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Background: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase located in the centriole of the chromosome during the cell cycle. PLK4 overexpression has been described in a variety of many common human epithelial tumors. Conversely, PLK4 acts as a haploinsufficient tumor suppressor in some situations, highlighting the importance of strict regulation of PLK4 expression, activity, and function. Meanwhile, the importance of chemoradiation resistance in rectal cancer is being emphasized more than ever. We aimed to analyze PLK4 expression and the tumor regression grade (TRG) in patients with rectal cancer, treated with chemoradiotherapy (CRT).Methods: A retrospective study was conducted on 102 patients with rectal cancer who received preoperative CRT. Immunohistochemistry for PLK4 in paraffin-embedded tissue was performed from the biopsy and surgical specimens. Results: We found significant association between high expression of PLK4 and poor response to neoadjuvant CRT (according to both Mandard and The Korean Society of Pathologists TRG systems) in the pre-CRT specimens. Other clinicopathologic parameters did not reveal any correlation with PLK4 expression. Conclusions: This study revealed an association between high expression of PLK4 in the pre-CRT specimens and TRG. Our results indicated that PLK4 could potentially be a new predictor for CRT effect in patients with rectal cancer.

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

Patients with multiple drug allergies (MDA) can be in danger during anesthesia due to their possibility of anaphylaxis. Perioperative anaphylaxis can occur more frequently in patients with any kind of allergic history. The physiological changes during pregnancy, the existence of the fetus itself, and consequent restrictions on drug use including anesthetics make anesthetic management for pregnant women with MDA more difficult than that for other patients. Appropriate anesthetic strategy based on detailed history taking, allergological evaluations and cooperation between surgeon and anesthesiologist are essential to performing successful anesthesia. To the best of our knowledge, although there have been some cases about anesthetic management in patients with MDA, there is no reported case about surgical anesthesia for Cesarean section in a pregnant woman with MDA. Here, we present a pregnant woman with MDA who showed a positive response to most of anesthetics and analgesics in the intradermal skin test, successfully managed with an anesthetic strategy using volatile induction and maintenance anesthesia (VIMA) for Cesarean section.

In the case of hemodynamically stable broad complex tachycardia, it is essential to evaluate the causes and to diagnose correctly in the selection of appropriate management and drugs. We report two neonates diagnosed with idiopathic ventricular tachycardia, which is extraordinarily rare. One presented with idiopathic fascicular ventricular tachycardia (right bundle branch block pattern with a superior axis), and the other presented with right ventricular outflow tract ventricular tachycardia (left bundle branch block pattern with an inferior axis). These two forms are representative of benign ventricular tachycardia. No features of cardiovascular shock were observed. While the recommended initial drug treatments are different, the conditions were well controlled by propranolol without the development of any adverse events. There was no recurrence of arrhythmia for several months in the outpatient clinic.

Ran Kim,1 Seung-Ah Choe,2 Eun A Park,1 Myung Joo Kim,1 Young-Sang Kim,1 You Shin Kim1 1Department of Obstetrics and Gynecology, CHA Fertility Center Seoul Station, CHA University School of Medicine, Seoul, 04637, Korea; 2Department of Preventive Medicine, Korea University College of Medicine, Seoul, 02841, KoreaCorrespondence: Seung-Ah ChoeDepartment of Preventive Medicine, Korea University College of Medicine, Department of Epidemiology & Health Informatics, Graduate School of Public Health, Korea University, 73 Goryeodae-ro, Seongbuk-gu, Seoul, 02841, KoreaTel +82-2-2286-1344Email seungah@korea.ac.krPurpose: To assess the impact of additional embryo transfer (ET) on pregnancy in young women, we used a natural-experiment approach.Patients and Methods: The design was based on the national policy of South Korea limiting the number of embryos transferred in vitro fertilization (IVF):≦2 embryos on day 2– 4 or one on day 5– 6 for patients aged < 35, with one extra embryo allowed for patients aged ≥ 35. Using the data from 1909 ET cycles of 1287 women aged ≥ 34 and ≤ 35, we calculated adjusted risk ratios (RRs) for pregnancy.Results: Half of cycles were undertaken by women aged 35, and additional ET was performed in 68.7% of them. Intrauterine pregnancy (45.2% vs 51.3%) and multiple gestation (30.5% vs 6.9%) were more common in women aged 35 than in those aged 34. The RR for intrauterine pregnancy was 1.34 (95% confidence interval: 1.12– 1.59) when comparing double ET to single ET in frozen day 5– 6 cycles.Conclusion: We observed no evidence of a higher probability of pregnancy with additional ET in fresh or frozen day 3– 4 ET, or in fresh day 5– 6 ET of women aged 35. Additional ET may not increase the successful pregnancy rate in the 35-year-old group, unless it is a frozen day 5– 6 ET cycle.Keywords: in vitro fertilization, single embryo transfer, pregnancy rate, multiple pregnancy

BackgroundMounting evidence implicates an association between ambient air pollution and impaired reproductive potential of human. Our study aimed to assess the association between air pollution and ovarian reserve in young, infertile women.MethodsOur study included 2276 Korean women who attended a single fertility center in 2016–2018. Women’s exposure to air pollution was assessed using concentrations of particulate matter (PM10and PM2.5), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3) that had been collected at 269 air quality monitoring sites. Exposure estimates were computed for 1, 3, 6, and 12 months prior to the ovarian reserve tests. Anti-Müllerian hormone (AMH) ratio (defined as an observed-to-expected AMH based on age) and low AMH (defined as ResultsThe mean age was 36.6 ± 4.2 years and AMH level was 3.3 ± 3.1 ng/mL in the study population. Average AMH ratio was 0.8 ± 0.7 and low AMH was observed in 10.3% of women (n=235). The average concentration of six air pollutants was not different between the normal ovarian reserve and low AMH groups for all averaging periods. In multivariable models, an interquartile range (IQR)-increase in 1 month-average PM10was associated with decrease in AMH ratio among total population (β= −0.06, 95% confidence interval: −0.11, 0.00). When we restrict our analysis to those living in Seoul, IQR-increases in 1 and 12 month-average PM2.5were associated with 3% (95% CI: −0.07, 0.00) and 10% (95% CI: −0.18, −0.01) decrease in AMH ratio. The ORs per IQR increase in the six air pollutants were close to null in total population and Seoul residents.ConclusionsIn a cohort of infertile Korean women, there was a suggestive evidence of the negative association between ambient PM concentration and ovarian reserve, highlighting the potential adverse impact of air pollution on women’s fertility.

Background Hysterectomy is one of the major gynecologic surgeries. Historically, several surgical procedures have been used for hysterectomy. The present study aims to evaluate the surgical trends and clinical outcomes of hysterectomy performed for benign diseases at the Yeungnam University Hospital. Methods We retrospectively reviewed patients who underwent a hysterectomy for benign diseases from 2013 to 2018. Data included the patients' demographic characteristics, surgical indications, hysterectomy procedures, postoperative pathologies, and perioperative outcomes. Results A total of 809 patients were included. The three major indications for hysterectomy were uterine leiomyoma, pelvic organ prolapse, and adenomyosis. The most common procedure was total laparoscopic hysterectomy (TLH, 45.2%), followed by open hysterectomy (32.6%). During the study period, the rate of open hysterectomy was nearly constant (29.4%-38.1%). The mean operative time was the shortest in the single-port laparoscopic assisted vaginal hysterectomy (LAVH, 89.5 minutes), followed by vaginal hysterectomy (VH, 96.8 minutes) and TLH (105 minutes). The mean decrease in postoperative hemoglobin level was minimum in single-port LAVH (1.8 g/dL) and VH (1.8 g/dL). Conversion to open surgery or multi-port surgery occurred in five cases (0.6%). Surgical complications including wound dehiscence, organ injuries, and conditions requiring reoperation were observed in 52 cases (6.4%). Conclusion Minimally invasive approach was used for most hysterectomies for benign diseases, but the rate of open hysterectomy has mostly remained constant. Single-port LAVH and VH showed the most tolerable outcomes in terms of operative time and postoperative drop in hemoglobin level in selected cases.

A 59-year-old man presented for possible durable ventricular assist device (VAD) implan-tation. He had previously been diagnosed with congenitally corrected transposition of the great arteries, a ventricular septal defect, an atrial septal defect, pulmonary valve stenosis, and aortic valve regurgitation. In the previous 22 years, he had undergone palliative cardi-ac surgery 3 times. VAD implantation as a bridge to transplantation was planned. Owing to severe adhesions, mesocardia, a left ascending aorta, and moderate aortic regurgitation, we performed VAD implantation and aortic valve closure via a dual left thoracotomy and partial sternotomy.

We evaluated the prognostic implications of the circulating tumor cell (CTC) count in non-metastatic, HER2-negative breast cancer patients who failed to achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT). A total of 173, non-metastatic breast cancer patients treated with NCT were prospectively enrolled. CTCs were obtained from blood drawn pre-NCT and post-NCT using a SMART BIOPSY SYSTEM isolation kit (Cytogen Inc., Seoul, Korea) with immunofluorescence staining. Excluding 26 HER2-positive patients, Relapse-free survival (RFS) and overall survival (OS) related to the CTC count and the association of the CTC count with the treatment response to given therapy were analyzed in 147 HER2-negative patients. Among 147 HER2-negative patients, 28 relapses (19.0%) and 13 deaths (8.8%, all breast cancer-specific) were observed during a median follow-up of 37.3 months. One hundred and seven patients (72.8%) were hormone receptor-positive, and 40 patients (27.2%) had triple-negative breast cancer (TNBC). One or more CTCs were identified in 88 of the 147 patients (59.9%) before NCT and 77 of the 134 patients (52.4%) after NCT. In the entire HER2-negative patient cohort, the initial nodal status was the most significant factor influencing RFS and OS. In TNBC, 11 patients (27.5%) achieved pCR and patients that failed to achieve pCR with ≥ 5 CTCs after NCT, showed worse RFS (HR, 10.66; 95% CI, 1.80–63.07; p = 0.009) and OS (HR, 14.00; 95% CI, 1.26–155.53; p = 0.032). The patients with residual tumor and a high number of the CTCs after NCT displayed the worse outcome. These findings could provide justification to launch a future, well designed trial with longer follow-up data to obtain regulatory approval for clinical use of the assay, especially for the ER-positive, HER2-negative breast cancer subset.

Although deep learning algorithms have demonstrated expert-level performance, previous efforts were mostly binary classifications of limited disorders. We trained an algorithm with 220,680 images of 174 disorders and validated it using Edinburgh (1,300 images; 10 disorders) and SNU datasets (2,201 images; 134 disorders). The algorithm could accurately predict malignancy, suggest primary treatment options, render multi-class classification among 134 disorders, and improve the performance of medical professionals. The area under the curves for malignancy detection were 0.928 ± 0.002 (Edinburgh) and 0.937 ± 0.004 (SNU). The area under the curves of primary treatment suggestion (SNU) were 0.828 ± 0.012, 0.885 ± 0.006, 0.885 ± 0.006, and 0.918 ± 0.006 for steroids, antibiotics, antivirals, and antifungals, respectively. For multi-class classification, the mean top-1 and top-5 accuracies were 56.7 ± 1.6% and 92.0 ± 1.1% (Edinburgh) and 44.8 ± 1.2% and 78.1 ± 0.3% (SNU), respectively. With the assistance of our algorithm, the sensitivity and specificity of 47 clinicians (21 dermatologists and 26 dermatology residents) for malignancy prediction (SNU; 240 images) were improved by 12.1% (P0.0001) and 1.1% (P0.0001), respectively. The malignancy prediction sensitivity of 23 non-medical professionals was significantly increased by 83.8% (P0.0001). The top-1 and top-3 accuracies of four doctors in the multi-class classification of 134 diseases (SNU; 2,201 images) were increased by 7.0% (P = 0.045) and 10.1% (P = 0.0020), respectively. The results suggest that our algorithm may serve as augmented intelligence that can empower medical professionals in diagnostic dermatology.

This study was performed to evaluate the restoration combined with resin infiltration (RI) of early cavitated smooth surface caries lesion in terms of microleakage. Flowable resin and resin-modified glass ionomer cement (RMGIC) were compared.Sound 20 extracted 3rd molars were divided into 2 groups randomly. Artificial decalcified lesion was induced. Cavities were prepared on the mesial and distal surfaces, and randomly set as experimental and control group. RI was applied to the experimental group before cavity restoration. The control group was restored without RI. In group I and II, flowable resin and RMGIC was used for restoration respectively. After thermocycling and silver nitrate immersion, microleakage was assessed by μ-CT.Depth of microleakage was lower in experimental group than control group only in group II (p = 0.05). Microleakage depth was lower in group II than group I in both experimental and control groups (p = 0.05).RI pretreatment before restoration of early cavitated caries lesions might reduce the microleakage and help long-term maintenance of restoration. In this study, RMGIC was less polymerization shrinkage. Restoration with RMGIC after RI pretreatment reduced the microleakage of the restoration compared to the flowable resin.

Background Approximately 100,000 women are diagnosed with cancer each year in Korea. According to a survey by the Korean central cancer registry in 2016, uterine cervical cancer, uterine corpus cancer, and ovarian cancer were the 5th, 7th, and 8th most prevalent cancers respectively among Korean women. The present study aims to review the clinico-pathologic characteristics of patients who were treated for major gynecological malignancies at Yeungnam University Medical Center. Methods Patients with invasive gynecological cancers from January 2012 to February 2019 were retrospectively identified. We analyzed the clinical features, demographic profiles, pathologic data, treatment modality used, adjuvant treatment used, complications, recurrence, and survival outcomes. Results A total of 287 patients (cervical cancer 115; corporal cancer 86; and ovarian, tubal, or primary peritoneal cancer 90) were included. Most cervical (82.7%) and corporal cancers (89.5%) were diagnosed in the early stages (stage I or II), while more than half (58.9%) the cases of ovarian, tubal or peritoneal cancers were diagnosed in the advanced stages (stage III or IV). Surgical complications were observed in 12.2% of cervical cancers, 16.3% of uterine corpus cancers, and 11.1% of ovarian, tubal, and peritoneal cancers, respectively. The 5-year overall survival rate was 94.1%, 91.0%, and 77.1% for cervical, corporal, and ovarian, tubal, or peritoneal cancers, respectively. Conclusion Surgical treatment was satisfactory in terms of the incidence of complications, and survival outcomes were generally good. Clinicians should be aware of the clinical and histopathological characteristics of patients with gynecological cancers to be able to provide optimal strategies and counseling.

Background We investigated whether leptin during the third trimester was associated with fetal growth compared to IGF-1. Methods One hundred five appropriate-for-gestational-age (AGA) infants born at ≥28 weeks’ gestation were enrolled. Cord blood leptin and insulin like growth factor 1 (IGF-1) were collected simultaneously during delivery. Enrolled infants were stratified into three groups according to GA as follows: 28 to Results Sixty-eight infants out of 105 infants were preterm (32.5 ± 2.5 weeks), and 37 infants were term (37.8 ± 1.2 weeks). BW, BL, HC, and BMI were higher with increasing gestational age among the three gestational age-specific groups. With regard to hormones, leptin and IGF-1 were higher with increasing gestational age. Log cord serum leptin was independently associated with BW and BL in multivariable linear regression analysis, after adjustment for confounding factors including gestational age, delivery mode, multiple pregnancy, pregnancy induced hypertension, gestational diabetes mellitus, infant’s BMI, and log cord blood IGF-1 levels. Conclusions During the third trimester, cord serum leptin was independently associated with fetal growth.

Background Recently, the number of nationwide medical researches on psoriasis using the National Health Insurance Service database has been on the rise. However, identification of psoriasis using diagnostic codes alone can lead to misclassification. Accuracy of the diagnostic codes and their concordance with medical records should be validated first to identify psoriasis patients correctly. Objective To validate the diagnostic codes of psoriasis (International Classification of Diseases, 10th Revision L40) and to find the algorithm for the identification of psoriasis. Methods We collected medical records of patients who received their first diagnostic codes of psoriasis during 5 years from five hospitals. Fifteen percent of psoriasis patients were randomly selected from each hospital. We performed a validation by reviewing medical records and compared 5 algorithms to identify the best algorithm. Results Total of 538 cases were reviewed and classified as psoriasis (n=368), not psoriasis (n=159), and questionable (n=11). The most accurate algorithm was including patients with ≥1 visits with psoriasis as primary diagnostic codes and prescription of vitamin D derivatives. Its positive predictive value was 96.5% (95% confidence interval [CI], 93.9%~98.1%), which was significantly higher than those of the algorithm, including patients with ≥1 visits with psoriasis as primary diagnostic codes or including ≥1 visits with diagnostic codes of psoriasis (primary or additional) (91.0% and 69.8%). Sensitivity was 90.8% (95% CI, 87.2%~93.4%) and specificity was 92.5% (95% CI, 86.9%~95.9%). Conclusion Our study demonstrates a validated algorithm to identify psoriasis, which will be useful for the nationwide population-based study of psoriasis in Korea.

The distinct clinical characteristics of patients at diagnosis of diffuse large B-cell lymphoma (DLBCL), who experience a late relapse compared with those who relapse early, require reappraisal in the era of R-CHOP. Data from the lymphoma registry of the Asan Medical Center between 2002 and 2015 were retrospectively reviewed. Among 846 DLBCL patients treated with first-line R-CHOP and achieved complete response, 169 (20%) relapsed, occurring late (2 years) in 51 (6%). Compared with early relapses, late relapses were associated with a lower International Prognostic Index score (

This paper proposes a flyback-circuit-based design of a trigger circuit for a high-power gas switch. By incorporating a flyback circuit in a high-power gas switch, it is possible to generate a high step-up ratio and high-voltage pulse by using a transformer. Furthermore, simple trigger circuit having the minimum possible number of components (transformer and switch) can be realized. When an inductor is used as an energy storage element, energy is stored as a current source, and thus, the element can operate reliably when low impedance exists between the trigger node of the switch after triggering. According to the fundamental operating principle of a flyback circuit, the proposed trigger circuit is designed considering the maximum trigger voltage and energy required for a high-power gas switch. To verify the proposed design procedure and feasibility of the trigger circuit, a compact trigger circuit (7.5 kV, 1.3 mJ/pulse) is simulated using the PSpice program and implemented. Based on this compact circuit, a trigger circuit (20 kV, 100 mJ/pulse) for a triggered vacuum switch (TVS) is developed, and the tests with an actual TVS (3.3 kJ) are carried out.

In this paper, a 25-kW bipolar pulsed-power supply for strategic mineral exploration has been described. A 500-V, 12.5-A unit module consisting of a highly efficient LCC resonant converter and a full-bridge-based bipolar pulse-switching unit is designed. The LCC resonant converter has a trapezoidal-shaped resonant current for reduced conduction loss. For achieving high power density, the leakage inductance of the transformer is used as resonant inductance without an external inductor. Moreover, the designed gate drive circuit based on the repetitive short pulse is proposed to operate the frequency range from dc to 8 kHz and reduce the size of the gate transformer. Four modules are connected in series and parallel in order to operate the power supply in either loop mode or grounded dipole mode. Depending on the load condition, the pulse power source capable of delivering the required high voltage and low current (2 kV, 12.5 A) or low voltage and high current (500 V, 50 A) is operated either in grounded dipole mode or loop mode, respectively. In order to satisfy the output voltage balancing of the four modules, the third wire is wound to compensate for the transformer of the LCC resonant converter. Finally, the design of the bipolar pulsed-power supply has been verified based on the experimental results of the field test.

Lennert lymphoma is a lymphoepithelioid variant of peripheral T-cell lymphoma (not otherwise specified) with characteristics that do not fit into other peripheral T-cell lymphoma categories. Lennert lymphoma is primarily a nodal disease, and skin involvement may be exhibited. Cutaneous manifestations in Lennert lymphoma are nonspecific and include erythematous papules, nodules, and small plaques. Histological examination of cutaneous involvement characteristically presents epithelioid histiocytes and atypical small lymphocytes around vessels or appendages. A lymph node (LN) biopsy is essential for Lennert lymphoma diagnosis. In Lennert lymphoma, immunohistochemistry of both LNs and the involved skin reveals T-cell marker positivity. Although most Lennert lymphoma cases present with a single-positive CD4/CD8 immunophenotype, few cases present with a double-positive CD4/CD8 immunophenotype. We report a case of a 54-year-old woman presenting with fever, chills, general weakness, and a skin rash of erythematous patches on the trunk, extremities, and buttocks. A skin biopsy of the buttocks revealed atypical lymphocytes around the dermal vessels. In immunohistochemistry, these atypical lymphocytes stained positive for CD3, CD4, CD8, and CD68 but negative for CD20, CD30, and granzyme B. Similarly, a biopsy of the axillary LN revealed numerous epithelioid cells with atypical lymphocytes, exhibiting positivity for CD3, CD4, CD8, and CD68 but negativity for CD20, CD30, and S-100. Ki-67 was overexpressed in both the skin and LN. The final diagnosis of the patient was Lennert lymphoma with cutaneous involvement and a rare double-positive CD4/CD8 immunophenotype. The patient was transferred to another hospital for chemotherapy as per her request.

This study evaluated the correlation between tumor-associated macrophages (TAMs) and long-term oncologic outcomes in colorectal cancer (CRC). We evaluated TAMs based on the expression of CD68, CD11c, and CD163 as optimal markers via immunohistochemistry in 148 patients with CRC who underwent surgical resection between September 1999 and August 2004. A high proportion of CD68-positive macrophages were associated with the occurrence of distant metastasis. A low proportion of CD11c-positive macrophages were associated with unfavorable overall survival (OS) and disease-free survival. CD11c-positive macrophages were found to act as independent prognostic factors for OS. An analysis of our long-term data indicated that TAMs are significantly associated with OS and prognosis in CRC.

Backgound: IVM has emerged as a safe and promising alternative procedure to conventional in vitro fertilization (IVF) for minimizing the risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS. Despite the comparable obstetric and perinatal outcomes, there are no definite factors known to affect the outcomes of IVM.Methods: Retrospective analysis of a total of 313 women with PCOS undergoing 427 hCG-primed IVM cycles between January 2010 and February 2016 at the Fertility Center of CHA Gangnam Medical Center, Seoul, Korea. The number of retrieved oocytes and maturation, fertilization, and implantation rates were analyzed. Results: After transferring a mean of 2.4 ± 0.5 fresh embryos, the clinical pregnancy rate was 39.1% (n = 167), and the live birth rate was 30.7% (n = 131) with the implantation rate of 20.9%. The numbers of retrieved (18.1 ± 9.7 vs. 15.6 ± 8.7, p = 0.014), fertilized (8.6 ± 5.2 vs. 6.6 ± 3.8, p < 0.001) oocytes; good-quality embryos (1.3 ± 0.9 vs. 1.0 ± 0.9, p = 0.001); and blastocyst transfer cycles (22 vs. 15, p < 0.001) were significantly higher in the live birth group than in the no live birth group. Among the factors associated with live births, retrieved oocytes had a slightly positive effect on live birth (RR = 1.03; 95% CI, 1.00, 1.06; p = 0.021).Conclusions: It seems that the number of retrieved oocytes has a favorable effect in increasing the clinical pregnancy rate and live birth rate during hCG-primed IVM procedure in women with PCOS. Physicians’ skills and cautious efforts may be required to retrieve a higher number of oocytes in IVM procedures.

Previous studies have shown that infiltration of capsaicin into the surgical site can prevent incision-induced spontaneous pain like behaviors and heat hyperalgesia. In the present study, we aimed to monitor primary sensory neuron Ca2+activity in the intact dorsal root ganglia (DRG) using Pirt-GCaMP3 male and female mice pretreated with capsaicin or vehicle before the plantar incision. Intraplantar injection of capsaicin (0.05%) significantly attenuated spontaneous pain, mechanical, and heat hypersensitivity after plantar incision. The Ca2+response inin vivoDRG and inin situspinal cord was significantly enhanced in the ipsilateral side compared with contralateral side or naive control. Primary sensory nerve fiber length was significantly decreased in the incision skin area in capsaicin-pretreated animals detected by immunohistochemistry and placental alkaline phosphatase (PLAP) staining. Thus, capsaicin pretreatment attenuates incisional pain by suppressing Ca2+response because of degeneration of primary sensory nerve fibers in the skin.SIGNIFICANCE STATEMENTPostoperative surgery pain is a major health and economic problem worldwide with ∼235 million major surgical procedures annually. Approximately 50% of these patients report uncontrolled or poorly controlled postoperative pain. However, mechanistic studies of postoperative surgery pain in primary sensory neurons have been limited toin vitromodels or small numbers of neurons. Using an innovative, distinctive, and interdisciplinaryin vivopopulational dorsal root ganglia (DRG) imaging (>1800 neurons/DRG) approach, we revealed increased DRG neuronal Ca2+activity from postoperative pain mouse model. This indicates widespread DRG primary sensory neuron plasticity. Increased neuronal Ca2+activity occurs among various sizes of neurons but mostly in small-diameter and medium-diameter nociceptors. Capsaicin pretreatment as a therapeutic option significantly attenuates Ca2+activity and postoperative pain.

Pseudomonas aeruginosa is a ubiquitous human pathogen that causes severe infections. Although antibiotics, such as tobramycin, are currently used for infection therapy, their antibacterial activity has resulted in the emergence of multiple antibiotic-resistant bacteria. The 6-gingerol analog, a structural derivative of the main component of ginger, is a quorum sensing (QS) inhibitor. However, it has a lower biofilm inhibitory activity than antibiotics and the possibility to cause toxicity in humans. Therefore, novel and more effective approaches for decreasing dosing concentration and increasing biofilm inhibitory activity are required to alleviate P. aeruginosa infections. In this study, a 6-gingerol analog was combined with tobramycin to treat P. aeruginosa infections. The combined treatment of 6-gingerol analog and tobramycin showed strong inhibitory activities on biofilm formation and the production of QS-related virulence factors of P. aeruginosa compared to single treatments. Furthermore, the combined treatment alleviated the infectivity of P. aeruginosa in an insect model using Tenebrio molitor larvae without inducing any cytotoxic effects in human lung epithelial cells. The 6-gingerol analog showed these inhibitory activities at much lower concentrations when used in combination with tobramycin. Adjuvant effects were observed through increased QS-disrupting processes rather than through antibacterial action. In particular, improved RhlR inactivation by this combination is a possible target for therapeutic development in LasR-independent chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin may be considered an effective method for treating P. aeruginosa infections. IMPORTANCE Pseudomonas aeruginosa is a pathogen that causes various infectious diseases through quorum-sensing regulation. Although antibiotics are mainly used to treat P. aeruginosa infections, they cause the emergence of resistant bacteria in humans. To compensate for the disadvantages of antibiotics and increase their effectiveness, natural products were used in combination with antibiotics in this study. We discovered that combined treatment with 6-gingerol analog from naturally-derived ginger substances and tobramycin resulted in more effective reductions of biofilm formation and virulence factor production in P. aeruginosa than single treatments. Our findings support the notion that when 6-gingerol analog is combined with tobramycin, the effects of the analog can be exerted at much lower concentrations. Furthermore, its improved LasR-independent RhlR inactivation may serve as a key target for therapeutic development in chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin is suggested as a novel alternative for treating P. aeruginosa infections.

Background and objectives: Ovarian cancer is one of the leading causes of death among women worldwide. Most newly diagnosed ovarian cancer patients are diagnosed in advanced stages of the disease. Despite various treatments, most patients with advanced stage ovarian cancer, including serous ovarian cancer (the most common subtype of ovarian cancer), experience recurrence, which is associated with extremely poor prognoses. In the present study, we aimed to identify core genes involved in ovarian cancer and their associated molecular mechanisms, as well as to investigate related clinicopathological implications in ovarian cancer. Materials and methods: Three gene expression cohorts (GSE14407, GSE36668, and GSE38666) were obtained from the Gene Expression Omnibus databases to explore potential therapeutic biomarkers for ovarian cancer. Nine up-regulated and six down-regulated genes were screened. Three publicly available gene expression datasets (GSE14407, GSE36668, and GSE38666) were analyzed. Results: A total of 14 differently expressed genes (DEGs) were identified, among which nine genes were upregulated (BIRC5, CDCA3, CENPF, KIF4A, NCAPG, RRM2, UBE2C, VEGFA, and NR2F6) and were found to be significantly enriched in cell cycle regulation by gene ontology analysis. Further protein–protein interaction network analysis revealed seven hub genes among these DEGs. Moreover, Kaplan–Meier survival analysis showed that a higher expression of CDCA3 and UBE2C was associated with poor overall patient survival regardless of tumor stage and a higher tumor histologic grade. Conclusion: Altogether, our study suggests that CDCA3 and UBE2C may be valuable biomarkers for predicting the outcome of patients with advanced serous ovarian cancer.

Introduction This study aimed to evaluate the early results of primary total hip arthroplasty (THA) using dual mobility (DM) cups in patients at a risk of dislocation and compare them with that of fixed bearing (FB) THA. Materials and methods This retrospective study included patients who had undergone primary THA between January 2016 and December 2018 and were at a risk of dislocation. A propensity score-matched analysis was conducted for 63 THA procedures with vitamin-E infused highly cross-linked polyethylene (VEPE) DM bearing and 63 THA procedures performed with FB from the same manufacturer for a mean follow-up period of 3.1 and 3.5 years, respectively. The radiologic outcomes at the last follow-up and incidence of postoperative complications were evaluated and compared statistically between the two groups. The modified Harris hip score (mHHS) was used to assess patient-reported outcomes. Results Postoperative dislocation occurred in 4 cases (6.3%) in the FB group, but did not occur in the DM group (p = 0.042). There was no difference in the radiologic outcomes and postoperative complications between the two groups. The mHHS at the last follow-up showed satisfactory outcomes in both the groups (DM group, 90.5; FB group, 88.1), without a statistical difference between the groups. Conclusion The early results of THA using VEPE DM bearing showed better outcomes than that of THA with FB for patients at a risk of dislocation. A longer follow-up period is recommended to assess the stability and overall outcomes.

Su-Jeong Kim,1,&ast; Jae-Ho Lee,2,&ast; Woo-Jae Park,1 Shin Kim3– 5 1Department of Biochemistry, College of Medicine, Gachon University, Yeonsu-gu, Incheon, 21999, Republic of Korea; 2Department of Anatomy, School of Medicine, Keimyung University, Dalseo-gu, Daegu, 42601, Republic of Korea; 3Department of Immunology, School of Medicine, Keimyung University, Dalseo-gu, Daegu, 42601, Republic of Korea; 4Institute of Medical Science, Keimyung University, Dalseo-gu, Daegu, 42601, Republic of Korea; 5Institute for Cancer Research, Keimyung University Dongsan Medical Center, Dalseo-gu, Daegu, 42601, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Shin Kim Email god98005@dsmc.or.krIntroduction: Sphingolipid metabolism is a highly controlled process that is involved in regulating bioactive lipid signaling pathways and serves important roles in several cellular processes in breast cancer. Invasive ductal carcinoma (IDC), which is characterized by the malignant proliferation of the ductal epithelium and stromal invasion, is the most common type of breast cancer. Recent advances in genetic research have accelerated the discovery of novel prognostic factors and therapeutic targets for the disease. The aim of the present study was to investigate the expression and prognostic significance of sphingolipid metabolism-related genes in female IDC.Methods: The present study used gene expression RNAseq data obtained from The Cancer Genome Atlas breast invasive carcinoma (TCGA BRCA) datasets.Results: Sphingolipid metabolism-related genes exhibited dysregulated mRNA expression levels in IDC. The Student’s t-test revealed that SMPDL3B, B4GALNT1, LPAR2, and LASS2 were significantly upregulated, while LASS3, LPAR1, B4GALT6, GAL3ST1, HPGD, ST8SIA1, UGT8, and S1PR1 were significantly downregulated in female IDC tissues compared with normal solid tissues. Kaplan–Meier survival analyses revealed that high SMPDL3B mRNA expression levels were associated with good prognosis in female IDC, suggesting that SMPDL3B plays a tumor suppressor role. To the best of our knowledge, the present study was the first to report that dysregulated expressions of SMPDL3B are significantly associated with age, estrogen receptor status, progesterone receptor status, and histological subtype.Conclusion: Taken together, our study indicated that SMPDL3B may have a pathophysiological role and serve as a novel prognostic biomarker in IDC.Keywords: SMPDL3B, sphingolipid metabolism, invasive ductal carcinoma, TCGA

Objective To investigate the ability of kobusone to reduce high glucose levels and promote β-cell proliferation. Methods Four-week-old female db/db mice were assigned to the kobusone (25 mg/kg body weight, intraperitoneally twice a day) or control group (same volume of PBS). Glucose levels and body weight were measured twice a week. After 6 weeks, intraperitoneal glucose tolerance tests and immunohistochemical studies were performed, and insulin levels were determined. The expression of mRNAs involved in cell proliferation, such as PI3K, Akt, cyclin D3 and p57Kip 2 , was measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results Kobusone reduced blood glucose levels after 3 weeks and more strongly increased serum insulin levels than the vehicle. Immunohistochemistry illustrated that kobusone increased 5-bromo-2′-deoxyuridine incorporation into islet β-cells, suggesting that it can stimulate islet β-cell replication in vivo. RT-qPCR indicated that kobusone upregulated the mRNA expression of PI3K, Akt, and cyclin D3 and downregulated that of p57Kip2. Conclusion Our findings suggest that kobusone is a potent pancreatic islet β-cell inducer that has the potential to be developed as an anti-diabetic agent.

BackgroundDendritic cells (DCs) are specialized antigen-presenting cells known to bridge innate and adaptive immune reactions. However, the relationship between circulating DCs and Orientia tsutsugamushi infection is unclear. Therefore, this study aimed to examine the level and function of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), two subsets of circulating DCs, in scrub typhus patients.MethodsThe study included 35 scrub typhus patients and 35 healthy controls (HCs). pDC and cDC levels, CD86 and CD274 expression, and cytokine levels were measured using flow cytometry.ResultsCirculating pDC and cDC levels were found to be significantly reduced in scrub typhus patients, which were correlated with disease severity. The patients displayed increased percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs in the peripheral blood. The alterations in the levels and surface phenotypes of pDCs and cDCs were recovered in the remission state. In addition, the production of interferon (IFN)-α and tumor necrosis factor (TNF)-α by circulating pDCs, and interleukin (IL)-12 and TNF-α by circulating cDCs was reduced in scrub typhus patients. Interestingly, our in vitro experiments showed that the percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs were increased in cultures treated with cytokines including IFN-γ, IL-12, and TNF-α.ConclusionsThis study demonstrates that circulating pDCs and cDCs are numerically deficient and functionally impaired in scrub typhus patients. In addition, alterations in the expression levels of surface phenotypes of pDCs and cDCs could be affected by pro-inflammatory cytokines.

The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive. The study aimed to characterize the clinicopathological features, including prognosis, of GCs with copy number gains in multiple protooncogenes. Three hundred thirty-three patients with advanced GC were analyzed for their gene ratios in EGFR, GATA6, IGF2, and SETDB1 using droplet dPCR (ddPCR) for an accurate assessment of CN changes in target genes. The number of GC patients with 3 or more genes with CN gain was 16 (4.8%). Compared with the GCs with 2 or less genes with CN gain, the GCs with 3 or more CN gains displayed more frequent venous invasion, a lower density of tumor-infiltrating lymphocytes, and lower methylation levels of L1 or SAT-alpha. Microsatellite instability-high tumors or Epstein–Barr virus-positive tumors were not found in the GCs with 3 or more genes with CN gain. Patients of this groups also showed the worst clinical outcomes for both overall survival and recurrence-free survival, which was persistent in the multivariate survival analyses. Our findings suggest that the ddPCR-based detection of multiple CN gain of protooncogenes might help to identify a subset of patients with poor prognosis.

Chemotherapy-induced peripheral neuropathy (CIPN) affects about 68% of patients undergoing chemotherapy and causes severe neuropathic pain which is debilitating health problem and greatly reduces quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing. Meclizine is an H1 histamine receptor antagonist which is known to have neuroprotective effects including anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN to test agonists of mGluR8 and group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests and in vivo entire DRG neurons Ca2+ imaging using genetically-encoded Ca2+ indicator, Pirt-GCaMP3 to monitor different drug interventions on a populational ensemble level. CIPN induced increased spontaneous Ca2+ activity in DRG neurons, increased Ca2+ transient amplitudes, and hyperresponses to mechanical, thermal, and chemical stimuli. We found mGluR8 agonist, DCPG, group II mGluR agonist, LY379268, and Histamine1 receptor antagonist, meclizine all significantly attenuated mechanical and thermal pain caused by CIPN. LY379268 and meclizine, but not DCPG, attenuated DRG neuronal Ca2+ activity elevated by CIPN. Furthermore, meclizine attenuated cisplatin-induced weight loss. These results suggest group II mGluR agonist, mGluR8 agonist, and meclizine are excellent candidates to study for mechanisms and new treatment option for CIPN.

Rehabilitation from alcohol addiction or abuse is challenging due to alcohol withdrawal symptoms. Headache is a severe alcohol withdrawal symptom that frequently contributes to rehabilitation failure. Despite the need for treating alcohol withdrawal-induced headache, there is no appropriate therapeutic option available. Development of improved therapeutics will depend on obtaining a clearer understanding of alcohol withdrawal-induced headache pain mechanisms. Here, we show that the mast cell-specific receptor MrgprB2 controls development of alcohol withdrawal-induced headache. Withdrawing alcohol from alcohol-acclimated mice induces strong headache behaviors, including facial allodynia, facial pain expressions, and reduced walking movement, symptoms often observed in humans suffering from headache. Observed pain behaviors were abolished in MrgprB2-deficient mice. We observed in vivo spontaneous activation and hypersensitization of trigeminal ganglia neurons in alcohol withdrawal mice, but not in MrgprB2-deficient mice. Corticotropin-releasing factor (CRF) was increased in dura mater after alcohol withdrawal. Injection of CRF into dura mater resulted in activation of trigeminal ganglia neurons and vasodilation, which was accompanied by headache behavior. In cells, CRF evoked Ca2+ transients via MrgprB2 or human MrgprX2. The results indicate that alcohol withdrawal causes headache via mast cell degranulation in dura mater. The process is under control of MrgprB2/MrgprX2, which would appear to represent a potential target for treating alcohol withdrawal-related headache.

Background: A causative role between cervical ureaplasma colonization and adverse outcomes during pregnancy has remained controversial. We investigated whether cervical ureaplasma colonization affects the biochemically or histologically intraamniotic inflammation in preterm birth.Methods: Amniotic fluid was retrieved during delivery. Various chorioamnionitis-related cytokines (interleukin (IL)-1β, -6, -8, -10, and tumor necrosis factor-α) and regulators (matrix metalloproteins (MMP)-8 and MMP-9) were measured with Human Magnetic Luminex screening assay. We tested cervical swab specimens using real-time polymerase chain reaction assays for the detection of ureaplasma spp. colonization. Considering the clinical situation that causes intraamniotic infection, we arbitrarily divided into three categories of preterm labor with intact membrane, preterm premature rupture of membrane (PPROM), and control group with no exposure to preterm labor or preterm premature rupture of membrane.Results: The incidence of cervical ureaplasma colonization was 49.3% (136/276). The incidence of histologic chorioamnionitis was 27.5% (76/200). All differences in cytokines and regulators according to histologic chorioamnionitis were significant. Of the 153 cases that experienced preterm labor with intact membrane, IL-10, MMP-8, and MMP-9 levels in the ureaplasma positive group were significantly higher than those of the ureaplasma negative group. According to logistic regression analysis adjusted to preterm labor with intact membrane, PPROM, and gestational age at delivery, cervical ureaplasma colonization was an independent risk factor of histologic chorioamnionitis (odd ratio: 2.622, 95% confidence interval: 1.443-4.766).Conclusions: Cervical ureaplasma colonization augments biochemically intraamniotic inflammation in preterm labor with intact membrane, and was an independent risk factor of histologic chorioamnionitis.

The oral cavity is a portal into the digestive system, which exhibits unique sensory properties. Like facial skin, the oral mucosa needs to be exquisitely sensitive and selective, in order to detect harmful toxins versus edible food. Chemosensation and somatosensation by multiple receptors, including transient receptor potential channels, are well-developed to meet these needs. In contrast to facial skin, however, the oral mucosa rarely exhibits itch responses. Like the gut, the oral cavity performs mechanical and chemical digestion. Therefore, the oral mucosa needs to be insensitive, to some degree, in order to endure noxious irritation. Persistent pain from the oral mucosa is often due to ulcers, involving both tissue injury and infection. Trigeminal nerve injury and trigeminal neuralgia produce intractable pain in the orofacial skin and the oral mucosa, through mechanisms distinct from those seen in the spinal area, which is particularly difficult to predict or treat. The diagnosis and treatment of idiopathic chronic pain, such as atypical odontalgia (idiopathic painful trigeminal neuropathy or post-traumatic trigeminal neuropathy) and burning mouth syndrome, remain especially challenging. The central integration of gustatory inputs might modulate chronic oral and facial pain. A lack of pain in chronic inflammation inside the oral cavity, such as chronic periodontitis, involves the specialized functioning of oral bacteria. A more detailed understanding of the unique neurobiology of pain from the orofacial skin and the oral mucosa should help us develop novel methods for better treating persistent orofacial pain.

Despite central nervous system (CNS) relapse occurring in >10% of high-risk diffuse large B-cell lymphoma (DLBCL) patients, the role of CNS-directed prophylaxis is controversial in the absence of randomized controlled trials. In this retrospective study, we aimed to evaluate the safety and efficacy of prophylactic high-dose methotrexate (HD-MTX) on CNS relapse and survival outcomes in 258 newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated high-risk DLBCL patients, based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX. Patients were classified into an ITT HD-MTX group (n = 128) and a non-ITT HD-MTX group (n = 130). The CNS relapse rate was not significantly different between these groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = 0.96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs 64.5% (P = 0.94) and 71.7% vs 71.4% (P = 0.7), respectively. Also, propensity score–matched analyses showed no significant differences in the time-to-CNS-relapse, progression-free survival, or overall survival. The ITT HD-MTX group showed a higher incidence of grade ≥ 3 oral mucositis and elevated alanine aminotransferase. Prophylactic HD-MTX does not improve CNS relapse rate or survival outcomes in high-risk DLBCL patients, and it is accompanied by increased toxicities.