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Abstract Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings reveal dysfunction of BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals.

Objective: To demonstrate the surgical techniques employed in the robotic single port (SP) transvaginal natural orifice transluminal endoscopic surgery (RSP-vNOTES) for hysterectomy utilizing a domestically developed robotic system in China. Methods: We performed two cases of RSP-vNOTES hysterectomy for patients presenting with persistent vaginal bleeding resulting in atypical endometrial hyperplasia per endometrial biopsy. Procedures were initiated with traditional TVH and seamlessly transitioned to the robotic platform when necessary to complete the entire process. The robotic docking process was executed smoothly. Two elbowed instruments, a bipolar grasper, a pair of monopolar scissors, and a facing-upward camera were used. The hysterectomies were carried out precisely, without complications. Bilateral salpingo-oophorectomy was performed in the first patient and bilateral salpingectomy in the second. The vaginal cuff was closed continuously through a transvaginal approach after undocking. Results: Both patients were discharged on the third postoperative day, with satisfactory surgical results and no complications. Conclusions: The domestically developed Chinese Robotic SP system demonstrates feasibility for RSP-vNOTES procedures of hysterectomy. This approach amalgamates the advantages of both vaginal and robotic surgeries, incorporating surgical triangulation with an elbowed function that simplifies surgical manipulation. However, further studies with larger sample sizes and potential comparative analyses are essential to validate the merits and safety of adopting this platform.

Transvaginal Natural Orifice Transluminal Endoscopic Surgery (NOTES) has become popular since its inception in 2012, offering advantages by combining vaginal surgery principles with laparoscopic instruments for procedures like hysterectomy and myomectomy. The da Vinci Xi robotic system for transvaginal NOTES has been used successfully in over 300 cases, including advanced surgeries like sacrocolpopexy and endometriosis procedures. The new da Vinci SP platform, designed for single-port surgery, was employed in the first transvaginal NOTES hysterectomy on November 11, 2023, at Baylor College of Medicine. The surgical steps and outcomes of the procedure are detailed in this case report, showcasing the feasibility and success of utilizing the da Vinci SP system for transvaginal NOTES. The patient was discharged on the same day with an unremarkable post-operative course, and pathology results revealed adenomyosis and endometriosis after the comprehensive surgery.

The safety assessment and control of large-diameter pipelines under tunnel blasting at ultrasmall clear distances is a significant problem faced in construction. However, there has been no reference case for the quantitative comparison of the disturbance degree of surrounding rock by using two blasting schemes of non-electric detonator design and electronic detonator design under a similar total blasting charge consumption. In this study, the blasting test was carried out based on the engineering background of drilling and blasting methods to excavate the tunnel under the water pipeline at a close distance. The peak particle velocity (PPV), stress, and deformation responses of the pipeline under the two construction methods of non-electric and electronic detonators were comparatively analyzed. The PPV can be remarkably reduced by 64.2% using the hole-by-hole initiation of the electronic detonators. For the large-diameter pipeline, the PPV on the blasting side was much larger than that on the opposite side because the blasting seismic wave propagated a longer distance and attenuated more rapidly, owing to its greater cavity vibration reduction effect. The PPV of the electronic detonators decayed more slowly than that of the non-electric detonators. The cumulative damage caused by consecutive hole-by-hole blasting using electronic detonators was less than that caused by simultaneous multi-hole initiation using non-electric detonators, with a reduction of about 50.5%. When the nearest peripheral holes away from the pipeline are detonated, the cumulative damage variable D and damage range increase rapidly. The PPV, dynamic tensile strength, and cumulative damage variables were used to evaluate the safety of the pipelines.

Intervertebral disc (IVD) degeneration is an age-related disease affecting the elderly population worldwide. The disease is contributed by degeneration of the cartilage tissue in the vertebral column. The current study explores the possibility of exploiting platelet derived growth factor (PDGF), a growth factor secreted by platelets, as a therapeutic agent against the IVD degeneration. BALB/c mice were exposed to nicotine at higher concentrations to induce IVD degeneration. Three different concentrations of PDGF (1 ng/mL, 2 ng/mL, 3 ng/mL) were used in the study. Oxidative stress parameters were assessed through Lipid peroxidation (LPO), Myeloperoxidase (MPO) and Nitric oxide (NO). Histopathology was done for assessing the extent of degeneration, collagen II, mucin, and calcium deposition by Haematoxylin and Eosin staining, immunohistochemistry, Alcian blue and Alizarin red staining respectively. Gene expression studies were carried out by quantitative real-time Polymerase chain reaction (RT-PCR) for Aggrecan, alkaline phosphatase, RUNX2, Collagen I alpha and osteocalcin. IVD degeneration was prominent and PDGF treatment restored the tissue as evidenced by H&E staining. Oxidative stress was induced by the nicotine treatment and all the biomarkers of oxidative stress were restored back to normal by PDGF in a dose dependent manner. Biomarkers of endochondral bone formation (aggrecan, alkaline phosphatase, RUNX2, Collagen I alpha and osteocalcin) was observed to be normalized by exposing to PDGF in mRNA level though RT-PCR. Mucin, calcium contents were also brought back to normal by PDGF treatment. In conclusion, current work strongly supports that PDGF could be used as a therapeutic agent for the treatment of IVD degeneration.

In the process of deep underground rock excavation, the surrounding rock of cave wall often causes some rockburst geological disasters due to the weakening of structural plane. In order to reveal the influence of the existence of structural plane on the rockburst induction mechanism, in this paper, adopting the finite element and discrete element coupled GDEM numerical simulation technology, the influences of the number and scale of vertical structural planes on the mechanical characteristics of rock cracking propagation, stress, displacement and slab velocity of deep hard rock straight arch tunnel under excavation and unloading are studied, and the evolutionary mechanism between wall cracking and structural plane rockburst is revealed. Results indicate that the failure modes and intensity for the surrounding rock with multiple structural planes are associated with the controlling effect of the structural plane, especially within 1.5 m away from the tunnel side, and the weak plane can act as the boundary of the rockburst cater. The uneven distribution of the tangential stress and the eccentric compression of the rock plates separated by the weak plane will induce intense slabbing rockburst. The size of the structural plane will also affect the intensity of the surrounding rock failure, and the stress transfer to the deep rockmass will be impeded. Three-jointed rock slab with large scale and high flexibility has high end load strength and obvious buckling effect of rock slab, which leads to radial internal rock slab buckling and triggering shear instability failure at the end of side wall surrounding rock slab and strong rock burst. However, with the small and medium scale three-jointed slab, the flexibility of the rock plate is small and the rock plate is stable, leading to the quasi-static brittle failure of the surrounding rock, and forming a small V-type destructive fracture port.

Vibration induced by near-field tunnel blasting can easily damage the surrounding rockmass. The vibration response, damage characteristics and attenuation law in front and rear of the tunnel face were studied under different types of holes blasting. A new prediction method for the near field PPV was proposed based on the far field monitoring data. The results showed that the maximum PPV of the surrounding rockmass near the tunnel face was generated by the peripheral holes blasting, and the propagation distance was the key influencing factor. In contrast, the maximum PPV away from the tunnel face was generated by cutting holes blasting, and the conditions of blasting free face and the charge weight had a greater influence than the propagation distance. Due to the cavity amplification effect of the excavated tunnel behind the tunnel face within a certain range of 2–6 m, the blasting seismic wave produces superposition in the vault behind the tunnel face. The vault PPV behind the tunnel face attenuated rapidly in the range of 0–2 m, then increased slightly in the range of 2–6 m, and then decreased slowly with the increase of propagation distance. By introducing the amplification coefficient, a modified formula was proposed to predict the near field PPV using the far-field monitoring data, which had effectively improved the prediction accuracy.

Drilling and blasting is still the most widely used method for tunnel excavation in hard rocks. However, this method causes damage to adjacent buildings and structures mainly because of tunnel blast-induced vibrations. Currently, no specific guidelines are available for optimizing the design of damping holes during controlled blasting. Therefore, this study analyzes the vibration reduction mechanism of damping holes. Six key factors, namely, hole radius, hole spacing, coverage length, arrangement type, number of rows, and row spacing, that can affect the blasting vibration reduction were analyzed theoretically. Six groups of 30 numerical models were established using LS-DYNA. The influences of the six factors on the average and maximum velocities and stress vibration reduction were analyzed to quantitatively evaluate their damping effects. Then, optimization design suggestions for damping holes were proposed. The results revealed that it is necessary to increase the hole diameter and reduce the hole and row spacings as much as possible. The reasonable coverage length of damping holes is 1.5 times the coverage length of blasting holes. The blossom-type arrangement is recommended for practical engineering applications and the number of rows of damping holes should not exceed four. Guidelines for reducing vibration in adjacent tunnel blasting were formulated. Finally, the optimized damping hole design was applied to a typical tunnel project, which verified its reasonability and applicability.

Spinal cord injury could cause irreversible neurological dysfunction by destroying the blood-spinal cord barrier (BSCB) and allowing blood cells like neutrophils and macrophages to infiltrate the spinal cord. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) found in the human umbilical cord have emerged as a potential therapeutic alternative to cell-based treatments. This study aimed to investigate the mechanism underlying the alterations in the BSCB permeability by human umbilical cord MSC-derived sEVs (hUC-MSCs-sEVs) after SCI. First, we used hUC-MSCs-sEVs to treat SCI rat models, demonstrating their ability to inhibit BSCB permeability damage, improve neurological repair, and reduce SCI-induced upregulation of prepro-endothelin-1 (prepro-ET-1) mRNA and endothelin-1 (ET-1) peptide expression. Subsequently, we confirmed that hUC-MSCs-sEVs could alleviate cell junction destruction and downregulate MMP-2 and MMP-9 expression after SCI, contributing to BSCB repair through ET-1 inhibition. Finally, we established an in vitro model of BSCB using human brain microvascular endothelial cells and verified that hUC-MSCs-sEVs could increase the expression of junction proteins in endothelial cells after oxygen-glucose deprivation by ET-1 downregulation. This study indicates that hUC-MSCs-sEVs could help maintain BSCB’s structural integrity and promote functional recovery by suppressing ET-1 expression.

Abstract Background Endometriosis is an estrogen-dependent inflammatory reproductive disease. Therefore, systematic estrogen depletion and anti-inflammatory drugs are the current treatment for endometriosis. However, current endometriosis treatments have low efficacy and cause adverse effects in endometriosis patients. Consequently, alternative endometriosis treatments targeting endometriosis-specific factors are in demand. In this context, ERβ was selected as a druggable target for endometriosis due to its critical role in progression. Therefore, selective targeting of ERβ without inhibiting ERα activity would be a new paradigm for endometriosis treatment to overcome the low efficacy and adverse effects of hormonal endometriosis therapy. Methods Cell-based ERβ and ERα activity assay systems were employed to define a selective ERβ-inhibiting chemical product from a library of natural products. A surgically induced endometriosis mouse model was used to determine whether an ERβ inhibitory drug suppressed endometriosis progression. Mice with endometriosis were randomly separated and then orally treated with vehicle or 25 mg/kg oleuropein (once a day for 21 days), an ERβ inhibitory drug. The volume of endometriotic lesions or luciferase activity of endometriotic lesions was examined to define the growth of ectopic lesions in mice with endometriosis. The metabolite and levels of metabolic enzymes of the liver and kidney were determined in the serum of female mice treated with vehicle and oleuropein (25 mg/kg, once a day for 21 days) to define the toxicity of oleuropein. The in vitro decidualization assay was conducted with normal human endometrial stromal cells and endometriotic stromal cells to determine whether oleuropein overcomes decidualization in endometriosis patients. The pregnancy rate and pup numbers of C57BL/6 J female mice with endometriosis treated with vehicle or oleuropein (n = 10/group) were determined after mating with male mice. The cytokine profile in endometriotic lesions treated with vehicle and oleuropein (25 mg/kg) was determined with a Mouse Cytokine Array Kit. Results Among natural products, oleuropein selectively inhibited ERβ but not ERα activity in vitro. Oleuropein treatment inhibited the nuclear localization of ERβ in human endometrial cells upon estradiol treatment. Oleuropein (25 mg/kg) treatment suppressed the growth of mouse (6.6-fold) and human (sixfold) ectopic lesions in mice with endometriosis compared to the vehicle by inhibiting proliferation and activating apoptosis in endometriotic lesions. Oleuropein treatment did not cause reproductive toxicity in female mice. Additionally, mice with endometriosis subjected to oleuropein treatment had a higher pregnancy rate (100%) than vehicle-treated mice (70%). Furthermore, oleuropein treatment partially recovered the decidualization impact of human endometriotic stromal cells from endometriotic lesions compared to the vehicle. Oleuropein-treated mice with endometriosis exhibited significantly lower levels of cytokines directly regulated by ERβ in ectopic lesions than vehicle-treated mice, illustrating the improvement in the hyperinflammatory state of mice with endometriosis. Conclusions Oleuropein is a promising and novel nutraceutical product for nonhormonal therapy of endometriosis because it selectively inhibits ERβ, but not ERα, to suppress endometriosis progression and improve the fertility of mice with endometriosis.

Our objective here is to demonstrate multidisciplinary teamwork in complex gynecological cases. To this end, we report a complicated case of ovarian remnant tissue after oophorectomy in the context of advanced-stage endometriosis. A 35-year-old G1P1001 woman with previous hysterectomy and bilateral salpingo-oophorectomy (BSO) presented with recurrence of pelvic pain less than one year after Da Vinci single-incision laparoscopic surgery (SILS) for resection of stage IV endometriosis. A multidisciplinary team of surgeons including minimally invasive gynecology, gynecologic oncology, urology and colorectal surgery was assembled to work collaboratively on this case. The patient underwent robotic-assisted removal of ovarian remnant tissue and endometriosis with bowel resection and ureterolysis. A novel technique involving indocyanine green fluorescence imaging was applied retrograde through cystoscopy guidance into ureters bilaterally to facilitate challenging dissections. The postoperative course was notable for development of a pelvic abscess leading to pleural effusion. Although recovery was prolonged, the patient has been disease-free to date after discharge. The breadth of surgical expertise allowed for the thorough removal of remnants.

Surgery in any patient has risks and benefits and minimally invasive routes are typically preferred, however these techniques may be challenging in obese patients these patients are already typically considered to have increased intraoperative and postoperative risks. The following case report describes a patient with BMI >70 who presented for surgical sterilization. Robotic vaginal natural orifice transluminal endoscopic surgery (robotic vNOTES) was used to perform bilateral salpingectomy. This technique combines the benefits of robotic surgery for improved visualization and fine surgical movement was as well as the vaginal, minimally invasive route. Various techniques were used for successful completion of the surgery and are described in detail in the following report.

ObjectiveTo describe the surgical techniques and short-term outcomes for 50 cases of modified sacrospinous ligament fixation via the anterior vaginal wall path for pelvic organ prolapseMethods100 patients with pelvic organ prolapse (stage III or stage IV based on POP-Q staging) from January 2018 to January 2020 were retrospectively analyzed. Among them, 50 patients received modified sacrospinous ligament fixation via the anterior vaginal wall path for pelvic organ prolapse (mSSLF group), while the other 50 patients received pelvic reconstruction using T4 mesh (T4 group). Operative time, blood loss, postoperative POP-Q score, length of the hospital stay, complications, and postoperative pain were compared between the two groups.ResultsThe duration of the operation in mSSLF group was (50 ± 15.2 min), which was shorter than that of the T4 group (60 ± 14.8 min) (p = 0.02). No intraoperative complications were reported from the mSSLF group, whereas one vascular injury occurred in the T4 group. In both groups, postoperative pain and painful intercourse was significantly lower in the mSSLF group than in the SSLF group (p

Study objective: To demonstrate the surgical techniques for removal and replacement of a prior cerclage, repair of a cervical injury caused by the prior abdominal cerclage placement resulting in PPROM during surgery, and methods to mitigate the risk. Design: Stepwise demonstration with narrated video footage. Setting: An academic tertiary care hospital. Our patient is a 32-year-old G4P1 with a complex obstetric history. Her first pregnancy ended with a miscarriage at 7 weeks. A transvaginal cerclage was performed during her second pregnancy at 12 weeks, and she subsequently suffered from PPROM at 24 weeks. The baby was delivered via cesarean section and was 18 months old at the time of the last follow-up. Another transvaginal cerclage was performed at 14 weeks for her third pregnancy, which ended with an IUFD at 16 weeks. She subsequently underwent the removal of the vaginal cerclage and a D&C. In her fourth pregnancy, an open abdominal cerclage was attempted at 14 weeks of pregnancy. The latter caused PPROM during the surgery due to blind needle placement, which resulted in the loss of the fetus. Perioperative notes regarding that particular surgery were not accessible to us at the time of submission. She presented to us as a non-gravid patient seeking the replacement of her abdominal cerclage. Given a complex obstetric history of multiple second-trimester losses with two vaginal cerclages and one open abdominal cerclage, an abdominal cerclage was indicated at the level of the internal cervical os, regardless of cervical length, in a non-pregnant patient. Interventions: Cervical insufficiency is a condition that results in painless, recurrent pregnancy loss before the second trimester in the absence of biochemical triggers. Epidemiologically, cervical incompetence occurs in 0.1–1% of the obstetric population.1 Though rare, this condition has devastating consequences for both the expectant parents and the healthcare system, with preterm births responsible for 70% of all neonatal morbidity and mortality.2 The two most common surgical interventions aimed at resolving this condition are the transvaginal and abdominal cerclages. An abdominal cerclage has a reported success rate of 79–100% when done via laparoscopic means.3 This is the primary intervention indicated in patients with a history of failed transvaginal cerclages, a shortened or absent cervix due to cervical surgery, or uterine anomalies. Though the intervention has minimal risks and complications for the experienced surgeon in a non-gravid uterus, the difficulty exponentially increases post-conception and even more with increasing gestational age. Owing to the engorged uterine vessels during pregnancy and the amniotic sac that flanks the sides of the internal cervical os, the clearance for safe needle passage during cerclage placement is limited. This technical difficulty lends itself to causing the most common complication of abdominal cerclage: rupture of the membranes. PPROM accounts for 38% of all complications that arise during an abdominal cerclage placement4 and one of the gravest consequences is the subsequent loss of the fetus. Minimal advancement has been made in the standard techniques used to place the cerclage that would minimize the risk. Besides blind needle placement and its clear risks and ultrasound-guided technique,5,6 which would necessitate multiple specialists on hand, the surgeon suggests a trans-broad ligament approach. There is a case report by the same surgeon who performed it with great success.7 Essentially, the technique exposes the bilateral uterine vessels, which reduces the possibility of accidental damage to the arteries and eliminates the risk of blind needle placement piercing through the amniotic sac, leading to rupture of membranes and subsequent pregnancy loss.7 Multiple abdominal cerclages have been performed this way by the surgeon with a success rate of 100%; however, further research needs to be undertaken with greater power.We demonstrate three things in the video: a needleless technique to remove and replace a prior abdominal cerclage; a method to repair the internal cervical os after a cervical injury caused by the prior placement; and an abdominal cerclage placed months after the removal of the first, using standard technique. We performed all three procedures using a robotic-assisted single-site platform on a non-gravid patient.At the beginning of the surgery, the Mersilene tape from the prior abdominal cerclage was identified. The placement was regarded as being in the correct location, however it was loose circumferentially. Therefore, the decision was made to replace the tape in the same location with tighter banding. The needleless technique involved suturing the previous tape into the new one and using the prior tape to pull the new one through. This eliminated the need for another blind needle placement. However, a hysteroscopy done after the placement showed the tape within the uterine cavity. The surgeon initiated the removal of the recently placed cerclage. During the creation of the bladder flap, a 2 cm defect at the level of the internal os at the location of the prior cerclage was noted. This gaping defect left the Rumi manipulator visible and extended laterally into the broad ligament. A mutual decision was made by the surgeon and the patient's husband to repair the uterine defect during the present surgery and defer the cerclage placement to a later date. The first surgery was completed after a hysteroscopy was done, and no sutures were visualized within the uterine cavity. Five months later, the patient followed up for her abdominal cerclage placement. A preliminary hysteroscopy noted a well-healed uterine cavity. Therefore, an abdominal cerclage was placed via a robotic-assisted platform using the blind needle technique. A concluding hysteroscopy and view in fire-fly mode demonstrated no Mersilene tape or sutures within the internal cervical os. There were no complications during either surgery, and the patient was discharged on the same day for both. Conclusion: Removal and replacement of prior cerclage can be done needleless under the correct conditions. For patients referred following a failed transabdominal cerclage especially due to intraoperative cervical injury, the surgeon recommends a preliminary hysteroscopy to determine the extent of damage and prevent redundant effort. Blind needle placement remains the most standard technique in performing abdominal cerclage, yet it is one of the highest cause of complications in the surgical intervention. The repair and replacement of the cerclage were necessitated in this case after the prior surgeon had impaled the amniotic sac during blind needle placement, resulting in the loss of the fetus. Currently, the trans-broad ligament approach offers a feasible and simple technique for surgeons seeking to reduce risks, although further research is needed.

ObjectiveThis study aims to investigate the feasibility and short-term efficacy of single-port laparoscopic-assisted transvaginal natural cavity endoscopic sacrospinous ligament suspensions (SvNOTES).MethodsA total of 30 patients diagnosed with anterior or/and middle pelvic organ prolapse Stages III and IV underwent natural vaginal cavity (SvNOTES), and 30 patients who underwent conventional sacrospinous ligament (SSLF) were used as a control group. The operation time, blood loss, postoperative POP-Q score, length of hospital stay, and complications were compared between the two groups.ResultsThe operation time for SvNOTE was (60 ± 13) min, which was longer than (30 ± 15) min for SSLF (P = 0.04). However, the bleeding amount in SvNOTE was 29.44 ± 2.56, significantly lower than that in the SSLF group (80 ± 10; P = 0.02), and the postoperative hospital stay in the SvNOTE group was (4 ± 2) days, longer than (3 ± 1) days in SSLF (P = 0.02). However, there were no intraoperative complications in the SvNOTE group, whereas one ureteral injury occurred in the SSLF group; in addition, the postoperative POP-Q score was significantly better in the SvNOTE group than that in the SSLF group with increasing time (P

Abstract Background To evaluate the effect of postoperative BP treatment on improving the fusion rate after lumbar spinal fusion surgery by performing a meta-analysis of randomized controlled trials (RCTs) and other comparative cohort studies. Methods A comprehensive search of PubMed, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trials was performed for RCTs and other comparative cohort studies on the effect of BP treatment on improving the fusion rate after lumbar spinal fusion surgery. The primary outcome measures were the number of patients with bone formation grades A, B, and C at 12 months of follow-up; fusion rates at 12 and 24 months of follow-up; vertebral compression fracture (VCF) at 12 and 24 months of follow-up; pedicle screw loosening at 24 months of follow-up; and cage subsidence, the Oswestry disability index (ODI), and the visual analogue score (VAS) at 12 months of follow-up. The final search was performed in July 2020. Results Seven studies with 401 patients were included. Compared with the placebo, BP treatment did not significantly alter the number of patients with bone formation grades A, B, and C, or the VAS at the 12-month follow-up or the fusion rates at the 12- and 24-month follow-ups. In addition, compared with the placebo, BPs significantly reduced the risks of VCF at the 12- and 24-month follow-ups, pedicle screw loosening at the 24-month follow-up, and cage subsidence and the ODI at the 12-month follow-up. Conclusions Postoperative BPs do not clearly improve bone formation and the fusion rate, but they reduce VCF, cage subsidence, and loosening of pedicle screws after lumbar fusion surgery compared with the control treatment.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with ill-defined pathogenesis, calling for urgent developments of new therapeutic regimens. Herein, we applied PandaOmics, an AI-driven target discovery platform, to analyze the expression profiles of central nervous system (CNS) samples (237 cases; 91 controls) from public datasets, and direct iPSC-derived motor neurons (diMNs) (135 cases; 31 controls) from Answer ALS. Seventeen high-confidence and eleven novel therapeutic targets were identified and will be released onto ALS.AI (http://als.ai/). Among the proposed targets screened in the c9ALS Drosophila model, we verified 8 unreported genes (KCNB2, KCNS3, ADRA2B, NR3C1, P2RY14, PPP3CB, PTPRC, and RARA) whose suppression strongly rescues eye neurodegeneration. Dysregulated pathways identified from CNS and diMN data characterize different stages of disease development. Altogether, our study provides new insights into ALS pathophysiology and demonstrates how AI speeds up the target discovery process, and opens up new opportunities for therapeutic interventions.

ObjectiveTo investigate the feasibility and short-term efficacy of gasless single-port laparoscopic inguinal lymphadenectomy through vulva incision (VEIL-V).MethodsThe data of 9 patients diagnosed as vulvar squamous cell carcinoma who underwent single-port laparoscopic inguinal lymph node dissection through vulvectomy incision were retrospectively analyzed. And 13 patients who underwent laparoscopic inguinal lymph node dissection through lower abdominal subcutaneous approach as the control group (VEIL-H). The operation time, blood loss, numbers of unilateral lymph nodes, hospitalization time, and complications between the two groups were compared.ResultsThe operation time of VEIL-V was 56.11 ± 5.94 min, which were shorter than that of VEIL-H (74.62 ± 5.50 min; P = 0.013). Bleeding amount in the VEIL-H was 29.44 ± 2.56, which was significantly lower than that of the VEIL-H group (43.08 ± 4.14 ml; P = 0.021). In the two groups, the numbers of unilateral lymph nodes harvested were similar. The differences in the postoperative hospital stay, skin, and lymphatic complications were not statistically significant.ConclusionCompared with VEIL-H, gasless single-port laparoscopic inguinal lymphadenectomy through vulva incision reduces the difficulty of operation with shorter operation time, and less blood loss, which can be a safe and mini-invasive surgical approach.

When shield machine traverses through hard rock mass, disc cutters will be abraded to different degrees. Excessive height difference exists between adjacent disc cutters, which critically affects the rock-breaking efficiency. Relying on a shield section of hard rock mass in Qingdao, the disc cutter abrasions are measured on site, and the reason for low construction efficiency is analysed. Subsequently, the discrete element method is used to study the rock-breaking law under different height differences of disc cutters. The ultimate cutter height difference for rock breaking is obtained. According to this, the cutter adjustment scheme is proposed to reduce the cutter height differences on site. Comparing shield tunnelling parameters before and after the cutter adjustment, it is found that the construction efficiency is significantly improved. The results are of great significance for improving the rock-breaking efficiency and increasing advancing speed of shield in hard rock mass.

Loosened rock circle is formed around the tunnel when the tunnel is constructed by the drilling and blasting method. The size of the loosened rock circle around the tunnel and the degree of internal rock fragmentation has an important influence on the support parameters, durability, and safety of the tunnel. Firstly, referencing an existing tunnel project, blasting tests using nonelectronic and electronic detonators were carried out to determine the influence of blasting construction on the scope of the rock loose circle and the degree of rock fragmentation. Then, a numerical simulation was used to study the contribution of the blasting impact and surrounding rock stress redistribution on the loosened rock circle around the tunnel. The results showed that the range of the loosened rock circle around the tunnel generated by the normal blasting of nonelectronic detonators was 1.5~2.3 m, and the wave velocity of the rock mass in the loosened rock circle around the tunnel decreased to 23~36%. The size of the loosened rock circle around the tunnel generated by the blasting impact was 0.66 m, accounting for 33% of the range of the loosened rock circle around the tunnel. The range of the loosened rock circle around the tunnel produced by electronic detonator blasting was 0~1.4 m. The wave velocity of the rock mass in the loosened rock circle around the tunnel decreased to 12~17%. The range of the loosened rock circle around the tunnel was approximately 60~76% of that of detonator blasting, and the broken degree of the surrounding rock in the loosened rock circle around the tunnel was small. The research results can provide a reference for the optimization design of preliminary support parameters of tunnels, such as anchors and steel arches in blasting construction.

Background: We report the application of transuterine suspension sutures (TUSSs) for manipulation and vaginal closure before colpotomy in laparoscopic radical hysterectomy for early-stage cervical cancer. Methodology: Eight patients with clinical stage IB1 cervical squamous cell cancer were treated with laparoscopic radical hysterectomy between October 2019 and May 2020. The procedure was performed without a traditional uterine manipulator, and the vaginal cuff was closed with a stapler before colpotomy to prevent tumour spillage. Results: All patients successfully underwent the surgery, with a median hospitalisation of 8 days (range 6–14). All drains and urethral catheters were removed after a median of 7 days (range 5–11) and 16 days (range 12–21), respectively. A median of 26 (range 20–32) pelvic lymph nodes were resected and no lymph-related complications were encountered post-operatively. With an enclosed colpotomy, no visible tumour tissues were exposed to the pelvic cavity, and all vaginal stumps healed well without complications. All pathological examinations of the vaginal margin were negative, and there were no residual lesions. At a median follow-up of 6 months, all patients were alive with no recurrence of disease. Conclusion: We found that laparoscopic radical hysterectomy with TUSS and vaginal closure before colpotomy is a useful and effective procedure to prevent tumour spillage for the treatment of cervical cancer.

Study objective: To demonstrate stepwise techniques for the successful use of the robotic-assisted transvaginal natural orifice transluminal endoscopy surgery high uterosacral ligament suspension (RvNOTES-HUS) technique for pelvic organ prolapse with and without uterine preservation. Design: Stepwise demonstration with narrated video footage (Canadian Task Force classification III). Setting: An academic tertiary care hospital. Case 1: A 62-year-old G0P0 with a symptomatic stage Ⅱ anterior vaginal prolapse and Stage Ⅱ uterine prolapse. The preoperative vaginal length was measured at 9 ​cm. Case 2: A 42-year-old G3P2 with a symptomatic fibroid uterus with stage Ⅱ anterior vaginal prolapse and Stage Ⅱ uterine prolapse. The preoperative vaginal length was measured at 8 ​cm. Interventions: Since the approval of the robotic platforms in gynecologic surgery by the Food and Drug Administration in 2005,1 robotic assisted surgery has been proliferating in the treatment of benign gynecological diseases including sacrocolpopexy, hysterectomy, myomectomy and endometriosis resection.2–5 In recent years, publications have demonstrated the feasibility and safety of traditional laparoscopic assisted high uterosacral ligament suspension for pelvic organ prolapse with long term follow up.6–8 However, robotic assisted RvNOTES-HUS has yet to be investigated in a publication. Utilizing the RvNOTES-HUS technique with or without uterine preservation operations greatly reduces the difficulty of intraperitoneal suture for the surgeon and postoperative pain for the patient. Nevertheless, this approach may be technically challenging.For patients requesting uterine preservation, posterior colpotomy is required to place the port. Contrasting with hysterectomy, after the uterine removal the port was placed through the vaginal cuff; the remaining steps show great similarities. The succeeding techniques were adopted to perform RvNOTES-HUS: the bilateral uterosacral ligaments were tagged with sutures prior to the vNOTES port placement, highlighting the ureters, plucking the tagged uterosacral ligament to aid in identifying the high uterosacral ligament, elevating the uterosacral ligament while suturing, and pulling on the suture post-placement to determine the correct location.The results were as follows:Case 1: The procedure was successfully performed with a postoperative vaginal length of 8 ​cm. Her pain level was 4/10 in the first week, 2/10 in the second week, 0/10 in the third week, 0/10 in the fourth week. Postoperative pelvic organ prolapse quantification was stage 0.Case 2: The procedure was successfully performed with a postoperative vaginal length of 7 ​cm. She had one day of post-operative pain. Postoperative pelvic organ prolapse quantification was stage 0. Conclusion: RvNOTES-HUS is a practical technique in women with uterine prolapse while choosing whether to preserve the uterus. This technique allows for the better exposure of the ureter, while the articulating robotic joints allow for increased precision of dissection and suturing.

The clinical trials employing neuroprotectants targeting single, early pathogenic mechanisms in stroke have so far been barely successful. We found in human postmortem stroke brains that in addition to apoptosis, necroptosis also contributed to neuronal damage. Thus, a new strategy targeting both mechanisms might be necessary. While brain-derived neurotrophic factor (BDNF) is a potent survival factor for neurons, its poor bioavailability including low diffusion rate and short half-life makes it unlikely a therapeutic agent. We recently developed a TrkB agonistic antibody (Ab4B19) that mimicked BDNF functionally but exhibited better physicochemical and pharmacological features. We showed that Ab4B19 halted neuronal death in vitro under multiple conditions that simulate ischemia/reperfusion injury, including oxygen-glucose deprivation (OGD), glutamate toxicity, oxidative stress and nutrient deprivation. In a rat model of ischemia/reperfusion, Ab4B19 suppressed both apoptosis and necroptosis, leading to a reduction in infarct volume and acceleration of functional recovery from sensorimotor impairments. In neurons derived from human embryonic stem cells (hESCs), Ab4B19 activated TrkB and its downstream signaling, and rescued neuronal death from OGD at a similar level as that in mouse neurons. Together, our study revealed necroptosis in human stroke brain, and demonstrated a BDNF-based strategy targeting both apoptosis and necroptosis for ischemic stroke treatment.

Abstract Background Pelvic endometriosis (EM) and adenomyosis (AM) have different effects on the fallopian tube. This study aimed to assess the transport capability of the fallopian tube in women with pelvic EM or AM. Methods Twenty women with uterine leiomyoma (control group), 20 with adenomyosis without pelvic EM (AM group) and 35 with pelvic EM without AM (EM group) were included. EM cases were further divided into the tubal EM and non-tubal EM subgroups. Ciliary beat frequency (CBF), percentage of ciliated cells, and smooth muscle contraction were measured. Results CBFs of the ampulla in EM cases were significantly lower than those of control and AM cases; CBFs of the ampulla and isthmus in tubal EM cases were significantly lower than those of the control group and non-tubal EM subgroup. In both the ampulla and isthmus segment, percentages of ciliated cells in EM patients were significantly lower than those of AM and control patients; the tubal EM subgroup showed significantly lower values than the control group and non-tubal EM subgroup. Amplitude-to-weight ratios of longitudinal muscular contractility in EM cases were significantly lower than control values; tubal EM cases showed significantly lower values than controls and the non-tubal EM subgroup. Contraction frequencies in EM cases were significantly lower than those of control and AM cases, in both longitudinal and circular muscles; tubal EM cases showed significantly lower values than controls and the non-tubal EM subgroup. Conclusion EM with tubal EM damaged transport function of the fallopian tube, to varying degrees, whereas tubal function in EM without tubal EM and in AM is not altered.

The reasonable delay time of millisecond-delay blasting using digital electronic detonators can significantly reduce the vibration effects induced by tunnel blasting. This study proposes a method for calculating the delay time for cut holes, easer holes and periphery holes, considering the rocks breaking effect as well as wave superposition theory. And then according to the actual layout diagram of the tunnel holes, the delay time calculation formulas of different holes are put forward. Then the delay times were calculated according to the formulas and applied in the field tests. The velocities, rocks breaking and wave superposition cancellation of the vibration using different delay times are analyzed with digital electronic detonators. Then the optimum delay times of different holes were obtained and applied to New Hongyan tunnel project. The velocity and frequency of the vibration with digital electronic detonators are analyzed, compared with non-electronic detonators. The effects of charge and delay time on the velocity and principal frequency of a blasting seismic wave are discussed. The results indicate that the delay time for the holes must be prioritized to achieve breaking effects in the rock with the simultaneous formation of a new free surface, next considering the wave superposition cancellation. When the delay time of cut holes was 5 ms, the rocks breaking effect and wave superposition cancellation effect both worked well. The velocity of the vibration induced by the cut holes blasting was about only 0.46-0.51 cm/s. When the delay time was 6 ms or much longer, the rocks breaking effect would fail. With regard to the easer holes and periphery holes, the optimum delay time of them were all 5ms. The vertical peak particle velocity was reduced from 2.974 cm/s to 0.901 cm/s with digital electronic detonators. Therefore, the velocity had decreased by 69.70% than non-electronic detonators, which was caused by reducing the single simultaneous explosive charge and setting optimum delay time. The proposed delay time calculation method is demonstrated to be sufficiently accurate and can thus be used as a guideline to reduce tunnel blasting vibrations.

Background. Endometriosis usually occurs in the pelvis and often involves the ovaries, the uterosacral and broad ligaments, and the pelvic peritoneum. In rare instances, it can occur in the vasculature of the pelvis. Patients with endometriosis present with abnormal pain, menstrual cycle disruption and infertility. Management of endometriosis is usually surgical with excision of the tissue via laparoscopic means. Case. A 42-year-old Gravida 5, Para 2-0-3-2 patient with a 22 year history of endometriosis, who had had multiple laparoscopic endometriosis resections, total abdominal hysterectomy, and an exploratory laparotomy with bilateral salpingo-oophorectomy, presented with left pelvic pain when standing, dyspareunia, and a 3.7 cm cyst on ultrasound. The patient underwent laparoscopic vessel endometriosis resection and excision of endometriotic nodules from external iliac vessels. Final pathology report showed evidence of old endometriosis in all locations. On interval follow-up, the patient reported sustained relief from pain. Conclusion. Complete resection of endometriosis from large vessels can be successfully achieved laparoscopically by a well-experienced surgeon with delicate, proper techniques.

Damage characteristics and dynamic stress response of aging masonry structures for blast-induced ground motion were performed using high-order local modal analysis method. A complete investigation of damage types and locations of aging masonry buildings due to tunnel blasting vibration were performed by on-site survey. A typical 2-storey aging masonry building located above a tunnel was selected for dynamic response analysis. The experimental dynamic characteristics of the structure were determined by using the operational modal analysis (OMA) method. Finite element models for the masonry structures were updated by modifying material parameters based on OMA results. The first five natural frequencies of the updated finite element models ranged from 8.80–24.99 Hz, and the first five modes were global modes. The sixth to twentieth natural frequencies ranged from 26.10–36.34 Hz, and the sixth to twentieth modes were local modes whose deformation was greater than the global deformation. Since the principal frequencies of the tunnel blast vibration were mostly higher than the natural global modes’ frequencies and were much closer to the natural frequencies of local members, local members experienced more intensive vibrations compared to the main body structure. The principal compressive stress (PCS) and principal tensile stress (PTS) of local members were several times greater than that of the main body structure. Therefore, local members of the masonry building suffered most from the tunnel blasting vibration. Corners due to stress concentration, the contact area between brick and concrete, local members, and precast floor seams are prone to damage during tunnel blasting. With the vibration velocity increasing, the PCS and PTS of local members gradually increase. But, the PTS ratio of local members decreases with the increase of peak particle velocities. The dynamic response analysis result and the damage locations using high-order local modal analysis method are in accordance with the damage found at the site.

Background. Heterotopic pregnancy occurs when two pregnancies occur simultaneously in the uterus and an ectopic location. Treatment includes removal of the ectopic pregnancy with preservation of the intrauterine pregnancy. Treatment is done laparoscopically with either a Laparoendoscopic Single-Site Surgery (LESS) or a multiport laparoscopic surgery. Case. We present a case of a first trimester heterotopic pregnancy in a 42-year-old gravida 5, para 0-1-3-1 female with previous history of left salpingectomy, who underwent laparoscopic right salpingectomy and lysis of adhesions (LOA) via Single-Incision Laparoscopic Surgery (SILS). Conclusion. Although LESS for benign OB/GYN cases is feasible, safe, and equally effective compared to the conventional laparoscopic techniques, studies have suggested no clinically relevant advantages in the frequency of perioperative complications between LESS and conventional methods. No data on the cost effectiveness of LESS versus conventional methods are available. LESS utilizes only one surgical incision which may lead to decreased pain and better cosmetic outcome when compared to multiport procedure. One significant undesirable aspect of LESS is the crowding of the surgical area as only one incision is made. Therefore, all instruments go through one port, which can lead to obstruction of the surgeon’s vision and in some cases higher rate of procedure failure resulting in conversion to multiport procedure.

Uterine prolapse complicating pregnancy is rare. Two cases are presented here: one patient had uterine prolapse at both her second and third pregnancy, and the other developed only once prolapse during pregnancy. This report will analyze etiology, clinical characteristics, complication, and treatment of uterine prolapse in pregnancy. Routine gynecologic examination should be carried out during pregnancy. If uterine prolapse occurred, conservative treatment could be used to prolong the gestational period as far as possible. Vaginal delivery is possible, but caesarean section seems a better alternative when prolapsed uterus cannot resolve during childbirth.

Endometrial ablation offers symptomatic relief for menorrhagia. Pregnancy after ablation is rare but is often complicated due to pregnancy loss, growth restriction, preterm premature rupture of membranes, preterm delivery, and morbidly adherent placentation, a dangerous complication that can result in hemorrhage, intensive care unit admission, and cesarean hysterectomy. We report a case of pregnancy conceived contemporaneously with endometrial ablation and tubal occlusion. Diagnosis of pregnancy was delayed due to low suspicion. Complications included cervical implantation and placenta percreta, necessitating hysterectomy with the fetus in situ. Intraoperatively, incomplete uterine rupture was noted. Abnormal neovascularization, fibrous adhesions, and anatomical distortion necessitated a complex surgical approach. Women undergoing endometrial ablation must be thoroughly counseled about the serious risks of postablation pregnancy, the need for contraception, and the risk of sterilization failure. Pregnancy should remain in the differential diagnosis for women of reproductive age, regardless of tubal occlusion. Cases of placenta percreta should be referred early to centers of excellence with multidisciplinary teams.

The aim of the study was to evaluate the role of Smad3, Smad7, and TGF-β1 in intrauterine adhesion (IUA) patients and experimental rabbit models. 60 IUA patients, 30 control participants, and 18 female rabbits were enrolled in this study. We found that the plasma concentrations and protein expressions of TGF-β1 were significantly increased in patients and experimental rabbits compared to those in controls (P

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1β-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer. [ABSTRACT FROM AUTHOR]