Labor management and neonatal outcomes in cardiotocography categories II and III (Review).

The safe care of both mothers and fetuses during labor is a primary goal of all health professionals. The assessment of fetal oxygenation and well-being is a key aspect of perinatal care provided. Fetal heart rate (FHR) auscultation became part of daily obstetric practice in a number of countries during the 20th century and remains a key method of fetal monitoring, particularly in low-risk pregnancies. Cardiotocography (CTG) is the continuous monitoring and recording of the FHR and uterine myometrial activity, making it possible to assess the fetal condition. It therefore plays a critical role in the detection of fetal hypoxia during labor, a condition directly related to short- and long-term complications in the newborn. Herein, particular reference is made to the management of CTG category II and III standards, as well as to the handling of childbirth. In addition, specific FHR patterns are associated with immediate neonatal outcomes based on updated studies conducted worldwide. Finally, the prognostic significance of CTG and its potential as a prospective avenue for further investigation are also highlighted herein. Given that the misinterpretation of CTG findings is the most common cause of medical-legal responsibility, this knowledge field requires more emphasis and attention. The aim of the present review was to further deepen the knowledge on issues that mainly concern the safety and monitoring of pregnant women and fetuses during childbirth.

Association of Anti-Ro/SSA and Anti-La/SSB Autoantibodies With Pregnancy Outcome in the General Population.

Background: Autoimmune diseases encompass a diverse array of disorders that disturb the optimal functioning of the immune system, which is to eliminate the 'foreign or/and dangerous' to mistakenly target the body's own tissues. Objective: The aim of this research is to evaluate the most effective approach to managing autoimmune diseases within the framework of pregnancy. Methods: The exact causes and etiologies of these diseases are multifactorial and mostly still unclear. Ro/SSA autoantibodies and La/SSB, could be found in Sjögren's disease (SJ), systemic lupus (SLE) and other autoimmune disorders. Smoking, stress, UV exposure, vitamin D deficiency, and other genetic and environmental factors have been identified as risk factors for rheumatic diseases. Results: Over the years, an ever-increasing incidence of these diseases has been observed in the general population, with the female sex being at increased risk for their occurrence. This fact raises the question of what should be the management of these pathological entities during pregnancy. Taking into account the very significant impact on the quality of paitients'daily life and the seemingly augmented prevalence of autoimmune diseases, as well as their preference in the female population, the reasonable question arises as to what should be the optimal management of these diseases in the context of pregnancy. Conclusion: Given the limited data of the global medical community regarding the etiological factors and mechanisms that trigger the onset of rheumatic diseases, the management of pregnant women is a complex conundrum that health professionals are challenged to face and solve.

ARID1 and BRG1 Expression in Endometrial Cancer.

BACKGROUND/AIM: Endometrial cancer (EC) is the predominant malignancy among gynecologic cancers and ranks fourth among all types of cancer. Recently, researchers have focused on the development of new prognostic biomarkers. Subunits of the SWI/SNF protein complex, like the ARID1 and BRG1, have been associated with the development of endometrial cancer. The present study aimed to evaluate the expression patterns of ARID1A and BRG1 in a collection of endometrioid adenocarcinomas of the uterus using immunohistochemistry. PATIENTS AND METHODS: The study comprised a total of thirty-three individuals diagnosed with stage I endometrioid endometrial cancer, treated with radical hysterectomy. The histological material was then examined to assess the cytoplasmic and nuclear expression of the proteins. RESULTS: ARID1A exhibited expression in both the cytoplasm and nucleus of cancer cells, whereas BRG1 was mainly expressed in the nuclei. In addition, ARID1A exhibited a notable decrease in expression in grade 3 histology, with no significant correlation with the depth of myometrial invasion. The reduced expression was highly related to tumor expansion into the endocervix. The findings demonstrated a total absence of ARID1A expression in 27% of endometrioid carcinomas, with a significant reduction in expression in an additional 51% of cancer cells. These findings align with the most recent published data. In contrast, in the current study, BRG1 was rarely down-regulated and was extensively expressed in the majority of endometrioid carcinomas, preventing the possibility of statistical analysis. CONCLUSION: In summary, ARID1A expression loss can be used as a biomarker to guide post-operative therapy; however, further investigation is needed, especially for early-stage endometrial cancer.

The Impact of Periodontal Disease on Preterm Birth and Preeclampsia.

This review delves into the possible connection between periodontitis and negative pregnancy outcomes, such as preeclampsia and preterm birth. It highlights the potential influence of an unidentified microbial factor on preeclampsia and the effects of inflammatory responses on the rate of preterm births. Furthermore, it underscores the prevalent occurrence of oral ailments within the populace and their significant repercussions on quality of life. Hormonal fluctuations during pregnancy may exacerbate oral conditions such as pregnancy gingivitis and periodontitis, necessitating bespoke therapeutic approaches that take into account potential fetal ramifications. Periodontal disease, characterized by microbial attack and inflammatory response, results in tissue destruction and tooth loss. The oral cavity's susceptibility to bacterial colonization, which is primarily due to its role as a site for food intake, is highlighted. Furthermore, research indicates a correlation between inflammatory responses and factors such as prostaglandin E2 and IL-1ß, and preterm birth. Therapeutic interventions are a focus of international research, with efforts being aimed at optimizing outcomes through larger studies involving pregnant women.

The Role of Urothelial Cancer-Associated 1 in Gynecological Cancers.

Gynecological cancers (GC) represent some of the most frequently diagnosed malignancies in women worldwide. Long-non-coding RNAs (lncRNAs) are regulatory RNAs increasingly being recognized for their role in tumor progression and metastasis in various cancers. Urothelial cancer-associated 1 (UCA1) is a lncRNA, first found deregulated in bladder cancer, and many studies have exposed its oncogenic effects in more tumors since. However, the role of UCA1 in gynecological malignancies is still unclear. This review aims to analyze and define the role of UCA1 in GC, in order to identify its potential use as a diagnostic, prognostic, or therapeutic biomarker of GC. By employing the search terms "UCA1", "breast cancer", "endometrial cancer", "ovarian cancer", "cervical cancer", "vaginal cancer", and "vulvar cancer" in the PubMed database for the literature review, we identified a total of sixty-three relevant research articles published between 2014 and 2024. Although there were some opposing results, UCA1 was predominantly found to be upregulated in most of the breast, endometrial, ovarian, cervical, and vulvar cancer cells, tissue samples, and mouse xenograft models. UCA1 overexpression mainly accounts for enhanced tumor proliferation and increased drug resistance, while also being associated with some clinicopathological features, such as a high histological grade or poor prognosis. Nonetheless, no reviews were identified about the involvement of UCA1 in vaginal carcinogenesis. Therefore, further clinical trials are required to explore the role of UCA1 in these malignancies and, additionally, examine its possible application as a target for upcoming treatments, or as a novel biomarker for GC diagnosis and prognosis.

Evaluation of the Histone Deacetylase 2 (HDAC-2) Expression in Human Breast Cancer.

BACKGROUND/AIM: Triple negative breast cancer belongs to the most aggressive breast cancer forms. Histone deacetylases (HDACs) constitute a class of enzymes that exhibit a significant role in breast cancer genesis and progression. In this study, we aimed at assessing the clinical importance of HDAC-2 in triple negative breast cancer. MATERIALS AND METHODS: A total of 138 breast cancer specimens were examined on an immunohistochemical basis. A statistical analysis was performed in order to examine the association between HDAC-2 and the survival and clinicopathological features of the patients. RESULTS: Increased HDAC-2 expression was observed in every fourth case of triple negative breast cancer with positive HDAC-2 staining, whereas only 12 out of 98 non-triple negative breast cancer samples showed high HDAC-2 expression. HDAC-2 overexpression correlated with prolonged overall survival (OS) and disease-free survival (DFS) in triple negative breast cancer. CONCLUSIONS: High HDAC-2 levels in triple negative breast cancer seem to positively influence patient survival, disease stage and recurrence.

The Impact of Endometriosis on Pregnancy.

Despite the increased frequency of endometriosis, it remains one of the most enigmatic disorders regarding its effects on pregnancy. Endometriosis adversely affects both natural and assisted conception. Impaired folliculogenesis, which causes follicular dysfunction and low egg quality, as well as luteal phase problems, reduced fertilization, and abnormal embryogenesis, are some of the mechanisms advocated to explain reproductive dysfunction. There is a rising need for a comprehensive study of the potential negative consequences of this condition on pregnancy outcomes, including the postpartum period, as more women with a medical history of endometriosis become pregnant. Obstetrical complications (small for gestational age [SGA], cesarean section [CS], miscarriage, hemorrhage, low placental adhesion, and preterm delivery) are statistically elevated in women with endometriosis. Furthermore, ruptured ovarian endometrioma, appendicitis, intestinal perforation, and hemoperitoneum have been described in pregnancy. Obstetricians are largely unfamiliar with these complications, as they have not been thoroughly investigated. The development and pathogenesis of endometriosis is an important field of study and has not yet been fully elucidated. Finding these mechanisms is crucial for the development of new and more effective strategies to treat this condition. Endometriosis can have an impact on obstetric and neonatal outcomes of pregnancy, in addition to its potential effects on conception. To date, no additional monitoring is recommended for pregnancies with a history of endometriosis. However, more studies are urgently needed to assess the need for the tailored pregnancy monitoring of women with endometriosis.

The Comparative Study of the Administration of the Combination Preparation of Isoflavones and Hyaluronic Acid in Menopausal Women for the Treatment of the Symptoms of Menopause, Urogenital Atrophy and Oteoporosis in Relation to Existing Hormone Replacement Therapies.

Background: Menopause is characterized by a series of symptoms and effects from the various systems and organs, for which, the decline in estrogen production from the ovaries is considered responsible. Objective: The aim of this study was to make comparative study of the administration of the combination preparation of isoflavones and hyaluronic acid in menopausal women for the treatment of the symptoms of menopause, urogenital atrophy and osteoporosis in relation to existing hormone replacement therapies. Methods: In this five-year, double-blind, placebo-controlled clinical study, a total of 274 postmenopausal women were enrolled and classified into three groups. Participants in group A, were 96 women who did not receive Hormone Replacement Therapy (HRT), in the second group, 92 received daily treatment with tibolone (2.5 mg) as monotherapy, and in the third group, 86 received treatment with a pharmaceutical formulation of hyaluronic acid 120 mg and isoflavones. MF11RCE 80 mg. Results: In the postmenopausal women of our study, a significant reduction of postmenopausal symptoms was found in both groups B and C of participants who received hormone replacement preparations compared to group A who did not receive HRT. Furthermore, no difference in efficacy was observed between the administered preparations of isoflavones and tibolone. Conclusion: The combination of isoflavones and hyaluronic acid has the same efficacy as tibolone in menopausal symptoms.

Retrospective Study of the Correlation Between Twin Pregnancies and Perinatal Outcome in Association to the Impact of Preterm Birth.

Background: Twin pregnancies make up 2% to 4% of all births. Incidence of spontaneous twin pregnancies varies around the world, with percentages ranging from 8/1000 to >17/1000 births. The variation in twin pregnancy rates is thought to be due to dizygotic pregnancies, since monozygotic pregnancies have a consistent incidence of 3.5/1000 to 4/1000 births. The incidence of twin pregnancies after the widespread use of assisted reproduction has increased significantly. Objective: The purpose of the present study is to investigate factors , who contribute to improve the perinatal outcome in twin pregnancies. Support will be provided by the results of twin pregnancies by the Department of Obstetrics and Gynaecology of Demokrition University of Thrace (Alexandroupolis, Greece) in the last fifteen years. Methods: From the above Department, data were collected on the number of twin pregnancies, maternal age, gestational age, mode of delivery (spontaneous delivery or caesarean section), birth weight and rate of twin pregnancies with assisted reproduction. Results: The results showed the increasing trend of twin pregnancies and births. A total of 304 twin pregnancies were identified (rate 2.75%). The rate of assisted reproduction was 34.83% in our sample, while the rate of cesarean deliveries was 95.5%, showing a large increase in recent years. In ten cases, normal delivery was successfully performed. The gestational age in twin pregnancies that ended with normal delivery was 37.37 + 3 weeks and the fetuses were both cephalic presentations. The main reason for admission of newborns to the NICU Department was prematurity. Conclusion: The constantly improving education of perinatalists and understanding of the pathophysiology may lead to individualization of their treatment, and improvement of their prognosis based on recent scientific data from other international centers.

Comparison of Gut Microbiome in Neonates Born by Caesarean Section and Vaginal Seeding with Gut Microbiomes of Neonates Born by Caesarean Section Without Vaginal Seeding and Neonates Born by Vaginal Delivery.

Background: Pregnancy is an admirable biological process, resulting in significant changes in many of the body's normal systems so that they can support the development of the fetus. These changes involve hormonal changes, weight gain, immune system regulation, and others that need to be synchronized to maintain both maternal and fetal health. Objective: The purpose of this study was to compare gut microbiome in neonates born by caesarean section and vaginal seeding with gut microbiomes of neonates born by caesarean section without vaginal seeding and neonates born by vaginal delivery. Methods: In Democritus University of Thrace, from 2019 to 2022, gut microbiomes were compared for three groups of neonates. Group A included 110 neonates born by CS who underwent vaginal seeding, group B included 85 neonates born by CS without vaginal seeding and group C included 95 neonates born by vaginal delivery. Results: Vaginal seeding in neonates born with CS resulted in gut microbiome which was similar to the gut microbiome of neonates born by vaginal delivery (including lactobacillus species and bacteroides). On the contrary, gut microbiome of neonates born by CS without vaginal seeding was "limited". Conclusion: According to our findings, vaginal seeding alters the gut microbiome of the neonates born with CS. However, there is a need for further investigation to prove its efficacy and its safety for the neonate.

Our Experience with Hydrogel-Coated Trisacryl Microspheres in Uterine Artery Embolization for the Treatment of Symptomatic Uterine Fibroids and Adenomyosis: A Follow-Up of 11 Years.

Uterine artery embolization (UAE) for the treatment of symptomatic uterine fibroids and non-controllable adenomyosis symptoms is a relatively new procedure for organ-preserving therapy. These benign conditions can become symptomatic in about 30% of women between the ages of 35 and 50. The purpose of the UAE either for fibroids or adenomyosis is the elimination of blood loss, the reduction in pain, and bulky or rectal pressure symptoms. The purpose of this study is to present our experience in UAE with the use of hydrogel-coated tris acryl microspheres for the treatment of symptomatic uterine fibroids and adenomyosis.

A Retrospective Study of Various Iron Preparations Oral Administration in Pregnant Women with Iron Deficiency Anemia.

During pregnancy anemia is a common medical condition, with iron deficiency and megaloblastic anemia being the most common. The symptoms range from very mild to severe and if left without proper medical treatment, there can be serious consequences for both mother and fetus. The most frequent pregnancy problem is anemia. The term "Iron Deficiency Anemia" refers to erythropoiesis under conditions of absolute iron deficiency. This presupposes the depletion of iron stores in the body. Iron deficiency anemia or Sideropenic anemia is the most common form of anemia worldwide. Special attention must be given to nutrition during pregnancy. In the current retrospective study, it was evaluated the contribution of various iron preparations substitution during the pregnancy and puerperium.

Life Quality in Premenopausal Women after Embolization of Uterine Myomas.

Objectives: Fibroids cause significant morbidity and are the most common indication for hysterectomies worldwide, delimiting a major public health problem. Uterine artery embolization (UAE) is an alternative therapy to surgical treatment of symptomatic fibroids; it has satisfactory long-time results and is no longer considered investigational for the treatment of symptomatic fibroids. This study was undertaken to evaluate changes in fibroid specific symptom severity and health-related quality of life (HRQOL) after UAE and to optimize the assessment of safety and outcomes measures for participants who receive UAE to objective compare UAE and surgical alternatives for therapy of symptomatic fibroids. Study design: The analysis was based on questionnaires completed by 270 pre-menopausal females with a mean age of 42 years (range, 38-50 years) who underwent UAE for uterine leiomyomas and/or adenomyosis from November 2013 through December 2019. Only symptomatic women were selected whose symptoms were not improving with medication and who did not wish to have children. The primary outcome measure was a change in fibroid symptoms and HRQOL (health related quality of life) after UAE. Secondary outcomes included the decrease in uterine volume after UAE. Results: Questionnaires were completed by 270 women (100%) at a mean of 12.1 months from UAE. The median follow-up period was two years. Uterine fibroid embolization led to a shrinkage at three months for the 90% of the participants. A reduction of bleeding symptoms, pain and bulk-related symptoms was observed in 89.7%, 88.9%, and 89.5% of the patients, respectively. In the long term, there was no significant difference in parameters assessed compared with the midterm follow-up findings. A total of 6 patients (2.3%) underwent fractional curettage an average of 32.1 months after intervention due to necrotic changes in submucosal fibroids. All participants continued to be satisfied with the intervention, and 240 patients (88.9%) answered that they would recommend uterine fibroid embolization to other patients. Conclusions: Women who undergo UAE have a significant decrease in symptom severity and increase in HRQOL which is associated with high levels of satisfaction with the procedure (even when subsequent therapies are pursued).

Breastfeeding and Breast Cancer Risk: Our Experience and Mini-review of the Literature.

Background: According to data from World Health Organization, breast cancer constitutes the second most common diagnosed malignancy after lung cancer and the second leading cause of death among women in 2020, worldwide. The protective role of breastfeeding in the emergence of breast malignancy has been mentioned in several studies, indicating the important part it can have in the effort of reducing breast cancer's incidence. Objective: To investigate a possible association between breastfeeding and breast cancer risk in Greek women. Methods: Totally, 391 women participated in our case-control retrospective study. In the case group included 238 women with breast cancer, while in control group 153 women without breast cancer who were enrolled in two breast clinics in Greece. All women were examined clinically and with breast ultrasound, while those older than 40 years old also with bilateral digital mammography. Results: The x2 (chi-square) test found a statistically significant reverse correlation between breast cancer and breastfeeding ⩾12 months (cumulative) (p = 0.001). It was observed that the percentages of patients who breastfed ⩾12 months were lower than those of healthy women. Conclusion: Breastfeeding and particularly the cumulative period of ⩾12 months is related to the maximum of the protection from breast cancer.

Overview of techniques to manage shoulder dystocia during vaginal birth.

Shoulder dystocia is an obstetric emergency which is unpredictable and complicates approximately 0.5-1% of vaginal births. This article discusses the risk factors and the associated fetal and maternal complications, while it is also an overview of techniques and algorithms to handle shoulder dystocia.

Embryonic Cell-free DNA in Spent Culture Medium: A Non-invasive Tool for Aneuploidy Screening of the Corresponding Embryos.

BACKGROUND/AIM: Preimplantation genetic testing (PGT) for chromosomal screening, based on embryo biopsy, has significant limitations. Cell-free DNA (cf-DNA) has been detected in spent culture medium (SCM), opening new horizons for the development of non-invasive PGT (ni-PGT). In this study, we evaluated the diagnostic performance of ni-PGT for aneuploidy (niPGT-A), comparing the results of trophectoderm biopsies (TE) and respective SCM from individually cultured embryos via Next Generation Sequencing (NGS). MATERIALS AND METHODS: Forty fresh embryos were analyzed. TE and SCM from blastocysts were collected and analyzed. RESULTS: We detected cfDNA in 100% of samples tested. The overall concordance rate between the ni-PGT-A and PGT-A was 27/33 (81.8%). The full concordance rate was 21/33 (63.6%). The aneuploidy agreement was 91.66%, and the euploidy agreement was 76.19%. CONCLUSION: We found a good accordance between TE and SCM analysis, suggesting that niPGT-A could be a reliable alternative for chromosomal abnormalities assessment of in vitro cultured embryos.

Expression of Delta Like Ligand 4 (DLL4) in endometrial carcinomas and tumor vasculature.

PURPOSE: Delta like ligand 4 (DLL4) is a transmembrane ligand of the Notch Signalling pathway, that regulates blood vessel sprouting and maturation. We investigated the expression of DLL4 in endometrial cancer. METHODS: DLL4 was assessed in the plasma (with ELISA) and tissues (with immunohistochemistry) 33 patients with endometrial cancer, treated with radical hysterectomy for stage I endometroid carcinoma. The angiogenic activity (AA) of endometrial cancer was quantified by assessing the CD31+ microvessel density (MVD) in the invading tumor front. Vascular maturation index (VMI), defined as the percentage of CD31+ microvessels expressing DLL4, was calculated as the ratio of the CD31+ MVD to the DLL4+ MVD. RESULTS: The angiogenic activity was directly related with the histological grade (p=0.01). The VMI ranged from 0.1 to 0.7 (median 0.34). The concentration of DLL4 in the plasma ranged from 55-81pg/ml (mean 62.8) before, and dropped to 55-62 (mean 58.2) after hysterectomy (p<0.05). DLL4 was also expressed by cancer cells in 17/33 cases. No correlation between DLL4-related parameters with histopathological variables was noted. CONCLUSION: This pilot study shows that DLL4 is overexpressed in endometrial cancer cells, vasculature and is also elevated in the plasma of a fraction of patients before surgery. The percentage of DLL4+ vessels in the penetrating sample ranged from 10-70%, indicating a large difference in the quality of angiogenesis produced between the endometrial tumors of the same histological type and differentiation.

Neonatal Birth Weight of the Woman as a Risk Factor for Breast Cancer in her Life: a Case-Control Bicentric Study.

BACKGROUND: It is a global fact that the birth weight is increasing during the years around the world and for this reason it is very important to be examined as a potential risk factor for breast cancer. According to data from World Health Organization, breast cancer is the second most frequent malignancy across the world, after lung cancer, in Europe including Greece in incidence and mortality for women between the ages 0-85 years old. OBJECTIVE: The aim of this study was to investigate a possible association between neonatal birth weight of the women and breast cancer risk in Greek women. Although that many studies concluded that birth weight is positively related with breast cancer reinforcing the theory that breast cancer may originate in utero, some studies found no association. Moreover, the results from previous studies are inconsistent maybe due to several factors such as the study design and the number of cases. METHODS: This study was a case-control retrospective bicentric study. The case group included 238 women with breast cancer, while the control group included 153 women without breast cancer who consulted in two breast clinics in Greece. In all women, a clinical examination and breast ultrasound were achieved. Moreover, digital bilateral mammography was performed in patients older than 40 years. RESULTS: According to Fisher's exact analysis, there is a statistically significant relationship between the higher women's neonatal birth weight and the risk for breast cancer (p<0.001). More specifically in the group of women with breast cancer, 61% of them had more than 3500 grams birth weight, in contrast with 7.8 % in the control group. In our cohort, women who had birth weight more than 3500 grams are more likely to develop breast cancer in their life. CONCLUSION: Our study trend to show that the increased neonatal birth weight may influence future risk of breast cancer. However, further studies with larger number of participants are needed in order to clarify the role of birth weight as a complementary risk factor of breast cancer.

Impact of SARS-CoV-2 on pregnancy outcomes (Review).

The impact of the pandemic outbreak associated with coronavirus 2019 disease (COVID-19) on pregnant women is of interest to obstetricians and gynecologists due to the vulnerability of this target group. In pregnant women and their infants, an exceptional clinical management is warranted. Current epidemiological findings provide information regarding the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant patients and potential adverse perinatal outcomes. Overall, these findings are a strong indication that an increased antenatal surveillance for pregnant patients infected with COVID-19 is warranted. The aim of the present narrative review was to summarize the data obtained to date regarding the health of women during pregnancy, as well as that of the fetus associated with the risk of severe infection due to COVID-19. The present review aimed to provide further insight into the effects of this pandemic on pregnancy, also providing the experience of the authors on this matter as an example.

Significance of changes in inflammatory parameters following uterine artery embolization in pre-menopausal females.

The purpose of the present study was to describe the course of changes in laboratory inflammatory markers following bilateral uterine artery embolization (UAE) as a treatment for leiomyomas and adenomyosis. The body temperature was measured and blood samples were collected to determine white blood cell (WBC) count and C-reactive protein (CRP) levels in 270 patients on the day prior to UAE and for up to 4 days post-embolization. Aside from a single case with a non-inflammatory complication, none of the other cases had any complications. Post-UAE leukocytosis with a mean maximum value of 10.8±3.5x109/l (range, 5.9-18.6x109/l) was observed one-year post-intervention. The mean leukocyte numbers were indicated to be higher on day 3 post-UAE. The CRP level was also increased post-UAE, with a mean maximum value of 7.75±3.5 mg/dl. Maximum levels were reached in 8 patients on the 2nd and in 11 patients on the 3rd post-operative day. The maximum pain score was ~5.5 and reached its lowest level at the end of the 12th week post-intervention. The present study did not consider an association between the embolic material used or uterus size with the level of treatment success. No complications were observed post-UAE; however, a significant increase in the WBC count was observed within the first 3 days, indicating mild leukocytosis.