Explainable Model Using Shapley Additive Explanations Approach on Wound Infection after Wide Soft Tissue Sarcoma Resection: "Big Data" Analysis Based on Health Insurance Review and Assessment Service Hub.

Background and Objectives: Soft tissue sarcomas represent a heterogeneous group of malignant mesenchymal tissues. Despite their low prevalence, soft tissue sarcomas present clinical challenges for orthopedic surgeons owing to their aggressive nature, and perioperative wound infections. However, the low prevalence of soft tissue sarcomas has hindered the availability of large-scale studies. This study aimed to analyze wound infections after wide resection in patients with soft tissue sarcomas by employing big data analytics from the Hub of the Health Insurance Review and Assessment Service (HIRA). Materials and Methods: Patients who underwent wide excision of soft tissue sarcomas between 2010 and 2021 were included. Data were collected from the HIRA database of approximately 50 million individuals' information in the Republic of Korea. The data collected included demographic information, diagnoses, prescribed medications, and surgical procedures. Random forest has been used to analyze the major associated determinants. A total of 10,906 observations with complete data were divided into training and validation sets in an 80:20 ratio (8773 vs. 2193 cases). Random forest permutation importance was employed to identify the major predictors of infection and Shapley Additive Explanations (SHAP) values were derived to analyze the directions of associations with predictors. Results: A total of 10,969 patients who underwent wide excision of soft tissue sarcomas were included. Among the study population, 886 (8.08%) patients had post-operative infections requiring surgery. The overall transfusion rate for wide excision was 20.67% (2267 patients). Risk factors among the comorbidities of each patient with wound infection were analyzed and dependence plots of individual features were visualized. The transfusion dependence plot reveals a distinctive pattern, with SHAP values displaying a negative trend for individuals without blood transfusions and a positive trend for those who received blood transfusions, emphasizing the substantial impact of blood transfusions on the likelihood of wound infection. Conclusions: Using the machine learning random forest model and the SHAP values, the perioperative transfusion, male sex, old age, and low SES were important features of wound infection in soft-tissue sarcoma patients.

The Role of the Aryl Hydrocarbon Receptor in Vascular Factors Related to Preeclampsia in a Smoking Mouse Model.

Smoking cigarettes is known to lower the risk of preeclampsia. The objective of this study is to evaluate the effect of smoking on the expression of soluble FMS-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF), and endoglin (sEng)-1 and the role of the aryl hydrocarbon receptor (AhR) in pregnant mice. We developed a smoking mouse model using a gas-filling system. One or two cigarettes per day were exposed to each of the five pregnant mice for five days a week throughout pregnancy. AhR agonist and antagonist were injected. Serum levels and expression in the placenta of sFlt-1, VEGF, and sEng-1 were analyzed and compared among the cigarette smoke and no-exposure groups after delivery. Compared to the no-smoke exposure group, the serum level of sFlt-1 was significantly decreased in the two-cigarette-exposed group (p < 0.001). When the AhR antagonist was added to the two-cigarette-exposed group, sFlt-1 levels were significantly increased compared to the two-cigarette group (p = 0.002). The levels of sFlt-1 in the AhR antagonist group did not change regardless of two-cigarette exposure (p = 0.064). With the AhR agonist, sFlt-1 decreased significantly compared to the control (p = 0.001) and AhR antagonist group (p = 0.002). The sFlt-1 level was significantly decreased after the injection of the AhR agonist compared to the control group (p = 0.001). Serum levels of VEGF were significantly decreased in the one-cigarette-exposed group compared to the control group; however, there was no difference between the control and the two-cigarette-exposed groups. The placental expression of sFlt-1, VEGF, and sEng were inconsistent. This study offers insights into the potential role of AhR on antiangiogenic sFlt-1 associated with preeclampsia. It may support the invention of a new treatment strategy for preeclampsia using AhR activation.

A Randomized, Multicenter, Double-Blind, Parallel, Non-Inferiority Clinical Study to Compare the Efficacy and Safety of Unicenta and Melsmon for Menopausal Symptom Improvement.

This study was conducted to evaluate the efficacy and safety of Unicenta in female subjects with menopausal symptoms by analyzing the changes in the Kupperman index (primary endpoint) and hormonal changes (secondary endpoint). It was a randomized, multi-center, double-blind, parallel, non-inferiority clinical study conducted at two different tertiary medical centers. A Unicenta injection was shown to be non-inferior to Melsmon based on the Kupperman index in both the intent-to-treat and per-protocol populations (p = 0.789 and p = 0.826, respectively). Additionally, there were no statistically significant differences in hormone levels (estradiol, follicular-stimulating hormone) or in the evaluation of facial flushes. There was no statistically significant difference in the incidence rate of adverse events between the two groups (p = 0.505). The study demonstrated that Unicenta is not inferior to Melsmon in terms of the change in the Kupperman index after 12 days of injection. The efficacy and safety of Unicenta were shown, resulting in the improvement of menopausal symptoms.

Investigating the regenerative effects of folic acid on human amniotic epithelial stem cells and amniotic pore culture technique (APCT) model in vitro using an integrated pharmacological-bioinformatic approach.

INTRODUCTION: Disruption of fetal membranes before the onset of labor is referred to as premature rupture of membranes (PROM). Lack of maternal folic acid (FA) supplementation reportedly leads to PROM. However, there is a lack of information on the location of FA receptors in the amniotic tissue. Additionally, the regulatory role and potential molecular targets of FA in PROM in vitro have rarely been investigated. METHODS: The three FA receptors (folate receptor α isoform [FRα], transporter of reduced folate [RFC], and proton-coupled folate transporter [PCFT]) in human amniotic epithelial stem cells (hAESCs) and amniotic tissue were localized using immunohistochemistry and immunocytochemistry staining. Effect and mechanism analyses of FA were performed in hAESCs and amniotic pore culture technique (APCT) models. An integrated pharmacological-bioinformatics approach was utilized to explore the potential targets of FA for the treatment of PROM. RESULTS: The three FA receptors were widely expressed in human amniotic tissue, especially in the hAESC cytoplasm. FA stimulated the amnion regeneration in the in vitro APCT model. This mimics the PROM status, in which cystathionine-ß-synthase, an FA metabolite enzyme, may play an important role. The top ten hub targets (STAT1, mTOR, PIK3R1, PTPN11, PDGFRB, ABL1, CXCR4, NFKB1, HDAC1, and HDAC2) of FA for preventing PROM were identified using an integrated pharmacological-bioinformatic approach. DISCUSSION: FRα, RFC, and PCFT are widely expressed in human amniotic tissue and hAESCs. FA aids the healing of ruptured membrane.

Correction: Kim et al. The Value of Posterior Cervical Angle as a Predictor of Vaginal Delivery: A Preliminary Study. Diagnostics 2021, 11, 1977.

In the original publication [...].

The Value of Posterior Cervical Angle as a Predictor of Vaginal Delivery: A Preliminary Study.

Accurate prediction of failure to progress and rapid decision making regarding the mode of delivery can improve pregnancy outcomes. We examined the value of sonographic cervical markers in the prediction of successful vaginal delivery beyond 34 weeks of gestation. A retrospective chart review was carried out. Medical information of singleton gestations delivered at a single center from 1 July 2019 to 30 August 2020 was collected. Transvaginal sonographic records of cervical length, anterior and posterior cervical angles, and cervical dilatation were obtained and re-measured. The value of these markers and clinical characteristics of mother and baby on vaginal delivery were investigated and compared to women who underwent cesarean section. A total of 90 women met the inclusion criteria. The rate of vaginal delivery was 75.6%. There were no differences found in terms of maternal age, rate of abortion, induction of labor, premature rupture of membranes, preterm labor, hypertension, diabetes, cervical length, and neonatal sex and weight. The prediction of vaginal delivery was provided by parity, maternal body mass index, and posterior cervical angle. The area under the receiver operating characteristic curve for prediction of vaginal delivery was 0.667 (95% CI 0.581-0.864, p = 0.017) for the posterior cervical angle, with a cutoff of 96.5°. Regression analysis revealed a posterior cervical angle ≥96.5° in the prediction of vaginal delivery (adjusted odds ratio: 6.24; 95% confidence interval: 1.925-20.230, p = 0.002). Posterior cervical angle ≥96.5° is associated with successful vaginal delivery. It is simple and easy to measure and can be useful in determining the mode of delivery.

Women with multiple gestations have an increased risk of development of hypertension in the future.

BACKGROUND: Multiple gestations are associated with an increased incidence of preeclampsia. However, there exists no evidence for an association between multiple gestations and development of hypertension(HTN) later in life. This study aimed to determine whether multiple gestations are associated with HTN beyond the peripartum period. METHODS: In this retrospective nationwide population-based study, women who delivered a baby between January 1, 2007, and December 31, 2008, and underwent a national health screening examination within one year prior to their pregnancy were included. Subsequently, we tracked the occurrence of HTN during follow-up until December 31, 2015, using International Classification of Diseases-10th Revision codes. RESULTS: Among 362,821 women who gave birth during the study period, 4,944 (1.36%) women had multiple gestations. The cumulative incidence of HTN was higher in multiple gestations group compared with singleton group (5.95% vs. 3.78%, p < 0.01, respectively). On the Cox proportional hazards models, the risk of HTN was increased in women with multiple gestations (HR 1.35, 95% CI 1.19, 1.54) compared with those with singleton after adjustment for age, primiparity, preeclampsia, atrial fibrillation, body mass index, blood pressure, diabetes mellitus, high total cholesterol, abnormal liver function test, regular exercise, and smoking status. CONCLUSIONS: Multiple gestations are associated with an increased risk of HTN later in life. Therefore, guidelines for the management of high-risk patients after delivery should be established.

Secular trends in cesarean sections and risk factors in South Korea (2006-2015).

OBJECTIVE: This study aimed to investigate trends in the rate of cesarean sections (CSs) in South Korea from 2006 to 2015 and identify the risk factors associated with these changes. METHODS: Using the National Health Insurance Corporation dataset, all women who gave birth between 2006 and 2015 were included in the study. We investigated 1) the mode of delivery, 2) the complication rates during pregnancy (i.e., preeclampsia and placenta previa), and 3) pre-pregnancy factors (body mass index, hypertension [HTN], diabetes mellitus [DM], and other pre-existing medical conditions), and their trends during the study period. RESULTS: Over 10 years, the rate of CS increased from 36.3% in 2006 to 40.6% in 2015 (P<0.01). The rate of CS increased in primiparous women, women with multiple pregnancy, and women with preeclampsia. Maternal age and the incidence of placenta previa also increased. In contrast, the rate of vacuum deliveries and vaginal birth after CS decreased during the study period. The rate of women with pre-pregnancy obesity and DM increased, but the rate of women with pre-pregnancy HTN decreased. CONCLUSION: The rate of CS in South Korea increased from 2006 to 2015. This trend may reflect changes in the rate of different risk factors. Identifying the causes of the increasing CS trend observed in this study will allow clinicians to monitor these factors and possibly reduce the rate of CS.

Serum sFlt-1, cystatin C and cathepsin B are potential severity markers in preeclampsia: a pilot study.

PURPOSE: Preeclampsia is associated with abnormal invasion of the trophoblast through decidua and subsequently altered remodeling of the maternal spiral arteries and endothelial dysfunction. This phenomenon is explained by the dysregulation of various kinds of vascular factors and proteases. The purpose of this study was to compare the circulating levels of sFlt-1, cathepsin B, and cystatin C in preeclamptic and normotensive pregnancies. STUDY DESIGN: Sixty-two pregnant women were enrolled in this prospective study. Twenty women were preeclamptic and 42 were normotensive. Serum levels of sFlt-1, cathepsin B, and cystatin C were measured using an enzyme-linked immunosorbent assay kit. RESULTS: Circulating levels of sFlt-1, cathepsin B, and cystatin C were significantly higher in preeclamptic than in normotensive pregnant women (p < 0.001; p = 0.017; p = 0.003). Preeclamptic women with severe features demonstrated significantly higher levels of cathepsin B (p = 0.05). Serum sFlt-1 and cystatin C levels were positively correlated with elevated systolic and diastolic blood pressure. The levels of cathepsin B were positively correlated with alanine and aspartate aminotransferase. The amount of 24 h proteinuria was positively, but non-significantly correlated with sFlt-1 and cystatin C. CONCLUSIONS: In addition to sFlt-1 levels, the serum levels of cathepsin B and cystatin C significantly change when preeclampsia develops. These markers are associated with severity markers of elevated blood pressure and liver injury in preeclampsia.

Prepregnancy Factors Are Associated with Development of Hypertension Later in Life in Women with Pre-Eclampsia.

Background: The aim of our study was to investigate the prepregnancy characteristics that are risk factors for the development of hypertension (HTN) and identify prepregnancy factors for the development of HTN in women affected by pre-eclampsia in their first pregnancy. Methods: We enrolled 1910 women who had undergone a National Health Screening Examination through the National Health Insurance Corporation between 2002 and 2003, and who had their first delivery affected by pre-eclampsia in 2004. Women were classified as having HTN if they were newly diagnosed with HTN from 2005 through 2012. Results: After 8 years of follow-up, 7.7% (148/1910) of pre-eclamptic women developed HTN. Using the Cox proportional hazards model, old age (hazard ratio [HR] 3.92, 95% confidence interval [CI] 2.47-6.23), a family history of HTN (HR 2.28, 95% CI 1.46-3.58), prepregnancy obesity (HR 3.74, 95% CI 2.50-5.59), and high blood pressure (BP) (HR 2.78, 95% CI 1.85-4.19) were independently associated with the development of HTN. Conclusions: The results show that the development of HTN in pre-eclamptic women is related to prepregnancy factors. Recognizing who subsequently develops HTN postpartum in pre-eclamptic women with these prepregnancy factors could lead to early identification and lifestyle interventions, which could reduce the burden of cardiovascular disease.

Effects of estradiol on HIF-1α expression and trophoblast differentiation in first trimester villous explant cultures.

OBJECTIVE: The purpose of this study was to investigate the effects of estradiol on the expression of hypoxia-inducible factor (HIF)-1α and the differentiation of trophoblasts in human first trimester villous explant cultures. METHODS: Villous explant cultures were established from first trimester human placentas (6-8 weeks of gestation, n=3). Normal villous tissues were explanted on Matrigel and incubated under 3% O2 tension for 5 days. To evaluate the effects of estradiol on the villous explant cultures, 1 ng/mL of estradiol was added to the culture medium. The morphological integrities and viabilities of the villous explants were monitored. Immunohistochemistry for α5 and α1 integrin was performed to assess differentiation of extravillous trophoblasts (EVTs). Expression of HIF-1α in villous explant cultures was evaluated by western blotting and densitometry. RESULTS: EVTs emerging from first trimester villous explant cultures formed outgrowths of cells from the distal ends and invaded the surrounding Matrigel. Exposure of villous explants to estradiol resulted in the decreased outgrowth of cells from the distal end and decreased expression of α5 integrin. However, estradiol treatment increased the invasion of villous explants into the surrounding Matrigel, concomitant with the increased expression of α1 integrin, indicating differentiation of EVTs into more invasive EVTs. On western blots, the expression of HIF-1α decreased significantly after treatment with estradiol under 3% O2 tension. CONCLUSION: Our findings suggest that estradiol may downregulate expression of HIF-1α in placenta, which in turn promote trophoblast differentiation into invasive phenotype.

Prepregnancy liver enzyme levels and risk of preeclampsia in a subsequent pregnancy: A population-based cohort study.

BACKGROUND & AIMS: Preeclampsia is a serious multisystemic disorder leading to maternal and neonatal adverse outcomes. However, little is known about the early markers of this disease. The aim of this study was to investigate the association between prepregnancy liver function and the development of preeclampsia. METHODS: We enrolled 192 571 Korean women who had their first delivery between January 1, 2008, and December 31, 2014, and had undergone a national health screening examination through the National Health Insurance Corporation during 1-2 years before delivery. RESULTS: Preeclampsia developed in 3973 (2.0%) women. The rate of development of preeclampsia was higher in women with abnormal prepregnancy liver enzyme levels than in those with normal liver enzyme levels before pregnancy. On multivariate analysis, women with abnormal alanine aminotransferase level before pregnancy had a 1.21-fold increased risk of developing preeclampsia than those with normal alanine aminotransferase level before pregnancy, after adjusting for age, family history of hypertension, hepatitis B virus carrier status, smoking, alcohol status, prepregnancy body mass index and blood pressure. Prepregnancy γ-glutamyltransferase and aspartate aminotransferase levels were not associated with the risk of preeclampsia development. CONCLUSION: Abnormal prepregnancy alanine aminotransferase level was associated with the development of preeclampsia in a subsequent pregnancy. Further studies are needed to evaluate whether early intervention for liver function before pregnancy can decrease the risk of preeclampsia.

Responses of human adipose-derived stem cells to interstitial level of extremely low shear flows regarding differentiation, morphology, and proliferation.

Human cells encounter a range of shear stress levels in situ and this natural variability in shear stress implies that realistic investigations of cell type characteristics may depend on nontrivial shear stress models. Human adipose-derived stem cells (hASCs) differentiate near the blood capillary vessels where interstitial flows predominate. However, the effects of interstitial levels of shear on hASCs are not fully understood. In this study, we propose a microfluidic shear generation system, in which a gradient distribution of the interstitial level of shear flow is created to investigate the effects of interstitial-level shear flow on hASCs. To generate such a gradient profile of interstitial-level shear stress, we fabricated a semicircle-shaped microfluidic channel, and generated an extremely low flow using an osmosis-driven pump. Changes to hASC morphology, proliferation, and differentiation were observed under shear stresses of 1.8 × 10-3-2.4 × 10-3 Pa. At higher shear stresses, we found higher proliferation rates, stronger actin structures, and lower differentiation. We also conducted computational simulations of a monolayer culture, which showed that the shear stress level even on a single cell varies owing to the change of the cell thickness between the pseudopodia and the nucleus. We found that hASCs detectably respond to extremely low levels of shear flow, above a threshold of ∼2.0 × 10-3 Pa. Our microplatform may be useful for quantitating biological responses and function changes of other stem cells and cancer cells to interstitial-level shear flows.

Features of Microsystems for Cultivation and Characterization of Stem Cells with the Aim of Regenerative Therapy.

Stem cells have infinite potential for regenerative therapy thanks to their advantageous ability which is differentiable to requisite cell types for recovery and self-renewal. The microsystem has been proved to be more helpful to stem cell studies compared to the traditional methods, relying on its advantageous feature of mimicking in vivo cellular environments as well as other profitable features such as minimum sample consumption for analysis and multiprocedures. A wide variety of microsystems were developed for stem cell studies; however, regenerative therapy-targeted applications of microtechnology should be more emphasized and gain more attractions since the regenerative therapy is one of ultimate goals of biologists and bioengineers. In this review, we introduce stem cell researches harnessing well-known microtechniques (microwell, micropattern, and microfluidic channel) in view point of physical principles and how these systems and principles have been implemented appropriately for characterizing stem cells and finding possible regenerative therapies. Biologists may gain information on the principles of microsystems to apply them to find solutions for their current challenges, and engineers may understand limitations of the conventional microsystems and find new chances for further developing practical microsystems. Through the well combination of engineers and biologists, the regenerative therapy-targeted stem cell researches harnessing microtechnology will find better suitable treatments for human disorders.

Translation and linguistic validation of Korean version of short form of pelvic floor distress inventory-20, pelvic floor impact questionnaire-7.

The short forms of pelvic floor distress inventory (PFDI) and pelvic floor impact questionnaire (PFIQ) are useful disease specific questionnaires evaluating symptoms, quality of life for pelvic floor disorders. The purpose is to develop linguistic validation of the PFDI-20 and PFIQ-7 questionnaires. Three types of Korean version of questionnaires have been used in four locations of University Hospitals in Korea. Each version of questionnaires was developed by forward translation and back-translation by bilingual translators and was verified by the patients with pelvic floor disorder and healthy persons. For harmonization of 3 types of questionnaires, four authors reviewed, discussed all discrepancies, incorporated and produced a new version. The multi-step processes of translation and linguistic validation of the Korean version of PFDI-20 and PFIQ-7 questionnaire were completed. Further process of validation of Korean version of these questionnaires is required.