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Sampling distortion product otoacoustic emissions (DPOAEs) at multiple fA map significance score was developed as a single measure of map change. Significance scores were evaluated before and after exposure to: loud music (LM), controlled noise (CN), and firing range noise (FR) in three separate sets of subjects. Scores were compared to audiometry and standard DPOAE results in the LM study.The LM and CN exposure studies involved 22, and 20 healthy young subjects respectively with normal hearing. Eight Marines were studied before and after FR exposure.After LM exposure, audiometry showed significant changes at 1, 2, 4, and 6 kHz. Standard DPOAE measures were also significantly different at several frequencies. Map significance scores detected changes more effectively and showed the distribution of DPOAE alterations.Map significance scores detected changes after noise exposure more reliably than audiometry and standard DPOAEs. Additionally, maps showed a diffuse response to sound exposure perhaps explaining why individual DP-grams appear less sensitive.

Background Birth-related third- and fourth-degree perineal trauma is common and associated with short- and long-term complications. Aim To conduct a review of clinical audits investigating management of women with perineal trauma. Materials and methods We identified all audits undertaken in eight New Zealand public hospitals between 2005 and 2014 that investigated whether women with birth-related third- and fourth-degree perineal trauma were receiving care according to clinical guidelines. We aggregated audit results and calculated the proportion of women receiving the recommended standard of care. Results During the review period, 25 audits investigated intra-operative (n = 11), post-operative (n = 14) and outpatient care (n = 18). Baseline audits showed variation in care by site; intra-operative care (range 39-96% for repair conducted under anaesthesia, 60-96% for repair by or under supervision of a senior clinician, and 33-54% for completion of Accident Compensation Corporation forms); post-operative care (range 40-93% for prescribed antibiotics and 33-96% for stool softeners) and outpatient care (45-84% for referral to outpatient clinic and 54-78% for physiotherapy follow-up). Sustained high quality of care and improvements in adherence with recommendations were seen for most of the follow-up audits (eg 90% adherence for prescribed stool softeners over three audits; over 50% increase in prescribed antibiotics over seven years). Conclusions These clinical audits exemplify the need to measure patient care against standards, learn from the findings, implement changes to improve patient experience and reduce life-long sequelae from perineal trauma. This review showed some progress in some care services and highlighted where further changes are needed to close evidence-practice gaps.

Background: Intrahospital transfer (IHT) of critically ill patients is associated with a high incidence of adverse events (AEs). This study aimed to determine whether the introduction of an intervention bundle could decrease AEs during, and immediately after IHT to the intensive care unit (ICU), as compared to event rates prior to the bundle’s introduction. Methods: This was a prospective, pre- and post-intervention trial, conducted in both a regional and tertiary hospital in Pietermaritzburg, South Africa. The intervention bundle consisted of an IHT protocol, a transport backpack, emergency drug container and simulation training. Primary outcomes were: 1) composite outcome of serious AEs, and 2) composite outcome of AEs contributing directly to morbidity or mortality. Secondary outcomes were miscellaneous complications, equipment-related AEs, total number of AEs, total number of IHTs complicated by AEs and the subjective measure of IHTs needing intervention within the first 30 minutes after arrival in ICU. Results: There were 381 pre-intervention IHTs and 264 post-intervention IHTs with one documented serious AE. Adverse events directly contributing to morbidity or mortality showed a reduction from 58.3% (CI 0.53–0.63) pre-intervention, to 56.1% (CI 0.50–0.62) post-intervention (p = 0.6). Miscellaneous complications yielded a reduction of 12.9% (CI 10.3–14.7%) pre-intervention to 9.5% (CI 8.3–11.1%) post-intervention (p = 0.2). Equipment-related AE reduced from 5.2% (CI 3.4–8%) to 1.9% (CI 0.8–4.5%) (p = 0.03). The total number of AEs reduced from 5% (CI 3.6–7.4%) to 4.1% (CI 2.4–6.8%) (p = 0.03), while the total number of transfers complicated by AEs reduced from 63.3% (CI 61.9–65.1%) to 60.6% (CI 58.8–63.1%) (p = 0.5). There was a reduction in IHTs requiring intervention within the first 30 minutes of arrival in ICU (34.6% to 22.7%; p = 0.001). Conclusion: These results support the use of an intervention bundle to decrease the incidence of AEs during IHT. The full article is available at https://doi.org/10.36303/SAJAA.2020.26.3.2343

South Texas has experienced local transmission of Zika virus and of other mosquito-borne viruses such as chikungunya virus and dengue virus in the last decades. Using a mosquito surveillance program in the Lower Rio Grande Valley (LRGV) and San Antonio, TX, from 2016 to 2018, we detected the presence of an insect-specific virus, cell fusing agent virus (CFAV), in the Aedes aegypti mosquito population. We tested 6,326 females and 1,249 males from the LRGV and 659 females from San Antonio for CFAV by RT-PCR using specific primers. Infection rates varied from 0 to 261 per 1,000 mosquitoes in the LRGV and 115 to 208 per 1,000 in San Antonio depending on the month of collection. Infection rates per 1,000 individuals appeared higher in females collected from BG Sentinel 2 traps compared to Autocidal Gravid Ovitraps, but the ratio of the percentage of infected pools did not differ by trap type. The natural viral load in individual males ranged from 1.25 x 102 to 5.50 x 106 RNA copies and in unfed females from 5.42 x 103 to 8.70 x 106 RNA copies. Gravid females were found to harbor fewer viral particles than males and unfed females.

Background: Avelumab, a human IgG1 anti–PD-L1 monoclonal antibody, has shown antitumor activity and a manageable safety profile in several tumor types. Talazoparib, an orally available PARP inhibitor, is approved for the treatment of patients with deleterious or suspected deleterious germline BRCA1/2-mutated HER2− locally advanced (LA) or metastatic (M) breast cancer (BC). Preclinical data suggest that PARP inhibitors may have synergistic activity when administered in combination with immune checkpoint inhibitors. We report results from patients with LA/MBC enrolled in the phase 1b/2, multicohort JAVELIN PARP Medley study (NCT03330405). Methods: In phase 1b (cohort 1), patients with advanced solid tumors who had received ≥1 prior standard of care chemotherapy (CT) regimen were treated with avelumab 800 mg IV every 2 weeks (Q2W) in combination with talazoparib 1.0 mg orally once daily (QD) (dose de-escalation to 0.75 or 0.5 mg permitted following toxicity). In 2 phase 2 cohorts, eligible patients had either LA/M triple-negative BC (TNBC, cohort 2A) or LA/M hormone receptor positive (HR+), HER2−, DNA damage repair defect-positive BC (cohort 2B). Patients in cohort 2A had received 0 to 2 prior CT regimens (no progression on prior platinum-based CT) and patients in cohort 2B had received prior standard of care hormone therapy in either the adjuvant and/or LA/M setting followed by 0 to 2 prior CT regimens (no progression on prior platinum-based CT). The primary endpoint for phase 1b was first-cycle dose-limiting toxicities (DLTs) and for phase 2 was objective response (investigator assessed per RECIST v1.1). Adverse events (AEs) were characterized using National Cancer Institute Common Terminology Criteria for AEs v4.03. Results: By the data cutoff on December 24, 2018, 34 patients had been treated in cohorts 1 and 2. Twelve patients with advanced solid tumors were treated in cohort 1 (including 2 patients with TNBC); 3 patients (25.0%) had a first-cycle DLT: grade 3 neutropenia, (n=1) and grade 3 thrombocytopenia, (n=2). Best overall response (BOR) was partial response (PR) in 1 patient, stable disease (SD) in 3, progressive disease (PD) in 6, and non-complete response/non-PD in 1 patient with metastatic castration-resistant prostate cancer and non-measurable disease at baseline; 1 patient was not evaluable for response. Both patients with TNBC had a BOR of SD and remained on treatment for ≥9 months. Objective response rate in this pre-treated and heterogenous population was 8.3% (95% CI, 0.2, 38.5). Based on the phase 1b data, the recommended phase 2 dose was avelumab 800 mg Q2W and talazoparib 1 mg QD. By data cutoff, 22 patients had been treated in cohorts 2A (n=19) and 2B (n=3); median age was 56 and 50 years, respectively. In cohort 2A, 12 patients were evaluable for disease assessment; BOR was PR in 1, SD in 6, and PD in 5. All 3 patients in cohort 2B were non-evaluable for response at data cutoff. Treatment-related AEs (TRAEs) of any grade occurred in 11 patients (91.7%) in cohort 1, and 18 (94.7%) patients in cohort 2A. In cohort 2A, the most common TRAEs were anemia (57.9%), nausea (26.3%), fatigue (21.1%) and thrombocytopenia (21.1%); 9 patients (47.4%) had grade ≥3 TRAEs. There were no treatment-related deaths. Safety data from cohort 2B are not reported owing to low patient numbers. Observed pharmacokinetic (PK) data for avelumab 800 mg Q2W were similar to simulated data derived from a population PK model developed using 10 mg/kg dosing. Conclusions: Avelumab 800 mg Q2W administered in combination with talazoparib 1 mg QD in patients with advanced solid tumors, showed preliminary antitumor activity and a manageable safety profile, which was comparable to the safety profiles of the single agents. The study is ongoing; updated safety and efficacy data, and biomarker data will be presented. Citation Format: Timothy A Yap, Panagiotis Konstantinopoulos, Melinda L. Telli, Smita Saraykar, J Thaddeus Beck, Matthew D. Galsky, Jame Abraham, David R. Wise, Mustafa Khasraw, Gabor Rubovszky, Mikhail Dvorkin, Anil A Joy, Mateusz Opyrchal, Daria Stypinski, Colombe Chappey, Ross Stewart, Rossano Cesari, Anita Scheuber, Aditya Bardia. JAVELIN PARP Medley, a phase 1b/2 study of avelumab plus talazoparib: Results from advanced breast cancer cohorts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-03.

Tactical athletes are individuals in service occupations with significant physical fitness and performance requirements such as law enforcement, firefighters, emergency responders, and military service members. Tactical athletes also may have specific administrative requirements related to documenting physical injuries. Musculoskeletal injuries are a large burden on the tactical athlete population, with incident rates varying based on the specific profession. Chronic exertional compartment syndrome (CECS) is difficult to manage in the tactical athlete population due to their limited ability to reduce impact activities and poor surgical outcomes. Botulinum neurotoxin-A and gait retraining show promise as alternative treatments for CECS. Heat injuries are frequent in the tactical athlete populations, and a graduated return to play process helps to prevent morbidity. Management of musculoskeletal injuries in tactical athletes requires consideration of operational schedules and adequate reconditioning, in addition to traditional injury evaluation.

Background: With rising rates of cesarean sections (CSs) in Canada and worldwide, nonclinical factors for CS warrant consideration. Objective: To determine the association between a primigravid wom...

Mosquito surveillance in large urban areas of the southern USA that border Mexico has become increasingly important due to recent transmission of Zika virus and chikungunya virus in the Americas as well as the continued threat of dengue and West Nile viruses. The vectors of these viruses, Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus, co-occur in residential areas, requiring vector control entities to deploy several different trap types, often expensive and labor-intensive, to surveil these ecologically different species. We evaluated the use of a single trap type, the US Centers for Disease Control and Prevention autocidal gravid ovitraps (AGOs), to monitor all 3 vector species across residential neighborhoods in San Antonio, TX, over 12 wk (epiweeks 24–35). Mosquito abundance was highest early in our surveillance period (epiweek 25) and was driven largely by Cx. quinquefasciatus. The AGOs collected significantly more Cx. quinquefasciatus than both Aedes species, with more Ae. aegypti collected than Ae. albopictus. The average number of Ae. aegypti captured per trap was consistent across most neighborhoods except for 2 areas where one had significantly the highest and the other with the lowest mosquitoes collected per trap. The average number of Ae. albopictus captured per trap varied with no clear pattern, and Cx. quinquefasciatus were trapped most often near forested hill country neighborhoods. These results indicate that AGOs are appropriate for detecting and tracking the relative abundance of Ae. aegypti, Ae. albopictus, and Cx. quinquefasciatus across a large and diverse urban landscape over time and therefore may be an inexpensive and streamlined option for vector surveillance programs in large cities.

PURPOSE OF REVIEW: Next-generation sequencing is becoming more accessible. This review focuses on the clinical application of somatic and germline sequencing to genitourinary oncology. RECENT FINDINGS: Germline variants have been increasingly recognized as contributing to the development of genitourinary malignancies, particularly in patients with advanced disease. A variety of commercial and institutional technologies are in use to detect variants, with newer tools focused on integrating these results into the clinical workflow. SUMMARY: DNA sequencing is becoming a valuable tool in caring for patients with genitourinary malignancies. Performing both somatic and germline sequencing will likely become standard practice. Interpretation and clinical application of these results can be challenging and often requires multidisciplinary expertise.

BACKGROUND Systematic approaches to information giving and decision support for women with previous caesarean sections are needed. AIM To evaluate decision support within a 'real-world' shared decision-making model. METHODS A pragmatic comparative effectiveness randomised trial in the Positive Birth After Caesarean Clinic. Women with one previous caesarean and singleton pregnancy

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 ).

Background In the absence of treatment, endometrial hyperplasia (EH) can progress to endometrial cancer, particularly in the presence of histologic nuclear atypia. The development of EH results from exposure of the endometrium to oestrogen unopposed by progesterone. Oral progestogens have been used as treatment for EH without atypia, and in some cases of EH with atypia in women who wish to preserve fertility or who cannot tolerate surgery. EH without atypia is associated with a low risk of progression to atypia and cancer; EH with atypia is where the cells are structurally abnormal, and has a higher risk of developing cancer. Oral progestogen is not always effective at reversing the hyperplasia, can be associated with side effects, and depends on patient adherence. The levonorgestrel-intrauterine system (LNG-IUS) is an alternative method of administration of progestogen and may have some advantages over non-intrauterine progestogens. Objectives To evaluate the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in women with endometrial hyperplasia (EH) with or without atypia compared to medical treatment with non-intrauterine progestogens, placebo, surgery or no treatment. Search methods We searched the following databases: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO, and conference proceedings of 10 relevant organisations. We handsearched references in relevant published studies. We also searched ongoing trials in ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry, and other trial registries. We performed the final search in May 2020. Selection criteria Randomised controlled trials (RCTs) and cross-over trials of women with a histological diagnosis of endometrial hyperplasia with or without atypia comparing LNG-IUS with non-intrauterine progestogens, placebo, surgery or no treatment. Data collection and analysis Two review authors independently performed study selection, risk of bias assessment and data extraction. Our primary outcome measures were regression of EH and adverse effects associated with the LNG-IUS device (such as pelvic inflammatory disease, device expulsion, uterine perforation) when compared to treatment with non-intrauterine progestogens, placebo, surgery or no treatment. Secondary outcomes included hysterectomy, hormone-related adverse effects (such as bleeding/spotting, pelvic pain, breast tenderness, ovarian cysts, weight gain, acne), withdrawal from treatment due to adverse effects, satisfaction with treatment, and cost or resource use. We rated the overall quality of evidence using GRADE methods. Main results Thirteen RCTs (1657 women aged 22 to 75 years) met the inclusion criteria. Two studies had insufficient data for meta-analysis, thus the quantitative analysis included 11 RCTs. All trials evaluated treatment duration of six months or less. The evidence ranged from very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding and poor reporting of study methods), inconsistency and imprecision. LNG-IUS versus non-intrauterine progestogens Primary outcomes Regression of endometrial hyperplasia The LNG-IUS probably improves regression of EH compared with non-intrauterine progestogens at short-term follow-up (up to six months) (OR 2.94, 95% CI 2.10 to 4.13; I² = 0%; 10 RCTs, 1108 participants; moderate-quality evidence). This suggests that if regression of EH following treatment with a non-intrauterine progestogen is assumed to be 72%, regression of EH following treatment with LNG-IUS would be between 85% and 92%. Regression of EH may be improved by LNG-IUS compared with non-intrauterine progestogens at long-term follow-up (12 months) (OR 3.80, 95% CI 1.75 to 8.23; 1 RCT, 138 participants; low-quality evidence), Adverse effects associated with LNG-IUS There was insufficient evidence to determine device-related adverse effects; only one study reported on expulsion with insufficient data for analysis. Secondary outcomes The LNG-IUS may be associated with fewer hysterectomies (OR 0.26, 95% CI 0.15 to 0.46; I² = 19%; 4 RCTs, 452 participants; low-quality evidence), fewer withdrawals from treatment due to hormone-related adverse effects (OR 0.41, 95% CI 0.12 to 1.35; I² = 0%; 4 RCTs, 360 participants; low-quality evidence) and improved patient satisfaction with treatment (OR 5.28, 95% CI 2.51 to 11.10; I² = 0%; 2 RCTs, 202 participants; very low-quality evidence) compared to non-intrauterine progestogens. The LNG-IUS may be associated with more bleeding/spotting (OR 2.13, 95% CI 1.33 to 3.43; I² = 78%; 3 RCTs, 428 participants) and less nausea (OR 0.52, 95% CI 0.28 to 0.95; I² = 0%; 3 RCTs, 428 participants) compared to non-intrauterine progestogens. Data from single trials for mood swings and fatigue had a similar direction of effect as for bleeding/spotting, nausea and weight gain. There was insufficient evidence to determine cost or resource use. LNG-IUS versus no treatment Regression of endometrial hyperplasia One study demonstrated that the LNG-IUS is associated with regression of EH without atypia (OR 78.41, 95% CI 22.86 to 268.97; I² = 0%; 1 RCT, 190 participants; moderate-quality evidence) compared with no treatment. This study did not report on any other review outcome. Authors' conclusions There is moderate-quality evidence that treatment with LNG-IUS used for three to six months is probably more effective than non-intrauterine progestogens at reversing EH in the short term (up to six months) and long term (up to two years). Adverse effects (device-related and hormone-related) were poorly and incompletely reported across studies. Very low quality to low-quality evidence suggests the LNG-IUS may reduce the risk of hysterectomy, and may be associated with more bleeding/spotting, less nausea, less withdrawal from treatment due to adverse effects, and increased satisfaction with treatment, compared to non-intrauterine progestogens. There was insufficient evidence to reach conclusions regarding device-related adverse effects, or cost or resource use.

Stereotactic body radiotherapy (SBRT) is an increasingly used radiation modality for the treatment of both localized and metastatic prostate cancer. Substantial data suggests that prostate cancer may be more sensitive to higher doses of radiation per fraction due to its low α/β ratio. This increased sensitivity raises important questions as to how SBRT should be combined with systemic therapy for clinically significant prostate cancer, including whether androgen deprivation therapy retains its beneficial effects when combined with SBRT. Furthermore, pre-clinical and clinical data suggest pronounced immunomodulatory effects of SBRT, including observed improvements in T cell priming and trafficking. These data support investigational strategies combining SBRT with immunotherapy. Here we aim to review the data for the use of SBRT in both the local and metastatic disease settings as well as ongoing translational and clinical research examining combinations with ADT, immunotherapy and other targeted agents.

Background The human placenta extrudes a variety of extracellular vesicles (EVs) into the maternal blood daily. These vesicles may be crucial to the adaptation of the maternal cardiovascular and immune systems to pregnancy. Quantifying the EVs that are released in early gestation is important to our understanding of how placental EVs may contribute to the regulation of maternal physiology. Methods EVs were isolated from first trimester placental explants and separated into micro- and nano-vesicles by differential centrifugation. The numbers of each type of EVs extruded from each milligram of placentae between gestational weeks 8 and 12 was determined by Nanoparticle Tracking Analysis. The total protein or DNA content of the vesicles was determined by BCA assay or Qubit® 2.0. Results Neither the number of micro- nor nano-EVs/mg explant (n = 49), nor the total protein (n = 19) and DNA content (n = 29) of these EVs changed significantly between 8 and 12 weeks of gestation. When the increasing placental weight with gestation was accounted for, the daily number of placental EVs extruded into the maternal blood increased by more than 100 fold between 8 and 12 weeks (micro-EVs 6.23 X 1014 and nano-EVs 1.84 X 1014 at 12 weeks, p = 0.0003). Discussion Constant production of micro- and nano-EVs per-milligram placenta, regardless of gestational age, and the increased daily burden of EVs across gestational age indicate these EVs have the potential to regulate maternal physiology from early pregnancy. Since total EV protein content, like EV numbers was, constant, this is a potentially reliable surrogate for quantifying EVs.

Objectives This study sought to determine whether social factors (neighbourhood education and income) and geographic factors (urban or rural dwelling and local service area) are associated with hysterectomy rates, proportion of hysterectomies performed minimally invasively, and hysterectomy complication and readmission rates in Ontario. Methods The Canadian Institute for Health Information Discharge Abstract Database was used to perform a population-based retrospective cross-sectional study on women who had an abdominal, vaginal, and laparoscopic hysterectomy in 2007 for benign gynaecologic conditions in hospitals in Ontario, Canada. Crude and age-standardized rates of hysterectomy, proportion of hysterectomy performed minimally invasively (vaginal or laparoscopic), and rates of surgical complications were analyzed by neighbourhood educational attainment, neighbourhood income, rural or urban residency, and health service delivery area (Canadian Task Force Classification of Study Design II). Results A total of 13 511 women who underwent hysterectomy were included. Age-standardized hysterectomy rates were higher for the lowest neighbourhood educational quartile compared with the highest (relative risk [RR] 1.49; 95% CI 1.39–1.60), higher with rural compared with urban dwelling (RR 1.54; 95% CI 1.47–1.61), varied with local health service delivery area (Local Health Integration Network [LHIN]) (range 133.4–439.5 per 100 000 women), and also varied non-linearly with neighbourhood income quintile. Proportion of hysterectomies performed minimally invasively did not vary with neighbourhood education or income, were higher for rural compared with urban areas (RR 1.10; 95% CI 1.03–1.19), and varied with LHIN (range 30.0–62.9 per 100 hysterectomies). Surgical complications varied with neighbourhood educational quartile, but not with income or urban or rural residence. Conclusions Considerable social and geographic variation exists in rates of hysterectomy in Ontario, whereas only geographic variation is seen in use of minimally invasive routes. Surgical complication rates vary only by neighbourhood education. Such findings suggest inequities in hysterectomy practice in Ontario, and there is a need to evaluate factors influencing patients' decision making, physicians' clinical and surgical practice, and health system policies to help address the observed disparities.

Background Counselling women for and managing birth after caesarean section are important. Research is needed on evaluation of antenatal factors that predict likelihood of successful trial of labour after caesarean section (TOLAC). Aim To evaluate the effect of gestational weight gain on mode of delivery in women having TOLAC. Materials and methods A retrospective cohort study of eligible women who underwent TOLAC (January 2012 to July 2015) at a large urban hospital. Gestational weight gain was classified as ‘excessive’ or ‘not excessive’ based on calculated pre-pregnancy body mass index. Multivariable logistic regression analysis was performed to estimate the association of gestational weight gain and vaginal birth, adjusting for socio-demographic and pregnancy-related factors. Results Of 534 women, those who gained excessive weight were less likely to have a vaginal birth as women who did not (adjusted odds ratio (aOR) 0.48, 95% confidence interval (CI) 0.29–0.81)). Women with previous vaginal birth were more likely to have a vaginal birth (aOR 3.74, 95% CI 1.90–7.36), while women ≥35, women who had an epidural, and women who delivered at 40 weeks, were less likely (aOR 0.58, 95% CI 0.35–0.97, aOR 0.12, 95% CI 0.07–0.22, and aOR 0.53, 95% CI 0.31–0.91, respectively). Conclusions Gaining excessive weight in pregnancy is potentially modifiable, and can be incorporated into individual antenatal counselling, and into risk prediction models, to assist with informed decision making around planned mode of delivery in women with previous caesarean section. Future research could focus on interventions to reduce gestational weight gain in women planning TOLAC.

Throughout human gestation, the placenta extrudes vast quantities of extracellular vesicles (EVs) of different sizes into the maternal circulation. Although multinucleated macro-vesicles are known to become trapped in the maternal lungs and do not enter the peripheral circulation, the maternal organs and cells that smaller placental micro-vesicles interact within vivoremain unknown. This study aimed to characterise the interaction between placental micro-vesicles and endothelial cellsin vitroand to elucidate which organs placental micro-vesicles localise toin vivo. Placental macro- and micro-vesicles were isolated from cultured human first trimester placental explants by sequential centrifugation and exposed to human microvascular endothelial cells for up to 72 h.In vivo, placental macro- and micro-vesicles were administered to both non-pregnant and pregnant CD1 mice, and after two or 30 min or 24 h, organs were imaged on an IVIS Kinetic Imager. Placental EVs rapidly interacted with endothelial cells via phagocytic and clathrin-mediated endocytic processesin vitro, with over 60% of maximal interaction being achieved by 30 min of exposure.In vivo, placental macro-vesicles were localised exclusively to the lungs regardless of time of exposure, whereas micro-vesicles were localised to the lungs, liver and kidneys, with different distribution patterns depending on the length of exposure and whether the mouse was pregnant or not. The fact that placental EVs can rapidly interact with endothelial cells and localise to different organsin vivosupports that different size fractions of placental EVs are likely to have different downstream effects on foeto–maternal communication.

Several mosquito-borne diseases affecting humans are emerging or reemerging in the United States. The early detection of pathogens in mosquito populations is essential to prevent and control the spread of these diseases. In this study, we tested the potential applicability of the Lawrence Livermore Microbial Detection Array (LLMDA) to enhance biosurveillance by detecting microbes present in Aedes aegypti, Aedes albopictus, and Culex mosquitoes, which are major vector species globally, including in Texas. The sensitivity and reproducibility of the LLMDA were tested in mosquito samples spiked with different concentrations of dengue virus (DENV), revealing a detection limit of >100 but

Background Approximately one in four pregnant women undergo an induction of labour. The purpose of this study is to investigate the clinical effectiveness, safety, and cost-effectiveness for mothers and babies of two methods of cervical ripening – inpatient care for women starting induction with vaginal prostaglandin E2 hormones, or allowing women to go home for 18 to 24 h after starting induction with a single-balloon catheter. Methods/design This is a multi-centre randomised controlled trial in New Zealand. Eligible pregnant women, with a live singleton baby in a cephalic presentation who undergo a planned induction of labour at term, will be randomised to outpatient balloon-catheter induction or in-hospital prostaglandin induction. The primary outcome is caesarean section rate. To detect a 24% relative risk reduction in caesarean rate from a baseline of 24.8%, with 80% power and 5% type 1 error, will require 1552 participants in a one to one ratio. Discussion If outpatient balloon-catheter induction reduces caesarean section rates, has additional clinical benefits, and is safe, cost-effective, and acceptable to women and clinicians, we anticipate change in induction of labour practice around the world. We think that home-based balloon-catheter induction will be welcomed as part of a patient-centred labour-induction care package for pregnant women. Trial registration Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN: 12616000739415. Registered on 6 June 2016.

Current guidelines recommend conservative management as the preferred option for most low-risk prostate cancer cases, with certain possible exceptions (age

Background Menorrhagia or heavy menstrual bleeding (HMB) is an excessive blood loss that impairs a woman's quality of life, either physical, emotional, social or material. It is benign and not associated with pregnancy or any other gynaecological or systemic disease. Medical treatments used to reduce excessive menstrual blood loss (MBL) include prostaglandin synthetase inhibitors, antifibrinolytics, oral contraceptive pills, and other hormones. The combined oral contraceptive pill (COCP) is claimed to have a variety of beneficial effects, inducing a regular shedding of a thinner endometrium and inhibiting ovulation, thus having the effect of both treating HMB and providing contraception. More recently, a contraceptive vaginal ring (CVR) has been trialled to investigate whether this treatment can provide similar benefits to COCP while lessening hormonal systemic exposure. This review is an update of a review which originally focused on COCP alone. The scope of the review has been widened to consider other types of delivery of combined hormonal contraceptives for reduction of MBL. Objectives To determine the efficacy of combined hormonal contraceptives (pills, vaginal ring or patch) compared with other medical therapies, placebo, or no therapy in the treatment of HMB. A secondary objective was to compare the COCP with the CVR. Search methods We searched the Gynecology and Fertility Group trials register, MEDLINE, Embase, CENTRAL, CINAHL and PsycINFO (search dates: Oct 1996, May 2002, June 2004, April 2006, June 2009, July 2017 and September 2018) for all randomised controlled trials (RCTs) of COCP and CVR for the treatment of HMB. We also searched trial registers and the reference lists of retrieved studies for additional trials. Selection criteria We included randomised controlled trials (RCTs) of the use of COCP or CVR compared with no treatment, placebo, or other medical therapies for women with HMB and regular menstrual cycles. Data collection and analysis All assessments of trial quality and data extraction were performed unblinded by at least two review authors. Our primary review outcomes were treatment success, menstrual bleeding (assessed objectively, semi-objectively or subjectively), and participant satisfaction with treatment. Secondary outcomes were adverse events, quality of life, and haemoglobin level. Main results We identified eight RCTs involving 805 participants. Two trials comparing COCP with placebo were considered to be moderate quality and the remaining studies were low to very low quality, mainly because of serious risk of bias from lack of blinding and concerns over precision.COCP versus placeboCOCP, with a step-down oestrogen and step-up progestogen regimen, improved response to treatment (return to menstrual 'normality') (OR 22.12, 95% CI 4.40 to 111.12; 2 trials; 363 participants; I2 = 50%; moderate-quality evidence), and lowered MBL (OR 5.15, 95% CI 3.16 to 8.40; 2 trials; 339 participants; I2 = 0%; moderate-quality evidence) when compared to placebo. The results suggested that, if the chance of 'successful' treatment was 3% in women taking placebo, then COCP increased this chance from 12% to 77% in women with unacceptable HMB. Minor adverse events, in particular breast pain, were more common with COCP. No study in this comparison reported semi-objectively assessed MBL or participant satisfaction with treatment.COCP versus other medical treatmentsNon-steroidal anti-inflammatory drugs (NSAIDs)There was insufficient evidence to determine whether the COCP reduced MBL when compared to NSAIDs (mefenamic acid and naproxen). No study in this comparison reported semi-objectively assessed MBL, subjectively assessed MBL, participant satisfaction with treatment or adverse events.Levonorgestrel-releasing intrauterine system (LNG IUS)The LNG IUS was more effective than COCP in reducing MBL (OR 0.21, 95% CI 0.09 to 0.48; 2 trials; 151 participants; I2 = 0%; low-quality evidence) but it was not clear whether satisfaction with treatment or adverse effects varied according to which treatment was used. No study in this comparison reported semi-objectively assessed MBL or subjectively assessed MBL.Contraceptive vaginal ring (CVR) versus other medical treatmentsCOCP COCP was compared with CVR in two trials. There were discrepancies between some of the findings and there was no evidence of a benefit for one treatment compared to the other for response to treatment, MBL or participant satisfaction with treatment. There was a greater likelihood of nausea with COCP. No study in this comparison reported objectively assessed MBL or subjectively assessed MBL.ProgestogensCVR was compared to long course progestogens in one trial. It is possible that CVR increased the odds of satisfaction; but we are uncertain whether CVR improved MBL. The evidence was based on small numbers of participants and was very low quality, so definitive conclusions could not be reached. No study in this comparison reported objectively assessed MBL, subjectively assessed MBL, or adverse events. Authors' conclusions Moderate-quality evidence suggests that the combined oral contraceptive pill over six months reduces HMB in women with unacceptable HMB from 12% to 77% (compared to 3% in women taking placebo). When compared with other medical options for HMB, COCP was less effective than the LNG IUS. Limited evidence suggested that COCP and CVR had similar effects. There was insufficient evidence to determine comparative efficacy of combined hormonal contraceptives with NSAIDs, or long course progestogens.

5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( > 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

41 Background: TMPRSS2, a cell surface protease which is commonly upregulated in prostate cancer (PC) and regulated by androgens, is a necessary component for SARS-CoV2 cellular entry into respiratory epithelial cells. PC patients receiving ADT were reported to have a lower risk of SARS-CoV-2 infection. However, whether ADT may have an impact on the severity of COVID-19 illness in this population is poorly understood. Methods: In this study performed across 7 US medical centers, we retrospectively evaluated patients with active PC and SARS-COV-2 viral detection by PCR between 03/01/20 and 05/31/20. We collected information on demographics; medical comorbidities; medications; PC Gleason score at initial diagnosis; presence of active disease, metastases, and castration resistance; ADT use as defined by GnRH analog or antagonist within 3 months or castration levels of testosterone < 50 ng/dL within 6 months of COVID-19 diagnosis, or history of bilateral orchiectomy; active non-ADT systemic therapies including, but not limited to, androgen-receptor-targeted therapies and chemotherapy; and COVID-19-related outcomes including hospitalization, supplemental oxygen use, mechanical ventilation requirement, WHO COVID-19 ordinal scale for clinical improvement, follow-up duration, and vital status. Multivariable mixed-effect logistic regression was performed to evaluate any difference in COVID-19 clinical outcomes between patients on and not on ADT. Survival analysis was done using adjusted Cox proportion-hazards regression model. All tests were two-sided at 0.05 significance level. Results: We identified 465 evaluable patients with median age of 71 (61-81) years. Median duration of follow-up was 60 (12-114.2) days. In this follow up period, there were 195 (41.9%) hospitalizations and 111 (23.9%) deaths. When adjusted for age, BMI, and PC clinical disease state, overall survival (HR 1.28 [95%CI 0.79-2.08], P = 0.32), hospitalization status (HR 1.07 [0.61-1.87], P = 0.82), supplemental oxygen use (HR 1.29 [0.77-2.17], P = 0.34), and use of mechanical ventilation (HR 1.07 [0.51-2.23], P = 0.87) were not statistically different between ADT and non-ADT cohorts. Similarly, in subgroup analysis, no statistical difference in overall survival was found between ADT and non-ADT cohorts for hospitalized patients (HR 1.42 [0.82-2.47], P = 0.21) and those receiving supplemental oxygen (HR 1.10 [0.65-1.85], P = 0.73). Conclusions: In this retrospective cohort of PC patients, use of ADT prior to COVID-19 diagnosis does not protect against severe COVID-19 illness as defined by hospitalization, supplemental oxygen use, or death. Further preclinical work in understanding TMPRSS2 expression and androgen regulation in respiratory epithelial cells is needed. As well, longer clinical follow-up and additional clinical studies inclusive of prospective data are warranted to fully address this question.

Preeclampsia is triggered by an as yet unknown toxin from the placenta. Antiphospholipid antibodies (aPL), a strong risk factor for preeclampsia, have been shown to induce the production of toxic trophoblastic debris from the placenta. High mobility group box 1 (HMGB1) is a proinflammatory danger signal, and the expression of it has been reported to be increased in preeclampsia. This study examined whether aPL or preeclamptic sera increase the expression of HMGB1 in the syncytiotrophoblast or trophoblastic debris. Trophoblastic debris from normal placental explants that had been cultured with aPL or preeclamptic sera was exposed to endothelial cells. Endothelial cell activation was quantified by cell-surface ICAM-1 expression and U937 monocyte adhesion. The expression of HMGB1 in placental explants and trophoblastic debris that had been treated with aPL or preeclamptic sera was measured by immunohistochemistry and western blotting. The expression of the receptor for advanced glycation end products (RAGE) in endothelial cells was quantified by western blotting. Compared with controls, the expression of HMGB1 in the cytoplasm of the syncytiotrophoblast and trophoblastic debris was increased by treating placental explants with aPL or preeclamptic sera. The increased levels of HMGB1 contributed to endothelial cell activation, mediated in part by the RAGE. Preeclamptic sera and aPL both induced an increase in the cytoplasmic levels of the danger signal HMGB1 in trophoblastic debris. This increased HMGB1 in trophoblastic debris may be one of the toxic factors released from the placenta in preeclampsia.

Objective: Obesity is a well-known risk factor for developing endometrial cancer. However, the incidence and survival rate of endometrial cancer are associated with ethnicity and geographical area. In addition, whether menopausal status is associated with developing endometrial cancer in obese women and whether obesity is associated with subtypes of endometrial cancer have not been fully investigated. Here, we investigated the effect of BMI on developing endometrial cancer in Chinese women taking into account menopausal status and cancer subtypes. Methods: Data on 1,127 women with endometrial cancer including body mass index (BMI), age at diagnosis, parity, menopausal status and cancer subtype were collected from the largest obstetrics & gynaecology hospital in China and analysed. Results: After adjusting for age and parity, the odds for developing endometrial cancer in overweight or obese perimenopausal women was significantly higher than that in women with normal weight (OR=2.6 with 95%CI:1.9-3.5, and OR=3.5 with 95%CI: 2.2-5.4, respectively). The odds of developing endometrial cancer in overweight postmenopausal women were significantly higher than that in women who were normal weight (OR=2.4 with 95%CI: 1.8-3.1), however this was not the case for obese postmenopausal women. We further found that BMI, menopausal status, age and parity were not associated with subtypes of endometrial cancer. Conclusion: Our data demonstrate that obesity is positively associated with the incidence of developing endometrial cancer in Chinese women, with more significant effects in perimenopausal women.

Mitreola petiolata and M. sessilifolia in the Loganiaceae are similar wetland annuals occurring in tropical, subtropical, and temperate regions in the southeastern U.S., Africa, Asia, and Oceania. The flowers of both species have previously been described to open briefly with an apparent window for outside pollination, followed by flower closure and massive pollen germination within the anthers with pollen tubes covering the adjacent stigma. The phenomenon was documented with field observations, floral dissections, and light and scanning electron microscopy. Both species open their flowers for a brief 6–8 hour window. Subsequently, pollen germinates within the closed or closing flower with pollen tubes completely covering the stigma. The prevalence and importance of selfing by precocious pollen germination are discussed.

TPS3166 Background: Siglec-15 (S15) is a member of the Siglec family (Sialic acid-binding Immunoglobulin Lectins), a distinct subgroup of immunoglobulin (Ig) superfamily proteins involved in discriminating self from non-self-immune regulation (Macauley MS et al. 2014). Nonclinical models demonstrate S15 mediates suppression of T cell proliferation and negatively regulates T cell function. NC318 is a first-in-class monoclonal antibody that blocks S15-mediated immune suppression and prevents tumor growth by normalizing T cell function and restoring anti-tumor immunity in the tumor microenvironment (Wang J et al. 2019). The clinical hypothesis of this study is that NC318 targeting of S15 can improve anti-tumor immune response and provide benefit in multiple oncology indications. Methods: This is a multi-center, first in human, phase 1/2, open-label, non-randomized study to determine the safety and tolerability, define maximum tolerated dose and/or pharmacologically active dose, assess preliminary efficacy, and explore predictive and pharmacodynamic biomarkers of NC318 in subjects with advanced or metastatic solid tumors. Key eligibility criteria included measurable disease based on RECIST v1.1 and consent for collection of biopsies at screening and on treatment (optional for phase 1). Phase 1 used a 3+3 dose escalation design to determine the recommended phase 2 dose (RP2D) and schedule of NC318 while identifying drug related toxicities (DLTs). Phase 2 enrollment is limited to non-small cell lung, ovarian, head and neck, and triple negative breast cancer subjects with PD-L1 tumor proportion scores

TPS384 Background: Men with intermediate risk prostate cancer are often recommended external beam radiation therapy (EBRT) with or without 4-6 months of androgen deprivation therapy (ADT). However, ADT can be associated with prolonged erectile dysfunction due to delayed testosterone recovery. Darolutamide is a second-generation androgen receptor with low blood-brain barrier penetration. We hypothesize that men who receive Darolutamide with RT rather than ADT with RT are able to achieve surrogate PSA endpoints indicative of long-term disease control while preserving erectile function. Methods: This is an open label, phase 2B, multi-center, randomized controlled trial. Eligibility criteria include intermediate risk prostate cancer, good erectile quality per the EPIC-26 questionnaire, and archival tissue suitable for submission to Decipher Biosciences (San Diego, CA). Men will be stratified by Decipher score (low/intermediate vs high), RT modality (EBRT vs Brachytherapy/stereotactic body radiation therapy/combination RT), and age (>65 vs

TPS272 Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.

344 Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p < 0.0005 and p < 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p < 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p < 0.005 and p < 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p < 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p < 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.

Background Germline testing is recommended for all men with metastatic prostate cancer (PCa), and for some with localized PCa meeting specific histologic or family history criteria. Germline genetic evaluation has important implications for PCa prognosis and management, as well as implications for family members and cancer screening. Despite the importance of germline evaluation, its utilization in urologic practice is unknown. Materials and Methods We conducted a 32-item survey of U.S. urologists to examine knowledge of germline testing guidelines and practice patterns. It was shared through email to 6 American Urological Association sections, the Veterans Affairs Urology Mailgroup, and social media. Results Among 132 total respondents from diverse practice settings across the U.S., 12% perform germline testing, 44% refer to a genetic counselor, 11% do both, and 33% do not test/refer. Only 4% had formal education in genetics. While 98% ask about PCa family history, only 76% and 52% ask about breast and ovarian cancer. When presented with hypothetical case scenarios where germline testing is indicated, many respondents indicated they would not offer genetic counseling or testing. Younger age (p = 0,03), academic practice (p = 0.04), and specializing in PCa/oncology (p = 0.007) were significantly associated with performing or referring for germline testing. Specializing in PCa/oncology was significantly associated with recommending germline testing for all case scenarios involving metastatic PCa (p = 0.0009) Conclusion Our results suggest significant gaps in knowledge of germline testing and alignment of practice with national guidelines among urologists. Germline testing education and facilitation of genetic evaluation in urologic practice is warranted.

This is a protocol for a Cochrane Review (Overview). The objectives are as follows:. To identify, systematically assess and summarise all evidence from Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), through a network meta-analysis. To compare the efficacy, satisfaction and safety of different treatments available for HMB (that have been assessed in Cochrane Reviews), performing direct and indirect comparisons through a network meta-analysis.

Children comprise a large proportion of the population in sub-Saharan Africa. The burden of paediatric surgical disease exceeds available resources in Africa, potentially increasing morbidity and mortality. There are few prospective paediatric perioperative outcomes studies, especially in low- and middle-income countries (LMICs).We conducted a 14-day multicentre, prospective, observational cohort study of paediatric patients (aged16 yrs) undergoing surgery in 43 government-funded hospitals in South Africa. The primary outcome was the incidence of in-hospital postoperative complications.We recruited 2024 patients at 43 hospitals. The overall incidence of postoperative complications was 9.7% [95% confidence interval (CI): 8.4-11.0]. The most common postoperative complications were infective (7.3%; 95% CI: 6.2-8.4%). In-hospital mortality rate was 1.1% (95% CI: 0.6-1.5), of which nine of the deaths (41%) were in ASA physical status 1 and 2 patients. The preoperative risk factors independently associated with postoperative complications were ASA physcial status, urgency of surgery, severity of surgery, and an infective indication for surgery.The risk factors, frequency, and type of complications after paediatric surgery differ between LMICs and high-income countries. The in-hospital mortality is 10 times greater than in high-income countries. These findings should be used to develop strategies to improve paediatric surgical outcomes in LMICs, and support the need for larger prospective, observational paediatric surgical outcomes research in LMICs.NCT03367832.

BACKGROUND:Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. OBJECTIVE:We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. METHODS:Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n=1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n=1,895). Asubset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. RESULTS:COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300cells/μL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300cells/μL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06-1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300cells/μL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. CONCLUSIONS:Patients with moderate-to-severe COPD and blood eosinophil counts of 300cells/μL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study.

Objectives To determine whether there was an increased risk of perinatal mortality among mothers booked for care with community lead maternity carer (LMC) midwives in their first compared with later years of practice. Design Retrospective cohort study using linked national maternity, mortality and workforce data; adjusted analysis using logistic regression. Setting New Zealand. Participants Women under community LMC midwifery care birthing 2008–2014. Main outcome measures Perinatal mortality (stillbirths and neonatal deaths of babies born from 20 weeks’ gestation to the 27th day of postnatal life), excluding terminations and deaths associated with congenital abnormalities. Results There were 2045 deaths among 344 910 births booked with midwives. First year of practice midwives cared for women with higher risk of perinatal mortality, including Māori, Pacific, Indian

Sexual reproduction in seed plants involves the production of male and female gametes that, if successful, lead to the formation of an embryo. In order to understand the process in reasonable detail, it is necessary to know the reproductive structures—in the case of flowering plants, the reproductive structure of interest is the flower. Whether one flower supports both male and female reproductive parts or separate flowers are employed, this chapter presents these prospects and then examines the basics of floral structure and later focuses on the anatomy of male reproductive structures. Detailed steps are used to show the development of pollen and its germination prior to pollination.

Background Compliance with maternity clinical practice guidelines developed by National Women's Health has been found to be low at audit. Objective To explore the reasons for poor compliance with maternity guidelines by evaluating the quality of a sample of National Women's Health guidelines using a validated instrument and assessing local guideline users' perceptions of and attitudes toward guidelines. Design Five independent reviewers evaluated the quality of 10 purposively selected guidelines for adherence to the Appraisal of Guidelines Research & Evaluation (AGREE) II instrument standards. A self-administered questionnaire for staff was undertaken regarding views of and barriers to guideline use. Results None of the guidelines attained a score over 50% for the following domains: stakeholder involvement, rigour of development, applicability, editorial independence. The highest scoring domain was clarity of presentation (mean 69%). All guidelines scored the minimum possible for editorial independence. Survey respondents had positive attitudes toward guidelines, believed that their use could improve quality of care within the service, and felt that encouragement from senior staff members and peers would encourage their use. Accessibility was the most commonly cited of many barriers identified. Conclusion The National Women's Health guidelines evaluated in this study cannot be considered to be high quality, and could be improved by reporting on methodology of the development process. Although poor guideline development may contribute to failure of the local maternity guidelines, it appears that accessibility is a major barrier to their use and implementation.

Rationale: FVC percent predicted (FVC%) is the primary outcome measure in clinical trials of systemic sclerosis interstitial lung disease. For interpretation of change in the FVC% over time, it is important to define whether these changes are clinically meaningful. Objectives:: To assess the reliability and the minimal clinically important differences (MCID) for FVC% in the Scleroderma Lung Study I and II (SLS-I and -II). Methods: Using data from SLS-I and -II (N = 300), we evaluated the test-retest reliability for FVC% (screening vs. baseline) using intraclass correlation. MCID estimates at 12 months were calculated in the pooled cohort (SLS-I and -II) using two anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the Medical Outcomes Short Form-36 Health Transition question (“Compared with one year ago, how would you rate your health in general now”?), where “somewhat better” or “somewhat worse” were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient-reported outcomes (PROs) and computer-assisted quantitation of extent of fibrosis (QLF) and of total interstitial lung disease (QILD) on high-resolution computed tomography. Student’s t test was used to compare the mean difference in outcomes between the MCID improvement/worsening and the “no change” group. Measurements and Main Results: Reliability of FVC%, assessed at a mean of 34 days, intraclass correlation was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0% to 5.3% and for worsening from −3.0% to −3.3%. FVC% improvement by greater than or equal to MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, whereas FVC% worsening greater than or equal to MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF. Conclusions: FVC% has acceptable test-retest reliability, and we have provided the MCID estimates for FVC% in systemic sclerosis interstitial lung disease–based changes at 12 months from baseline in two clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT00004563 for SLS-I and NCT00883129 for SLS-II).

BACKGROUND For parents who experience stillbirth, knowing the cause of their baby's death is important. A post mortem examination is the gold standard investigation, but little is known about what may influence parents' decisions to accept or decline. AIM We aimed to identify factors influencing maternal decision-making about post mortem examination after late stillbirth. METHODS In the New Zealand Multicentre Stillbirth Study, 169 women with singleton pregnancies, no known abnormality at recruitment, and late stillbirth (≥28weeks gestation), from seven health regions were interviewed within six weeks of birth. The purpose of this paper was to explore factors related to post mortem examination decision-making and the reasons for declining. We asked women if they would make the same decision again. RESULTS Maternal decision to decline a post mortem (70/169, 41.4%) was more common among women of Māori (adjusted odds ratio (aOR) 4.99 95% confidence interval (CI) 1.70-14.64) and Pacific (aOR 3.94 95% CI 1.47-10.54) ethnicity compared to European, and parity two or more (aOR 2.95 95% CI 1.14-7.62) compared to primiparous. The main reason for declining was that women 'did not want baby to be cut'. Ten percent (7/70) who declined said they would not make this decision again. No woman who consented regretted her decision. CONCLUSION Ethnic differences observed in women's post mortem decision-making should be further explored in future studies. Providing information of the effect of post mortem on the baby's body and the possible emotional benefits of a post mortem may assist women faced with this decision in the future.

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10(-8)) and PPP4R4/SERPINA1 (P = 1.01 X 10(-8)) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, similar to 0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

Introduction The incidence of acute deep venous thrombosis as a result of penetrating proximity extremity trauma (PPET) to the thigh has been demonstrated to be 16% in a single report. The purpose of the current study is to demonstrate the incidence and clinical significance of venous injury as a result of proximity trauma to the thigh in a large cohort screened with colour flow duplex (CFD) ultrasound and to identify factors predictive of defining a wound in proximity to a major vascular structure. Patients and methods A prospective observational study was conducted from January 1st, 2010 to January 1st, 2012 on all patients presenting with penetrating extremity trauma. Data on injury location, mechanism, associated extremity and non-extremity injuries, use and results of CFD, as well as the admitting trauma surgeon were recorded and analysed. Results 220 thigh wounds with a normal physical examination were identified, of which 167 (75.9%) underwent CFD due to proximity. The incidence of acute venous injury was 4.8% (8/167). 37.5% (3/8) of these injuries resulted in morbidity. Injury mechanism and which attending physician was on call were predictive of a wound being defined as in proximity, whereas an injury with an associated fracture was a negative predictor. Conclusions Occult venous injuries as a result of PPET occur in 4.8% of patients with thigh wounds in proximity to a major vascular structure. The designation of a wound as being in “proximity” was influenced by injury mechanism, associated fractures, and the judgement of the on-call attending. Colour flow duplex is a valuable tool with the ability to identify not only occult arterial injuries, but also venous injuries with the potential to cause significant morbidity as well.

Background: Increased expression and neomorphic mutations of the histone methyltransferase EZH2 are often observed in cancer, leading to repression of genes associated with apoptosis and differentiation. High EZH2 expression and low expression of EZH2 target genes in mCRPC correlate with poor prognosis. CPI-1205 is a potent, reversible, cofactor-competitive small molecule inhibitor of EZH2. Preclinical studies revealed that prostate cancer models dependent on androgen receptor signaling (ARS) are sensitive to EZH2 inhibition, and that CPI-1205, when combined with novel ARS inhibitors, results in synergistic cell growth inhibition (Bradley 2018). Here we report preliminary results from the Phase Ib component. Methods: In this multicenter Phase Ib/II study, patients (pts) with mCRPC previously treated with a novel ARS inhibitor were enrolled in different cohorts exploring two regimens of oral CPI-1205 on a continuous 28-day cycle: 800 mg TID or 400 mg BID with cobicistat, a CYP3A4 inhibitor, combined with the standard dose of E (160 mg QD) or standard dose of A/P (1000 mg QD/5 mg BID). Prior chemotherapy was allowed. The primary objective in Phase Ib is to determine safety, a recommended Phase II dose, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 11/16/2018, 35 pts were enrolled in four cohorts (two cohorts of CPI-1205 + E; two cohorts of CPI-1205 + A/P) and were treated for ≥1 cycle. Age ranged from 55 to 90 years (median 72). 63% were ECOG 0 and 37% ECOG 1. 13 pts (37%) tested positive for ARV7. 21 pts (60%) had unfavorable circulating tumor cells (CTC) counts at baseline. 6 pts (17%) had prior taxane-based chemotherapy for mCRPC. 16 pts received CPI-1205 + E and 19 pts received CPI-1205 + A/P. Only 1 DLT (asymptomatic reversible ALT increase, Grade 4) was reported in the CPI-1205 + A/P + cobicistat. No serious AE related to the study drug was reported in any cohort. Overall, the commonly reported drug-related treatment-emergent adverse events (TEAEs ≥10%) were low-grade diarrhea (n= 11, 31%), fatigue and nausea (n= 9, 26% each), and decreased appetite (n=5, 14%). Grade ≥3 TEAEs were fatigue and elevated ALT (n=2, 6% each), and nausea, pruritus, hypokalemia, and muscular weakness (n=1, 3% each). 16 pts remain on treatment. Cases of PSA >80% reduction, CTC ≥30% reduction, and RECIST response were observed. Both CPI-1205 regimens resulted in significant target engagement (reduced H3K27me3 in PBMCs and CTCs). Patient sample analysis to maximize biomarker identification is ongoing. PK data will be presented. Conclusions: Both CPI-1205 800 mg PO TID and 400 mg PO BID plus cobicistat, combined with full doses of either E or A/P, are well tolerated, with acceptable safety. Encouraging clinical activity has been observed. CPI-1205 800 mg PO TID + E or A/P has been selected for phase 2 expansion, and patient enrollment is ongoing Citation Format: Mary-Ellen Taplin, Arif Hussain, Satish Shah, Neal D. Shore, William Jeffery Edenfield, Oliver A. Sartor, Luke T. Nordquist, Manish Agrawal, William Clark, David R. Wise, William K. Oh, Mark T. Fleming, James E. Butrynski, Gurkamal S. Chatta, Manojkumar Bupathi, Claudia Lebedinsky, Adrian Senderowicz, Jian Li, Gozde Colak, David Nash, Patrick Trojer, William D. Bradley, Jessica Piel, Emmanuel S. Antonarakis. Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT094.

Background Although the incidence of injury to the upper extremity screened with angiography as a result of proximity penetrating trauma is similar to that of the lower extremity, intervention rates seem to be higher. However, studies evaluating the incidence of injury as a result of proximity penetrating trauma have primarily focused on the lower extremity. This study shows the incidence and clinical significance of vascular injury as a result of proximity trauma to the upper extremity in a large cohort of patients screened with color-flow duplex. Materials and Methods A retrospective study was conducted from January 1, 2005 to January 1, 2012 on all patients undergoing color-flow duplex as a result of proximity penetrating trauma to the upper extremity. Data on injury location, mechanism, associated extremity and nonextremity injuries, and use and results of color-flow duplex were recorded and analyzed. Results A total of 341 patients were identified who underwent color-flow duplex because of proximity penetrating trauma to the upper extremity. Injuries occurred in 370 extremities, with 253 located in the upper arm and 117 in the forearm. Overall, 18 (4.9%) injuries were identified on screening duplex ultrasound, of which 12 (3.2%) were arterial and 5 (1.4%) were venous. The therapeutic intervention rate for detected injuries to the upper arm was 1.6% (4/253), whereas no injuries of the forearm were identified that necessitated intervention. Conclusions Although color-flow duplex is an inexpensive and noninvasive means of detecting injuries as a result of proximity penetrating trauma, screening upper extremity wounds is unlikely to detect clinically significant arterial injuries in need of therapeutic intervention. Venous injuries in the form of deep venous thromboses were detected in only 1.4% of patients. These findings suggest that screening for proximity penetrating trauma of the upper extremity is unlikely to detect injuries at a rate that would prove cost-effective on formal decision analysis.

Preeclampsia is characterised by systemic endothelial cell dysfunction thought to be triggered by toxic/dangerous factors from the placenta, including placental extracellular vesicles (EVs). Why placental EVs become toxic is unknown. We previously reported that preeclamptic sera produced toxic/dangerous placental macrovesicles but whether small EVs are also toxic/dangerous in preeclampsia is unknown.First trimester placental explants were treated with 10% preeclamptic or control sera (n=10) for 24h. Micro- and nano-vesicles were harvested by sequential centrifugation. Micro- or nano-vesicles were also exposed to monolayers of endothelial cells in the presence or absence of nifedipine (50μg/ml) or labetalol (0.5μg/ml) which are well-known anti-hypertensives in clinical practices.The number and size of micro- and nano-vesicles were counted. Endothelial cell-surface intercellular adhesion molecule 1 (ICAM-1) and high mobility group box 1 (HMGB1) levels in micro- or nano-vesicles were measured by immunoassays.Neither the amount nor size of both micro- and nano-vesicles was different after treating placental explants with preeclamptic or control sera. The levels of HMGB1 were significantly increased in both micro- and nano-vesicles from preeclamptic sera treated placental explants (p0.03). Exposing endothelial cells to micro- or nano-vesicles from preeclamptic sera-treated placental explants induced endothelial activation, but it was reversed by co-incubation with nifedipine (p=0.004) or labetalol (p=0.002).Our data demonstrate that preeclamptic sera produce toxic/dangerous micro- and nano-placental EVs which activated endothelial cells. This effect was reversed by antihypertensives. The increased levels of HMGB1 in EVs may contribute to endothelial cell activation.