Treatment of three pediatric AML co-expressing NUP98-NSD1, FLT3-ITD, and WT1.

During the treatment of 89 pediatric patients with Acute Myeloid Leukemia (AML) at the Hematology Department of Kunming Medical University's Children's Hospital from 2020 to 2023, three patients were identified to co-express the NUP98-NSD1, FLT3-ITD, and WT1 gene mutations. The bone marrow of these three patients was screened for high-risk genetic mutations using NGS and qPCR at the time of diagnosis. The treatment was administered following the China Children's Leukemia Group (CCLG)-AML-2019 protocol. All three patients exhibited a fusion of the NUP98 exon 12 with the NSD1 exon 6 and co-expressed the FLT3-ITD and WT1 mutations; two of the patients displayed normal karyotypes, while one presented chromosomal abnormalities. During the induction phase of the CCLG-AML-2019 treatment protocol, the DAH (Daunorubicin, Cytarabine, and Homoharringtonine) and IAH (Idarubicin, Cytarabine, and Homoharringtonine) regimens, in conjunction with targeted drug therapy, did not achieve remission. Subsequently, the patients were shifted to the relapsed/refractory chemotherapy regimen C + HAG (Cladribine, Homoharringtonine, Cytarabine, and G-CSF) for two cycles, which also failed to induce remission. One patient underwent Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HSCT) and achieved complete molecular remission during a 12-month follow-up period. Regrettably, the other two patients, who did not receive transplantation, passed away. The therapeutic conclusion is that pediatric AML patients with the aforementioned co-expression do not respond to chemotherapy. Non-remission transplantation, supplemented with tailor-made pre- and post-transplant strategies, may enhance treatment outcomes.

Application of Free Flaps in Reconstruction of Head and Neck Soft Tissue Defects With Bone Exposure.

BACKGROUND: Reconstruction of head and neck soft tissue defects with bone exposure is both challenging and technically demanding for plastic surgeon. Objectives in head and neck soft tissue defects with bone exposure reconstruction are consistent restoration of functionality while also improving appearance. This study retrospectively analyzed the results of head and neck reconstructions using various types of free flaps over the past 4 years. METHODS: A retrospective analysis was conducted from June 2019 to June 2023 on 12 patients treated at our hospital for head and neck soft tissue defects with bone exposure due to various causes. These included 4 cases of trauma from car accidents, 1 burn case, and 7 postoperative malignant tumor removals. The defect sizes ranged from 4 × 6 to 15 × 45 cm. Different free flaps were used for repair based on the defect, including 6 anterolateral thigh flaps, 3 forearm flaps, 2 latissimus dorsi flaps, and 1 dorsalis pedis flap. Flaps were designed and harvested to match the defect size and transplanted via anastomosed vessels. RESULTS: All 12 flaps survived successfully. One patient required flap thinning surgery postoperatively. All patients were followed up for over 3 months, showing good color and texture of the transplanted flaps, satisfactory healing, and significant aesthetic improvement. Donor sites showed significant scarring without functional impairment. CONCLUSION: Free flap repair for head and neck soft tissue defects with bone exposure is feasible and yields good results.

Hair follicle extraction combined with an expanded scalp flap for facial organ reconstruction.

BACKGROUND: Use of scalp skin for facial organ reconstruction represents a mainstream procedure for organ reconstruction. In most cases, adequate amounts of skin can be obtained by using tissue expanders, but harvesting sufficient scalp tissue in patients with low hairlines is challenging. Hair follicular unit extraction (FUE) is one approach to resolve this problem. With FUE, hair follicles are removed from the scalp skin, which can then be prepared as a donor site to obtain sufficient amounts of hairless skin. OBJECTIVES: To evaluate the safety and efficacy of FUE when combined with an expanded scalp flap for facial organ reconstruction. MATERIAL AND METHODS: Patients with low hairlines requiring facial organ reconstruction were selected for this study. The area of skin extension and hair removal were determined prior to surgery, a process which was performed in three stages. Stage I consisted of hair follicle removal using the FUE technique at the donor site. Stage II involved expander implantation using water injections. In Stage III facial organ reconstruction was completed. RESULTS: With the use of the FUE technique, hair follicles from the donor scalp were thoroughly removed and the donor scalp tissue was successfully expanded. Postoperatively, no evident scar formation at the reconstruction site or contracture of the expanded flap was observed. All patients were satisfied with the outcome of their reconstruction procedure. CONCLUSION: FUE provides a means for hair follicle removal from the donor site and can be employed to achieve a safe and effective procedure for facial reconstruction in patients with low hairlines.

GM-CSF improves endometrial receptivity in a thin endometrium rat model by upregulating HOXA10.

Endometrial receptivity is a prerequisite for the success of assisted reproduction. Patients with a consistently thin endometrium frequently fail to conceive, owing to low endometrial receptivity, and there are currently very few therapeutic options available. Our previous study demonstrated that intrauterine granulocyte-macrophage colony-stimulating factor (GM-CSF) administration resulted in a significant improvement in clinical pregnancy and implantation rates and was an effective means of increasing endometrial thickness on the day of embryo transfer in patients with thin endometrium. In order to explore the underlying process, an animal model with a thin endometrium was constructed, the homeobox A10 gene (HOXA10) was downregulated, and an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway (MAPK/ERK) was employed. Our findings strongly suggest a marked decrease in GM-CSF levels in the thin endometrial rat model, and the suppression of HOXA10 impeded the therapeutic efficacy of GM-CSF in this model. Moreover, we showed that GM-CSF significantly increases endometrial receptivity in the rat model and upregulates HOXA10 via the MAPK/ERK pathway. Our data provide new molecular insights into the mechanisms underlying formation of a thin endometrium and highlight a novel, potential clinical treatment strategy as well as directions for further research.

Quantitative Analysis on Cartilage Growth Between Ipsilateral and Contralateral Donor Sites in Microtia Patients.

BACKGROUND: Costal cartilage harvest is required in patients with unilateral microtia when autologous reconstruction is being considered. However, whether an ipsilateral or contralateral donor site should be used remains controversial. This is the first study to compare cartilaginous growth between ipsilateral and contralateral donor sites in patients with unilateral microtia. METHODS: In this retrospective study of 58 patients, the lengths of the sixth to ninth costal cartilages and 3 position-defining measurements with respect to the sixth to ninth costochondral junctions were calculated using 3-dimensional costal cartilage imaging. Patients were divided into subgroups, and the lateral differences between isolated microtia and hemifacial microsomia and between the growing and adult age groups, were compared. RESULTS: In the isolated group, the sixth and seventh costal cartilages were longer on the contralateral side. The transverse dimension on the contralateral side, with respect to the sixth and seventh costochondral junctions, was also larger than that on the ipsilateral side in growing patients. However, no significant difference was observed between the 2 sides in the hemifacial microsomia group; there was also no difference between the age-related groups in this regard (P > 0.05). CONCLUSIONS: These findings suggest that age- and side-related differences in donor sites should be considered in patients with isolated microtia.

Clinical impact of c-KIT and CEBPA mutations in 33 patients with corebinding factor (Non-M3) acute myeloid leukemia.

BACKGROUND: Corebinding factor acute myeloid leukemia (CBF-AML) is the most common cytogenetic subtype of pediatric AML. CBF-AML is associated with a relatively favorable outcome, although the relapse rate of approximately 40% indicates a high degree of clinical heterogeneity. The clinical impact of additional cytogenetic aberrations, including c-KIT and CEBPA mutations, in pediatric CBF-AML has not been well characterized, especially in the multi-ethnic region of Yunnan Province in China. METHODS: In this study, we retrospectively analyzed the clinical features, gene mutations, and prognoses of 72 pediatric patients newly diagnosed with non-M3 AML in Kunming Children's Hospital, China, from January 1, 2015 to May 31, 2020. RESULTS: Of the 72 pediatric patients with AML, 46% (33/72) had CBF-AML. Thirteen patients with CBF-AML (39%) had c-KIT mutations, five (15%) had CEBPA mutations, and eleven (33.3%) had no other cytogenetic aberrations. The c-KIT mutations, resulting from single nucleotide substitutions and small insertions or deletions, occurred in exons 8 and 17. All of the CBF-AML-associated CEBPA mutations were single mutations and occurred in patients with RUNX1-RUNX1T1 fusion. We found no significant differences in the clinical data between CBF-AML patients with c-KIT or CEBPA mutations and CBF-AML patients without other aberrations, and no prognostic significance was established for these mutations. CONCLUSION: Our study is the first to report the clinical impact of c-KIT and CEBPA mutations in pediatric patients with non-M3 CBF-AML from the multi-ethnic Yunnan Province, China. c-KIT and CEBPA mutations occurred at a higher frequency in CBF-AML cases and were associated with unique clinical characteristics; however, no potential molecular prognostic markers were identified.

Poly (ɛ-Caprolactone-co-l,l-Lactide) Vascular External Sheath Carrying Prednisone for Improving Patency Rate of the Vein Graft.

Coronary artery bypass graft (CABG) surgery is an impactful treatment for coronary heart disease. Intimal hyperplasia is the central reason for the restenosis of vein grafts (VGs) after CABG. The introduction of external vascular sheaths around VGs can effectively inhibit intimal hyperplasia and ensure the patency of VGs. In this study, the well-known biodegradable copolymer poly (ɛ-caprolactone-co-l,l-lactide) (PLCL) was electrospun into high porosity external sheaths. The prednisone loaded in the PLCL sheath was slowly released during the degradation process of PLCL. Under the combined effects of sheath and prednisone, intimal hyperplasia was inhibited. For the cell experiments, all sheaths show low cytotoxicity to L929 cells at different concentrations at different time intervals. The ultrasonography and histological results showed prominent dilation and intimal hyperplasia of VG without sheath after 2 months of surgery. But there was no dilation in PLCL and PLCLPrednisone groups. Of note, the prednisone-loaded sheath group exhibited efficacy in inhibiting intimal hyperplasia and ensured graft patency. Impact statement To inhibit intimal hyperplasia after coronary artery bypass graft, the use of external vascular sheaths can prevent vein graft (VG) dilatation, then reduce turbulent blood flow shear stress to vessel wall, and lower the stimulation of shear stress to smooth muscle cells (SMCs), so as to prevent the proliferation and migration of vascular SMC. We provide a biodegradable sheath electrospun by poly (ɛ-caprolactone-co-l,l-lactide) (PLCL) loading prednisone and utilize it around VG in animal models. Vascular ultrasound examinations show strong evidence of vascular patency. The histological alterations of VGs in PLCLPrednisone group gave a narrower intima layer owing to the inhibition effect of prednisone.

Effects of TPMT, NUDT15, and ITPA Genetic Variants on 6-Mercaptopurine Toxicity for Pediatric Patients With Acute Lymphoblastic Leukemia in Yunnan of China.

Background: 6-Mercaptopurine (6-MP) is the cornerstone of current antileukemia regimen and contributes greatly to improve the survival of pediatric acute lymphoblastic leukemia (ALL) patients. However, 6-MP dose-related toxicities limit its application. TPMT, NUDT15, and ITPA are pharmacogenetic markers predicting 6-MP-related toxicities, but their genetic polymorphisms differ from those of ethnic populations. In Yunnan province, a multiethnic region of China, we had no genetic data to predict 6-MP toxicities. In this study, we evaluated the most common variants involved in 6-MP metabolism-TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) variants-in our cohort of pediatric ALL patients. Methods: A total of 149 pediatric ALL patients in the Affiliated Children's Hospital of Kunming Medical University (Yunnan Children's Medical Center) from 2017 to 2019 were enrolled in this retrospective study. We assessed the TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) frequencies and evaluated association between genotypes and 6-MP toxicities, 6-MP dose, and event-free survival (EFS) in these ALL patients. Results: The allele frequencies of TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) were 1.34%, 14.43%, and 18.79%, respectively. Only NUDT15 c.415C>T (rs116855232) was strongly associated with 6-MP toxicity and 6-MP tolerable dose. NUDT15 c.415C>T was related to leukopenia, p = 0.008, OR = 2.743 (95% CI: 1.305-5.768). The T allele was significantly correlated with 6-MP tolerable dose, dose of NUDT15 c.415C>T wild genotype CC 39.80 ± 1.32 mg/m2, heterozygotes CT 35.20 ± 2.29 mg/m2, and homozygotes TT 18.95 ± 3.95 mg/m2. 6-MP tolerable dose between CC and TT had a significant difference, p = 0.009. Between CC and CT, and CT and TT, they had no significant difference. EFS showed no significant difference among NUDT15 c.415C>T genotypes. Conclusion: NUDT15 c.415C>T (rs116855232) was an optimal predictor for 6-MP toxicity and tolerable dose in pediatric ALL patients from Yunnan province, a multiethnic region in China, and would play an important role in precise therapy for ALL.

Computer-assisted mandibular curved osteotomy: An automatic method to design the new aesthetic gonion and osteotomy line.

BACKGROUND: Digital technology has been widely used in mandibular curved osteotomy to improve accuracy. However, the planning process still highly dependent on the experience and judgement of the surgeon. This study describes an automatic method to design the new gonion and osteotomy line based on the aesthetic standards in attractive women, and assesses its clinical outcomes. METHODS: An automatic surgical planning method for mandibular curved osteotomy was developed based on our previous research of mandibular angle aesthetics. A prospective clinical study was conducted from April 2016 to April 2018. Twenty-five female patients with prominent mandibular angle were enrolled. Pre- and postoperative skull computed tomography (CT) was performed. Three-dimensional (3D) CT data were obtained and processed by Mimics 18.0. Surgical templates were designed according to the automatic surgical planning method and 3D printed for the surgery. Preoperative measurements, surgical simulation and postoperative measurements were taken to evaluate the surgical outcomes. RESULTS: There were significant differences between the preoperative and the postoperative groups' results (p < 0.01). There was no difference between the surgical simulation and the postoperative results. All postoperative measurements were consistent with aesthetic features of mandibles. Patients were satisfied with their outcomes in terms of outline, symmetry and lower facial width. CONCLUSIONS: Our study developed an automatic method to position the new aesthetic gonion and osteotomy line for prominent mandibular angle patients. We proved that this method is safe, effective and reliable.

Novel biallelic mutations in MEI1: expanding the phenotypic spectrum to human embryonic arrest and recurrent implantation failure.

STUDY QUESTION: Are any novel mutations and corresponding new phenotypes, other than recurrent hydatidiform moles, seen in patients with MEI1 mutations? SUMMARY ANSWER: We identified several novel mutations in MEI1 causing new phenotypes of early embryonic arrest and recurrent implantation failure. WHAT IS KNOWN ALREADY: It has been reported that biallelic mutations in MEI1, encoding meiotic double-stranded break formation protein 1, cause azoospermia in men and recurrent hydatidiform moles in women. STUDY DESIGN, SIZE, DURATION: We first focused on a pedigree in which two sisters were diagnosed with recurrent hydatidiform moles in December 2018. After genetic analysis, two novel mutations in MEI1 were identified. We then expanded the mutational screening to patients with the phenotype of embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss, and found another three novel MEI1 mutations in seven new patients from six families recruited from December 2018 to May 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine primary infertility patients were recruited from the reproduction centers in local hospitals. Genomic DNA from the affected individuals, their family members, and healthy controls was extracted from peripheral blood. The MEI1 mutations were screened using whole-exome sequencing and were confirmed by the Sanger sequencing. In silico analysis of mutations was performed with Sorting Intolerant From Tolerant (SIFT) and Protein Variation Effect Analyzer (PROVEAN). The influence of the MEI1 mutations was determined by western blotting and minigene analysis in vitro. MAIN RESULTS AND THE ROLE OF CHANCE: In this study, we identified five novel mutations in MEI1 in nine patients from seven independent families. Apart from recurrent hydatidiform moles, biallelic mutations in MEI1 were also associated with early embryonic arrest and recurrent implantation failure. In addition, we demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1. LIMITATIONS, REASONS FOR CAUTION: Owing to the lack of in vivo data from the oocytes of the patients, the exact molecular mechanism(s) involved in the phenotypes remains unknown and should be further investigated using knock-out or knock-in mice. WIDER IMPLICATIONS OF THE FINDINGS: Our results not only reveal the important role of MEI1 in human oocyte meiosis and early embryonic development, but also extend the phenotypic and mutational spectrum of MEI1 and provide new diagnostic markers for genetic counseling of clinical patients. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Development Program of China (2018YFC1003800, 2017YFC1001500, and 2016YFC1000600), the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, and 81971382), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Shanghai Health and Family Planning Commission Foundation (20154Y0162), the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine, Ferring Pharmaceuticals and the Chinese Academy of Sciences (FIRMC200507) and the Chongqing Key Laboratory of Human Embryo Engineering (2020KFKT008). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.

BACKGROUND: Observational retrospective data suggest that an artificial cycle frozen embryo transfer may be associated with a higher risk of hypertensive disorder of pregnancy than a natural cycle frozen embryo transfer among women with regular ovulatory cycles. The corpus luteum, which is not present in the artificial frozen cycles, is at least partly responsible for this poor obstetrical outcome. However, an artificial cycle is the most frequently used regimen for women with polycystic ovary syndrome undergoing frozen embryo transfer. Whether the risk of hypertensive disorder of pregnancy could be mitigated by employing physiological frozen embryo transfer protocols that lead to the development of a corpus luteum in patients with polycystic ovary syndrome remains unknown. OBJECTIVE: This study aimed to investigate the impact of letrozole use during frozen embryo transfer cycles on obstetrical and perinatal outcomes of singleton and twin pregnancies compared with artificial frozen cycles among women with polycystic ovary syndrome. STUDY DESIGN: This retrospective cohort study involved women with polycystic ovary syndrome who had undergone artificial frozen cycles or letrozole-stimulated frozen cycles during the period from 2010 to 2018 at a tertiary care center. The primary outcome was the incidence of hypertensive disorder of pregnancy. A multivariable logistic regression analysis was performed to control for the relevant confounders. RESULTS: A total of 2427 women with polycystic ovary syndrome were included in the final analysis. Of these women, 1168 underwent artificial cycles and 1259 underwent letrozole treatment, of which 25% of women treated with letrozole alone and 75% of women receiving letrozole combined with gonadotropins. After controlling for maternal characteristics and treatment variables, no significant difference was noticed regarding gestational diabetes mellitus, abnormal placentation, and preterm premature rupture of membranes between groups in both singleton and twin pregnancies. For birth outcomes, the prevalence rates of preterm birth, perinatal death, and birthweight outcomes were all comparable between groups in both singletons and twins. However, singleton pregnancies resulting from letrozole-stimulated cycles had a lower risk of hypertensive disorder of pregnancy than those conceived by artificial cycles (adjusted odds ratio, 0.63; 95% confidence interval, 0.40-0.98). Furthermore, a decreased risk of hypertensive disorder of pregnancy was seen among women with twin deliveries resulting from letrozole-stimulated cycles vs artificial cycles (adjusted odds ratio, 0.52; 95% confidence interval, 0.30-0.87). In addition, the cesarean delivery rate was significantly lower for singletons but not for twins in the letrozole group compared with pregnancies from the artificial cycle group (adjusted odds ratio, 0.63; 95% confidence interval, 0.50-0.78, and adjusted odds ratio, 1.20; 95% confidence interval, 0.65-2.23, respectively). CONCLUSION: In women with polycystic ovary syndrome undergoing frozen embryo transfer, letrozole use for endometrial preparation was associated with a lower risk of hypertensive disorder of pregnancy than artificial cycles for endometrial preparation. Our findings provided a foundation that the increased risk of hypertensive disorder of pregnancy associated with frozen embryo transfer might be mitigated by utilizing physiological endometrial preparation protocols that lead to the development of a corpus luteum, such as a mild ovarian stimulation cycle for oligo- or anovulatory women.

Novel mutations in LHCGR (luteinizing hormone/choriogonadotropin receptor): expanding the spectrum of mutations responsible for human empty follicle syndrome.

PURPOSE: To screen novel mutations in LHCGR responsible for empty follicle syndrome and explore the pathological mechanism of mutations. METHODS: Four affected individuals diagnosed with infertility-associated anovulation or oligo-ovulation from three independent families were recruited. Sanger sequencing was used to identify the LHCGR mutations in affected individuals. Western blot was performed to evaluate the effects of mutations on LHCGR protein levels. Immunofluorescence was done to explore the effects of mutations on LHCGR subcellular localization. The ATP levels were measured to infer the functional effects of the mutations on LHCGR. RESULTS: In the present study, three novel biallelic mutations in LHCGR were identified in four affected individuals from three independent families with empty follicle syndrome or oligo-ovulation. All biallelic mutations were inherited from the proband of their parents. The western blot showed that the identified mutations decreased LHCGR protein level and altered the glycosylation pattern. The immunofluorescence showed an ectopic subcellular localization of LHCGR in cultured HeLa cells. Besides, the mutations in LHCGR also reduced the cellular ATP consumption. CONCLUSION: These findings confirm previous studies and expand the mutational spectrum of LHCGR, which will provide genetic diagnostic marker for patients with empty follicle syndrome.

Therapeutic role of granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with persistent thin endometrium: A prospective and randomized study.

OBJECTIVE: To assess the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) on unresponsive thin (<7 mm) endometrium in women undergoing frozen-thawed embryo transfer. METHODS: A single-center, randomized, prospective study enrolled 304 women with thin unresponsive endometrium from Shanghai Ninth People's Hospital between March 2017 and May 2018. Of them, 161 patients received an intrauterine infusion of GM-CSF and 143 patients served as controls. After hysteroscopy, a gel with or without GM-CSF was administered to fill the uterine cavity completely or up to 5 mL only. The primary outcome was confirmed pregnancy and secondary outcomes included endometrial thickness and implantation rate. RESULTS: Patients who were administered GM-CSF had a significantly higher chemical pregnancy rate (35.3% vs 20.0%; P=0.009) and clinical pregnancy rate (28.6% vs 13.3%; P=0.005) compared with patients in the control group. Patients treated with GM-CSF had significantly higher endometrial thickness compared with controls (7.83 ± 1.45 mm vs 7.37 ± 0.70 mm, P=0.003). CONCLUSION: GM-CSF therapy can effectively increase endometrial thickness and improve the clinical pregnancy rate in patients with persistent thin endometrium. The therapeutic role of GM-CSF for infertile women under in vitro fertilization and embryo transfer (IVF-ET) treatment can be further explored. CHINESE CLINICAL TRIAL REGISTER: ChiCTR-IPR-17011242.

Oral exposure of sulpiride promotes the proliferation of Brown-Norway rat prostates.

The aim of the present study was to establish an animal model of prostatic hyperplasia to explore the mechanisms of this disease. Sulpiride, a specific type 2 dopamine receptor antagonist, causes prostate toxicity by stimulating prolactin (PRL) production. Male Brown-Norway (BN) rats were treated intragastrically (i.g.) with sulpiride (40 and 120 mg/kg daily) and vehicle (i.g., daily) for 4 weeks. The results demonstrated that sulpiride-treatment resulted in increased prostate size, prostate lobe weight, epithelial height and acinar luminal area. Furthermore, prostate lobe weight, epithelial height and acinar luminal area of lateral lobes (LP) significantly increased. These effects were dose dependent. Sulpiride treatment increased serum PRL, follicle-stimulating hormone and testosterone levels, while serum luteinizing hormone levels were reduced. Immunohistochemical analysis revealed that proliferating cell nuclear antigen and B-cell lymphoma-2 were significantly increased in certain sulpiride treated groups. Furthermore, estrogen receptor (ER)-α and androgen receptors were upregulated, while ERß was downregulated in LP. The expression of stromal cell biomarkers, including vimentin, fibronectin and α-smooth muscle actin were significantly increased in LP following 40 mg/kg sulpiride administration. These results suggest that sulpiride causes LP hyperplasia in BN rats by promoting proliferation and inhibiting prostate cell apoptosis via ERα and AR signaling.

Validity and reliability of three-dimensional costal cartilage imaging for donor-site assessment and clinical application in microtia reconstruction patients: A prospective study of 22 cases.

OBJECTIVES: This study assesses the ability to reconstruct costal cartilage images by using three-dimensional visualisation software (Mimics) based on semi-automated segmentation algorithm and to investigate its reliability and validity with an anthropometric analysis. DESIGN: Observational prospective study. SETTING: Plastic surgery department of a tertiary hospital. PARTICIPANTS: Twenty-two microtia patients who underwent autologous ear reconstruction. MAIN OUTCOME MEASURES: Preoperative thoracic computed tomography data were processed to Mimics software for three-dimensional costal cartilage imaging. The length, width, thickness and volume of the 9th costal cartilages were calculated from these images and compared with the direct measurements (DM) obtained intraoperatively. RESULTS: The intra-examiner reliability and inter-examiner reliability were high in terms of all four measurements (intraclass correlation coefficients, ICC: 0.876-0.984). There were no significant differences between image-based anthropometry and DM in the linear measurements except for the volume (P < .05). The mean volume calculation error of Mimics was -0.08 ± 0.13 mL. No correlation was found between the anthropometric variables and the absolute errors (P > .05). Furthermore, Bland-Altman plots were used to evaluate the agreement between the two methods. CONCLUSIONS: Despite a very small error was found in volume calculation, Mimics software was accurate and reliable in linear calculation. Three-dimensional costal cartilage imaging was found to be an efficient tool for morphological evaluation of costal cartilages. We believe that with the application of individualised cartilage models based on three-dimensional printing, the use of customised ear framework carving will be practicable in surgical training.

Effect of endometrial thickness on birthweight in frozen embryo transfer cycles: an analysis including 6181 singleton newborns.

STUDY QUESTION: Does endometrial thickness (EMT) have an impact on singleton birthweight in frozen embryo transfer (FET) cycles? SUMMARY ANSWER: An EMT <8 mm was associated with a lower mean birthweight and gestational age- and gender-adjusted birthweight (Z-scores) of singletons resulting from FET. WHAT IS KNOWN ALREADY: Previous studies have examined the impact of EMT on IVF success rates. Little is known, however, regarding the relationship between EMT and neonatal birthweight. STUDY DESIGN, SIZE, DURATION: This retrospective study involved singleton live births born to women undergoing frozen-thawed Day 3 embryo transfer during the period from January 2010 to December 2017 at a tertiary care centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 6181 women who fulfilled the inclusion criteria were included and were grouped into five groups depending on the EMT: <8 mm, 8-9.9 mm, 10-11.9 mm, 12-13.9 mm and ≥14 mm. EMT between 10 and 11.9 mm was taken as a reference group. Singleton birthweight was the primary outcome measure. A multivariable linear regression analysis was performed to detect a relationship between EMT and newborns' birthweight after controlling for a number of potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: A modest but significant decrease in birthweight was observed in the EMT <8 mm group as compared with groups with EMT ≥10 mm, with a mean difference of 89-108 g. Also, singletons from the EMT <8 mm group (0.24 ± 1.04) had a significantly lower birthweight Z-scores than those from the EMT 10-11.9 mm (0.41 ± 1.02; P = 0.032) or EMT 12-13.9 mm (0.46 ± 1.07; P = 0.004) groups. Further, multiple linear regression analyses indicated that parental BMIs, gestational age, newborn gender, pregnancy complications and EMT <8 mm were all independent predictors of neonatal birthweight. LIMITATIONS, REASONS FOR CAUTION: The present study was limited by its retrospective design. Future prospective studies are required to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provided new insight into the relationship between EMT and neonatal outcomes by showing that a thin endometrium is associated with a decrease in singleton birthweight. STUDY FUNDING/COMPETING INTEREST(S): National Key Research and Development Program of China (2018YFC1003000); the National Natural Science Foundation of China (81771533, 81571397, 31770989, 81671520); the China Postdoctoral Science Foundation (2018M630456). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Letrozole use during frozen embryo transfer cycles in women with polycystic ovary syndrome.

OBJECTIVE: To investigate whether live birth rate (LBR) following frozen-thawed embryo transfer in letrozole-stimulated cycles (L-FET) differs from LBR after artificial-cycle frozen-thawed embryos transfers (AC-FET) in women with polycystic ovary syndrome (PCOS). DESIGN: Retrospective cohort study. SETTING: Tertiary-care academic medical center. PATIENT(S): A total of 2,664 patients with PCOS who fulfilled the inclusion criteria were enrolled in the period from 2011 to 2016. INTERVENTIONS(S): Letrozole use versus hormone replacement therapies during FET. MAIN OUTCOME MEASURE(S): LBR per embryo transfer was the primary outcome. The secondary end points included ongoing and clinical pregnancy rate, cancellation rate, endometrial thickness, and pregnancy loss rate. Multivariable logistic regression analysis was performed to adjust for potential confounders. RESULT(S): In our crude analysis, LBR per embryo transfer was similar between groups (54.4% in the L-FET vs. 50.7% for the AC-FET). The crude odds of pregnancy loss was significantly lower in L-FET compared with AC-FET (9.1% vs. 17%). Nonetheless, after adjusting for possible confounding factors, LBR was significantly higher in L-FET compared with AC-FET. Moreover, the rates of pregnancy loss remained consistently lower in the L-FET group than in the AC-FET group. CONCLUSION(S): In patients with PCOS undergoing FET, letrozole use for endometrial preparation was associated with higher LBR compared with artificial cycles, albeit after statistical adjustment for confounding factors. Future prospective randomized studies are needed to verify our findings.

A pannexin 1 channelopathy causes human oocyte death.

Connexins and pannexins are two protein families that play an important role in cellular communication. Pannexin 1 (PANX1), one of the members of pannexin family, is a channel protein. It is glycosylated and forms three species, GLY0, GLY1, and GLY2. Here, we describe four independent families in which mutations in PANX1 cause familial or sporadic female infertility via a phenotype that we term "oocyte death." The mutations, which are associated with oocyte death, alter the PANX1 glycosylation pattern, influence the subcellular localization of PANX1 in cultured cells, and result in aberrant PANX1 channel activity, ATP release in oocytes, and mutant PANX1 GLY1. Overexpression of a patient-derived mutation in mice causes infertility, recapitulating the human oocyte death phenotype. Our findings demonstrate the critical role of PANX1 in human oocyte development, provide a genetic explanation for a subtype of infertility, and suggest a potential target for therapeutic intervention for this disease.

Effect of hysteroscopy before starting in-vitro fertilization for women with recurrent implantation failure: A meta-analysis and systematic review.

OBJECTIVE: To study if hysteroscopy (HSC) before starting an in-vitro fertilization (IVF) cycle improves IVF outcomes in women with recurrent implantation failure (RIF). METHODS: The Medline, Cochrane, EMBASE, and Google Scholar databases were searched using the following keywords until March 31, 2017: in-vitro fertilization; infertility; hysteroscopy; recurrence; embryo implantation; and pregnancy. Randomized controlled trials (RCTs), two-arm prospective studies, and retrospective studies were included. RESULTS: Three RCTs, 3 nonrandomized prospective studies, and 2 retrospective cohort studies were included. The eligible studies included 3932 women with RIF: 1841 in the HSC group and 2091 in the control group. The clinical pregnancy rate and implantation rate was significantly higher in the HSC group compared with the control group (for clinical pregnancy rate, pooled odds ratio [OR] = 1.64, 95% confidence intervals [CI]: 1.30-2.07, P < 0.001; for implantation rate, pooled OR = 1.22, 95% CI: 1.02-1.45, P = 0.025). The live birth rate (pooled OR = 1.30, 95% CI: 0.90-1.88, P = 0.168) and the miscarriage rate (pooled OR = 0.94, 95% CI: 0.66-1.35, P = 0.744) of the 2 groups were not statistically significantly. CONCLUSIONS: HSC improved the implantation rate and clinical pregnancy rates, but failed to improve live birth rate and did not affect the miscarriage rate in women with RIF undergoing IVF. Since HSC plays a significant role in pregnancy and birth outcomes of women with RIF, further studies are warranted.

Assessment of a Novel Standardized Training System for Mandibular Contour Surgeries.

IMPORTANCE: Mandibular contour surgeries (MCS) involving reduction gonioplasty and genioplasty are rewarding for patients with square faces; however, the procedure has inherently difficult clinician learning curves and unpredictable skill acquisitions. To our knowledge, there has been no effective, validated training model that might improve training and surgical outcomes for MCS. OBJECTIVE: To establish and evaluate a standardized intraoral MCS training system. DESIGN, SETTING, AND PARTICIPANTS: Intraoral MCS training models were constructed by 3-dimensional (3D) skull models covered with elastic head cloths. From April 2016 to April 2018, 90 consecutive MCS patients (30 per group) and 15 craniofacial surgery fellow physicians (5 per group) were enrolled in the prospective observational study. They were randomly divided into intervention groups (A and B) and a control group (C). Intervention groups A and B completed 5 training sessions on the intraoral MCS training models before each clinical case. Group A performed both the model training sessions and clinical surgeries with surgical templates. Control group C had no extra training before clinical surgeries. All groups completed clinical surgery under supervision on 6 patients. The duration of follow-up was at least 3 months postoperatively. INTERVENTIONS: Intraoral MCS training models were provided to intervention groups (A and B) before clinical surgeries. Surgical templates were provided to intervention group A both in training sessions and clinical surgeries. MAIN OUTCOMES AND MEASURES: The completion time, surgical accuracy, learning curves, operating confidence, surgical skill, and outcome satisfaction of each procedure were recorded and analyzed with paired t test and 1-way analysis of variance test by blinded observers. RESULTS: All 90 patients (14 men, 76 women; mean [SD] age, 26 [5] years) were satisfied with their postoperative mandible contours. The intervention groups (A and B), especially the group with surgical templates (A) showed improvements in clinical surgery time (mean [SD], group A 147.2 [24.71] min; group B, 184.47 [16.28] min; group C, 219.3 [35.3] min; P = .001), surgical accuracy (mean [SD], group A, 0.68 [0.22] mm; group B, 1.22 [0.38] mm; group C, 1.88 [0.54] mm; P < .001), learning curves, and operators' confidence and surgical skill. CONCLUSIONS AND RELEVANCE: The intraoral MCS training model was effective and practical. The optimal intraoral MCS training system included intraoral MCS training models and surgical templates. The system significantly decreased clinical surgery time, improved surgical accuracy, shortened the learning curve, boosted operators' confidence, and was associated with better acquisition of surgical skills. LEVEL OF EVIDENCE: NA.