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The aim of the study was to assess patient, treatment and cycle characteristics in relation to the risk of multiple conception following ovulation induction in order to reduce the prevalence of this complication of treatment. We performed a retrospective analysis of 208 pregnancy cycles achieved in the Middlesex Hospital outpatient fertility unit. These pregnancies were achieved in 175 anovulatory women who conceived after gonadotrophin or pulsatile GnRH therapy. The multiple conception rate was 13.4%. After spontaneous reductions and abortions the multiple delivery rate was 9.6%. Clinical features associated with an increased risk of multiple pregnancies were the presence of polycystic ovary syndrome and secondary infertility. Comparison between different protocols of ovulation induction revealed no relationship with the risk of multiple conceptions. Although total number of follicles was increased in the multiple conception cycles, the distribution of follicles according to their diameter on the day of human chorionic gonadotrophin (HCG) administration was similar in multiple and singleton conception cycles. Thus, the risk of multiple conception could not be attributed to an increased number of follicles of any particular size but directly related to the total number of the cohort follicles ( > or = 14 mm) and leading follicles > or = 17 mm), rising from 7% with one follicle to 33% with six or more follicles. As we could not find a specific pattern of follicular development that could be associated with multiple conception, we conclude that the difference in the ovarian response leading to multiple conception is quantitative rather than qualitative. The data presented enable the assessment of the risk of multiple conception in any given cycle. [ABSTRACT FROM AUTHOR]

The results of in-vitro cervical mucus—sperm penetration tests and cross-hostility tests in 178 couples with repeatedly negative post-coital tests were recorded. Using a protocol of three cycles with intra-uterine inseminations (IUI) followed by three cycles with ovulation induction + IUI, the association between the cause of infertility, results of the in-vitro tests and the outcome of infertility treatment was investigated. We found that repeatedly negative post-coital tests are a good indicator of a cervical mucus — sperm penetration problem. The crosshostility test clearly differentiates the abnormal factor in this interaction, and a good performance of the donors' spermatozoa in the cervical mucus correlates with increased pregnancy rate. In male factor infertility, failure of the husbands' spermatozoa to penetrate cervical mucus was not indicative of a deficient fertilization potential . In these patients a serious attempt should therefore be made to reverse the infertility by treatment with IUI or ovulation induction + IUI before attempting assisted reproduction. Women with polycystic ovaries and repeatedly negative post-coital tests should be investigated for sperm receptivity of the cervical mucus. Low receptivity of the cervical mucus may imply that endometrial receptivity and oocyte quality are also low. Ovulation induction and not IUI alone should therefore be used as the preferred mode of treatment to improve pregnancy rate. [ABSTRACT FROM PUBLISHER]

The choice of treatment for clomiphene-resistant anovulation associated with polycystic ovary syndrome (PCOS) is presently arbitrary and selection criteria are not available. A total of 144 women with anovulatory infertility associated with PCOS who failed to conceive on clomiphene were treated with either pure follicle stimulating hormone (FSH) (n = 29), or human menopausal gonadotrophin (HMG) (n = 60), or gonadotrophin-releasing hormone analogue (GnRHa) and HMG (n = 55). Analysis of 306 treatment cycles and 53 pregnancies revealed a cumulative conception rate at 4 months of 23% with FSH, 47% with HMG and 69% with GnRHa + HMG. The miscarriage rate was highest in the HMG group (44%) and consequently the cumulative live birth rate was superior when GnRHa was used in combination with HMG. There were no significant differences in the basal clinical and endocrinological features of those who conceived compared with those who did not, either in the whole group, or in the individual treatment groups. Thus, the choice of treatment for clomiphene-resistant women with PCOS cannot be guided by the basal clinical or endocrinological features of this heterogeneous syndrome with the present state or knowledge. [ABSTRACT FROM AUTHOR]

The choice of treatment for clomiphene-resistant anovulation associated with polycystic ovary syndrome (PCOS) is presently arbitrary and selection criteria are not available. A total of 144 women with anovulatory infertility associated with PCOS who failed to conceive on clomiphene were treated with either pure follicle stimulating hormone (FSH) ( = 29), or human menopausal gonadotrophin (HMG) ( = 60), or gonadotrophin-releasing hormone analogue (GnRHa) and HMG ( = 55). Analysis of 306 treatment cycles and 53 pregnancies revealed a cumulative conception rate at 4 months of 23% with FSH, 47% with HMG and 69% with GnRHa + HMG. The miscarriage rate was highest in the HMG group (44%) and consequently the cumulative live birth rate was superior when GnRHa was used in combination with HMG. There were no significant differences in the basal clinical and endocrinological features of those who conceived compared with those who did not, either in the whole group, or in the individual treatment groups. Thus, the choice of treatment for clomiphene-resistant women with PCOS cannot be guided by the basal clinical or endocrinological features of this heterogeneous syndrome with the present state or knowledge. [ABSTRACT FROM PUBLISHER]

The most important aspect of diminished ovarian reserve is the associated decline in reproductive potential. Assessment of ovarian reserve is mainly based on measurement of early follicular phase follicle stimulating hormone (FSH) concentration. The objective of this study was to report the identification of a group of 12 infertile women initially diagnosed as having unexplained or anovulatory infertility, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins. All developed ovarian failure within a relatively short time span. Non-response to ovarian stimulation was defined by failure to achieve development of follicles >12 mm and failure to raise oestradiol concentration >350 pmol/l in two successive cycles of human menopausal gonadotrophin (HMG) doses of up to five ampoules per day for 5-8 days. Within a mean of 9 months following the failed attempts of ovarian stimulation the mean day 3 FSH concentrations rose from 5.4 +/- 2.7 IU/l to 53.5 +/- 19.7 IU/l. In these patients, day 3 FSH concentration failed to indicate the low ovarian reserve manifested only by lack of clinical response to treatment with gonadotrophins which was the first sign of impending ovarian failure. We conclude that women with normal early follicular phase serum FSH concentrations who do not respond to ovarian stimulation by HMG are at risk of developing ovarian failure within several months. [ABSTRACT FROM PUBLISHER]

The effect of uterine leiomyoma on infertility is subject to controversy. Two main mechanisms associating leiomyomata and infertility have been suggested: the obstruction of gamete transport and impaired implantation. In-vitro fertilization (IVF) is a unique setting for examining the effect of leiomyomata on the implantation rate. This study was designed to determine the impact of uterine leiomyomata on the results of IVF. In a retrospective analysis of IVF cycles, 46 women with documented uterine leiomyoma were compared with a control group with mechanical infertility. The implantation rate and pregnancy outcome in relation to the leiomyoma were observed. Implantation (22.1%/transfer, 6.8%/embryo) and abortion rates (36%) in the study group were similar to the results in the control group with pure mechanical factor. An analysis of IVF results according to the hysteroscopic pretreatment findings revealed that impaired implantation is associated with leiomyoma only where uterine intracavitary abnormalities co-exist. We conclude that implantation rate and pregnancy outcome are impaired in women with uterine leiomyomata only when they cause deformation of the uterine cavity. In patients with leiomyomata associated with an abnormal uterine cavity, surgical treatment should be considered prior to IVF because of the reduced implantation rate. [ABSTRACT FROM AUTHOR]

The objective of our study was to assess the value of intraamniotic injection of urograffin in the diagnosis of premature rupture of membranes (PROM). Intra-amniotic injection of urograffin with the concomitant insertion of a vaginal tampon was performed in 30 consecutive patients who were admitted because of suspected PROM and the presence of a heavy bloody vaginal secretion. The vaginal tampons were X-rayed for the presence of radio-opacity. In 23 patients, traces of urograffin were found in the vaginal tampons by X-ray. No fetal or maternal complications were observed during delivery and puerperium. We suggest the use of intraamniotic injection of urograffin for the diagnosis of PROM in cases where heavy bloody vaginal discharge is present. [ABSTRACT FROM AUTHOR]

A significant increase in endometrial thickness and volume was observed in 30 patients given oestrogen and progestin supplementation following curettage for first trimester abortions, compared with 30 women who received no treatment. This indicates an enhanced regeneration of the endometrium following treatment. The ability to induce this response, creating a space between the intra-cavity surface area a short time after abortion, may theoretically be suggested as preventative treatment to reduce the risk of intrauterine adhesions. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflicts of interest None disclosed.

Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype in human cells. Expression of H3E50K is sufficient to transform human cells as evidenced by a dramatic increase in cell migration and invasion, and a statistically significant increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K perturbs proximal H3 post-translational modifications globally and dysregulates gene expression, activating the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional histone H3 mutations have the potential to be oncogenic drivers and function through distinct mechanisms that dysregulate gene expression.

Pyrroloiminoquinone alkaloids are a large class of natural products that display a wide range of biological activities. Synthetic approaches to these natural products typically rely on a common late-stage C10-oxygenated pyrroloiminoquinone intermediate, but these strategies often lead to lengthy synthetic sequences that are not amenable to divergent syntheses. We devised an alternative approach aimed at the early introduction of the C10 nitrogen, which we hypothesized would enable late-stage diversification. This strategy hinged upon a Larock/Buchwald-Hartwig annulation/cyclization to quickly access the core of these alkaloids. We report the development of this cascade process, which was facilitated by a dual ligand system in addition to selective functionalization of the key intermediate, to provide efficient syntheses of makaluvamines A, C, and D and isobatzelline B, and the first total synthesis of makaluvamine N., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: We aimed to assess whether ovulation induction treatments affect obstetric and neonatal outcomes., Study Design: This was a historic cohort study of deliveries in a single university-affiliated medical center between November 2008 and January 2020. We included women who had one pregnancy following ovulation induction and one unassisted pregnancy. The obstetric and perinatal outcomes were compared between pregnancies following ovulation induction and unassisted pregnancies, so that each woman served as her own control. The primary outcome measure was birth weight., Results: A total of 193 deliveries following ovulation induction and 193 deliveries after unassisted conception by the same women were compared. Ovulation induction pregnancies were characterized by a significantly younger maternal age and a higher rate of nulliparity (62.7 vs. 8.3%, p  < 0.001). In pregnancies achieved by ovulation induction, we found a higher rate of preterm birth (8.3 vs. 4.1%, p  = 0.02) and instrumental deliveries (8.8 vs. 2.1%, p  = 0.005), while cesarean delivery rates were higher following unassisted pregnancies. Birth weight was significantly lower in ovulation induction pregnancies (3,167 ± 436 vs. 3,251 ± 460 g, p  = 0.009), although the rate of small for gestational age neonates was similar between the groups. On multivariate analysis, birth weight remained significantly associated with ovulation induction after adjustment for confounders, while preterm birth did not., Conclusion: Pregnancies following ovulation induction treatments are associated with lower birth weight. This may be related to an altered placentation process following uterine exposure to supraphysiological hormonal levels., Key Points: · Ovulation induction entails lower birthweight.. · This may relate to supraphysiological hormonal levels.. · Monitoring fetal growth is advised in such cases.., Competing Interests: None declared., (Thieme. All rights reserved.)

Lysine dimethylation (Kme 2 ) is a crucial post-translational modification (PTM) that regulates biological processes and is implicated in diseases. There is significant interest in globally identifying these methylation marks. Unfortunately, this remains challenging due to the lack of robust technologies for selectively labeling Kme 2 . To address this, we present a chemical method named tertiary amine coupling by oxidation (TACO). This method selectively modifies Kme 2 to aldehydes using Selectfluor and a base. The resulting aldehydes from Kme 2 were then functionalized using reductive amination, thiolamine, and oxime chemistry. We successfully demonstrated the versatility of TACO in selectively labeling Kme 2 peptides and proteins in complex cell lysate mixtures with varying payloads, including affinity tags and fluorophores. We further showed the application of TACO chemistry for the identification of Kme 2 sites at a single-molecule level by fluorosequencing. We discovered novel 30 Kme 2 sites, in addition to previously known 5 Kme 2 sites, by proteomics analysis of TACO-modified nuclear extracts. Our work establishes a unique strategy for covalently modifying Kme 2 , facilitating the global identification of low-abundance Kme 2 -PTMs and their sites within complex cell lysate mixtures.

Objective: Planned oocyte cryopreservation (OC) is being increasingly utilized worldwide. However, some women cannot accumulate sufficient oocytes because of poor response to stimulation. The POSEIDON classification is a novel system to classify patients with 'expected' or 'unexpected' inappropriate ovarian response to exogenous gonadotropins. Our study aimed to examine the prevalence of POSEIDON patients among women undergoing planned OC., Study Design: We retrospectively reviewed the first cycles of 160 consecutive patients undergoing planned OC. Patients were classified into the four POSEIDON groups or as 'non-POSEIDON' based on age, AMH level and the number of oocytes retrieved. The primary outcome measure was the prevalence of POSEIDON patients., Results: Overall, 63 patients (39.4 %) were classified as POSEIDON patients, 12 in group 1, 12 in group 2, 8 in group 3, and 31 in group 4. Compared to non-POSEIDON patients, POSEIDON patients had increased basal FSH levels and reduced serum AMH levels and antral follicle counts, required higher FSH starting doses and increased gonadotropin requirements and reached lower peak serum estradiol levels. Additionally, POSEIDON patients had a lower number of oocytes retrieved (7.6 ± 3.1 vs.20.2 ± 9.9, p < 0.001) and vitrified (5.8 ± 2.9 vs.14.7 ± 6.8, p < 0.001) than non-POSEIDON counterparts, respectively., Conclusion: We found a high prevalence of patients being classified as low prognosis according to the POSEIDON criteria among patients seeking planned OC. POSEIDON patients had increased gonadotropin requirements and a significantly lower number of oocytes retrieved and vitrified. This novel, unexpected finding adds clinically relevant information for counselling and management of patients undergoing planned OC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Stress urinary incontinence (SUI) is a risk of robotic-assisted radical prostatectomy (RP) which can be a frustrating problem for both surgeons and patients. We aim to compare short-term continence outcomes between patients undergoing Retzius Sparing RP (RS-RP) and those undergoing standard RP with the inclusion of a PUS suture technique and suprapubic tube (PUS-RP). A retrospective review of 105 consecutive patients who underwent RP was performed, comparing patients who underwent RS-RP and PUS-RP. Our main outcome was pad usage as a surrogate for SUI. Patients were evaluated 4 weeks following RP and again at approximately 3 months. Continence was defined as no pad usage or up to one safety pad per day. Risk factors associated with not being continent were identified using univariate and multivariate analyses. In our cohort, 52 patients underwent RS-RP and 53 patients underwent PUS-RP. The two groups had similar patient demographics. Although not statistically significant, there was a higher rate of a positive surgical margin in the RS-RP compared to PUS-RP (25% vs 15%, p = 0.204). At one month follow-up for PUS-RP and RS-RP, there was no significant difference in the frequency of continent men (69.2% vs. 76.9%, p = 0.302). At 3-month follow-up for the two groups of patients, again, there was no significant difference in the frequency of continence for PUS-RP and RS-RP (86.2% vs 88%, p = 0.824). Patients who underwent RS-RP had similar rates of continence to those patients undergoing PUS-RP in the short-term post-operative period., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Aleutianamine is a recently isolated pyrroloiminoquinone natural product that displays potent and selective biological activity toward human pancreatic cancer cells with an IC 50 of 25 nM against PANC-1, making it a potential candidate for therapeutic development. We report a synthetic approach to aleutianamine wherein the unique [3.3.1] ring system and tertiary sulfide of this alkaloid were constructed via a novel palladium-catalyzed dearomative thiophene functionalization. Other highlights of the synthesis include a palladium-catalyzed decarboxylative pinacol-type rearrangement of an allylic carbonate to install a ketone and a late-stage oxidative amination. This concise and convergent strategy will enable access to analogues of aleutianamine and further investigation of the biological activity of this unique natural product.

Introduction: Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can be associated with autoimmune and inflammatory diseases. This study aimed to describe kidney involvement in patients with CMML, their treatments, and outcomes., Methods: We conducted a French and American multicenter retrospective study in 15 centers, identifying patients with CMML with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities., Results: Sixteen patients (males, n  = 14; median age 76.5 years [71.9-83]) developed a kidney disease 6 months [1.6-25.6] after the diagnosis of CMML. At the time of kidney disease diagnosis, median urinary protein-to-creatinine ratio was 2 g/g [1.25-3.4], and median serum creatinine was 2.26 mg/dl [1.46-2.68]. Fourteen patients (87.5%) underwent a kidney biopsy, and the 2 main pathological findings were lysozyme nephropathy (56%) and renal infiltration by the CMML (37.5%). Ten patients received a new treatment following the CMML-associated kidney injury. Among patients with monitored kidney function, and after a median follow-up of 15 months [9.9-34.9], 4 patients had CKD stage 3, 4 had CKD stage 4, 1 had an end-stage kidney disease. In our patient series, 2 patients evolved to an acute myeloid leukemia (AML), and 5 died. Compared with 116 CMML controls, patients who had a kidney involvement had a higher monocyte count ( P  < 0.001), had more CMML-1 ( P  = 0.005), were more susceptible to develop an AML ( P  = 0.02), and were more eligible to receive a specific hematologic treatment, with hydroxyurea, or hypomethylating agents ( P  < 0.001), but no survival difference was seen between the 2 groups ( P  = 0.6978)., Conclusion: In this cohort of patients with CMML with a kidney injury, the 2 most frequent renal complications were lysozyme-induced nephropathy and renal infiltration by the CMML. Kidney involvement should be closely monitored in patients with CMML., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Objective: To compare comprehensive continence outcomes in patients receiving pelvic floor muscle training (PFMT) vs standard unsupervised home pelvic floor exercise therapy (UPFE)., Methods: As part of the UVA prostatectomy functional outcomes program, participating patients complete a 12-month PFMT program under FPMRS specialist supervision. We performed a retrospective review of prospectively collected longitudinal outcomes in patients receiving PFMT vs UPFE through 12-month follow-up. Primary study outcome was ICIQ-MLUTS SUI domain score (SDS). Secondary outcomes included daily pad use (PPD), SUI Cure (SDS=0), and quality of life score (IIQ-7). Multilevel mixed effects linear regression was used to model SDS over time., Results: Analysis included 40 men. No difference in patient characteristics was seen in comparison of PFMT vs UPFE cohorts (P = NS, all comparisons). Mean predicted SDS was significantly better in the PFMT vs UPFE cohorts at 6-month (0.81 ± 0.21 vs 1.75 ± 0.34, respectively) (P = .014) and 12-month (0.72 ± 0.17 vs 1.67 ± 0.30, respectively) (P = .004) time points. At 12-month follow-up, 11 (55%) vs 4 (20%) patients reported absence of SUI in PFMT vs UPFE cohorts, respectively. Predicted probabilities of SUI cure in PFMT vs UPFE cohorts at 12months were 0.52 ± 0.14 vs 0.23 ± 0.13, respectively (P = .14). At 12-month follow-up, the mean predicted PPD and IIQ score was 0.19 ± 0.10 vs 0.79 ± 0.33 and 2.86 ± 0.86 vs 2.55 ± 1.07 in PFMT vs UPFE cohorts, respectively (P = NS)., Conclusion: In-person, FMPRS-directed PFMT is associated with improved SUI domain scores following robotic-assisted laparoscopic prostatectomy, a finding durable through 12-month follow-up., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aliphatic aldehydes are reactive electrophilic carbonyls that cross-link with DNA and proteins leading to cellular toxicity and disease pathogenesis. This toxicity is due to the cooperative effect of multiple aldehydes via a common mechanism. Therefore, live-cell imaging of total aliphatic aldehydes, small-to-long chain (C 1 -C 10 ), is highly desired to decipher their physiological and pathological functions. However, sensors for imaging total cellular aliphatic aldehydes are currently lacking despite their high concentrations (∼80 to >500 μM) inside cells. Herein, we report chemical sensors that generate a benzimidazole moiety upon reaction with aliphatic aldehydes of different chain lengths (C 1 -C 10 ), resulting in turn-on fluorescence. These sensors exhibit high quantum yields, high dynamic range, and enable the quantification of changes in both the exogenous administration of aldehydes and endogenous real-time formation of aliphatic aldehydes in live mammalian cells. This tool has great potential to transform aldehyde research by illuminating cellular metabolites that have remained elusive in living systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: Stress urinary incontinence (SUI) is a well-known adverse outcome following robotic-assisted laparoscopic prostatectomy (RALP). Although postoperative SUI has been extensively studied, little focus has been placed on understanding the natural history and impact of urgency symptoms following RALP. The UVA prostatectomy functional outcomes program (PFOP) was developed to comprehensively assess and optimize continence outcomes following RALP. The present study focuses on assessing urgency outcomes in this cohort., Methods: PFOP patients with a minimum of 6-months follow up following RALP were included. The PFOP includes prospectively assessed incontinence and quality of life outcomes utilizing ICIQ-MLUTS, Urgency Perception Score (UPS), and IIQ-7 questionnaires. The primary study outcome was urgency urinary incontinence (UUI) as determined by ICIQ-MLUTS UUI domain. Secondary outcomes included urgency (UPS score) and quality of life (IIQ-7)., Results: Forty patients were included with median age 63.5 years. Fourteen (35%) patients reported UUI at baseline. UUI and QOL scores worsened compared to baseline at all time-points. Urgency worsened at 3-weeks and 3-months but returned to baseline by 6-months. Notably, 63% of patients without baseline UUI reported de-novo UUI at 6 months. Although QOL was lower in patients with versus without UUI (IIQ-7 score 3.0 vs 0.0, p = 0.009), severity of UUI was not associated with QOL when controlling for SUI severity., Conclusion: Our data demonstrate significantly worsened UUI from baseline and a large incidence of de-novo UUI following RALP. Further study is needed to inform how urgency and UUI and its treatment affect health-related quality of life following RALP., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Incontinence and urgency are common after prostatectomy. The University of Virginia prostatectomy functional outcomes program (PFOP) was developed to comprehensively assess and optimise continence outcomes following robotic-assisted laparoscopic prostatectomy (RALP). Patients are prospectively evaluated by a Female Pelvic Medicine and Reconstructive Surgery specialist. This study assessed for predictors of 3- and 6-month stress urinary incontinence (SUI) and urgency symptom outcomes following RALP., Methods: We performed a post hoc review of patients from our PFOP receiving a minimum of 6-month follow-up. Urinary symptoms are prospectively assessed using the validated International Consultation on Incontinence Questionnaire-Male Lower Urinary Tract Symptoms (ICIQ-MLUTS) questionnaire and daily pad use (pads per day [PPD]). Primary study outcomes included ICIQ-MLUTS SUI and urgency domain scores and PPD. Multivariable linear regression was performed to identify variables associated with outcomes at 3 and 6 months postoperatively. Variables included patient, oncologic and surgical factors. Each variable was run in a separate model with pelvic floor muscle therapy and surgeon to reduce confounding and prevent overfitting., Results: Forty men were included. In assessment of ICIQ-MLUTS SUI domain score, at 3 months, body mass index (BMI) was associated with worse scores, and at 6 months, BMI, hypertension and estimated blood loss (EBL) were associated with worse scores, whereas bilateral nerve-sparing technique was associated with better scores. For ICIQ-MLUTS Urgency domain score, at 3 months, preoperative use of benign prostatic hyperplasia (BPH) medication was associated with better scores. No covariates predicted 6-month ICIQ-MLUTS Urgency domain scores. For PPD use, at both 3 and 6 months, BMI was a positive predictor, while preoperative use of BPH medication was a negative predictor., Conclusion: Increased BMI, EBL and hypertension are associated with worsened SUI outcomes following RALP, whereas bilateral nerve-sparing technique and preoperative BPH medication are associated with improved SUI outcomes. These data may inform patient counselling and help identify patients who may benefit from closer surveillance and earlier anti-incontinence intervention., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

The high frequency of aberrant PI3K pathway activation in hormone receptor-positive (HR + ) breast cancer has led to the development, clinical testing, and approval of the p110α-selective PI3K inhibitor alpelisib. The limited clinical efficacy of alpelisib and other PI3K inhibitors is partially attributed to the functional antagonism between PI3K and estrogen receptor (ER) signaling, which is mitigated via combined PI3K inhibition and endocrine therapy. We and others have previously demonstrated chromatin-associated mechanisms by which PI3K supports cancer development and antagonizes ER signaling through the modulation of the H3K4 methylation axis, inhibition of KDM5A promoter H3K4 demethylation and KMT2D/MLL4-directed enhancer H3K4 methylation. Here we show that inhibition of the H3K4 histone methyltransferase MLL1 in combination with PI3K inhibition impairs HR + breast cancer clonogenicity and cell proliferation. While combined PI3K/MLL1 inhibition reduces PI3K/AKT signaling and H3K4 methylation, MLL1 inhibition increases PI3K/AKT signaling through the dysregulation of gene expression associated with AKT activation. These data reveal a feedback loop between MLL1 and AKT whereby MLL1 inhibition reactivates AKT. We show that combined PI3K and MLL1 inhibition synergizes to cause cell death in in vitro and in vivo models of HR + breast cancer, which is enhanced by the additional genetic ablation of the H3K4 methyltransferase and AKT target KMT2D/MLL4. Together, our data provide evidence of a feedback mechanism connecting histone methylation with AKT and may support the preclinical development and testing of pan-MLL inhibitors., Significance: Here the authors leverage PI3K/AKT-driven chromatin modification to identify histone methyltransferases as a therapeutic target. Dual PI3K and MLL inhibition synergize to reduce clonogenicity and cell proliferation, and promote in vivo tumor regression. These findings suggest patients with PIK3CA-mutant, HR + breast cancer may derive clinical benefit from combined PI3K/MLL inhibition., Competing Interests: No disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Research Question: Does SARS-CoV-2 mRNA vaccination affect the ovarian reserve of infertile women undergoing IVF?, Design: This was a prospective observational study at a single university-affiliated IVF unit that included infertile women aged 18-44 years who were undergoing IVF/intracytoplasmic sperm injection between November 2020 and September 2021, had received two doses of SARS-CoV-2 mRNA vaccination and had undergone measurement of baseline anti-Müllerian hormone (AMH) concentration within the 12 months preceding their recruitment. AMH concentrations before and after vaccination were evaluated and compared., Results: Overall, 31 women were included in the study. The median AMH concentrations before and after COVID-19 vaccine were comparable (1.7 versus 1.6 g/ml, respectively, P = 0.96). No correlation was found between the participant's anti-COVID-19 antibody titre and the change in AMH concentration., Conclusions: SARS-CoV-2 mRNA vaccination does not adversely affect ovarian reserve, as shown by comparing serum AMH concentrations before and after vaccination. These findings may serve as a counselling tool for clinicians to reassure women undergoing fertility treatment that SARS-CoV-2 mRNA vaccination is safe., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Can serial measurements of serum oestradiol, progesterone and β-human chorionic gonadotrophin (HCG) concentrations, starting from the day of the first positive pregnancy test, predict live birth after natural cycle frozen-thawed embryo transfer (NC-FET)?, Design: This was a historical cohort study of women with a positive pregnancy test following NC-FET, between March 2009 and January 2020. Serum β-HCG, oestradiol and progesterone concentrations were measured on the day of the first pregnancy test and 48 and 96 h later. Pregnancies resulting in a live birth were compared with non-viable pregnancies., Results: Of 101 women with a positive pregnancy test included in the study, 78 had a live birth and 23 had a non-viable pregnancy. Serum β-HCG concentrations were comparable on the day of the first pregnancy test (P = 0.09) but became significantly higher in women with a live birth 48 and 96 h later (P = 0.018 and P = 0.003). Serum oestradiol concentrations were higher in women with a live birth at all three measurements (P = 0.02, P = 0.007 and P = 0.02). Serum progesterone concentrations were higher 48 h after the first pregnancy test in women with a live birth (P = 0.04). On multivariate analysis, after controlling for the women's ages and number of embryos transferred, serum concentrations above the 25th percentile for oestradiol (>488-526 pmol/L) and progesterone (>63-70 nmol/L) were independent predictors of live birth at all three measurements., Conclusions: Increased serum oestradiol and progesterone concentrations in early NC-FET pregnancies are associated with increased likelihood of live birth. Oestradiol and progesterone concentrations can be used in conjunction with β-HCG to predict pregnancy viability and assist in patient counselling., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: This systematic review aimed to identify baseline patient demographic and controlled ovarian stimulation characteristics associated with a suboptimal response to GnRHa triggering, and available options for prevention and management of suboptimal response., Methods: PubMed, Google Scholar, Medline, and the Cochrane Library were searched for keywords related to GnRHa triggering, and peer-reviewed articles from January 2000 to September 2021 included., Results: Thirty-seven studies were included in the review. A suboptimal response to GnRHa triggering was more likely following long-term or recent oral contraceptive use and with a low or high body mass index. Low basal serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol serum levels were correlated with suboptimal oocyte yield, as was a low serum LH level on the day of triggering. A prolonged stimulation period and increased gonadotropin requirements were correlated with suboptimal response to triggering. Post-trigger LH < 15 IU/L best correlated with an increased risk for empty follicle syndrome and a lower oocyte retrieval rate. Retriggering with hCG may be considered in patients with suboptimal response according to post-trigger LH, as in cases of failed aspiration., Conclusion: Pre-treatment assessment of patient characteristics, with pre- and post-triggering assessment of clinical and endocrine cycle characteristics, may identify cases at risk for suboptimal response to GnRHa triggering and optimize its utilization., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Proteome profiling by activated esters identified >9000 ligandable lysines but they are limited as covalent inhibitors due to poor hydrolytic stability. Here we report our efforts to design and discover a new series of tunable amine-reactive electrophiles (TAREs) for selective and robust labeling of lysine. The major challenges in developing selective probes for lysine are the high nucleophilicity of cysteines and poor hydrolytic stability. Our work circumvents these challenges by a unique design of the TAREs that form stable adducts with lysine and on reaction with cysteine generate another reactive electrophiles for lysine. We highlight that TAREs exhibit substantially high hydrolytic stability as compared to the activated esters and are non-cytotoxic thus have the potential to act as covalent ligands. We applied these alternative TAREs for the intracellular labeling of proteins in different cell lines, and for the selective identification of lysines in the human proteome on a global scale., (© 2021 Wiley-VCH GmbH.)