Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.

Mutations in BRCA1 or BRCA2 (BRCA) is synthetic lethal with poly(ADP-ribose) polymerase inhibitors (PARPi). Lethality is thought to derive from DNA double-stranded breaks (DSBs) necessitating BRCA function in homologous recombination (HR) and/or fork protection (FP). Here, we report instead that toxicity derives from replication gaps. BRCA1- or FANCJ-deficient cells, with common repair defects but distinct PARPi responses, reveal gaps as a distinguishing factor. We further uncouple HR, FP, and fork speed from PARPi response. Instead, gaps characterize BRCA-deficient cells, are diminished upon resistance, restored upon resensitization, and, when exposed, augment PARPi toxicity. Unchallenged BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1, but aberrantly low XRCC1 consistent with defects in backup Okazaki fragment processing (OFP). 53BP1 loss resuscitates OFP by restoring XRCC1-LIG3 that suppresses the sensitivity of BRCA1-deficient cells to drugs targeting OFP or generating gaps. We highlight gaps as a determinant of PARPi toxicity changing the paradigm for synthetic lethal interactions.

ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia.

Metabolic reprogramming is a common feature of many human cancers, including acute myeloid leukemia (AML). However, the upstream regulators that promote AML metabolic reprogramming and the benefits conferred to leukemia cells by these metabolic changes remain largely unknown. We report that the transcription factor ATF3 coordinates serine and nucleotide metabolism to maintain cell cycling, survival, and the differentiation blockade in AML. Analysis of mouse and human AML models demonstrate that ATF3 directly activates the transcription of genes encoding key enzymatic regulators of serine synthesis, one-carbon metabolism, and de novo purine and pyrimidine synthesis. Total steady-state polar metabolite and heavy isotope tracing analyses show that ATF3 inhibition reduces de novo serine synthesis, impedes the incorporation of serine-derived carbons into newly synthesized purines, and disrupts pyrimidine metabolism. Importantly, exogenous nucleotide supplementation mitigates the anti-leukemia effects of ATF3 inhibition. Together, these findings reveal the dependence of AML on ATF3-regulated serine and nucleotide metabolism.

BRCA1 Mutational Complementation Induces Synthetic Viability.

BRCA1 promotes the DNA end resection and RAD51 loading steps of homologous recombination (HR). Whether these functions can be uncoupled, and whether mutant proteins retaining partial activity can complement one another, is unclear and could affect the severity of BRCA1-associated Fanconi anemia (FA). Here we generated a Brca1CC mouse with a coiled-coil (CC) domain deletion. Brca1CC/CC mice are born at low frequencies, and post-natal mice have FA-like abnormalities, including bone marrow failure. Intercrossing with Brca1Δ11, which is homozygous lethal, generated Brca1CC/Δ11 mice at Mendelian frequencies that were indistinguishable from Brca1+/+ mice. Brca1CC and Brca1Δ11 proteins were individually responsible for counteracting 53BP1-RIF1-Shieldin activity and promoting RAD51 loading, respectively. Thus, Brca1CC and Brca1Δ11 alleles represent separation-of-function mutations that combine to provide a level of HR sufficient for normal development and hematopoiesis. Because BRCA1 activities can be genetically separated, compound heterozygosity for functional complementary mutations may protect individuals from FA.

BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.

BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Here we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA. Loss of RNF168 negates the synthetic rescue of BRCA1 deficiency by 53BP1 deletion, and it predisposes BRCA1 heterozygous mice to cancer. BRCA1+/-RNF168-/- cells lack RAD51 foci and are hypersensitive to PARP inhibitor, whereas forced targeting of PALB2 to DNA breaks in mutant cells circumvents BRCA1 haploinsufficiency. Inhibiting the chromatin ubiquitin pathway may, therefore, be a synthetic lethality strategy for BRCA1-deficient cancers.

The online competition between pro- and anti-vaccination views.

Distrust in scientific expertise1-14 is dangerous. Opposition to vaccination with a future vaccine against SARS-CoV-2, the causal agent of COVID-19, for example, could amplify outbreaks2-4, as happened for measles in 20195,6. Homemade remedies7,8 and falsehoods are being shared widely on the Internet, as well as dismissals of expert advice9-11. There is a lack of understanding about how this distrust evolves at the system level13,14. Here we provide a map of the contention surrounding vaccines that has emerged from the global pool of around three billion Facebook users. Its core reveals a multi-sided landscape of unprecedented intricacy that involves nearly 100 million individuals partitioned into highly dynamic, interconnected clusters across cities, countries, continents and languages. Although smaller in overall size, anti-vaccination clusters manage to become highly entangled with undecided clusters in the main online network, whereas pro-vaccination clusters are more peripheral. Our theoretical framework reproduces the recent explosive growth in anti-vaccination views, and predicts that these views will dominate in a decade. Insights provided by this framework can inform new policies and approaches to interrupt this shift to negative views. Our results challenge the conventional thinking about undecided individuals in issues of contention surrounding health, shed light on other issues of contention such as climate change11, and highlight the key role of network cluster dynamics in multi-species ecologies15.

Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study.

STUDY QUESTION: What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER: For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION: Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; Giudice et al., 2022) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo→relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo→relugolix CT and delayed relugolix CT groups. LIMITATIONS, REASONS FOR CAUTION: The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS: In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER: NCT03654274.

Nonlinear spreading behavior across multi-platform social media universe.

Understanding how harmful content (mis/disinformation, hate, etc.) manages to spread among online communities within and across social media platforms represents an urgent societal challenge. We develop a non-linear dynamical model for such viral spreading, which accounts for the fact that online communities dynamically interconnect across multiple social media platforms. Our mean-field theory (Effective Medium Theory) compares well to detailed numerical simulations and provides a specific analytic condition for the onset of outbreaks (i.e., system-wide spreading). Even if the infection rate is significantly lower than the recovery rate, it predicts system-wide spreading if online communities create links between them at high rates and the loss of such links (e.g., due to moderator pressure) is low. Policymakers should, therefore, account for these multi-community dynamics when shaping policies against system-wide spreading.

A cross-sectional study of discipline-based self-perceived digital literacy competencies of nursing students.

AIMS: This study offers an empirical exploration of self-assessed digital competencies of students, most of whom studied in nursing courses, using a discipline-based self-assessment survey tool. A range of digital competencies were explored: information and communication technology proficiency and productivity, information literacy, digital creation, digital research, digital communication, digital learning and development, digital innovation, digital identity management and digital well-being. DESIGN: A cross-sectional empirical study. METHODS: Quantitative data were collected from November to December 2021 via a questionnaire survey administered to students. Quantitative results were reported through descriptive statistical analysis. Mann-Whitney (U-test) and Kruskal-Wallis non-parametric statistical tests were used to identify statistically significant differences based on age demographics and pre- or post-registration course. Thematic analysis was utilized for survey open-ended questions data. RESULTS: Students reported low competencies in the following digital literacy dimensions, all of which were imperative for their studies and for their future professional careers: information literacy, digital research, digital innovation. Significant statistical subgroup differences were found between age demographics and pre/post-registration within most of the digital competence dimensions. The survey open-ended comments revealed that students encountered challenges around digital skills they had mostly developed via everyday life experiences and trial-and-error approaches. CONCLUSION: Increasing awareness of existing digital gaps and offering tailored digital skills enhancement can empower students as future-proof evidence-based practitioners in an evolving digital healthcare landscape. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Highlights the importance of embedding digital literacy within nursing study programmes, as preparation for comprehensive patient healthcare. IMPACT: Offers insights into digital competencies gaps of nursing students. Proposes targeted educational digital skills training interventions. Stresses the value of academic staff supporting nursing students to develop digital skills in important areas of professional practice. REPORTING METHOD: JBI critical appraisal checklist. No patient or public contribution.

Ultrasound-guided Lipiodol® hysterosalpingography: A prospective study on pregnancy and complication rates.

BACKGROUND: Fluoroscopic hysterosalpingography (HSG) with Lipiodol® is safe and has a therapeutic effect on fertility: transient in endometriosis-related infertility and sustained in unexplained infertility. Ultrasound is replacing fluoroscopy as the preferred imaging modality for HSG due to comfort and radiation safety (no ionising radiation). The safety of ultrasound-guided Lipiodol® HSG is uncertain. AIMS: Prospectively observe pregnancy and complication rates after ultrasound-guided Lipiodol® HSG. MATERIALS AND METHODS: A single-centre prospective study of women with unexplained infertility undergoing ultrasound-guided Lipiodol® uterine bathing and tubal flushing after tubal patency confirmed with ExEm® Foam HyFoSy (hysterosalpingo-foam-sonography). Pregnancy outcomes at six months and serum and urinary thyroid function at one, three and eight weeks were recorded. Pain scores were recorded during and immediately after HSG. Descriptive statistics are reported. RESULTS: Fifty-two participants were enrolled between July 2019 and April 2021, median age 33 years (range 21-45). Only 45 (87%, 45/52) completed the Lipiodol® HSG; 5/7 experienced intravasation during initial HyFoSy. Of 30 women at follow-up, 57% had biochemical (17/30, 95% CI 37%-75%), 53% clinical (16/30 95% CI 34%-72%) and 35% ongoing pregnancies (11/30, 95% CI 20%-56%). The rate of subclinical hypothyroidism (SCH) at two months was 41% (7/17). One intravasation event occurred during Lipiodol® HSG (2%, 1/45). Median pain score was 5/10 (range 0-9, interquartile range 2.5-7). No anaphylaxis, infection or oil embolism was observed. CONCLUSION: Outpatient ultrasound-guided Lipiodol® HSG was safe, with pregnancy rates comparable to previous studies of fluoroscopic guidance. Rates of intravasation and SCH were also similar, confirming the need to monitor thyroid function.

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

Pediatric and Young Adult Image-Guided Percutaneous Bone Biopsy-A New Standard of Care?

BACKGROUND: There are no consensus guidelines regarding the use of percutaneous needle biopsy for the diagnosis of soft tissue and bone tumors. The aim of this study was to understand the efficacy of image-guided percutaneous biopsy for pediatric patients with soft tissue and bony masses, the role of intraoperative image guidance, and diagnostic accuracy. PATIENTS AND METHODS: A retrospective institutional chart review was performed on patients who underwent percutaneous biopsy of soft tissue or bone tumors between 2007 and 2017. Data collected included preoperative imaging, type of biopsy, demographics, insurance status, number of samples taken, and pathologic results. RESULTS: One hundred forty-one children and young adults underwent 169 biopsies. Female patients received 48.2% of biopsies. The mean age was 14.3 ± 7.0 years. Core needle biopsies made up 89.4% of procedures, while 10.6% were fine needle aspirate. The mean number of samples per patient was 3.6 ± 2.5. All patients had imaging guidance, with computed tomography used in 44.7% of patients, 9.9% using fluoroscopy, 7.1% using ultrasound for guidance, and 53 (37.6%) patients had more than one modality. Diagnostic specimens were obtained in 97.9% of biopsies. The most common overall pathology was osteoid osteoma. The most common malignant tumors were osteosarcoma and Ewing's sarcoma. CONCLUSION: Image-guided percutaneous biopsy is a safe and effective method of obtaining accurate tissue samples in children and young adults with soft tissue or bone masses. LEVEL OF EVIDENCE: Level 4-Study of diagnostic test.

Emergence of Polarization in Coevolving Networks.

Polarization is a ubiquitous phenomenon in social systems. Empirical studies document substantial evidence for opinion polarization across social media, showing a typical bipolarized pattern devising individuals into two groups with opposite opinions. While coevolving network models have been proposed to understand polarization, existing works cannot generate a stable bipolarized structure. Moreover, a quantitative and comprehensive theoretical framework capturing generic mechanisms governing polarization remains unaddressed. In this Letter, we discover a universal scaling law for opinion distributions, characterized by a set of scaling exponents. These exponents classify social systems into bipolarized and depolarized phases. We find two generic mechanisms governing the polarization dynamics and propose a coevolving framework that counts for opinion dynamics and network evolution simultaneously. Under a few generic assumptions on social interactions, we find a stable bipolarized community structure emerges naturally from the coevolving dynamics. Our theory analytically predicts two-phase transitions across three different polarization phases in line with the empirical observations for the Facebook and blogosphere data sets. Our theory not only accounts for the empirically observed scaling laws but also allows us to predict scaling exponents quantitatively.

Shockwavelike Behavior across Social Media.

Online communities featuring "anti-X" hate and extremism, somehow thrive online despite moderator pressure. We present a first-principles theory of their dynamics, which accounts for the fact that the online population comprises diverse individuals and evolves in time. The resulting equation represents a novel generalization of nonlinear fluid physics and explains the observed behavior across scales. Its shockwavelike solutions explain how, why, and when such activity rises from "out-of-nowhere," and show how it can be delayed, reshaped, and even prevented by adjusting the online collective chemistry. This theory and findings should also be applicable to anti-X activity in next-generation ecosystems featuring blockchain platforms and Metaverses.

Surgical approach to hysterectomy for benign gynaecological disease.

BACKGROUND: Currently, there are five major approaches to hysterectomy for benign gynaecological disease: abdominal hysterectomy (AH), vaginal hysterectomy (VH), laparoscopic hysterectomy (LH), robotic-assisted hysterectomy (RH) and vaginal natural orifice hysterectomy (V-NOTES). Within the LH category we further differentiate the laparoscopic-assisted vaginal hysterectomy (LAVH) from the total laparoscopic hysterectomy (TLH) and single-port laparoscopic hysterectomy (SP-LH). OBJECTIVES: To assess the effectiveness and safety of different surgical approaches to hysterectomy for women with benign gynaecological conditions. SEARCH METHODS: We searched the following databases (from their inception to December 2022): the Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO. We also searched the trial registries and relevant reference lists, and communicated with experts in the field for any additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which clinical outcomes were compared between one surgical approach to hysterectomy and another. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials, assessed risk of bias and performed data extraction. Our primary outcomes were return to normal activities, satisfaction and quality of life, intraoperative visceral injury and major long-term complications (i.e. fistula, pelvic-abdominal pain, urinary dysfunction, bowel dysfunction, pelvic floor condition and sexual dysfunction). MAIN RESULTS: We included 63 studies with 6811 women. The evidence for most comparisons was of low or moderate certainty. The main limitations were poor reporting and imprecision. Vaginal hysterectomy (VH) versus abdominal hysterectomy (AH) (12 RCTs, 1046 women) Return to normal activities was probably faster in the VH group (mean difference (MD) -10.91 days, 95% confidence interval (CI) -17.95 to -3.87; 4 RCTs, 274 women; I2 = 67%; moderate-certainty evidence). This suggests that if the return to normal activities after AH is assumed to be 42 days, then after VH it would be between 24 and 38 days. We are uncertain whether there is a difference between the groups for the other primary outcomes. Laparoscopic hysterectomy (LH) versus AH (28 RCTs, 3431 women) Return to normal activities may be sooner in the LH group (MD -13.01 days, 95% CI -16.47 to -9.56; 7 RCTs, 618 women; I2 = 68%, low-certainty evidence), but there may be more urinary tract injuries in the LH group (odds ratio (OR) 2.16, 95% CI 1.19 to 3.93; 18 RCTs, 2594 women; I2 = 0%; moderate-certainty evidence). This suggests that if the return to normal activities after abdominal hysterectomy is assumed to be 37 days, then after laparoscopic hysterectomy it would be between 22 and 25 days. It also suggests that if the rate of ureter injury during abdominal hysterectomy is assumed to be 0.2%, then during laparoscopic hysterectomy it would be between 0.2% and 2%. We are uncertain whether there is a difference between the groups for the other primary outcomes. LH versus VH (22 RCTs, 2135 women) We are uncertain whether there is a difference between the groups for any of our primary outcomes. Both short- and long-term complications were rare in both groups. Robotic-assisted hysterectomy (RH) versus LH (three RCTs, 296 women) None of the studies reported satisfaction rates or quality of life. We are uncertain whether there is a difference between the groups for our other primary outcomes. Single-port laparoscopic hysterectomy (SP-LH) versus LH (seven RCTs, 621 women) None of the studies reported satisfaction rates, quality of life or major long-term complications. We are uncertain whether there is a difference between the groups for rates of intraoperative visceral injury. Total laparoscopic hysterectomy (TLH) versus laparoscopic-assisted vaginal hysterectomy (LAVH) (three RCTs, 233 women) None of the studies reported satisfaction rates or quality of life. We are uncertain whether there is a difference between the groups for rates of intraoperative visceral injury or major long-term complications. Transvaginal natural orifice transluminal endoscopic surgery (V-NOTES) versus LH (two RCTs, 96 women) We are uncertain whether there is a difference between the groups for rates of bladder injury. Our other primary outcomes were not reported. Overall, adverse events were rare in the included studies. AUTHORS' CONCLUSIONS: Among women undergoing hysterectomy for benign disease, VH appears to be superior to AH. When technically feasible, VH should be performed in preference to AH because it is associated with faster return to normal activities, fewer wound/abdominal wall infections and shorter hospital stay. Where VH is not possible, LH has advantages over AH including faster return to normal activities, shorter hospital stay, and decreased risk of wound/abdominal wall infection, febrile episodes or unspecified infection, and transfusion. These advantages must be balanced against the increased risk of ureteric injury and longer operative time. When compared to LH, VH was associated with no difference in time to return to normal activities but shorter operative time and shorter hospital stay. RH and V-NOTES require further evaluation since there is a lack of evidence of any patient benefit over conventional LH. Overall, the evidence in this review has to be interpreted with caution as adverse event rates were low, resulting in low power for these comparisons. The surgical approach to hysterectomy should be discussed with the patient and decided in the light of the relative benefits and hazards. Surgical expertise is difficult to quantify and poorly reported in the available studies and this may influence outcomes in ways that cannot be accounted for in this review. In conclusion, when VH is not feasible, LH has multiple advantages over AH, but at the cost of more ureteric injuries. Evidence is limited for RH and V-NOTES.

Objectively measured teacher and preschooler vocalizations: Phonemic diversity is associated with language abilities.

Over half of US children are enrolled in preschools, where the quantity and quality of language input from teachers are likely to affect children's language development. Leveraging repeated objective measurements, we examined the rate per minute and phonemic diversity of child and teacher speech-related vocalizations in preschool classrooms and their association with children's end-of-year receptive and expressive language abilities measured with the Preschool Language Scales (PLS-5). Phonemic diversity was computed as the number of unique consonants and vowels in a speech-related vocalization. We observed three successive cohorts of 2.5-3.5-year-old children enrolled in an oral language classroom that included children with and without hearing loss (N = 29, 16 girls, 14 Hispanic). Vocalization data were collected using child-worn audio recorders over 34 observations spanning three successive school years, yielding 21.53 mean hours of audio recording per child. The rate of teacher vocalizations positively predicted the rate of children's speech-related vocalizations while the phonemic diversity of teacher vocalizations positively predicted the phonemic diversity of children's speech-related vocalizations. The phonemic diversity of children's speech-related vocalizations was a stronger predictor of end-of-year language abilities than the rate of children's speech-related vocalizations. Mediation analyses indicated that the phonemic diversity of teacher vocalizations was associated with children's receptive and expressive language abilities to the extent that it influenced the phonemic diversity of children's own speech-related vocalizations. The results suggest that qualitatively richer language input expands the phonemic diversity of children's speech, which in turn is associated with language abilities.

Ectopic RNF168 expression promotes break-induced replication-like DNA synthesis at stalled replication forks.

The RNF168 E3 ubiquitin ligase is activated in response to double stranded DNA breaks (DSBs) where it mono-ubiquitinates γH2AX (ub-H2AX). RNF168 protein expression and ubiquitin signaling are finely regulated during the sensing, repair and resolution of DNA damage in order to avoid excessive spreading of ubiquitinated chromatin. Supra-physiological RNF168 protein expression levels have been shown to block DNA end resection at DSBs and increase PARP inhibitor (PARPi) sensitivity. In this study, we examined the impact of ectopic RNF168 overexpression on hydroxyurea (HU)-induced stalled replication forks in the setting of BRCA1 deficiency. Surprisingly, RNF168 overexpression resulted in the extension of DNA fibers, despite the presence of HU, in BRCA1 deficient cells. Mechanistically, RNF168 overexpression recruited RAD18 to ub-H2AX at HU-induced DNA breaks. Subsequently, a RAD18-SLF1 axis was responsible for initiating DNA synthesis in a manner that also required the break-induced replication (BIR) factors RAD52 and POLD3. Strikingly, the presence of wild-type BRCA1 blocked RNF168-induced DNA synthesis. Notably, BIR-like repair has previously been linked with tandem duplication events found in BRCA1-mutated genomes. Thus, in the absence of BRCA1, excessive RNF168 expression may drive BIR, and contribute to the mutational signatures observed in BRCA1-mutated cancers.

Endometriosis Classification Systems: An International Survey to Map Current Knowledge and Uptake.

OBJECTIVE: In the field of endometriosis, several classification, staging and reporting systems have been developed, but do clinicians routinely use these classification systems, which system do they use and what are the clinicians' motivations? DATA SOURCES: A cross-sectional study was performed to gather data on the current use of endometriosis classification systems, problems encountered and interest in a new simple surgical descriptive system for endometriosis. Of particular focus were three systems most commonly used: the Revised American Society for Reproductive Medicine (rASRM) classification, the Endometriosis Fertility Index (EFI), and the ENZIAN classification. Data were analysed by SPSS. A survey was designed using the online SurveyMonkey tool consisting of 11 questions concerning three domains-participants background, existing classification systems and intentions with regards to a new classification system for endometriosis. Replies were collected between 15 May and 1 July 2020. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION AND RESULTS: The final dataset included the replies of 1178 clinicians, including surgeons, gynecologists, reproductive endocrinologists, fertility specialists and sonographers, all managing women with endometriosis in their clinical practice. Overall, 75.5% of the professionals indicate that they currently use a classification system for endometriosis. The rASRM classification system was the best known and used system, the EFI system and ENZIAN system were known by a majority of the professionals but used by only a minority. The lack of clinical relevance was most often selected as a problem with using any system. The findings of the survey suggest that clinicians worldwide are open to using a new classification system for endometriosis that can achieve standardized reporting, and is clinically relevant and simple. The findings therefore support future initiatives for the development of a new descriptive system for endometriosis and provide information on user expectations and conditions for universal uptake of such a system. CONCLUSION: Even with a high uptake of the existing endometriosis classification systems (rASRM, ENZIAN and EFI), most clinicians managing endometriosis would like a new simple surgical descriptive system for endometriosis.

The Benefits of Crowdsourcing to Seed and Align an Algorithm in an mHealth Intervention for African American and Hispanic Adults: Survey Study.

BACKGROUND: The lack of publicly available and culturally relevant data sets on African American and bilingual/Spanish-speaking Hispanic adults' disease prevention and health promotion priorities presents a major challenge for researchers and developers who want to create and test personalized tools built on and aligned with those priorities. Personalization depends on prediction and performance data. A recommender system (RecSys) could predict the most culturally and personally relevant preventative health information and serve it to African American and Hispanic users via a novel smartphone app. However, early in a user's experience, a RecSys can face the "cold start problem" of serving untailored and irrelevant content before it learns user preferences. For underserved African American and Hispanic populations, who are consistently being served health content targeted toward the White majority, the cold start problem can become an example of algorithmic bias. To avoid this, a RecSys needs population-appropriate seed data aligned with the app's purposes. Crowdsourcing provides a means to generate population-appropriate seed data. OBJECTIVE: Our objective was to identify and test a method to address the lack of culturally specific preventative personal health data and sidestep the type of algorithmic bias inherent in a RecSys not trained in the population of focus. We did this by collecting a large amount of data quickly and at low cost from members of the population of focus, thereby generating a novel data set based on prevention-focused, population-relevant health goals. We seeded our RecSys with data collected anonymously from self-identified Hispanic and self-identified non-Hispanic African American/Black adult respondents, using Amazon Mechanical Turk (MTurk). METHODS: MTurk provided the crowdsourcing platform for a web-based survey in which respondents completed a personal profile and a health information-seeking assessment, and provided data on family health history and personal health history. Respondents then selected their top 3 health goals related to preventable health conditions, and for each goal, reviewed and rated the top 3 information returns by importance, personal utility, whether the item should be added to their personal health library, and their satisfaction with the quality of the information returned. This paper reports the article ratings because our intent was to assess the benefits of crowdsourcing to seed a RecSys. The analysis of the data from health goals will be reported in future papers. RESULTS: The MTurk crowdsourcing approach generated 985 valid responses from 485 (49%) self-identified Hispanic and 500 (51%) self-identified non-Hispanic African American adults over the course of only 64 days at a cost of US $6.74 per respondent. Respondents rated 92 unique articles to inform the RecSys. CONCLUSIONS: Researchers have options such as MTurk as a quick, low-cost means to avoid the cold start problem for algorithms and to sidestep bias and low relevance for an intended population of app users. Seeding a RecSys with responses from people like the intended users allows for the development of a digital health tool that can recommend information to users based on similar demography, health goals, and health history. This approach minimizes the potential, initial gaps in algorithm performance; allows for quicker algorithm refinement in use; and may deliver a better user experience to individuals seeking preventative health information to improve health and achieve health goals.

Iodine and fertility: do we know enough?

Iodine is a vital micronutrient and its importance in thyroid function is well established. However, abnormalities in iodine intake may also have other effects. In particular, iodine is taken up avidly by the ovary and endometrium. Iodine deficiency is associated with reduced fertility. The use of high iodine concentration contrast media has recently been shown to improve conception rates in couples with unexplained infertility (UI). We hypothesize that this improvement could be related to the iodine excess and mechanisms independent of its action on thyroid. In this article, the metabolism of iodine and its potential role in fertility will be discussed, including the impact of both iodine deficiency and excess states and the importance of iodine in normal fetal development. This will include insights from animal studies on the effect of iodine in the uterine and ovarian structural environment, hormonal milieu and immunological factors affecting implantation. We speculate that iodine may well have a role as a potential therapy for UI.