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Mutations in the cilia-centrosomal protein Retinitis Pigmentosa GTPase Regulator (RPGR) are a frequent cause of retinal degeneration. The RPGR gene undergoes complex alternative splicing and encodes multiple protein isoforms. To elucidate the function of major RPGR isoforms (RPGR 1-19 and RPGR ORF15), we have generated isoform-specific antibodies and examined their expression and localization in the retina. Using sucrose-gradient centrifugation, immunofluorescence and co-immunoprecipitation methods, we show that RPGR isoforms localize to distinct sub-cellular compartments in mammalian photoreceptors and associate with a number of cilia-centrosomal proteins. The RCC1-like domain of RPGR, which is present in all major RPGR isoforms, is sufficient to target it to the cilia and centrosomes in cultured cells. Our findings indicate that multiple isotypes of RPGR may perform overlapping yet somewhat distinct transport-related functions in photoreceptors. [ABSTRACT FROM AUTHOR]

The gastrointestinal epithelium serves as a critical barrier separating intestinal lumen contents from the underlying tissue environment. Structure and function of the apical junctional complex (AJC), comprising tight and adherens junctions, are essential for establishing and maintaining a polarized and functional epithelial barrier. In this study, we investigated mechanisms by which an apical polarity protein Crumbs homolog 3 (CRB3) regulates AJC assembly and barrier function in primary murine intestinal epithelial cells. Using primary colonic epithelial cells (colonoids) derived from inducible and conditional Crb3 knockdown (Crb3 ERΔIEC ) and control mice (Crb3 fl/fl ), we demonstrate that Crb3 loss leads to compromised epithelial barrier function that was associated with hypercontractile perijunctional actomyosin and defective assembly of the AJC. We identified CRB3 associates with the Band 4.1 family of cytoskeletal linker proteins, Merlin (NF2) via FERM (band4.1/ezrin/radixin/moesin) binding domain (FBD) of CRB3. Interestingly, NF2 knockdown in cultured intestinal epithelial cells phenocopied the effect of CRB3 deletion, supporting a coordinated role in AJC formation and barrier assembly. Moreover, increased active Rho was detected in assembling junctions of Crb3-null cells and inhibition of ROCKII and myosin II alleviated the hypercontractile phenotype, highlighting involvement of Rho/ROCK signaling. Additionally, increased vinculin localization at the AJC seen in Crb3-null epithelial cells indicates elevated tension at junctions. Our findings underscore the important role of Crb3 and NF2 in regulating contractility of the perijunctional actomyosin ring, mechanical tension at the AJC and barrier function via Rho/ROCK signaling during junctional assembly in intestinal epithelial cells.

The decision to add hysterectomy to planned adnexectomy is often nuanced and likely increases the complexity of the planned procedure; however, these risks are not well characterized in practice. We conducted a comprehensive search in the PubMed database for English-language articles from 1997 to 2022, identifying studies reporting complication rates for open and minimally invasive surgery (MIS) hysterectomy and adnexal surgeries. We calculated medians and first and third quartiles for each complication and used a Mann-Whitney U test to calculate differences between complications for minimally invasive hysterectomy and adnexal case data. We identified 135 appropriate studies for inclusion. There were higher prevalences of blood loss requiring transfusion (1.70% versus 0.13%, P = 0.01) and urinary tract injury (0.80% versus 0.20%, P = 0.001) in MIS hysterectomy cases compared with MIS adnexal surgery, respectively. MIS hysterectomy cases were similar to MIS adnexal surgery cases in the risk of surgical site infection (1.20% versus 1.49%, P = 0.74), bowel injury (0.50% versus 0.35%, P = 0.45), vascular injury (0.20% versus 0.9%, P = 0.82), and conversion to laparotomy (1.95% versus 3.84%, P = 0.49). There were not enough data on open adnexal surgery complications to make a meaningful comparison between complications of open hysterectomy and adnexal-only cases. Patients should be counseled that the addition of hysterectomy to planned MIS adnexal surgery likely increases the risk of blood loss requiring transfusion and urinary tract injury. The increased comorbidity associated with adding hysterectomy to planned open adnexal removal is less clear., (© 2024 International Federation of Gynecology and Obstetrics.)

Objective: To test whether providing relevant clinical trial registry information to peer reviewers evaluating trial manuscripts decreases discrepancies between registered and published trial outcomes., Design: Stepped wedge, cluster-randomised trial, with clusters comprised of eligible manuscripts submitted to each participating journal between 1 November 2018 and 31 October 2019., Setting: Thirteen medical journals., Participants: Manuscripts were eligible for inclusion if they were submitted to a participating journal during the study period, presented results from the primary analysis of a clinical trial, and were peer reviewed., Interventions: During the control phase, there were no changes to pre-existing peer review practices. After journals crossed over into the intervention phase, peer reviewers received a data sheet describing whether trials were registered, the initial registration and enrolment dates, and the registered primary outcome(s) when enrolment began., Main Outcome Measure: The presence of a clearly defined, prospectively registered primary outcome consistent with the primary outcome in the published trial manuscript, as determined by two independent outcome assessors., Results: We included 419 manuscripts (243 control and 176 intervention). Participating journals published 43% of control-phase manuscripts and 39% of intervention-phase manuscripts (model-estimated percentage difference between intervention and control trials = -10%, 95% CI -25% to 4%). Among the 173 accepted trials, published primary outcomes were consistent with clearly defined, prospectively registered primary outcomes in 40 of 105 (38%) control-phase trials and 27 of 68 (40%) intervention-phase trials. A linear mixed model did not show evidence of a statistically significant primary outcome effect from the intervention (estimated difference between intervention and control=-6% (90% CI -27% to 15%); one-sided p value=0.68)., Conclusions: These results do not support use of the tested intervention as implemented here to increase agreement between prospectively registered and published trial outcomes. Other approaches are needed to improve the quality of outcome reporting of clinical trials., Trial Registration Number: ISRCTN41225307., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: no support from any commercial organisation for the submitted work; CJ has received research grants from AstraZeneca, Vapotherm, Abbott, and Ophirex outside the submitted work. SS is a full time employee at BMJ but is not involved in editorial decision-making on manuscripts. BM is an employee of the Department of Health and Human Services in the Office of Research Integrity. DLS is an associate editor at JAMA and a deputy editor at Annals of Emergency Medicine. TFP-M is an employee of Ophirex; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Elective surgical procedures were suspended during the coronavirus disease pandemic (COVID-19) in New York City (NYC) between March 16 and June 15, 2020. This study characterizes the impact of the ban on surgical delays for patients scheduled for surgery during this first wave of the COVID-19 outbreak., Methods: Patients who were scheduled for surgical treatment of malignant or pre-invasive disease by gynecologic oncologists at three NYC hospitals during NYC's ban on elective surgery were included. Outcomes of interest were the percentage of patients experiencing surgical delay and the nature of delays. Kruskal-Wallis, chi-square, and logistic regression tests were performed with significance set at p < 0.05., Results: Of the 145 patients with malignant or pre-invasive diseases scheduled for surgery during the ban on elective surgery, 40% of patients experienced one or more surgical delays, 10% experienced two or more and 1% experienced three surgical delays. Of patients experiencing an initial delay, 77% were hospital-initiated and 11% were due to known or suspected personal COVID-19. Overall, 81% of patients completed their planned treatment, and 93% of patients underwent their initially planned surgery. Among patients for whom adjuvant therapy was recommended, 67% completed their planned treatment, and the most common reasons for not completing treatment were medically indicated followed by concerns regarding COVID-19., Conclusion: During the ban on elective surgery in NYC during the first outbreak of the COVID-19 pandemic, many patients experienced minor surgical delays, but most patients obtained appropriate, timely care with either surgery or alternative treatment., Competing Interests: 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., (© 2022 Published by Elsevier Inc.)

Objective: Patients with advanced or recurrent gynecologic malignancies occasionally take breaks from systemic treatment colloquially referred to as "treatment holidays" or "chemotherapy holidays." There are no data from the patient perspective that help describe this experience., Methods: Patients with recurrent or advanced primary gynecologic malignancies who had decided to enter a treatment holiday were recruited and interviewed. A treatment holiday was defined as a planned temporary break or delay in treatment for a patient with recurrent or advanced primary gynecologic malignancy for reasons other than pursuit of hospice or best supportive care, research protocol violation or unacceptable toxicity. Interviews were audiotaped, transcribed and then analyzed using an inductive thematic analysis., Results: Of 6 total patients identified for participation, 5 completed interviews with ages ranging from 57 to 80 years. Two participants returned to their previous treatment regimen after their holiday therapy, two switched therapies, and one remained on an extended break from systemic treatment. Treatment holidays were experienced as a break from the physical and psychological routine of being a cancer patient, but also brought about feelings of a lack of structure, uncertainty, and led to a confrontation with mortality issues. Overall, participants had favorable experiences which were initiated by their providers in whom they had a deep sense of trust., Conclusion: Patients experience treatment holidays as a positive and valuable break from the physical and psychosocial routine of cancer treatment and illness. These experiences produce distinct emotional needs that clinicians should address to best support patients electing treatment holidays., Competing Interests: 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., (© 2021 The Authors. Published by Elsevier Inc.)

Objective: We sought to characterize the variability of CCNE1 amplification among metastatic sites of CCNE1 amplified high grade serous carcinoma (HGSC) cases to investigate the feasibility of targeting this alteration for therapeutic purposes., Methods: Patients with CCNE1 amplified HGSC who underwent surgical cytoreduction with metastatic sites were identified from institutional molecular profiling reports and a population of HGSC cases screened using digital droplet PCR (ddPCR). Cases with normal CCNE1 copy number were included as controls. Slides from metastatic sites were cut from formalin-fixed paraffin-embedded tissue blocks, dissected for tumor of > 50% purity, and underwent DNA extraction. CCNE1 copy number was determined by ddPCR. Tumor purity was confirmed with mutant TP53 allele fraction from targeted massively parallel sequencing., Results: Four of 15 patients from an institutional database screened by ddPCR were found to have CCNE1 amplification. Three additional patients were identified from a query of institutional commercial clinical reports. Among these 7 CCNE1 amplified cases (2 uterine, 5 ovarian), 5 showed preservation of CCNE1 amplification (copy number > 5) among all metastatic sites. The remaining 2 cases had multiple metastatic sites without preserved CCNE1 amplification. Non-amplified cases had predominantly normal CCNE1 copy number across metastatic sites., Conclusions: CCNE1 amplification is an early genomic event in HGSC and is preserved in most metastatic sites suggesting a uniform response to pathway targeting therapies., Competing Interests: 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., (© 2021 The Author(s).)

Objective: To implement a quality-improvement intervention aimed at reducing unnecessary opioid prescriptions for patients who are undergoing gynecologic surgery., Methods: This was a retrospective cohort study that included data from the pre- and post-quality-improvement initiative cohorts. Patients at an urban, tertiary academic medical center who were undergoing scheduled minimally invasive surgery and open abdominal surgery by a gynecologic oncologist were included. Patients underwent preoperative counseling, standardization of perioperative analgesia, and a postoperative opioid prescribing algorithm. Descriptive statistics were calculated for demographic and perioperative characteristics, process measures, and outcome measures., Results: A total of 532 abdominal surgeries were analyzed. The total percentage of patients discharged with an opioid prescription decreased from 82.7% (n=229/276) to 23.1% (n=59/256) (P<.001) and was significantly reduced for all routes of surgery. The mean number of opioid tablets prescribed for all patients was significantly reduced from 7.2 tablets (SD=5.7) to 1.8 tablets (SD=4.3) (P<.001). Eighty-three percent of patients (n=97/117) who underwent minimally invasive hysterectomy and were discharged on postoperative day 0 or day 1 were not provided an opioid prescription. Fifty-one percent of patients who underwent laparotomy were discharged without an opioid prescription. The percentage of patients who required an opioid refill or new prescription in the preintervention and postintervention cohorts remained constant (6.5%, n=18/276 vs 5.9%, n=15/256, P=.75), as did postoperative calls for pain (8.3%, n=23/276 vs 10.9%, n=33/256)., Conclusion: Patients who are undergoing scheduled abdominal gynecologic surgery can be safely discharged without opioid prescriptions with appropriate education and perioperative analgesia prescribing practices. These protocols and prescribing practices profoundly limit opioid prescriptions, which is an important factor in combating the ongoing opioid crisis.

Background: The differential diagnosis for women who present with a vaginal mass after undergoing a hysterectomy is dependent on the indication, type and timing of the hysterectomy. The differential diagnosis includes cervical dysplasia, malignancy, nabothian cysts, prolapsed endocervical polyp/fibroid, abscess, hematoma, granulation tissue, or dehiscence with organ evisceration., Case: We introduce a case of a woman who presented with a vaginal apex mass and had a remote history of a total hysterectomy for an unknown indication. She was ultimately diagnosed with high grade serous carcinoma of a prolapsed fallopian tube., Conclusion: This is the first reported case of serous carcinoma of a prolapsed fallopian tube and highlights the importance of maintaining a wide differential diagnosis for women who present with vaginal apex masses., Competing Interests: 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., (© 2020 The Authors.)

Background: Data regarding the prognostic significance of lymphovascular space invasion (LVSI) for stage IA1 and IA2 cervical cancer are limited. Specifically, the role of LVSI as an independent risk factor for mortality in stage IA disease has not been shown., Objective: We examined the association between LVSI and nodal metastases and survival for women with stage IA1 and IA2 cervical cancer., Study Design: We used the National Cancer Database to identify patients with stage IA adenocarcinoma or squamous carcinoma of the cervix from January 2010 through December 2015 for whom LVSI status was known. Mixed-effect log-Poisson models were used to identify predictors of LVSI. Cox proportional hazard models and Kaplan-Meier curves were used to compare all-cause mortality., Results: We identified 3239 patients with stage IA1 and 1049 patients with stage IA2 carcinoma of the cervix. Among patients with stage IA1 and IA2 disease, 10.5% and 18.8% had LVSI, respectively. Less than 1% of patients with stage IA1 disease without LVSI had positive nodes compared with 7.8% of those with LVSI (p<0.001). Lymphatic metastases were identified in 1.7% of stage IA2 cases without LVSI versus 14.6% for those with LVSI (p<0.001). Among both stage IA1 and IA2 patients, squamous histology, grade 3 tumor differentiation, and white race were associated with LVSI (p<0.05 for all). In a univariable model, the hazard ratio for death associated with LVSI was 1.05 (95% CI 0.45 to 2.45) for women with stage IA1 tumors and 2.36 (95% CI 1.04 to 5.33) for those with IA2 neoplasms., Conclusions: LVSI is associated with lymph node metastases in patients with stage IA cervical cancer. LVSI is associated with decreased survival for women with stage IA2 cervical cancer., Competing Interests: Competing interests: Dr. Wright received consulting fees from Clovis Oncology and research funding from Merck, (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)