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BACKGROUNDDespite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment.METHODSWe evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.RESULTSPositive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8+ T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.CONCLUSIONThe tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy.FUNDINGOvarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

Abstract We analyze the relationship between geothermal energy production and seismic hazards in the Salton Sea Geothermal Field (SSGF) between 1972 and 2022. A clear increase in seismic activity accompanies geothermal energy production and is greatest to the east of the Brawley fault, where the amount of injection exceeds the amount of production. We estimate that, whereas there was a 2% chance of a M6.07 earthquake nucleating inside the SSGF within a fifty-year period prior to energy production (pre-production), there is an equal probability that a M6.70 earthquake nucleates there in a fifty-year period during which historically average energy production conditions persist (syn-production). Similarly, we estimate a 2% chance of a M7.15 and M6.92 occurring in the broader Brawley Seismic Zone (excluding the SSGF) within a fifty-year period during the pre- and syn-production eras, respectively. We find that linear regression models fail to reliably forecast the background seismicity rate as a function of fluid production and injection.

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

Abstract Wildlife crossing structures and road calming measures are frequently implemented to improve habitat connectivity and mitigate the risks of wildlife–vehicle collisions on roads. Although Southeast Asia is a known biodiversity hotspot, majority of studies assessing effectiveness of such structures were conducted outside the region. Existing studies also tended to be non‐comparative and focused on crossing structures in silo. We addressed this gap by simultaneously surveying and comparing the usage frequency of mammals across three crossing types—culverts, roads and rope bridges—along a road surrounded by forests in Singapore. This allowed us to evaluate the preferences of mammals, assess usage patterns and investigate factors influencing the use of different crossing types. Using camera traps and closed‐circuit televisions, we documented 1133 independent crossing events across a 9‐month study period from March to November 2021. Fourteen mammal species were detected across all crossing types, with wild boar (Sus scrofa) being the most prevalent species (68.2%). Locally critically endangered species such as the Malayan porcupine (Hystrix brachyura), Sunda pangolin (Manis javanica), and Raffles' banded langur (Presbytis femoralis femoralis) were also recorded to use culverts, roads, and rope bridges for crossings, respectively. Although many species used multiple crossing types, most species had a preferred crossing method. Between culverts and roads, factors that influenced crossing preferences included group size for wild boars and time of day and presence of fences for other mammals. Even though such culverts were intended for drainage, they were still widely used by mammals. Overall, all three crossing methods were crucial in facilitating the movement of animals between habitats. Thus, a variety of infrastructure and measures to accommodate the diversity of wildlife moving across forest patches in a fragmented landscape is recommended.

BackgroundThe role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.MethodsLOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source.ResultsLOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes.ConclusionsLOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

BackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Abstract Communal bird roosts serve as information centres and a means of thermoregulation for many species. While some communally roosting species are major pests and cause dis‐amenities, others are of conservation concern. Estimating the population of roosting birds can provide a useful proxy of population size and possibly a more reliable estimate than other sampling techniques. However, estimating these populations is challenging as some roosts are large and often occluded in foliage. Previous acoustic methods such as paired sampling, microphone arrays and use of call rate have been used to estimate bird abundances; however, these are less suited for estimating large roost populations where hundreds of individuals are calling in unison. To address this challenge, we explored using machine learning techniques to estimate a roost population of the Javan myna, Acridotheres javanicus, an invasive species in Singapore. While one may expect to use sound intensity to estimate roost sizes, it is affected by various factors such as distance to the recorder, local propagation conditions (e.g. buildings and trees), weather conditions, and noise from other sources. Here, we used a deep neural network to extract higher order statistics from the sound recordings and use those to help estimate roost sizes. Additionally, we validated our method using automated visual analysis with a dual‐camera setup and manual bird counts. Our estimated bird counts over time using our acoustic model matched the automated visual estimates and manual bird counts at a selected Javan myna roost, thus validating our approach. Our acoustic model estimated close to 400 individual mynas roosting in a single tree. Analyses of additional recordings of Javan myna roosts conducted on two separate occasions and at a different roost location using our acoustic model showed that our roost estimates over time also matched our automated visual estimates well. Practical implication: Our novel approach of estimating communal roost sizes can be achieved robustly using a simple portable acoustic recording system. Our method has multiple applications such as testing the efficacy of avian roost population control measures (e.g. roost tree pruning) and monitoring the populations of threatened bird species that roost communally.

Abstract House crows (Corvus splendens) are considered an invasive species and are prevalent in parts of Europe, Africa, and Southeast Asia. Existing crow management measures include food limitation, habitat modification, and direct population control. The latter method provides a more immediate solution, particularly in nesting locations where crow attacks occur more frequently. Crow ladder traps are widely adopted to capture crows, but a thorough examination of the environmental conditions that optimize trapping efficacy is lacking. We assessed factors affecting crow trap efficacy in Singapore to better advise future deployment strategies of crow traps. We obtained data from 170 crow trapping operations including the identities of the contractors conducting the trapping operations, operation start date, crow density, intensity of bird feeding, various land use cover proportions, and an index to quantify the spatial‐temporal proximity to previous trapping operations. We used a spatial gamma generalized linear mixed model (GLMM) to determine the factors affecting the daily number of crows captured and a spatial binomial GLM to determine the factors affecting the probability that crows will be captured. The number of bird‐feeding incidents had a negative effect on crow trap efficacy suggesting that crows are probably less inclined to enter traps if proximate anthropogenic food abundance is high. Trapping efficacy increased if traps were placed in high crow‐density areas, likely because more crows could detect the traps. The probability of capture also declined if the traps were placed closer to prior trapping locations or with a shorter time interval from previous trapping operations. Capture rates of crows can be increased by placing traps in high crow density areas, limiting bird‐feeding incidences, and lengthening the spatial and temporal proximities to previous trapping operations. The deployment of ladder traps is a viable means to control the population of house crows and consideration of environmental conditions and trapping history can improve capture rates.

ObjectiveThe presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery.MethodsThis analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS.ResultsMenopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53).ConclusionsThe association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.

PurposeAdvanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental designDiscovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).ResultsInfiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).ConclusionsAn infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

ObjectiveTo evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis.DesignPooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium.SettingPopulation-based.Patient(s)We included 8,500 women with ovarian cancer, 13,592 control women.Intervention(s)Ten well-established ovarian cancer risk factors.Main outcome measure(s)Risk of ovarian cancer for women with and without endometriosis.Result(s)Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

BackgroundPrevious studies on the association between reproductive factors and ovarian cancer survival are equivocal, possibly due to small sample sizes.MethodsUsing data on 11,175 people diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer (ovarian cancer) from 16 studies in the Ovarian Cancer Association Consortium (OCAC), we examined the associations between survival and age at menarche, combined oral contraceptive use, parity, breastfeeding, age at last pregnancy, and menopausal status using Cox proportional hazard models. The models were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study and stratified on stage and histotype.ResultsDuring the mean follow-up of 6.34 years (SD = 4.80), 6,418 patients passed away (57.4%). There was no evidence of associations between the reproductive factors and survival among patients with ovarian cancer overall or by histotype.ConclusionsThis study found no association between reproductive factors and survival after an ovarian cancer diagnosis.ImpactReproductive factors are well-established risk factors for ovarian cancer, but they are not associated with survival after a diagnosis of ovarian cancer.

BackgroundThere is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects.MethodsThis analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data.ResultsThere was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54).ConclusionsA higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival.ImpactGiven that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

ObjectiveTo evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association.MethodsWe conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs).ResultsOverall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99).ConclusionsThe hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.

BackgroundParity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.MethodsA pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.ResultsEver having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.ConclusionsIncomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

PurposeGene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.Experimental designAdopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.ResultsGene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.ConclusionsWe validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.

PurposePrior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival.MethodsData from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery.ResultsUse of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend

This paper explores the possibility of constructing two-terminal mechanical devices (one-ports) which are lossless and adjustable. To be lossless, the device must be passive (i.e., not requiring a power supply) and nondissipative. To be adjustable, a parameter of the device should be freely variable in real time as a control input. For the simplest lossless one-ports, the spring and inerter, the question is whether the stiffness and inertance may be varied freely in a lossless manner. We will show that the typical laws which have been proposed for adjustable springs and inerters are necessarily active, and that it is not straightforward to modify them to achieve losslessness, or indeed, passivity. By means of a physical construction using a lever with moveable fulcrum, we will derive device laws for adjustable springs and inerters which satisfy a formal definition of losslessness. We further provide a construction method which does not require a power supply for physically realizable translational and rotary springs and inerters. The analogous questions for lossless adjustable electrical devices are examined.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Abstract Breast tissue enhances on contrast MRI and is called background parenchymal enhancement (BPE). Having high BPE has been associated with an increased risk of breast cancer. We examined the relationship between BPE and the amount of fibroglandular tissue on MRI (MRI-FGT) and breast cancer risk factors. This was a cross-sectional study of 415 women without breast cancer undergoing contrast-enhanced breast MRI at Memorial Sloan Kettering Cancer Center. All women completed a questionnaire assessing exposures at the time of MRI. Prevalence ratios (PR) and 95% confidence intervals (CI) describing the relationship between breast cancer risk factors and BPE and MRI-FGT were generated using modified Poisson regression. In multivariable-adjusted models a positive association between body mass index (BMI) and BPE was observed, with a 5-unit increase in BMI associated with a 14% and 44% increase in prevalence of high BPE in pre- and post-menopausal women, respectively. Conversely, a strong inverse relationship between BMI and MRI-FGT was observed in both pre- (PR = 0.66, 95% CI 0.57, 0.76) and post-menopausal (PR = 0.66, 95% CI 0.56, 0.78) women. Use of preventive medication (e.g., tamoxifen) was associated with having low BPE, while no association was observed for MRI-FGT. BPE is an imaging marker available from standard contrast-enhanced MRI, that is influenced by endogenous and exogenous hormonal exposures in both pre- and post-menopausal women.

Wildlife crossing structures and road calming measures are frequently implemented to improve habitat connectivity and mitigate the risks of wildlife–vehicle collisions on roads. Although Southeast Asia is a known biodiversity hotspot, majority of studies assessing effectiveness of such structures were conducted outside the region. Existing studies also tended to be non‐comparative and focused on crossing structures in silo. We addressed this gap by simultaneously surveying and comparing the usage frequency of mammals across three crossing types—culverts, roads and rope bridges—along a road surrounded by forests in Singapore. This allowed us to evaluate the preferences of mammals, assess usage patterns and investigate factors influencing the use of different crossing types. Using camera traps and closed‐circuit televisions, we documented 1133 independent crossing events across a 9‐month study period from March to November 2021. Fourteen mammal species were detected across all crossing types, with wild boar (Sus scrofa) being the most prevalent species (68.2%). Locally critically endangered species such as the Malayan porcupine (Hystrix brachyura), Sunda pangolin (Manis javanica), and Raffles' banded langur (Presbytis femoralis femoralis) were also recorded to use culverts, roads, and rope bridges for crossings, respectively. Although many species used multiple crossing types, most species had a preferred crossing method. Between culverts and roads, factors that influenced crossing preferences included group size for wild boars and time of day and presence of fences for other mammals. Even though such culverts were intended for drainage, they were still widely used by mammals. Overall, all three crossing methods were crucial in facilitating the movement of animals between habitats. Thus, a variety of infrastructure and measures to accommodate the diversity of wildlife moving across forest patches in a fragmented landscape is recommended. [ABSTRACT FROM AUTHOR]

In developed cities, bird communities are typically comprised of a few dominant invasive species that can cause considerable social and economic costs. While various studies advocate restricting anthropogenic food as a suitable management approach, a significant knowledge gap persists regarding how these species interact and respond to such an intervention. Here, we evaluate whether limiting a shared food resource may affect their abundances similarly and assess whether such limitations influence their niche dynamics.In Singapore, open food centres for people, colloquially known as hawker centres, serve as key food sources for three highly adapted urban birds: feral pigeons, Javan mynas and house crows. We counted these three species across 63 hawker centres and analysed their niche dynamics across different phases—before, during COVID‐19 social restrictions when dining‐in was prohibited, and during an enforcement phase mandating the return of crockery. We modelled their counts, diet niche widths and niche overlaps, considering predictors which include the sampling phases, food availability, structural characteristics of hawker centres and spatial attributes such as distance to public housing.During social restrictions, feral pigeon and Javan myna counts showed a significant decline, while the count proportions of the three species compared to each other remained relatively stable. Hawker centres closer to bridges and public housing, and those that structurally more open, attracted more birds.The niche widths of feral pigeons and Javan mynas significantly narrowed during social restrictions due to reduced food availability. However, their niche overlaps remained consistent across sampling phases, indicating resource partitioning strategies to cope with extreme food shortages—feral pigeons adapted by foraging more on grass verges outside, while Javan mynas frequented tray return stations. This resilience in maintaining species proportions and the absence of significant niche overlap suggested the existence of an ecological balance despite substantial reductions in available food.Synthesis and applications. Our study underscores the importance of controlling human‐provided food to collectively manage dominant urban bird commensals. Beyond the two social restriction phases, curbing the availability of anthropogenic food through enforcement also kept nuisance birds away, validating a cost‐effective approach in reducing their counts. [ABSTRACT FROM AUTHOR]

Abstract COVID‐19 has heightened the dependence of urban dwellers on cultural ecosystem services provided by urban green spaces (UGS), specifically in regard to the provision of recreational opportunities, and psychological and physical health benefits arising from their use. As different types and levels of cultural ecosystem services are provided by different types of UGS, people may seek out different UGS to satisfy personal needs over various phases of COVID‐19 mobility restrictions imposed by cities. We report on a study that took advantage of the different phases of COVID‐19 mobility restrictions to assess the demand for and perception of different types of UGS in Singapore. The study utilised four datasets to compare demand for and visitorship patterns of UGS before the pandemic (Pre‐Circuit Breaker), the duration of the strictest mobility restrictions (Circuit Breaker), and after the measures were relaxed (Post‐Circuit Breaker). We used Google Search trends as a proxy for UGS demand, Google mobility data for an overview of population visitorship trends, visitor counts for granular insights on actual visitorship trends, and qualitative data on perception of parks by park visitors after restrictions eased. Parks were categorised as manicured and less manicured UGS for analysis. Search interest for UGS overall fell by more than 50% from during Circuit Breaker but the post‐Circuit Breaker levels exceeded pre‐Circuit Breaker, with a 70.9% increase for less manicured UGS compared to 20.8% for manicured UGS. This corroborated with Google mobility and visitor counts, which showed a steep decrease in park use followed by a rapid increase in the same periods, and with increased visitorship in the less manicured UGS. The perception study also showed that more than 50% of respondents reported visiting parks that they have never visited before, and there was a greater appreciation and use of UGS after the pandemic and preference for less manicured and more naturalistic landscapes. The pandemic has heightened the demand for cultural ecosystem services provided by UGS. Our study showed that this demand is not uniform across different types of UGS, with an increase visitorship and preference for less manicured green spaces. Read the free Plain Language Summary for this article on the Journal blog.

Abstract The feral pigeon (Columba livia) is a globally commensal bird that can cause dis‐amenities such as soiling and is a potential vector of various diseases. Aside to limiting food as a management strategy, reducing the availability of roosting and nesting sites can help regulate feral pigeon populations. Despite their prevalence, current knowledge of their roosting and nesting preferences is lacking. Feral pigeons commonly use railway viaduct expansion gaps in Singapore for roosting and nesting. These gaps provided an ideal experimental platform to examine feral pigeon roost and nest site selection while controlling for differing cavity sizes which can significantly affect their reproductive success and site selection decisions. We also conducted an in‐situ experiment to test the efficacy of nest removal as a management option. Our nationwide surveys of 80.3 km of railway viaducts and 6048 gaps revealed that feral pigeon day roosting and nesting preferences are influenced by structural height and more importantly, their proximity to human food sources. There was a significantly higher probability of feral pigeon roosting in a gap if it had more pigeon feeding incidences in its vicinity and was higher. The probability of feral pigeon nesting in gap was higher if it was closer to a railway station, lower and further from water bodies. In our field experiment, we did not find any significant differences in the proportions of the abundances of feral pigeon to other urban commensal bird species at the gaps before and after nests were removed. Overall, our results suggest that a concerted effort to reduce anthropogenic food availability to feral pigeons is central in limiting their reproductive success and controlling their population.