W/Kg for 3.5 GHz, and 0.665 W/Kg for 5.5 GHz when the applied input power is 10 mW. Overall, the proposed antenna in this study demonstrates superior performance compared to existing tri-band implantable antennas in terms of size, bandwidth, gain, and SAR values.

Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.

Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

Molecular Biology of Brain Metastases.

Brain metastases (BMs) often occur in patients with lung cancer, breast cancer, and melanoma and are the leading cause of morbidity and mortality. The incidence of BM has increased with advanced neuroimaging and prolonged overall survival of cancer patients. With the advancement of local treatment modalities, including stereotactic radiosurgery and navigation-guided microsurgery, BM can be controlled long-term, even in cases with multiple lesions. However, radiation/chemotherapeutic agents are also toxic to the brain, usually irreversibly and cumulatively, and it remains difficult to completely cure BM. Thus, we must understand the molecular events that begin and sustain BM to develop effective targeted therapies and tools to prevent local and distant treatment failure. BM most often spreads hematogenously, and the blood-brain barrier (BBB) presents the first hurdle for disseminated tumor cells (DTCs) entering the brain parenchyma. Nevertheless, how the DTCs cross the BBB and settle on relatively infertile central nervous system tissue remains unknown. Even after successfully taking up residence in the brain, the unique tumor microenvironment is marked by restricted aerobic glycolysis metabolism and limited lymphocyte infiltration. Brain organotropism, certain phenotype of primary cancers that favors brain metastasis, may result from somatic mutation or epigenetic modulation. Recent studies revealed that exosome secretion from primary cancer or over-expression of proteolytic enzymes can "pre-condition" brain vasculoendothelial cells. The concept of the "metastatic niche," where resident DTCs remain dormant and protected from systemic chemotherapy and antigen exposure before proliferation, is supported by clinical observation of BM in patients clearing systemic cancer and experimental evidence of the interaction between cancer cells and tumor-infiltrating lymphocytes. This review examines extant research on the metastatic cascade of BM through the molecular events that create and sustain BM to reveal clues that can assist the development of effective targeted therapies that treat established BMs and prevent BM recurrence.

Ludicidade e idosas: uma análise de princípios na prática pedagógica com institucionalizadas / Ludic activities and the elderly: an analysis of principles in the pedagogical practice with institutionalized individuals

Este trabalho analisou contribuições teórico-metodológicas da ludicidade com idosas institucionalizadas. Para isso, contou com a Hermenêutica-Dialética como método, que busca na compreensão de falas, texto e contexto, a concepção dos fenômenos estudados, os quais foram evidenciados pela entrevista semiestruturada com 19 (dezenove)participantes envolvidos num programa de extensão com intervenção em Instituição de Longa Permanência para Idosos (ILPI) da cidade do Recife. As falas tratadas pela análise de conteúdo categorial por temática revelaram duas categorias empíricas, das quais, optamos pela ludicidade. Como conclusão, foram evidenciados princípios lúdicos, a saber: alegria, diversão, gratuidade, imaginação, plenitude, liberdade e cultura, sendo facetas que fundamentam a prática lúdica num viés teórico-metodológico, revelando contribuições para a melhoria da interação social em ILPI.

This work analyzed the theoretical-methodological contributions of ludic activities with institutionalized elderly women. To this end, it was based on the Hermeneutics-Dialectics as a method, which pursues understanding in speeches, text and context, the conception of the phenomena studied, these were evidenced through a semi-structured interview with 19 participants who were involved in an extension program with intervention in a Long-Stay institution for the Elderly (LSIE), in the city of Recife. The speeches dealt with categorical content analysis by theme and revealed two empirical categories, from which, we opted for playfulness. In conclusion, ludic principles were evidenced, namely: joy, fun, gratuity, imagination, fullness, freedom and culture, these being facets that base the ludic practice on a theoretical-methodological bias, thus revealing contributions to the improvement of social interaction in LSIE.

Leptomeningeal Metastasis in Gliomas : Clinical Characteristics and Risk Factors.

OBJECTIVE: Our objective is to analyze the occurrence, clinical course and risk factors for glioma patients with leptomeningeal metastasis (LM) according to different metastasis patterns and clinical variables. METHODS: We retrospectively reviewed data from 376 World Health Organization (WHO) grade II-IV adult glioma patients who were treated in the National Cancer Center from 2001 to 2020. Patients who underwent surgery at other institutions, those without initial images or those with pathologically unconfirmed cases were excluded. LM was diagnosed based on magnetic resonance imaging (MRI) findings or cerebrospinal fluid (CSF) cytology. The metastasis pattern was categorized as nodular or linear according to the enhancement pattern. Tumor proximity to the CSF space was classified as involved or separated, whereas location of the tumor was dichotomized as midline, for tumors residing in the thalamus, basal ganglia and brainstem, or lateral, for tumors residing in the cerebral and cerebellar hemispheres. RESULTS: A total of 138 patients were enrolled in the study. A total of 44 patients (38%) were diagnosed with LM during a median follow-up of 9 months (range, 0-60). Among the clinical variables, tumor proximity to CSF space, the location of the tumor and the WHO grade were significant factors for LM development in univariate analysis. In multivariate analysis, the midline location of the tumor and WHO grade IV gliomas were the most significant factor for LM development. The hazard ratio was 2.624 for midline located gliomas (95% confidence interval [CI], 1.384-4.974; p=0.003) and 3.008 for WHO grade IV gliomas (95% CI, 1.379-6.561; p=0.006). CONCLUSION: Midline location and histological grading are an important factor for LM in glioma patients. The proximity to the CSF circulation pathway is also an important factor for WHO grade IV glioma LM. Patients carrying high risks should be followed up more thoroughly.

Korean guidelines for the management of gout

Gout is the most common form of arthritis, with the prevalence increasing worldwide. The present treatment guidelines provide recommendations for the appropriate treatment of acute gout, management during the inter-critical period, and prevention of chronic complications. The guidelines were developed based on evidence-based medicine and draft recommendations finalized after expert consensus. These guidelines are designed to provide clinicians with clinical evidence to enable efficient treatment of gout.

Does intravenous patient-controlled analgesia or continuous block prevent rebound pain following infraclavicular brachial plexus block after distal radius fracture fixation? A prospective randomized controlled trial / 대한마취과학회지

Background@#The purpose of this study was to investigate the role of opioid-based intravenous patient-controlled analgesia (IV PCA) or continuous brachial plexus block (BPB) in controlling rebound pain after distal radius fracture (DRF) fixation under BPB as well as total opioid consumption. @*Methods@#A total of 66 patients undergoing surgical treatment for a displaced DRF with volar plate fixation were randomized to receive a single infraclavicular BPB (BPB only group) (n = 22), a single infraclavicular BPB with IV PCA (IV PCA group) (n = 22), or a single infraclavicular BPB with continuous infraclavicular BPB (continuous block group) (n = 22). The visual analog scale (VAS) for pain and the amount of pain medication were recorded at 4, 6, 9, 12, 24, and 48 h and two weeks postoperatively. @*Results@#At postoperative 9 h, the pain VAS score was significantly higher in the BPB only group (median: 2; Q1, Q3 [1, 3]) than in the IV PCA (0 [0, 1.8], P = 0.006) and continuous block groups (0 [0, 0.5], P = 0.009). At postoperative 12 h, the pain VAS score was significantly higher in the BPB only group (3 [3, 4]) than in the continuous block group (0.5 [0, 3], P = 0.004). The total opioid equivalent consumption (OEC) was significantly higher in the IV PCA group (350.3 [282.1, 461.3]) than in the BPB only group (37.5 [22.5, 75], P < 0.001) and continuous block group (30 [15, 75], P < 0.001); however, OEC was not significantly different between the BPB only group and the continuous block group (P = 0.595). @*Conclusions@#Although continuous infraclavicular BPB did not reduce total opioid consumption compared to BPB only, this method is effective for controlling rebound pain at postoperative 9 and 12 h following DRF fixation under BPB.

Association Between Plasma Homocysteine Level and Mortality:A Mendelian Randomization Study

Background and Objectives@#In previous studies, high homocysteine levels were associated with high cardiovascular mortality. However, these results were inconsistent with those of randomized controlled trials. We aimed to evaluate the causal role of homocysteine on allcause and cardiovascular mortality using Mendelian randomization (MR) analysis. @*Methods@#This study included the 10,005 participants in the Namwon Study. In conventional observational analysis, age, sex, survey years, lifestyles, body mass index, comorbidities, and serum folate level were adjusted using multivariate Cox proportional regression. MR using 2-stage least squares regression was used to evaluate the association between genetically predicted plasma homocysteine levels and mortality. Age, sex, and survey years were adjusted for each stage. The methylenetetrahydrofolate reductase (MTHFR) polymorphism was used as an instrumental variable for predicting plasma homocysteine levels. @*Results@#Observed homocysteine levels were positively associated with all-cause (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26–1.54) and cardiovascular (HR, 1.62; 95% CI, 1.28–2.06) mortality when plasma homocysteine levels doubled. However, these associations were not significant in MR analysis. The HRs of doubling genetically predicted plasma homocysteine levels for all-cause and cardiovascular mortality were 0.99 (95% CI, 0.62–1.57) and 1.76 (95% CI, 0.54–5.77), respectively. @*Conclusions@#This MR analysis did not support a causal role for elevated plasma homocysteine concentrations in premature deaths.

Association Between Serum Bilirubin and Atrial Fibrillation: A Mendelian Randomization Study

Background and Objectives@#The association between bilirubin and atrial fibrillation (AF) has been evaluated previously in observational studies but with contradictory results. This study evaluated the causal association between serum bilirubin level and AF using Mendelian randomization (MR) analysis. @*Methods@#This cross-sectional study includes 8,977 participants from the Dong-gu Study.In the observational analysis, multivariate logistic regression was performed to evaluate the association between bilirubin and prevalent AF. To evaluate the causal association between bilirubin and AF, MR analysis was conducted by using the UGT1A1 rs11891311 and rs4148323 polymorphisms as instrumental variables. @*Results@#Elevated serum bilirubin levels were associated with an increased risk for AF in observational analysis (total bilirubin: odds ratio [OR], 1.31; 95% confidence interval [95% CI], 1.15–1.48 per 1 standard deviation [SD]; direct bilirubin: OR, 1.31; 95% CI, 1.18–1.46 per 1 SD), whereas the genetically predicted serum bilirubin levels in MR analysis did not show this association (total bilirubin: OR, 1.02; 95% CI, 0.67–1.53 per 1 SD; direct bilirubin: OR, 1.03; 95% CI, 0.61–1.73 per 1 SD). @*Conclusions@#Genetically predicted bilirubin levels were not associated with prevalent AF.Thus, the observational association between serum bilirubin levels and AF may be noncausal and affected by reverse causality or unmeasured confounding.

Korean guidelines for the management of gout

Gout is the most common form of arthritis, with the prevalence increasing worldwide. The present treatment guidelines provide recommendations for the appropriate treatment of acute gout, management during the inter-critical period, and prevention of chronic complications. The guidelines were developed based on evidence-based medicine and draft recommendations finalized after expert consensus. These guidelines are designed to provide clinicians with clinical evidence to enable efficient treatment of gout.

Aneurysmectomy and graft interposition for giant thrombosed proximal internal carotid artery aneurysm: Technical details

A giant thrombosed extracranial internal carotid artery aneurysm (ECCA) is extremely rare and its treatment is challenging. Despite the advance of endovascular technique, open surgery is still considered a first-line treatment in giant thrombosed ECCA. We describe a case of giant thrombosed ECCA which was successfully treated by aneurysmectomy and graft interposition with the technical details.