OBJECTIVE:To characterize epidemiology, treatment efficacy, and prognosis in cervical cancer patients aged <25 years using SEER data and institutional validation, and propose personalized strategies. METHODS:We analyzed 73,869 SEER database patients (2000-2021), including 544 aged <25 years. Epidemiological trends, histology, and staging were assessed. Survival models compared 3-/5-year survival rates: surgical (n = 25) vs. non-surgical (n = 9) treatment for stage IB3; surgical (n = 18) vs. non-surgical (n = 4) for stage IIA2; and adjuvant chemotherapy (n = 51) vs. non-chemotherapy (n = 6) for stages IIIA-IIIB. Findings were validated against institutional data (n = 12; 2009-present). RESULTS:Among SEER Database, the proportion of young patients significantly declined from 1.36% (2004) to 0.39% (2021), with poorly differentiated carcinoma predominating (51.65%). Squamous cell carcinoma accounted for the majority (59.56%), rare histological subtypes accounted for (12.68%) including small cell neuroendocrine carcinoma and clear cell carcinoma, with notable prognostic implications. Most young patients presented with early-stage disease (77.94%, n = 298/424). For stage IB3, surgery yielded higher 3-year (84% vs 55.56%) and 5-year survival (80% vs 44.44%) than non-surgical management. Stage IIA2 comparisons showed conflicting trends (potentially due to small samples). In stages IIIA-IIIB, adjuvant chemotherapy was associated with trends toward improved survival, and cumulative risk analysis suggested a potential reduction in long-term mortality risk in the chemotherapy group versus non-chemotherapy. Institutional data mirrored SEER treatment patterns. Histologic subtype emerged as a critical prognostic determinant; Both institutional deaths occurred in patients with rare histologies (stage IVB small cell neuroendocrine carcinoma; stage IIB clear cell carcinoma), suggesting histology may represent an important prognostic factor, potentially interacting with stage. CONCLUSION:Most young cervical cancer patients present with early-stage, poorly differentiated disease. Surgery may be beneficial for early-stage (≤IIB) disease in selected patients localized disease, while concurrent chemoradiotherapy (CCRT) plus brachytherapy remains the standard for advanced stages (IIIA-IIIB); the role of Adjuvant chemotherapy did not demonstrate a significant survival benefit and should be interpreted with caution. Tumor histology may outweigh stage as a prognostic determinant in this population. These findings are exploratory and require validation in prospective studies.

Small-cell neuroendocrine cancer (SCNEC) of the uterine cervix is an exceedingly rare, highly aggressive tumor with an extremely poor prognosis. The cellular heterogeneity, origin, and tumorigenesis trajectories of SCNEC of the cervix remain largely unclear. We performed single-cell RNA sequencing and whole-exome sequencing on tumor tissues and adjacent normal cervical tissues from two patients diagnosed with SCNEC of the cervix. Here, we provide the first comprehensive insights into the cellular composition, HPV infection-related features, and gene expression profiles of SCNEC of the cervix at single-cell resolution. Correlation analyses suggested that SCNEC of the cervix may originate from squamous epithelial cells, and this observation was validated with bulk RNA-seq data from external cervical neuroendocrine cancer. Furthermore, sex-determining region Y-box 2 (SOX2), a key transcription factor that functions in direct neural differentiation, was located in the copy number gain region and highly expressed in neuroendocrine tumor cells from both patients. Notable, the distributions of the HPV-infected epithelium and SOX2 highly expressed epithelium were consistent with each other. Therefore, we supposed that high-risk HPV infection and amplification of SOX2 in the squamous epithelium may contribute to the progression of small-cell neuroendocrine tumorigenesis in the cervix.

目的 探讨不同法则对早期子宫内膜癌淋巴结转移风险的评估价值,以评价最优法则.方法 选取首都医科大学附属北京妇产医院2019年1月至2022年10月收治的158例子宫内膜癌患者,基于内膜活检病理和增强MRI检查,应用改良Mayo法则(病灶长径界值为2cm)及其调整法则(病灶长径界值为3、5cm)进行术前淋巴结转移风险分层,最终比较规范手术的病理分期.另外,应用ESMO及GOG-99法则,基于手术病理结果进行淋巴结转移风险分层并进行比较分析.结果 基于改良Mayo法则判定,158例患者中低危组90例,高危组68例.与手术病理结果进行比较发现,低危组有8例术后升级为高危,其中6例G3、2例ⅠB期;高危组有25例术后降级为低危,主要为宫腔肿瘤病灶长径＞2cm,但没有肌层浸润或浅肌层浸润,1例为术前外院增强MRI提示肌层浸润＞1/2,术后证实为浅肌层浸润.术前淋巴结转移风险评估的敏感度为76.6％、特异度为84.3％,阳性预测值(positive predictive value,PPV)为91.1％、阴性预测值(negative predictive value,NPV)为63.2％,将57.0％(90例)患者划为低风险人群.若将肿瘤病灶长径界值调整为3cm,淋巴结转移风险评估的敏感度为84.8％、特异度为89.1％,PPV为95.0％、NPV为70.7％,将63.3％(100例)患者划为低风险人群.若将肿瘤病灶长径界值调整为5cm,其特异度下降明显.本研究共发现36例淋巴脉管间隙浸润(lymphovascular space invasion,LVSI)阳性患者,占比为22.8％,其中ⅠA期17例(12.5％)、ⅠB期9例(75％)、Ⅱ期6例(100％)、ⅢC1期1例(100％)、ⅢC2期3例(100％).纳入LVSI指标的ESMO及GOG-99法则均为基于手术病理结果进行淋巴结转移风险分层,二者均准确预测了淋巴结转移患者.ESMO法则将55.0％(87例)患者划分为低危,其预测淋巴结转移的敏感度为100.0％、特异度为56.5％、假阳性率为43.5％、NPV为100％.GOG-99法则将80.4％(127例)患者划分为低危,其预测淋巴结转移的敏感度为100.0％、特异度为82.5％、假阳性率为17.5％、NPV为100％.相比ESMO法则,GOG-99法则使25.4％(40例)的患者避免了淋巴结清扫,并使假阳性率降低了26％.结论 采用经典的改良Mayo法则,将肿瘤病灶长径界值提升到3cm时,预期可获得更优的检测结果.采用ESMO及GOG-99法则时,摒弃肿瘤病灶长径指标,纳入更有检测效力的LVSI,并依据手术病理结果进行风险分层,可明显提升低危人群获益的比例,且具有更好的检测效果,尤其是GOG-99法则最具前景,值得进一步临床应用.

Objective: To investigate the clinical characteristics of patients with acute phosphine poisoning, and to follow up and evaluate the prognosis of patients. Methods: In May 2022, 12 patients with phosphine poisoning by respiratory inhalation in Beijing Chao-Yang Hospital of Capital Medical University were analyzed. The patients were treated with symptomatic support therapy. Three months later, patients were re-evaluated the symptoms of poisoning, pulmonary function and magnetic resonance imaging (MRI) of the brain to understand the prognosis of the phosphine poisoning. Results: The main symptoms of 12 patients were respiratory and central nervous system symptoms with hypoxia. The symptoms of poisoning improved after treatment. Follow-up found that the patients had different degrees of residual symptoms. Pulmonary function showed increased airway resistance. Airway challenge test was positive in some patients. MRI of the head of some patients showed small ischemic focus in bilateral frontal lobes. Conclusion: Acute phosphine poisoning may cause persistent damage to the respiratory system and central system, and residual symptoms after 3 months.

目的 探讨宫腔镜联合磁共振成像(magnetic resonance imaging,MRI)在术前对子宫内膜癌淋巴结转移进行风险分层的准确性,以进一步指导手术方案的制订.方法 本研究为前瞻性研究.选取2019年1月至2022年10月首都医科大学附属北京妇产医院收治的早期子宫内膜癌患者为研究对象,以系统手术的病理结果为金标准,分析宫腔镜诊刮病理联合MRI对早期子宫内膜癌淋巴结转移高危因素及风险分层的评估价值,同时探讨了前哨淋巴结(sentinel lymph node,SLN)检测淋巴结转移的准确性.结果 共158例患者纳入本研究.宫腔镜诊刮病理类型诊断的准确率为98.7％,组织学分级诊断的准确率为81.6％.MRI评估子宫肌层浸润的敏感度为99.1％,特异度为96.0％,评估宫颈间质受累的准确率为100％,1例宫颈黏膜受累未检出.宫腔镜联合MRI评估淋巴结转移风险的敏感度、特异度、阳性预测值、阴性预测值分别为87.2％、81.9％、85.2％、84.2％,87.2％,可将55.7％的患者划分为淋巴结转移低风险人群.SLN成功检出全部盆腔淋巴结转移,但未能检出腹主动脉旁淋巴结转移.结论 宫腔镜联合MRI评估子宫内膜癌淋巴结转移风险的准确性高,可将55.7％的患者划为低风险人群,使其免于淋巴结切除;联合SLN检测有望进一步提高淋巴结转移风险评估的准确性.

Background: An improved understanding of the clinical presentations, histological character, and therapeutic approaches relevant to ovarian Sertoli-Leydig cell tumors (SLCTs), is of value to better treat this disease. Methods: We reviewed the medical records of 18 ovarian SLCT patients seen in our center over the last 10 years. Combined with available literature, we conducted a retrospective study and analysis of this patient group. Results: We observed that the patients initially presented at ages ranging from 23 to 72 years, displayed various clinical disease manifestations, and all patients were diagnosed with stage I tumors. Most tumors were solid masses, unilateral lesions, and carried a favorable prognosis. Conclusions: Data gathered favor both improved clinical management and better prognostic for patients with SLCT.

目的 探讨紫杉醇联合卡铂新辅助化疗对局部晚期宫颈癌患者的疗效及其对免疫功能和远期预后的影响.方法 选取2015年3月至2018年12月首都医科大学附属北京妇产医院收治的74例局部晚期宫颈癌患者作为研究对象.随机分为观察组和对照组,每组37例.在行广泛性子宫切除术及盆腔淋巴结清扫术前,观察组采用紫杉醇联合卡铂新辅助化疗,对照组采用卡铂新辅助化疗.治疗后,比较两组的疗效.比较两组治疗前后CD3+、CD4+、CD8+水平并计算CD4+/CD8+.比较两组不良反应发生情况.采用Kaplan-Meier生存曲线分析预后.结果 观察组总有效率(81.08％)高于对照组(59.46％),差异具有统计学意义(P<0.05);治疗后,两组CD3+、CD4+、CD4+/CD8+均高于同组治疗前,CD8+低于同组治疗前,且观察组CD3+、CD4+、CD4+/CD8+均高于对照组,CD8+低于对照组,差异具有统计学意义(P<0.05);两组骨髓抑制、贫血、胃肠道反应、肝肾功能损害等不良反应发生率比较,差异无统计学意义(P>0.05);观察组总体生存率(64.86％)高于对照组(40.54％),差异具有统计学意义(P<0.05);观察组中位生存时间(38个月)大于对照组(30个月),差异具有统计学意义(P<0.05).结论 紫杉醇联合卡铂新辅助化疗用于局部晚期宫颈癌患者能够提高疗效,恢复免疫功能并改善远期预后.

目的 探讨负压引流装置在妇科恶性肿瘤开腹手术腹壁切口愈合中的作用.方法 选取2018年4月至2019年4月因妇科恶性肿瘤于首都医科大学附属北京妇产医院妇瘤科接受开腹手术的患者287例,根据切口缝合方式分为负压引流缝合组(试验组, 146例)和传统缝合组(对照组,141例).比较分析两组患者的临床资料、住院天数、切口感染、切口脂肪液化及甲级愈合等.结果 两组患者的年龄、术前血红蛋白、术后血红蛋白、体重指数、切口感染率差异无显著性(P＞0.05).与对照组相比,试验组患者手术切口脂肪液化率、二次缝合率均更低,住院天数更短,切口甲级愈合率更高,差异有显著性(P＜0.05).结论 负压引流装置可提高妇科恶性肿瘤开腹手术患者腹壁切口愈合率,降低切口脂肪液化及二次缝合率,缩短住院时间,提高患者生存质量,操作简单.

This study aims to evaluate the survival outcome between different postoperative radiation and chemotherapy modes in locally advanced cervical cancer (LACC).

目的 分析高危型人乳头瘤病毒(HR-HPV)阳性液基薄层细胞学检测( TCT)阴性女性的宫颈上皮组织病理学结果.方法 收集2015年5月至2018年6月就诊于首都医科大学附属北京妇产医院妇瘤科门诊的1 139例女性患者,其宫颈细胞学检查结果未见上皮内病变细胞或恶性细胞,HPV检查结果阳性.所有患者均取宫颈上皮组织进行病理检查及行阴道镜检查,并比较不同型别、不同年龄段HR-HPV感染患者及HPV单纯感染与多重感染患者的宫颈上皮组织病理检查结果.结果 不同分型HR-HPV感染患者的宫颈上皮内瘤变( CIN)Ⅱ级及以上病变检出率比较差异有统计学意义(P＜0. 01),其中宫颈炎症588例(51. 62% ),CINⅠ级387例(33. 98% ),CINⅡ～Ⅲ级153例(13. 43% ),宫颈癌11例(0. 97% ).不同年龄段患者的CINⅡ级及以上病变检出率比较差异无统计学意义(P＞0. 05). HPV16、HPV18、HPV52单纯感染与多重感染的CINⅡ级及以上检出率比较比较差异无统计学意义(P＞0. 05);HPV58单纯感染与多重感染的CINⅡ级及以上检出率比较差异有统计学意义( P＜0. 01).结论感染HPV16、HPV52、HPV58及25～39岁的女性宫颈上皮组织CINⅡ级及以上病变检出率较高.

Objective In this meta-analysis, we aimed to evaluate the oncological outcomes of preoperative neoadjuvant chemotherapy followed by radical surgery compared with radical surgery alone for treatment of International Federation of Gynecology and Obstetrics (FIGO) stage I–II cervical cancer. Method We searched for studies comparing the safety and efficacy of neoadjuvant chemotherapy plus surgery versus surgery alone in treatment outcomes of locally advanced cervical cancer. Meta-analysis was used to calculate the pooled odds ratios with corresponding 95% confidence intervals (CI). Results Sixteen studies were included in our analysis. Pooled analysis of overall survival rate [odds ratio (OR) = 1.09, 95% CI: 0.83–1.43] and progression-free survival rate (OR = 1.10, 95% CI: 0.77–1.57) showed that preoperative neoadjuvant chemotherapy did not have a benefit compared with surgery alone in terms of survival rates. The pooled results for postoperative parameters indicated that preoperative neoadjuvant chemotherapy followed by radical surgery was associated with a high rate of vascular space involvement (OR = 0.25, 95% CI: 0.17–0.35) and parametrial infiltration (OR = 0.60, 95% CI: 0.45–0.79). Conclusions This meta-analysis indicated that surgery following neoadjuvant chemotherapy for FIGO stage I–II cervical cancer and surgery alone had similar oncological outcomes.

Aim: This systematic review was designed to evaluate the efficacy of neoadjuvant chemotherapy with radical surgery vs radical surgery alone for cervical cancer. Methods: A computerized search was done for trials from PubMed, EMBASE, CENTRAL, and Cochrane Database of Systematic Reviews. The trials included neoadjuvant chemotherapy plus radical surgery vs radical surgery alone. We measured overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), local and distant recurrence, lymph node metastasis, and parametrial infiltration per patient. Results: In all, 13 studies involving 2,158 subjects were included. In regard to OS, DFS, PFS, local and distant recurrence, and parametrial infiltration, neoadjuvant chemotherapy plus radical surgery was similar to radical surgery alone. Among them, subgroup analysis of eight studies involving 1,544 patients with locally advanced cervical cancer (FIGO stage IB2-IIB) showed that neoadjuvant chemotherapy (NACT) plus radical surgery significantly improved OS, and decreased local and distant recurrence rates, lymph node metastasis rate, and the level of parametrial infiltration compared to radical surgery alone. Conclusion: The present study demonstrates that preoperative NACT is now an accepted effective procedure in selected patients with locally advanced cervical cancer (FIGO stage IB2-IIB). However, the relationship between NACT and longer DFS and PFS cannot be demonstrated by this meta-analysis. Thus, the decision to use or not to use NACT before radical surgery depends on the surgeon's experience and clinical judgment. Nevertheless, further research in this field is urgently needed to confirm it.

OBJECTIVES:We aimed to identify an optimal regimen for low-risk gestational trophoblastic neoplasia (LR-GTN) providing reduction in dosage and toxicity/side effects, enhancement of therapeutic efficacy, and a shorter treatment duration.METHODS:A total of 149 LR-GTN patients were enrolled in the affiliated Beijing Maternity Hospital of Capital Medical University from January 2014 to January 2017 and randomly divided into 3 groups with 50 cases in the methotrexate (MTX) group, 49 in actinomycin D (ACT-D) group, and 50 in ACT-D+MTX group. Follow-up recorded symptoms, physical and bimanual gynecological examinations, routine blood test, serum β-HCG level, liver and renal functions, electrolytes, electrocardiogram before each treatment course, and pelvic and abdominal B-mode ultrasound or pelvic/abdominal/chest computed tomography.RESULTS:Serum complete remission (SCR) was 96.0, 87.8, and 83.7% for the ACT-D+MTX, ACT-D, and MTX groups, respectively, with SCR being highest in the ACT-D+MTX group, statistically higher than in the MTX group. Vomiting was the only side effect differing significantly by chemotherapy regimen, with a distinctly higher incidence in the ACT-D+MTX group compared with the MTX group (p = 0.028). The reduction rate of serum β-HCG in the ACT-D+MTX group was significantly greater than in the other 2 groups.CONCLUSION:Combined ACT-D+MTX chemotherapy achieved overall better efficacy and showed less toxicity than ACT-D or MTX alone, and thus can be prioritized for the treatment of LR-GTN.

Objective: This study aimed to identify proteins related to paclitaxel and carboplatin chemoresistance in cervical cancer.Methods: Quantitative proteomic analysis was performed on normal SiHa cells and those treated with paclitaxel and carboplatin for 14 days, with isobaric tags for relative and absolute quantitation (iTRAQ) analysis.Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to identify related processes and differentially expressed proteins.Results: A total of 67 and 96 differentially expressed proteins were identified in the paclitaxel-and carboplatin-treated groups, respectively.GO and KEGG enrichment analyses identified 53 (43 upregulated and 10 downregulated) and 85 differentially expressed proteins (70 upregulated and 15 downregulated) in the paclitaxel-and carboplatin-treated groups, respectively.The cell counting kit-8 results revealed that APOA1 was overexpressed in both the paclitaxel-and carboplatin-resistant SiHa cells compared with the control cells.Immunohistochemistry showed that APOA1 was highly expressed in the paclitaxel-and carboplatin-resistant squamous cell carcinoma of the cervix. Conclusion:This study is the first to use iTRAQ to identify paclitaxel-and carboplatinresistance proteins in cervical cells.We identified several proteins previously unassociated with paclitaxel and carboplatin resistance in cervical cancer, thereby expanding our understanding of paclitaxel and carboplatin resistance mechanisms.Moreover, these findings indicate that the APOA1 protein could serve as a potential marker for monitoring and predicting paclitaxel and carboplatin resistance levels.

卵巢癌是常见的妇科恶性肿瘤,临床表现不典型,主要表现为腹胀、腹部肿物等,病理类型多样,异质性特征明显.肿瘤细胞系模型、转基因动物模型是最为常见的卵巢癌研究模型,应用其取得了长足的进步,但缺点明显.卵巢癌人源肿瘤异种移植瘤(PDX)模型为最新的卵巢癌研究模型,本文概述了卵巢癌PDX模型在卵巢癌研究中的应用基础及前景.

Placental site trophoblastic tumor (PSTT) is a rare trophoblastic tumor with complete hysterectomy as the primary treatment. Here the authors report one case received lesionectomy with fertility preserved under the patient's desire of reproduction. A 24-year-old woman was admitted because of four-month irregular vaginal bleeding following a natural delivery of a full-term baby nine months ago. As the tumor was confined to the uterus, a cross-wall wedge cut was made to remove the lesion together with 1 cm of surrounding healthy tissues. Immunohistochemistry of biopsy accorded with PSTT. No recurrence was evident during 15-month postoperative follow-up. Referring to literature, the authors recommend that patients with reproduction requirement with PSTT restricted to uterus could undergo a lesionectomy to retain fertility. Chemotherapy could be supplemental when high-risk factors exist.

目的 探讨乳腺癌术后服用他莫昔芬(TAM)对子宫内膜的病理影响.方法 收集2011年1月至2017年12月首都医科大学附属北京妇产医院收治的乳腺癌手术治疗患者共622例,术后197例服用TAM,其中59例患者因异常阴道流血或超声子宫内膜异常行宫腔镜诊刮术,将其分为绝经前组及绝经后组,以服药时间3年及5年为界值,分析子宫内膜病理情况.子宫内膜异常增生包括子宫内膜癌、子宫内膜不典型增生,其余为良性子宫内膜病变及正常子宫内膜,根据子宫内膜病理结果分析绝经前及绝经后超声诊断异常子宫内膜增生的标准.结果 乳腺癌术后服用TAM患者197例,其中59例行宫腔镜诊刮术,因异常阴道流血就诊者占32.2％(19/59),经病理证实有子宫内膜病变者占76.3％ (45/59),其中子宫内膜息肉的发生率最高;绝经前子宫内膜癌发生率为3.4％(1/29),子宫内膜不典型增生发生率为20.7％(6/29);绝经后子宫内膜癌发生率为20.0％ (6/30),无子宫内膜不典型增生的发生.TAM服用时间超过3年或5年,子宫内膜癌及不典型增生的发生率均增加(P＜0.05).绝经前子宫内膜厚度与子宫内膜异常增生有关(P=0.035),当超声子宫内膜厚度达15mm时可作为诊断绝经前异常子宫内膜增生的最佳超声诊断阈值;而绝经后子宫内膜厚度与子宫内膜异常增生无关(P=0.631).结论 乳腺癌术后服用TAM能够引起子宫内膜息肉及子宫内膜增生,绝经前患者亦有子宫内膜癌及不典型增生的发生,不可忽视对服用TAM绝经前妇女子宫内膜的监测.服用TAM时间超过3年者,需更加警惕子宫内膜病变的发生.绝经前超声子宫内膜厚度15mm可作为诊断异常子宫内膜增生的最佳超声诊断闽值;绝经后仍以超声子宫内膜厚度5mm作为子宫内膜异常增生标准.

目的 探讨不同部位注射吲哚菁绿在子宫内膜癌前哨淋巴结(sentinel lymph node,SLN)检测中的应用价值,探寻子宫内膜癌最优化的SLN示踪技术.方法 选取2016年1月至2018年9月于首都医科大学附属北京妇产医院接受手术治疗的临床Ⅰ—Ⅲ期子宫内膜癌患者89例,采用随机数字表法分为宫颈组(35例)和宫腔镜组(54例).术中分别将吲哚菁绿于宫颈和宫腔镜下多点注射,腹腔镜下观察显影的第一站淋巴结并将其切除单独送病理学检查,之后所有患者均规范行子宫、附件切除及系统盆腔+/-腹主动脉旁淋巴结切除术.比较两种方式用于子宫内膜癌SLN定位的检出率、阴性预测值、敏感度.结果 89例患者SLN检出率为57.3％,占切除淋巴结总数的9.2％.SLN最常位于髂外区(36.6％),然后依次为髂内(23.8％)、髂总(22.1％)、闭孔(9.3％)、腹主动脉旁(5.2％)和宫旁(2.9％).宫颈组SLN术中检出率为60％,阴性预测值为85.7％,敏感度为50％,宫腔镜组SLN检出率为55.6％,阴性预测值为82.6％,敏感度33.3％,两组间比较差异无显著性(P>0.05).结论 子宫内膜癌患者术中使用吲哚菁绿识别SLN对淋巴结清扫范围有指导意义,宫颈与宫腔两种注射方式均可行,检出率没有明显差异.

目的 探讨宫腔镜在葡萄胎治疗中的临床价值.方法 回顾性分析宫腔镜下行清宫术的42例葡萄胎患者的临床资料,分析治疗结局.结果 42例患者中,5例患者为第1次宫腔镜监测下行清宫术,术后病理证实为葡萄胎,术后血人绒毛膜促性腺激素(β-HCG)平均38.25天降至正常.37例患者为葡萄胎清宫术后的患者,超声提示宫腔残留,行宫腔镜下再次清宫术,术后血β-HCG平均45.49天降至正常.42例患者手术顺利,均为宫腔镜下一次性清除干净,无手术并发症的发生.结论 宫腔镜下葡萄胎再次清宫术,安全有效;宫腔镜应用于葡萄胎首次清宫术需进一步研究.