TOR complex 2 contributes to regulation of gene expression via inhibiting Gcn5 recruitment to subtelomeric and DNA replication stress genes.

The fission yeast TOR complex 2 (TORC2) is required for gene silencing at subtelomeric regions and for the induction of gene transcription in response to DNA replication stress. Thus, TORC2 affects transcription regulation both negatively and positively. Whether these two TORC2-dependent functions share a common molecular mechanism is currently unknown. Here, we show that Gad8 physically interacts with proteins that regulate transcription, including subunits of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex and the BET bromodomain protein Bdf2. We demonstrate that in the absence of TORC2, Gcn5, the histone acetyltransferase subunit of SAGA, accumulates at subtelomeric genes and at non-induced promoters of DNA replication genes. Remarkably, the loss of Gcn5 in TORC2 mutant cells restores gene silencing as well as transcriptional induction in response to DNA replication stress. Loss of Bdf2 alleviates excess of Gcn5 binding in TORC2 mutant cells and also rescues the aberrant regulation of transcription in these cells. Furthermore, the loss of either SAGA or Bdf2 suppresses the sensitivity of TORC2 mutant cells to a variety of stresses, including DNA replication, DNA damage, temperature and nutrient stresses. We suggest a role of TORC2 in transcriptional regulation that is critical for gene silencing and gene induction in response to stress and involves the binding of Gcn5 to the chromatin.

An amino acid shuffle activates mTORC1.

The mammalian target of rapamycin complex 1 (mTORC1), which promotes cell growth, is regulated by specific nutrients such as the amino acid leucine. In this issue, Nicklin et al. (2009) describe a mechanism by which glutamine facilitates the uptake of leucine, leading to mTORC1 activation.

The association of endometrial closure during cesarean section to the risk of developing uterine scar defect: a randomized control trial.

PURPOSE: The surgical technique for uterine closure following cesarean section influences the healing of the cesarean scar; however, there is still no consensus on the optimal technique regarding the closure of the endometrium layer. The aim of this study was to compare the effect of closure versus non-closure of the endometrium during cesarean section on the risk to develop uterine scar defect and associated symptoms. METHODS: A randomized prospective study was conducted of women undergoing first elective cesarean section at a single tertiary medical center. Exclusion criteria included previous uterine scar, preterm delivery and dysmorphic uterus. Women were randomized for endometrial layer closure versus non-closure. Six months following surgery, women were invited to the ambulatory gynecological clinic for follow-up visit. 2-D transvaginal ultrasound examination was performed to evaluate the cesarean scar characteristics. In addition, women were evaluated for symptoms that might be associated with uterine scar defect. Primary outcome was defined as the residual myometrial thickness (RMT) at the uterine cesarean scar. Data are presented as median and interquartile range. RESULTS: 130 women were recruited to the study, of them follow-up was achieved in 113 (86.9%). 61 (54%) vs. 52 (46%) of the women were included in the endometrial closure vs. non-closure groups, respectively. Groups were comparable for patient's demographic, clinical characteristics and follow-up time for postoperative evaluation. Median RMT was 5.3 (3.0-7.7) vs. 4.6 (3.0-6.5) mm for the endometrial closure and non-closure groups, respectively (p = 0.38). Substantially low RMT (< 2.5 mm) was measured in four (6.6%) women in the endometrial closure group and three (5.8%) of the women in the non-closure group (p = 0.86). All other uterine scar sonographic measurements, as well as dysmenorrhea, pelvic pain and intermenstrual bleeding rates were comparable between the groups. CONCLUSION: Closure versus non-closure of the endometrial layer during cesarean uterine incision repair has no significant difference in cesarean scar characteristics and symptom rates at 6 months follow-up.

Pediatric Epistaxis-Effectiveness of Conservative Management.

OBJECTIVES: Epistaxis is an emergency medical condition that sometimes requires admission to the emergency department. Pediatric epistaxis differs from epistaxis in the older population in terms of etiology, severity, and management. Our objective was to identify the distinctive features of pediatric epistaxis and determine the appropriate management. METHODS: This was a retrospective study of 231 medical records of children (<18 years old) with epistaxis of a total of 1171 cases in the general population who presented to our medical center's emergency department between 2013 and 2018. RESULTS: Among 231 admissions, 10 children (4.3%) presented more than once. Male patients accounted for the majority of cases (64.5%), and the average age was 9.4 years. Two children were treated with aspirin because of cardiac valve disease. Anterior bleeding was detected in 101 cases (43.7%), whereas posterior origin was observed in 8 cases (3.5%). In 122 cases (52.8%), there was no active bleeding observed. Nose injury was the cause of epistaxis in 24 cases (10.4%), and 16 admissions (6.9%) followed nasal surgical interventions. Nineteen children (8%) had abnormal coagulation tests, and 7 patients (3%) received blood transfusions. Chemical cauterization was performed in 89 cases (39.3%), and anterior packing was needed in only 9 cases (3.9%). Nine children required hospitalization (3.9%), and 2 needed surgical intervention to control bleeding. Compared with the adult population, there were significantly fewer cases of active bleeding, recurrent epistaxis, anterior packing, or need for hospitalization in the pediatric population. CONCLUSIONS: Epistaxis is significantly less severe in the pediatric population, with only a few cases requiring major intervention. Endoscopic examination of the entire nasal cavity and routine coagulation tests are not mandatory unless there is a history of recurrent epistaxis, known coagulopathy, antiplatelet/anticoagulation therapy, or a suspicion of juvenile idiopathic angiofibroma. We suggest using absorbable packs, which offer advantages over cauterization or nonabsorbable packs.

Performance of ChatGPT in Israeli Hebrew Internal Medicine National Residency Exam.

BACKGROUND: Completing internal medicine specialty training in Israel involves passing the Israel National Internal Medicine Exam (Shlav Aleph), a challenging multiple-choice test. multiple-choice test. Chat generative pre-trained transformer (ChatGPT) 3.5, a language model, is increasingly used for exam preparation. OBJECTIVES: To assess the ability of ChatGPT 3.5 to pass the Israel National Internal Medicine Exam in Hebrew. METHODS: Using the 2023 Shlav Aleph exam questions, ChatGPT received prompts in Hebrew. Textual questions were analyzed after the appeal, comparing its answers to the official key. RESULTS: ChatGPT 3.5 correctly answered 36.6% of the 133 analyzed questions, with consistent performance across topics, except for challenges in nephrology and biostatistics. CONCLUSIONS: While ChatGPT 3.5 has excelled in English medical exams, its performance in the Hebrew Shlav Aleph was suboptimal. Factors include limited training data in Hebrew, translation complexities, and unique language structures. Further investigation is essential for its effective adaptation to Hebrew medical exam preparation.

The association between history of retained placenta and success rate of misoprostol treatment for early pregnancy failure.

BACKGROUND: To date, the association between retained placenta and treatment success rate of misoprostol for early pregnancy failure has yet to be evaluated. The aim of this study was to evaluate this association and further investigated the connection between medical, clinical and sonographic parameters and treatment success. METHODS: We conducted a retrospective cohort study of women with early pregnancy failure treated with misoprostol from 2006 to 2021. The success rate of misoprostol treatment was compared between patients with history of retained placenta including women who underwent manual lysis of the placenta following delivery or patients who were found to have retained products of conception during their post-partum period (study group) and patients without such history (controls). Demographic, clinical, and sonographic characteristics as well as treatment outcomes were compared between the groups. RESULTS: A total of 271 women were included in the study (34 women in the study group compared to 237 women in the control group). Two-hundred and thirty-three women (86.0%) presented with missed abortion, and 38 (14.0%) with blighted ovum. Success rates of misoprostol treatment were 61.8% and 78.5% for the study and control groups, respectively (p = 0.032). Univariate analysis performed comparing successful vs. failed misoprostol treatment showed advanced age, gravidity, parity and gestational sac size (mm) on TVUS were associated with higher misoprostol treatment failure rate. Following a multivariate logistic regression model these variables did not reach statistical significance. CONCLUSION: Women who have an event of retained placenta following childbirth appear to have decreased success rate of treatment with misoprostol for early pregnancy failure. Larger studies are needed to confirm this finding.

TOR Complex 2- independent mutations in the regulatory PIF pocket of Gad8AKT1/SGK1 define separate branches of the stress response mechanisms in fission yeast.

The Target of rapamycin (TOR) protein kinase forms part of TOR complex 1 (TORC1) and TOR complex 2 (TORC2), two multi-subunit protein complexes that regulate growth, proliferation, survival and developmental processes by phosphorylation and activation of AGC-family kinases. In the fission yeast, Schizosaccharomyces pombe, TORC2 and its target, the AGC kinase Gad8 (an orthologue of human AKT or SGK1) are required for viability under stress conditions and for developmental processes in response to starvation cues. In this study, we describe the isolation of gad8 mutant alleles that bypass the requirement for TORC2 and reveal a separation of function of TORC2 and Gad8 under stress conditions. In particular, osmotic and nutritional stress responses appear to form a separate branch from genotoxic stress responses downstream of TORC2-Gad8. Interestingly, TORC2-independent mutations map into the regulatory PIF pocket of Gad8, a highly conserved motif in AGC kinases that regulates substrate binding in PDK1 (phosphoinositide dependent kinase-1) and kinase activity in several AGC kinases. Gad8 activation is thought to require a two-step mechanism, in which phosphorylation by TORC2 allows further phosphorylation and activation by Ksg1 (an orthologue of PDK1). We focus on the Gad8-K263C mutation and demonstrate that it renders the Gad8 kinase activity independent of TORC2 in vitro and independent of the phosphorylation sites of TORC2 in vivo. Molecular dynamics simulations of Gad8-K263C revealed abnormal high flexibility at T387, the phosphorylation site for Ksg1, suggesting a mechanism for the TORC2-independent Gad8 activity. Significantly, the K263 residue is highly conserved in the family of AGC-kinases, which may suggest a general way of keeping their activity in check when acting downstream of TOR complexes.

Performance of ChatGPT in Israeli Hebrew OBGYN national residency examinations.

PURPOSE: Previous studies of ChatGPT performance in the field of medical examinations have reached contradictory results. Moreover, the performance of ChatGPT in other languages other than English is yet to be explored. We aim to study the performance of ChatGPT in Hebrew OBGYN-'Shlav-Alef' (Phase 1) examination. METHODS: A performance study was conducted using a consecutive sample of text-based multiple choice questions, originated from authentic Hebrew OBGYN-'Shlav-Alef' examinations in 2021-2022. We constructed 150 multiple choice questions from consecutive text-based-only original questions. We compared the performance of ChatGPT performance to the real-life actual performance of OBGYN residents who completed the tests in 2021-2022. We also compared ChatGTP Hebrew performance vs. previously published English medical tests. RESULTS: In 2021-2022, 27.8% of OBGYN residents failed the 'Shlav-Alef' examination and the mean score of the residents was 68.4. Overall, 150 authentic questions were evaluated (one examination). ChatGPT correctly answered 58 questions (38.7%) and reached a failed score. The performance of Hebrew ChatGPT was lower when compared to actual performance of residents: 38.7% vs. 68.4%, p < .001. In a comparison to ChatGPT performance in 9,091 English language questions in the field of medicine, the performance of Hebrew ChatGPT was lower (38.7% in Hebrew vs. 60.7% in English, p < .001). CONCLUSIONS: ChatGPT answered correctly on less than 40% of Hebrew OBGYN resident examination questions. Residents cannot rely on ChatGPT for the preparation of this examination. Efforts should be made to improve ChatGPT performance in other languages besides English.

Surgical outcomes in patients aged 70 years and older following uterosacral ligament suspension: a comparative study.

PURPOSE: The number of elderly patients bothered by pelvic organ prolapse symptoms is growing rapidly. The aim of this study was to evaluate the relationship between age and surgical outcomes in women undergoing uterosacral ligament suspension for treatment of apical prolapse. METHODS: We performed a retrospective cohort study including women who underwent uterosacral ligament suspension between 2010 and 2020. The cohort was divided into two groups: (1) Patients 70 years or older; (2) Patients under the age of 70. Outcome measures included clinical, anatomical, and composite outcomes as well as patient satisfaction. RESULTS: A total of 271 patients were included in the final analysis. Of them 209 patients were under age 70 and 62 patients 70 years or older. Mean age was 59 ± 6 vs. 73 ± 3 for the young and elderly age groups, respectively. Clinical success was high for both groups, reaching 94% vs. 89% for elderly and young patients, respectively (p = 0.34). Anatomical and composite outcome success were higher in the young age group (76% vs. 56%, p < 0.01 and 70% vs. 54%, p = 0.02, respectively); however, following multivariate analysis these differences were no longer statistically significant. Following multivariate logistic regression analysis for the dependent parameter of anatomical success, increased pre-operative genital hiatus and vaginal surgical route were associated with anatomical failure while performing a concomitant posterior colporrhaphy increased likelihood for anatomical success. CONCLUSION: Women over the age of 70 undergoing uterosacral ligament suspension for treatment of apical prolapse have comparable outcomes to younger patients.

Absorbable versus Permanent Suture for Vaginal Uterosacral Ligament Suspension for Treatment of Apical Prolapse.

STUDY OBJECTIVE: The aim of this study was to compare surgical outcomes in women undergoing vaginal uterosacral ligament suspension using permanent as opposed to absorbable sutures. We also aimed to assess for specific risk factors for suture complications. DESIGN: Retrospective cohort study. SETTING: Female pelvic medicine and reconstructive surgery unit at a university-affiliated tertiary medical center. PATIENTS: Women with apical prolapse who underwent vaginal hysterectomy with uterosacral ligament suspension during the study period. INTERVENTIONS: none. MEASUREMENTS AND MAIN RESULTS: A total of 197 women were included in the study. Of them, 118 (59.9%) underwent the procedure using a permanent suture and 79 (40.1%) using an absorbable suture. Women in the permanent suture group were less sexually active and had less prolapse of point C on pre-operative exam. With regard to intra-operative and postoperative data, women in the permanent suture group had increased frequency of concomitant procedures, regional anesthesia, surgical time, duration of hospital stay, and change in hemoglobin. Clinical, anatomical, and composite success did not differ between groups. Patient satisfaction recorded using the Patient Global of Improvement Questionnaire was similar as well. Women in the permanent suture group had a higher frequency of suture exposure compared with the absorbable suture group (9.3% vs 0.0%, p = .006). In order to assess for risk factors leading to suture complications, a comparison was performed between women who had suture exposure or granulation tissue and those who did not. Increasing parity by 1 increased the odds of having suture exposure or granulation tissue by a factor of approximately 1.2 (adjusted odds ratio = 1.24; Confidence interval, 1.05-1.47). Women with stage IV prolapse had 3.4 times the odds of suture complication compared with women with stage III prolapse (adjusted odds ratio = 3.4; Confidence interval, 1.1-10.6). CONCLUSION: Use of an absorbable suture affords comparable success and lower frequency of suture exposure compared with permanent sutures in women undergoing vaginal uterosacral ligament suspension for treatment of apical prolapse.

The Effect of Age on Surgical Outcomes Following Uterine Preserving Surgery for Treatment of Apical Prolapse.

STUDY OBJECTIVE: The aim of this study was to evaluate the effect of age on outcomes after uterine-preserving surgical treatment for apical prolapse. DESIGN: Retrospective cohort study. SETTING: Female pelvic medicine and reconstructive surgery unit at a tertiary, university-affiliated teaching medical center. PATIENTS: Women who underwent surgical management of apical prolapse with uterine preservation between 2010 and 2020. Excluded were women who had ≤1 month of follow-up and those for whom medical records were substantially incomplete. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Included in the study were 140 women who underwent apical prolapse repair with uterine preservation and who met the inclusion criteria. The cohort was divided into 2 groups: (1) women aged 65 years and older (≥65 group) and (2) women younger than 65 years of age (<65 group). Pre-, intra-, and postoperative data were compared between the groups. A total of 103 women (73.6%) were in the <65 group and 37 women (26.4%) in the ≥65 group. Mean age for the entire cohort was 58 ± 9.8 years, body mass index 25.9 ± 4.8 kg/m2, and duration of follow-up was 25.9 ± 21.0 months. Women in the ≥65 group had more comorbidities, were less sexually active, and were less likely to have a midurethral sling performed during their surgery. Clinical and anatomical success rates were somewhat higher in the ≥65 group; however, these differences did not reach statistical significance (97.3% vs 85.4%, p = .069 and 89.2% vs 81.2%, p = .264, respectively). Composite outcome success was higher in the ≥65 group (89.2% vs 72.5%, p = .039). Patient satisfaction recorded using the Patient Global Impression of Improvement questionnaire was high for both groups. A multivariable logistic regression analysis for the dependent parameter of composite outcome success was performed, during which none of the parameters investigated reached statistical significance. Subgroup analysis was performed including only women who were postmenopausal. This was done to address the possible confounding effect that menopausal status may have had on our results. No differences were found between the groups with regard to clinical, anatomical, and composite outcomes. CONCLUSION: Uterine-preserving surgery is a safe and effective surgical treatment for women aged ≥65 years.

Pediatric and adolescent females are at higher risk of adnexal torsion recurrence-A large-scale retrospective study.

AIM: Recurrence of adnexal torsion (rAT) is reported mainly in small series. Normal and small appearing ovaries are associated with an increased risk for rAT. Nevertheless, updated data of larger cohorts is lacking. We aimed to investigate the predictors for rAT in a cohort of women who had surgical intervention for primary adnexal torsion (pAT). METHODS: A retrospective case-control study from a single institution between 2011 and 2020. Women with a primary occurrence of surgically proven adnexal torsion were included. We compared those who had experienced rAT to those who had not. Univariate and multivariate analysis were performed to study independent predictors for rAT. RESULTS: Overall, 358 women were included. Of those, 35 (9.8%) had a rAT. Women who experienced rAT were younger (mean age 26 vs. 30 years, p = 0.01). Women experiencing rAT had smaller mean ovarian cyst diameter in the pAT episode (42 vs. 59 mm. p < 0.001). Performance of laparoscopic detorsion was only associated with rAT (odds ration [OR] 95% confidence interval [CI] 2.13 [1.02-4.42], p = 0.03), while the performance of additional cystectomy was negatively associated with rAT (OR 95% CI 0.10 [0.01-0.79], p = 0.006). Multivariate analysis demonstrated that age ≤15 and smaller cyst diameter at pAT were independently associated with the risk for rAT (aOR 95% CI 5.0 [1.09-23.2] and 1.47 [1.08-2.0], for every 10 mm decrease in cyst diameter, respectively). CONCLUSIONS: Adolescents and pediatric females and women with smaller ovarian cysts at pAT are at higher risk for future recurrence of adnexal torsion.

A validated predictive model for adnexal torsion pre-operative diagnosis.

PURPOSE: To develop a simple predictive model for pre-operative diagnosis of adnexal torsion (AT). METHODS: A retrospective cohort study with a retrospective validation, including 669 separate episodes of women who underwent laparoscopy due to a suspected AT between January 2011 and June 2020. We compared the pre-operative characteristics between women with surgically confirmed AT and those without. RESULTS: The derivation cohort included 615 episodes of suspected AT. AT was surgically confirmed in 445 episodes (72%). The retrospectively collected validation cohort included 54 episodes, with 31 (57.4%) surgically confirmed AT. In a multivariate regression analysis, vomiting, neutrophils to lymphocytes ratio > 3.5 and sonographic finding of enlarged ovary were independently associated with AT [OR 95% CI 2.78 (1.21-6.36), 3.15 (1.42-6.97) and 2.80 (1.33-5.88), respectively]. In the derivation cohort, the PPV for AT diagnosis was 69.7%, 84.5% and 93.1% if 1, 2 and 3 risk factors were present, respectively. Retrospective validation analysis underlined a PPV of 67.6%, 82.6 and 66.6% for 1, 2 and 3 risk factors, respectively. CONCLUSION: We have developed and validated a simple predictive model for pre-operative diagnosis of AT, based on three parameters. Our model may assist clinicians while evaluating patients with suspected AT and improve pre-operative diagnosis.

Chemotherapy-based gonadotoxicity risk evaluation as a predictor of reproductive outcomes in post-pubertal patients following ovarian tissue cryopreservation.

BACKGROUND: The sterilizing effect of cancer treatment depends mostly on the chemotherapy regimen and extent of radiotherapy. Prediction of long-term reproductive outcomes among cancer survivors according to chemo-radiotherapy regimen may improve pre-treatment fertility preservation counseling and future reproductive outcomes. METHODS: The aim of this study was to evaluate long term reproductive outcomes in cancer survivors according to gonadotoxicity risk estimation of the chemo-radiotherapy regimens utilized. This retrospective cohort study was comprised of post-pubertal female patients referred for fertility preservation during 1997 and 2017 was performed. Eligible adult patients were addressed and asked to complete a clinical survey regarding their ovarian function, menstruation, reproductive experience and ovarian tissue auto-transplantation procedures. Results were stratified according to the gonadotoxic potential of chemotherapy and radiotherapy they received-low, moderate and high-risk, defined by the regimen used, the cumulative dose of chemotherapy administered and radiation therapy extent. RESULTS: A total of 120 patients were eligible for the survey. Of those, 92 patients agreed to answer the questionnaire. Data regarding chemotherapy regimen were available for 77 of the 92 patients who answered the questionnaire. Menopause symptoms were much more prevalent in patients undergoing high vs moderate and low-risk chemotherapy protocol. (51.4% vs. 27.3% and 16.7%, respectively; p < 0.05). Spontaneous pregnancy rates were also significantly lower in the high-risk compared with the low-risk gonadotoxicity regimen group (32.0% vs. 58.3% and 87.5%, respectively; p < 0.05). CONCLUSION: Patients scheduled for aggressive cancer treatment have significantly higher rates of menopause symptoms and more than double the risk of struggling to conceive spontaneously. Improving prediction of future reproductive outcomes according to treatment protocol and counseling in early stages of cancer diagnosis and treatment may contribute to a tailored fertility related consultation among cancer survivors.

Urinary dysfunction in women following total mesorectal excision versus partial mesorectal excision for treatment of rectal cancer.

BACKGROUND: Colorectal cancer is a condition which is associated with substantial morbidity and mortality. The aim of this study was to assess urinary dysfunction and its effect on quality of life in women who underwent total mesorectal excision compared to women treated by partial mesorectal excision for treatment of rectal cancer. METHODS: We performed a retrospective cohort study at a tertiary university hospital between January 2014 and December 2019. A comparison was performed between women who underwent total mesorectal excision as opposed to partial mesorectal excision for treatment of rectal cancer. Pre-operative, intra-operative and post-operative data were compared between groups. Data regarding radiation therapy was recorded and compared as well. Urinary dysfunction and its impact on quality of life were assessed using UDI-6 and USIQ questionnaires. Further univariate and multivariate analyses were performed in the attempt of assessing risk factors for urinary dysfunction. RESULTS: A total of 107 women were included in the study, 73 women underwent partial mesorectal excision as opposed to 34 women who were treated by total mesorectal excision. Twenty-five women in the TME group underwent radiation therapy prior to surgery as opposed to none in the PME group (p < 0.001). Urinary dysfunction following surgery as assessed using the UDI-6 questionnaire did not differ between groups. Similar findings were recorded with regard to the impact of urinary dysfunction on quality of life as assessed using the USIQ questionnaire. Following multivariate analysis longer hospital stay was associated with increased risk of some degree of urinary dysfunction. CONCLUSIONS: Women undergoing total mesorectal excision have comparable results to partial mesorectal excision with regard to urinary dysfunction.

Vaginal Colposuspension Using the Uphold Lite Mesh System versus Transvaginal Hysterectomy with Uterosacral Ligament Suspension for Treatment of Apical Prolapse: A Comparative Study.

STUDY OBJECTIVE: To compare clinical and anatomic outcomes as well as patient satisfaction in women undergoing vaginal colposuspension using the Uphold Lite system (Boston Scientific Corporation, Marlborough, MA) and transvaginal hysterectomy with uterosacral ligament suspension (VUSLS) for the treatment of apical prolapse. DESIGN: Retrospective cohort study. SETTING: Female pelvic medicine and reconstructive surgery unit at a university-affiliated tertiary medical center. PATIENTS: Women with apical prolapse who underwent either vaginal colposuspension using the Uphold Lite system (uterine-preserving as well as after previous hysterectomy) or VUSLS from 2010 to 2019. Excluded were women with 1 month or less of follow-up. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 164 women were included in the study: 112 women underwent VUSLS, and 52 underwent colposuspension using the Uphold Lite mesh system. Age, body mass index, maximal birth weight, comorbidity rates, and pelvic organ prolapse severity were similar between the groups. The clinical cure rate was similarly high in both groups, with 91.1% in the women who underwent VUSLS and 88.5% in those in the Uphold Lite group (p = .60). No differences were noted between the groups with regard to anatomic cure rate or composite outcome success rate (73.9% vs 76.0%, p = .77 and 70.3% vs 74.0%, p = .63, in the VUSLS and Uphold Lite groups, respectively). An advantage was noted in the VUSLS group with regard to patient satisfaction with 98.1% of the women stating that their condition was very much better (Patient Global Impression of Improvement questionnaire: A) or much better (Patient Global Impression of Improvement questionnaire: B) compared with 83.9% of the women in the Uphold Lite group (p = .023). In an attempt to assess the association between different variables and the composite outcome, a multivariate analysis was performed in which increased body mass index, menopausal status, and increased preoperative genital hiatus were found to decrease composite outcome success. CONCLUSION: Vaginal colposuspension using the Uphold Lite system and VUSLS for the treatment of apical prolapse have comparable results with high clinical success rates.

Recurrent Tubal Ectopic Pregnancy Management and the Risk of a Third Ectopic Pregnancy.

STUDY OBJECTIVE: To evaluate the rate of a third ectopic pregnancy according to the modality of treatment of the second ectopic pregnancy. DESIGN: Retrospective cohort study. SETTING: University-affiliated tertiary medical center. PATIENTS: One hundred eleven women who had 2 ectopic pregnancies and a third consecutive pregnancy between 2003 and 2018. INTERVENTIONS: Surgery or medical treatment as required. MEASUREMENTS AND MAIN RESULTS: With regard to the modality of treatment of the second ectopic pregnancy, the patients were divided into 3 groups: expectant management, medical treatment with methotrexate, and laparoscopic salpingectomy. Univariate and multivariate analyses were conducted to assess the association of various parameters of the second ectopic pregnancy with the occurrence of a third ectopic pregnancy in the consecutive pregnancy. Twenty women (18.0%) were managed expectantly, 55 (49.6%) were treated with methotrexate, and 36 (32.4%) underwent surgery. Expectant management resulted in significantly higher rates of a third ectopic pregnancy compared with treatment with methotrexate or surgical intervention (50.0% vs 18.2% and 13.8%, respectively; p = .005). In the cases of 2 ipsilateral ectopic pregnancies, the interventional approach (medical or surgical treatment) resulted in lower recurrence rates compared with expectant management (25.7% vs 60.0%, respectively; p = .043). CONCLUSION: The risk of a third episode of an ectopic pregnancy after expectant management of a second ectopic pregnancy is extremely high. An interventional approach by treatment with methotrexate or salpingectomy is therefore preferred for recurrent ectopic pregnancy management, especially in ipsilateral recurrences.

Surgically confirmed adnexal torsion during pregnancy: Does the trimester make a difference?

AIM: To investigate the clinical and the sonographic characteristics of adnexal torsion (AT) during pregnancy and to underline differences in AT manifestation between pregnancy trimesters. METHODS: This is a retrospective cohort study in a tertiary medical center. The study included all pregnant women with surgically confirmed AT between March 2011 and April 2020. The patients were divided into three groups according to pregnancy trimesters, and the clinical and sonographic characteristics were compared between the groups. RESULTS: The study cohort included 140 cases of AT. Ninety-nine (70.7%) of the cases occurred during the 1st trimester, and 31 (22.1%) and 10 (7.1%) occurred during the 2nd and the 3rd trimesters, respectively. Conception by assisted-reproductive technologies (ART), nausea, and finding of enlarged ovary on ultrasound scan were all more common among patients in the 1st trimester group as compared to the 3rd trimester group (p = 0.001, 0.015, and 0.024, respectively). The mean time from admission to surgery was significantly shorter in the 1st trimester group as compared to late pregnancy (p = 0.001). The majority of cases were right-sided. There was a significant difference in the organs involved in every trimester of pregnancy-ovary only, ovary and fallopian tube, and fallopian tube only (p = 0.023). CONCLUSIONS: Most AT cases during pregnancy occurred during the 1st trimester. Conception by ART and enlarged ovary on ultrasound scan were also more common in AT cases during early pregnancy. Time from admission to surgery was longer as pregnancy progressed and organs involved differed between trimesters. Understanding the difference in manifestation of AT in every trimester might improve the preoperative evaluation of AT in pregnancy.

The cytosolic form of aspartate aminotransferase is required for full activation of TOR complex 1 in fission yeast.

The evolutionarily conserved TOR complex 1 (TORC1) activates cell growth and proliferation in response to nutritional signals. In the fission yeast Schizosaccharomyces pombe, TORC1 is essential for vegetative growth, and its activity is regulated in response to nitrogen quantity and quality. Yet, how TORC1 senses nitrogen is poorly understood. Rapamycin, a specific TOR inhibitor, inhibits growth in S. pombe only under conditions in which the activity of TORC1 is compromised. In a genetic screen for rapamycin-sensitive mutations, we isolated caa1-1, a loss-of-function mutation of the cytosolic form of aspartate aminotransferase (Caa1). We demonstrate that loss of caa1+ partially mimics loss of TORC1 activity and that Caa1 is required for full TORC1 activity. Disruption of caa1+ resulted in aspartate auxotrophy, a finding that prompted us to assess the role of aspartate in TORC1 activation. We found that the amino acids glutamine, asparagine, arginine, aspartate, and serine activate TORC1 most efficiently following nitrogen starvation. The glutamine synthetase inhibitor l-methionine sulfoximine abolished the ability of asparagine, arginine, aspartate, or serine, but not that of glutamine, to induce TORC1 activity, consistent with a central role for glutamine in activating TORC1. Neither addition of aspartate nor addition of glutamine restored TORC1 activity in caa1-deleted cells or in cells carrying a Caa1 variant with a catalytic site substitution, suggesting that the catalytic activity of Caa1 is required for TORC1 activation. Taken together, our results reveal the contribution of the key metabolic enzyme Caa1 to TORC1 activity in S. pombe.

TOR complex 2 in fission yeast is required for chromatin-mediated gene silencing and assembly of heterochromatic domains at subtelomeres.

The conserved serine/threonine protein kinase target of rapamycin (TOR) is a major regulator of eukaryotic cellular and organismal growth and a valuable target for drug therapy. TOR forms the core of two evolutionary conserved complexes, TOR complex 1 (TORC1) and TORC2. In the fission yeast Schizosaccharomyces pombe, TORC2 responds to glucose levels and, by activating the protein kinase Gad8 (an orthologue of human AKT), is required for well-regulated cell cycle progression, starvation responses, and cell survival. Here, we report that TORC2-Gad8 is also required for gene silencing and the formation of heterochromatin at the S. pombe mating-type locus and at subtelomeric regions. Deletion of TORC2-Gad8 resulted in loss of the heterochromatic modification of histone 3 lysine 9 dimethylation (H3K9me2) and an increase in euchromatic modifications, including histone 3 lysine 4 trimethylation (H3K4me3) and histone 4 lysine 16 acetylation (H4K16Ac). Accumulation of RNA polymerase II (Pol II) at subtelomeric genes in TORC2-Gad8 mutant cells indicated a defect in silencing at the transcriptional level. Moreover, a concurrent decrease in histone 4 lysine 20 dimethylation (H4K20me2) suggested elevated histone turnover. Loss of gene silencing in cells lacking TORC2-Gad8 is partially suppressed by loss of the anti-silencer Epe1 and fully suppressed by loss of the Pol II-associated Paf1 complex, two chromatin regulators that have been implicated in heterochromatin stability and spreading. Taken together, our findings suggest that TORC2-Gad8 signaling contributes to epigenetic stability at subtelomeric regions and the mating-type locus in S. pombe.