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Primary cutaneous mucinous carcinoma (PCMC) is a rare malignancy of the sweat glands that most commonly affects the periorbital area. It is characterized by slow growth over a prolonged period, and its morphology can be easily confused with a benign tumor, such as an epidermal cyst. Consequently, many patients experience recurrence after undergoing multiple resections. However, there are few reports concerning the surgical management of PCMC. We present two cases of PCMC originating in the periorbital area. The first case involved a 76-year-old man with a mass measuring 3.0× 1.5 cm that had been increasing in size. The second case was a 61-year-old man with two masses, each measuring 1.0× 1.0 cm, that were also growing. Both patients underwent wide excision with a 5-mm safety margin, which was determined based on the widest view of the cross-section of the mass on the magnetic resonance imaging. Subsequently, based on the intraoperative frozen biopsy results, both patients underwent additional excision with a 5-mm safety margin in only one direction. This report shows that, when determining the surgical margin of PCMC in periorbital area, employing imaging modalities and intraoperative frozen biopsies can be helpful for narrowing the surgical margin.
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Objective@#The purpose of this study was to evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on clinical outcomes among high-risk patients. @*Methods@#This retrospective study involved 1,368 patients and the same number of cycles, including 520 cycles with PGT-A and 848 cycles without PGT-A. The study participants comprised women of advanced maternal age (AMA) and those affected by recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), or severe male factor infertility (SMF). @*Results@#PGT-A was associated with significant improvements in the implantation rate (IR) and the ongoing pregnancy rate/live birth rate (OPR/LBR) per embryo transfer cycle in the AMA (39.3% vs. 16.2% [p<0.001] and 42.0% vs. 21.8% [p<0.001], respectively), RIF (41.7% vs. 22.0% [p<0.001] and 47.0% vs. 28.6% [p<0.001], respectively), and RPL (45.6% vs. 19.5% [p<0.001] and 49.1% vs. 24.2% [p<0.001], respectively) groups, as well as the IR in the SMF group (43.3% vs. 26.5%, p=0.011). Additionally, PGT-A was associated with lower overall incidence rates of early pregnancy loss in the AMA (16.7% vs. 34.3%, p=0.001) and RPL (16.7% vs. 50.0%, p<0.001) groups. However, the OPR/LBR per total cycle across all PGT-A groups did not significantly exceed that for the non-PGT-A groups. @*Conclusion@#PGT-A demonstrated beneficial effects in high-risk patients. However, our findings indicate that these benefits are more pronounced in carefully selected candidates than in the entire high-risk patient population.
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Background/Aims@#This study aimed to review the indications, methods, cooperation, complications, and outcomes of percutaneous endoscopic gastrostomy (PEG). @*Methods@#Questionnaires were sent to 200 hospitals, of which 62 returned their questionnaires, with a response rate of approximately 30%. Descriptive statistics were calculated to analyze the responses to the questionnaires. @*Results@#In 2019, a total of 1,052 PEGs were performed in 1,017 patients at 62 hospitals. The main group who underwent PEG was older adult patients with brain disease, particularly stroke.Nutritional supply was an important purpose of the PEG procedure. “The pull method” was the most commonly used for initial PEG insertion. The complications related to PEG were mostly mild, with leakage being the most common. Patients who underwent PEG procedures were primarily educated regarding the post-procedure management and complications related to PEG.Preoperative meetings were skipped at >50% of the institutions. Regarding the cooperation between the nutrition support team (NST) and the physician performing PEG, few endoscopists answered that they cooperated with NST before and after PEG. Moreover, the rate of NST certification obtained by physicians performing PEG and the frequency of attendance at NST-related conferences were relatively low. @*Conclusions@#This study shows a similar trend to that found in the previous PEG guidelines.However, it covers new aspects, including team-based work for PEG procedure, nutrition support, and education for patients and guardians. Therefore, each medical institution needs to select an appropriate method considering the medical environment and doctor’s abilities.
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A 22-year-old male patient presented to the clinic with severe pain in the preauricular area with an inability to completely occlude the jaw. Facial computed tomography and magnetic resonance imaging revealed a well-defined lesion that was tentatively diagnosed as a benign tumor or cystic mass. Surgical approach of a lesion in the condyle is delicate and problematic as many vulnerable anatomical structures are present. There are several methods for surgery in this area. Typically, an extraoral approach is dangerous because of potential injuries to nerves and arteries. The intraoral approach also presents difficulties due to the lack of visibility and accessibility. On occasion, coronoidectomy may be performed. The goal here was to determine an easier and safer new surgical approach to the condyle. We reached the anterior part of the pterygoid plate in the same method as in Le Fort I surgery.From this point, through the external pterygoid muscle, approaching the anterior aspect of the condyle is relatively easy and safe, with minimal damage to the surrounding tissues. Pus was drained at the site, and the lesion was diagnosed as an abscess. Pain and inability to close the mouth resolved without recurrence.
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Purpose@#The role of paraaortic lymph node dissection (PALND) in colorectal cancer (CRC) has been less evaluated than surgical treatments for other distant metastases. We evaluated surgical outcomes after PALND and identified prognostic factors. @*Methods@#The medical records of patients who underwent PALND for paraaortic lymph node metastasis (PALNM) were reviewed retrospectively. All patients were categorized into the M1a group (isolated PALNM, n = 27), and the M1bc group (distant metastases other than PALNM, n = 26). Three severity factors (PALNM-SF: number of harvested paraaortic lymph nodes [hLN], ≥14; number of metastatic paraaortic lymph nodes [mLN], ≥5; and lymph nodes ratio [mLN/hLN], ≥0.5) were defined to determine their effects on survival. @*Results@#The 5-year overall survival (OS) of the M1a and M1bc groups were 61.1% and 6.4%, respectively (P = 0.0013). The 5-year disease-free survival (DFS) of the M1a group was 47.4%, and the 3-year DFS of the M1bc group was 9.1% (P < 0.001).Patients with 2 or more PALNM-SFs showed worse OS than those with 1 PALNM-SF (P = 0.017). In multivariate analysis, M1bc (non-isolated PALNM) was the only significant factor for survival. In the M1a group, patients with 2 or more PALNMSFs showed significantly worse survival than those with a single PALNM-SF. In multivariate analysis, 2 or more PALNM-SF was a significant factor for survival. @*Conclusion@#PALND for CRC provided favorable outcomes in the survival of an isolated PALNM, although this was uncertain for non-isolated PALNMs. The PALNM-SFs helped assess the prognosis after PALND.
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Innate immunity is a first line defence system in the body which is for sensing signals of danger such as pathogenic microbes or host-derived signals of cellular stress. Pattern recognition receptors (PRR’s), which present in the cell memebrane, are suspect the infection through pathogen-associated molecular patterns (PAMP), and activate innate immunity with response to promote inflammation via inflammatory cells such as macrophages and neutrophils, and cytokines. Inflammasome are protein complexes which are part of innate immunity in inflammation to remove pathogens and repair damaged tissues. What is the important role of inflammation in disease? In this review, we are focused on the action mechanism of NLRP3 inflammasome in inflammatory diseases such as asthma, atopic dermatitis, and sepsis.
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Background@#The clinical characteristics of pediatric nasal fractures can vary depending on the child’s age, social activities, and environment. Therefore, this study aimed to analyze these characteristics in different age groups. @*Methods@#We retrospectively reviewed of a series of patients aged under 12 years who received treatment between 2013 and 2021. The initial study design involved dividing the patients into four age groups, corresponding to different developmental ages, but there were no cases in infants aged 0 to 1 year. Therefore, the patients were divided into three groups: group I, between 2 and 5; group II, between 6 and 9; and group III, between 10 and 12 years of age. The following parameters were evaluated: sex, age, etiology, fracture type and severity, and the incidence of septal injuries. @*Results@#In total, 98 patients were included in this study. In group III, the ratio of boys to girls was 3.88:1, exceeding the overall ratio of 1.97:1. The most common cause varied with age: slipping down in group I, bumping accidents in group II, and sports accidents in group III. Concomitant septal injuries were present in 4.17% of patients in group I, 5.71% of patients in group II, and 28.21% of patients in group III. @*Conclusion@#Increasing age was accompanied by a greater tendency for male predominance and a higher prevalence of sports-related causes and septal injuries. Violence was infrequent but started to become a contributing factor during school age. These varying environmental factors across age groups can offer valuable insights into the epidemiology and clinical characteristics of pediatric nasal bone fractures.
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Background@#Daratumumab is a human monoclonal antibody targeting CD38 used widely in various related conditions. Caution is advised when interpreting the pretransfusion tests in daratumumab-treated patients because they may show nonspecific reactions with red blood cells. This paper provides experimental evidence for the false-positive interference phenomena induced by daratumumab in in-vitro and ex-vivo experiments and experimental support for resolving it using dithiothreitol (DTT). @*Methods@#Fifteen crossmatching pairs, four cardiac amyloidosis (CA) patients treated with daratumumab, and three healthy individuals were included. The flow cytometry crossmatch (FCMXM) was conducted with negatively selected T and B cells. After spiking the sera with 500 μg/mL daratumumab, the T and B cells were treated with DTT. The prospective FCMXM was conducted with the sera of CA patients treated with daratumumab. The CD38 expression levels in T, B, and NK cells were measured without and with a DTT or pronase treatment. @*Results@#Five hundred μg/mL of daratumumab spiking was sufficient to elicit a false positive effect in T cell FCMXM. In particular, the administration of 0.1 M DTT efficiently resolved the induced false positivity in flow cytometry. Moreover, DTT caused a decrease in the CD38 expression levels in T, B, and NK cells. @*Conclusion@#A typical therapeutic dose of daratumumab causes false-positive FCMXM, which was effectively addressed by a DTT treatment. Therefore, information about the patient’s medical condition and the use of immunotherapeutics, such as daratumumab, is needed, given its impact on diverse CD38-expressing cells.
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Abstract Background Both predictions and predictors of difficult laryngoscopy are controversial. Machine learning is an excellent alternative method for predicting difficult laryngoscopy. This study aimed to develop and validate practical predictive models for difficult laryngoscopy through machine learning. Methods Variables for the prediction of difficult laryngoscopy included age, Mallampati grade, body mass index, sternomental distance, and neck circumference. Difficult laryngoscopy was defined as grade 3 and 4 by the Cormack-Lehane classification. Pre-anesthesia and anesthesia data of 616 patients who had undergone anesthesia at a single center were included. The dataset was divided into a base training set (n = 492) and a base test set (n = 124), with equal distribution of difficult laryngoscopy. Training data sets were trained with six algorithms (multilayer perceptron, logistic regression, supportive vector machine, random forest, extreme gradient boosting, and light gradient boosting machine), and cross-validated. The model with the highest area under the receiver operating characteristic curve (AUROC) was chosen as the final model, which was validated with the test set. Results The results of cross-validation were best using the light gradient boosting machine algorithm with Mallampati score x age and sternomental distance as predictive model parameters. The predicted AUROC for the difficult laryngoscopy class was 0.71 (95% confidence interval, 0.59-0.83; p= 0.014), and the recall (sensitivity) was 0.85. Conclusion Predicting difficult laryngoscopy is possible with three parameters. Severe damage resulting from failure to predict difficult laryngoscopy with high recall is small with the reported model. The model's performance can be further enhanced by additional data training.
Subject(s)
Humans , Intubation, Intratracheal/methods , Laryngoscopy/methods , Prospective Studies , Retrospective Studies , Machine LearningABSTRACT
Guillain-Barre syndrome (GBS) is an immune-mediated acute polyradiculoneuropathy and commonly occurs after a preceding infection or immunization sequalae. Following the severe acute respiratory syndrome-coronavirus-2 virus pandemic with co-introduction of massive vaccinations, several GBS cases associated with coronavirus disease 2019 (COVID-19) infection per se or after vaccination for COVID-19 were reported internationally. Herein, we report two cases of Korean GBS presenting with tetraplegia after two different COVID-19 vaccinations (42-year old man by AstraZeneca and 48-year woman by Pfizer vaccines) within four weeks after vaccination. The patients were diagnosed with clinical examination, serial electromyography, and compatible laboratory results and improved after comprehensive rehabilitative treatment and intravenous immunoglobulin therapy. Furthermore, we performed an electrodiagnostic follow-up study of each case to examine their unique characteristics.
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All living beings on earth have an important mechanism of 24-h periodicity, which controls their physiology, metabolism, and behavior. In humans, 24-h periodicity is regulated by the superchiasmatic nucleus (SCN) through external and environmental cues.Peripheral organs demonstrate circadian rhythms and circadian clock functions, and these are also observed in cultured cell lines.Every cell contains a CLOCK: BMAL1 loop for the generation of circadian rhythms. In this review, we focused on cell autonomous circadian rhythms in immune cells, the inflammatory diseases caused by disruption of circadian rhythms in hormones, and the role of clock genes in inflammatory diseases.
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Purpose@#Sentinel lymph node biopsy (SLNB) has become a standard axillary staging surgery for early breast cancer, and the proportion of patients requiring axillary lymph node dissection (ALND) is decreasing. We aimed to evaluate the association between the number of sentinel lymph nodes (SLNs) retrieved and the risk of lymphedema of the ipsilateral arm. @*Methods@#Prospectively collected medical records of 910 patients were reviewed.Lymphedema was defined as a difference in circumference > 2 cm compared to the contralateral arm and/or having clinical records of lymphedema treatment in the rehabilitation clinic. @*Results@#Together with an objective and subjective assessment of lymphedema, 36 patients (6.1%) had lymphedema in the SLNB group and 85 patients (27.0%) had lymphedema in the ALND group (p < 0.001). In a multivariate analysis of the whole cohort, risk factors significantly associated risk with the development of lymphedema were body mass index, mastectomy (vs.breast-conserving surgery), ALND, and radiation therapy. In logistic regression models in the SLNB group only, there was no correlation between the number of retrieved SLNs and the incidence of lymphedema. In addition, in the Pearson correlation analysis, no correlation was observed between the number of retrieved SLNs and the difference in circumference between the ipsilateral and contralateral upper extremities (correlation coefficients = 0.067, p = 0.111). @*Conclusion@#The risk of lymphedema in breast cancer surgery and adjuvant treatments is multifactorial. The number of retrieved lymph nodes during sentinel biopsy was not associated with the incidence of lymphedema.
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Purpose@#Neoadjuvant chemoradiotherapy has been accepted as a standard treatment for stage II–III rectal cancer. This study aimed to evaluate the clinical characteristics of patients who underwent neoadjuvant chemoradiotherapy for rectal cancer and effects on overall survival (OS) of neoadjuvant chemoradiotherapy in South Korea. @*Methods@#Patients who underwent curative resection for rectal cancer from 2014 to 2016 were retrospectively reviewed from the database of the National Quality Assessment program in South Korea. Patients were categorized into the upfront surgery group and neoadjuvant chemoradiotherapy group. We evaluated factors associated with the administration of neoadjuvant chemoradiotherapy and its effects on OS. Inverse probability of treatment weighting was performed to account for baseline differences between subgroups. @*Results@#A total of 6,141 patients were categorized into the upfront surgery group (n = 4,237) and neoadjuvant chemoradiotherapy group (n = 1,904). The neoadjuvant chemoradiotherapy was more frequently administered to male, midrectal cancer, and younger patients. In the neoadjuvant chemoradiotherapy group, old age, underweight, and pathologic stage were significant risk factors of OS, and male sex, the level of tumor and clinical stages were not associated with OS.After adjustment, the OS of the neoadjuvant chemoradiotherapy group followed the OS of the upfront surgery group of the same pathologic stage. @*Conclusion@#Male sex and the level of tumor were not related to the OS of rectal cancer patients with neoadjuvant chemoradiotherapy. The OS of patients who underwent neoadjuvant chemoradiotherapy was decided by their pathologic stages regardless of clinical stages.
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Background/Aims@#Cholecystitis can occur after the placement of covered self-expandable metallic stents for distal malignant biliary obstructions. We aimed to identify risk factors for cholecystitis following covered self-expandable metallic stent placement. @*Methods@#We investigated risk factors related to cholecystitis following covered self-expandable metallic stent placement in 118 patients with distal malignant biliary obstructions between January 1, 2015 and April 30, 2019. Endoscopic assessments and tumor invasion to the arteries feeding the gallbladder were determined by a pancreaticobiliary endoscopist and a radiologist, respectively. @*Results@#The median patient age was 72 years (men, 61.0%). The flow of the contrast agent into the gallbladder and tumor involvement in the orifice of the cystic duct were observed in 35 (29.7%) and 35 (29.7%) patients, respectively. During the observation period (median, 179 days), cholecystitis occurred in 18 (15.3%) patients. Multivariate analysis revealed the flow of the contrast agent into the gallbladder (p=0.023) and tumor involvement in the orifice of the cystic duct (p=0.005) as significant independent risk factors associated with cholecystitis. @*Conclusions@#The flow of the contrast agent into the gallbladder and tumor involvement in the orifice of the cystic duct are potential independent risk factors for cholecystitis following the placement of covered self-expandable metallic stents. A follow-up prospective study is warranted to validate their influence.
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Purpose@#Sentinel lymph node biopsy (SLNB) has become a standard axillary staging surgery for early breast cancer, and the proportion of patients requiring axillary lymph node dissection (ALND) is decreasing. We aimed to evaluate the association between the number of sentinel lymph nodes (SLNs) retrieved and the risk of lymphedema of the ipsilateral arm. @*Methods@#Prospectively collected medical records of 910 patients were reviewed.Lymphedema was defined as a difference in circumference > 2 cm compared to the contralateral arm and/or having clinical records of lymphedema treatment in the rehabilitation clinic. @*Results@#Together with an objective and subjective assessment of lymphedema, 36 patients (6.1%) had lymphedema in the SLNB group and 85 patients (27.0%) had lymphedema in the ALND group (p < 0.001). In a multivariate analysis of the whole cohort, risk factors significantly associated risk with the development of lymphedema were body mass index, mastectomy (vs.breast-conserving surgery), ALND, and radiation therapy. In logistic regression models in the SLNB group only, there was no correlation between the number of retrieved SLNs and the incidence of lymphedema. In addition, in the Pearson correlation analysis, no correlation was observed between the number of retrieved SLNs and the difference in circumference between the ipsilateral and contralateral upper extremities (correlation coefficients = 0.067, p = 0.111). @*Conclusion@#The risk of lymphedema in breast cancer surgery and adjuvant treatments is multifactorial. The number of retrieved lymph nodes during sentinel biopsy was not associated with the incidence of lymphedema.
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Purpose@#Neoadjuvant chemoradiotherapy has been accepted as a standard treatment for stage II–III rectal cancer. This study aimed to evaluate the clinical characteristics of patients who underwent neoadjuvant chemoradiotherapy for rectal cancer and effects on overall survival (OS) of neoadjuvant chemoradiotherapy in South Korea. @*Methods@#Patients who underwent curative resection for rectal cancer from 2014 to 2016 were retrospectively reviewed from the database of the National Quality Assessment program in South Korea. Patients were categorized into the upfront surgery group and neoadjuvant chemoradiotherapy group. We evaluated factors associated with the administration of neoadjuvant chemoradiotherapy and its effects on OS. Inverse probability of treatment weighting was performed to account for baseline differences between subgroups. @*Results@#A total of 6,141 patients were categorized into the upfront surgery group (n = 4,237) and neoadjuvant chemoradiotherapy group (n = 1,904). The neoadjuvant chemoradiotherapy was more frequently administered to male, midrectal cancer, and younger patients. In the neoadjuvant chemoradiotherapy group, old age, underweight, and pathologic stage were significant risk factors of OS, and male sex, the level of tumor and clinical stages were not associated with OS.After adjustment, the OS of the neoadjuvant chemoradiotherapy group followed the OS of the upfront surgery group of the same pathologic stage. @*Conclusion@#Male sex and the level of tumor were not related to the OS of rectal cancer patients with neoadjuvant chemoradiotherapy. The OS of patients who underwent neoadjuvant chemoradiotherapy was decided by their pathologic stages regardless of clinical stages.
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Background/Aims@#Cholecystitis can occur after the placement of covered self-expandable metallic stents for distal malignant biliary obstructions. We aimed to identify risk factors for cholecystitis following covered self-expandable metallic stent placement. @*Methods@#We investigated risk factors related to cholecystitis following covered self-expandable metallic stent placement in 118 patients with distal malignant biliary obstructions between January 1, 2015 and April 30, 2019. Endoscopic assessments and tumor invasion to the arteries feeding the gallbladder were determined by a pancreaticobiliary endoscopist and a radiologist, respectively. @*Results@#The median patient age was 72 years (men, 61.0%). The flow of the contrast agent into the gallbladder and tumor involvement in the orifice of the cystic duct were observed in 35 (29.7%) and 35 (29.7%) patients, respectively. During the observation period (median, 179 days), cholecystitis occurred in 18 (15.3%) patients. Multivariate analysis revealed the flow of the contrast agent into the gallbladder (p=0.023) and tumor involvement in the orifice of the cystic duct (p=0.005) as significant independent risk factors associated with cholecystitis. @*Conclusions@#The flow of the contrast agent into the gallbladder and tumor involvement in the orifice of the cystic duct are potential independent risk factors for cholecystitis following the placement of covered self-expandable metallic stents. A follow-up prospective study is warranted to validate their influence.
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Purpose@#This study aimed to compare the short-term outcomes of the open and laparoscopic approaches to 2-stage restorative proctocolectomy (RPC) for Korean patients with ulcerative colitis (UC). @*Methods@#We retrospectively analyzed the medical records of 73 patients with UC who underwent elective RPC between 2009 and 2016. Patient characteristics, operative details, and postoperative complications within 30 days were compared between the open and laparoscopic groups. @*Results@#There were 26 cases (36%) in the laparoscopic group, which had a lower mean body mass index (P = 0.025), faster mean time to recovery of bowel function (P = 0.004), less intraoperative blood loss (P = 0.004), and less pain on the first and seventh postoperative days (P = 0.029 and P = 0.027, respectively) compared to open group. There were no deaths, and the overall complication rate was 43.8%. There was no between-group difference in the overall complication rate; however, postoperative ileus was more frequent in the open group (27.7% vs. 7.7%, P = 0.043). Current smoking (odds ratio [OR], 44.4; P = 0.003) and open surgery (OR, 5.4; P = 0.014) were the independent risk factors for postoperative complications after RPC. @*Conclusion@#Laparoscopic RPC was associated with acceptable morbidity and faster recovery than the open approach. The laparoscopic approach is a feasible and safe option for surgical treatment for UC in selective cases.
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The process of drug discovery and drug development consumes billions of dollars to bring a new drug to the market. Drug development is time consuming and sometimes, the failure rates are high. Thus, the pharmaceutical industry is looking for a better option for new drug discovery. Drug repositioning is a good alternative technology that has demonstrated many advantages over de novo drug development, the most important one being shorter drug development timelines. In the last two decades, drug repositioning has made tremendous impact on drug development technologies. In this review, we focus on the recent advances in drug repositioning technologies and discuss the repositioned drugs used for inflammatory diseases such as sepsis, asthma, and atopic dermatitis.
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Objectives@#. To investigate the correlation of objective audiometry with user satisfaction as measured with the questionnaire scores. @*Methods@#. Twenty patients with hearing loss, who agreed to wear a hearing aid and were referred for hearing aid fitting, were included in this prospective clinical study. All patients used the in-the-canal type of Wide7 hearing aid provided by BSL Co., Ltd. We performed the Korean version of the Hearing Handicap Inventory for the Elderly (K-HHIE) and the International Outcome Inventory for Hearing Aids (K-IOI-HA) before and 1, 3, and 6 months after wearing the hearing aid. We also performed pure tone audiometry (PTA), speech audiometry (SA), functional gain (FG), hearing in noise test (HINT), and central auditory processing disorder tests, such as frequency pattern test (CA-f), duration pattern test (CA-d), and dichotic test (CA-Di). Patients were divided into two groups (group A-HHIE, improved; group B-HHIE, same or worse) by comparing the score of K-HHIE before and 6 months after wearing the hearing aid. In the 6-month K-IOI-HA questionnaire, 21 points were considered as the average score. Based on this, we further divided patients into two groups (group A-IOI, >21 points; group B-IOI, ≤21 points). @*Results@#. Group A-HHIE included six patients and group B-HHIE included 14 patients. In PTA, SA, HINT, CA-d, and CA-Di, group A-HHIE showed higher improvements than group B-HHIE, which were not statistically significant. Group A-IOI included 12 patients and group B-IOI included eight patients. No statistically significant difference was noted in the improvement of audiometric results over a period of 6 months after wearing the hearing aid between groups A-IOI and B-IOI. @*Conclusion@#. There were no significant and consistent audiometric results to reflect patient’s satisfaction with the hearing aid. Therefore, when analyzing the hearing aid-fitting outcome, both the objective audiometric tests and subjective questionnaire should be performed together for validating hearing aid performance.