Testosterone Influence on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

Purpose: Sjögren syndrome is an autoimmune disorder that occurs almost exclusively in women and is associated with extensive inflammation in lacrimal tissue, an immune-mediated destruction and/or dysfunction of glandular epithelial cells, and a significant decrease in aqueous tear secretion. We discovered that androgens suppress the inflammation in, and enhance the function of, lacrimal glands in female mouse models (e.g., MRL/MpJ-Tnfrsf6lpr [MRL/lpr]) of Sjögren syndrome. In contrast, others have reported that androgens induce an anomalous immunopathology in lacrimal glands of nonobese diabetic/LtJ (NOD) mice. We tested our hypothesis that these hormone actions reflect unique, strain- and tissue-specific effects, which involve significant changes in the expression of immune-related glandular genes. Methods: Lacrimal glands were obtained from age-matched, adult, female MRL/lpr and NOD mice after treatment with vehicle or testosterone for up to 3 weeks. Tissues were processed for analysis of differentially expressed mRNAs using CodeLink Bioarrays and Affymetrix GeneChips. Data were analyzed with bioinformatics and statistical software. Results: Testosterone significantly influenced the expression of numerous immune-related genes, ontologies, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in lacrimal glands of MRL/lpr and NOD mice. The nature of this hormone-induced immune response was dependent upon the autoimmune strain, and was not duplicated within lacrimal tissues of nonautoimmune BALB/c mice. The majority of immune-response genes regulated by testosterone were of the inflammatory type. Conclusions: Our findings support our hypothesis and indicate a major role for the lacrimal gland microenvironment in mediating androgen effects on immune gene expression

The History of Neurosurgical Management of Ischemic Stroke

Stroke remains a major public health issue and the second leading cause of death worldwide. The Hippocratic Corpus used the word apoplexy to describe a person collapsing while retaining pulse and respiration. This is believed to be the first written description of stroke. The theories of what caused stroke evolved over the years. When autopsies were performed stroke was attributed to emboli and thrombi formation. Carotid endarterectomies (CEA) were then performed for the treatment of stroke. Originally CEA were seen with skepticism but the North American Symptomatic Carotid Endarterectomy trial (NASCET) and the European Carotid Surgery trial (ECS) helped restore their efficacy in the management of ischemic stroke. A milestone in the management of ischemic stroke was the use of intravenous tissue plasminogen activator (tPA). Secondary to the limitations of the use of tPA other avenues were sought which included intraarterial recombinant prourokinase and mechanical thrombectomy. The field of mechanical thrombectomy continues to be rapidly changing and evolving. Various randomized controlled trials and meta-analysis have been conducted in order to evaluate who will benefit from mechanical thrombectomies, the timing, the best device to use and the role of combining this intervention with the administration of intravenous tPA

An enhanced MOSFET threshold voltage model for the 6–300 K temperature range

An enhanced threshold voltage model for MOSFETs operating over a wide range of temperatures (6–300K) is presented. The model takes into account the carrier freeze-out effect and the external field-assisted ionization to address the temperature dependence of MOS transistors. For simplicity, an empirical function is incorporated to predict short channel effects over the temperature range. The results from the proposed model demonstrate good agreement with NMOS and PMOS transistors measured from fabricated chips

Development of complex executive function over childhood : Longitudinal growth curve modeling of performance on the Groton Maze Learning Task

Abstract This longitudinal study modeled children's complex executive function (EF) development using the Groton Maze Learning Task (GMLT). Using a cohort-sequential design, 147 children (61 males, 5.5–11 years) were recruited from six multicultural primary schools in Melbourne and Perth, Australia. Race/ethnicity data were not available. Children were assessed on the GMLT at 6-month intervals over 2-years between 2010 and 2012. Growth curve models describe age-related change from 5.5 to 12.5 years old. Results showed a quadratic growth trajectory on each measure of error—that is, those that reflect visuospatial memory, executive control (or the ability to apply rules for action), and complex EF. The ability to apply rules for action, while a rate-limiting factor in complex EF, develops rapidly over early-to-mid childhood

Pralidoxime in Acute Organophosphorus Insecticide Poisoning-A Randomised Controlled Trial

Background: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit. Methods and Findings: We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio HR] 1.69, 95% confidence interval CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 21.5%], placebo 24/114 21.1%], adjusted HR 1.27 95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit. Conclusions: Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required

Commercialization of the Internet: The Interaction of Public Policy and Private Actions,” in

seminar participants for comments. I am particularly grateful to Zvi Griliches who encouraged this research when it was at a formative stage. All remaining errors are mine alone. Abstract Why did commercialization of the Internet go so well? This paper examines events in the Internet access market as a window on this broad question. The study emphasizes four themes. First, commercializing Internet access did not give rise to many of the anticipated technical and operational challenges. Entrepreneurs quickly learned that the Internet access business was commercially feasible. Second, Internet access was malleable as a technology and as an economic unit. Third, privatization fostered attempts to adapt the technology in new uses, new locations, new market settings, new applications and in conjunction with other lines of business. These went beyond what anyone would have forecast by examining the uses for the technology prior to 1992. Fourth, and not trivially, the NSF was lucky in one specific sense. The Internet access industry commercialized at a propitious moment, at the same time as the growth of an enormous new technological opportunity, the World Wide Web. As it turned out, the Web thrived under market-oriented, decentralized and independent decision making. The paper draws lessons for policies governing the commercialization of other government managed technologies and for the Internet access market moving forward. 1 Motivation The "commercialization of the Internet" is shorthand for three nearly simultaneous events: the removal of restrictions by the National Science Foundation (NSF) over use of the Internet for commercial purposes, the browser wars initiated by the founding of Netscape, and the rapid entry of tens of thousands of firms into commercial ventures using technologies which employ the suite of TCP/IP standards. These events culminated years of work at NSF to transfer the Internet into commercial hands from its exclusive use for research activity in government funded laboratories and universities. Sufficient time has passed to begin to evaluate how the market performed after commercialization. Such an evaluation is worth doing. Actual events have surpassed the forecasts of the most optimistic managers at NSF. Was this due to mere good fortune or something systematic whose lessons illuminate the market today? Other government managed technologies usually face vexing technical and commercial challenges that prevent the technology from diffusing quickly, if at all. Can we draw lessons from this episode for the commercialization of other government managed technologies? In that spirit, this paper examines the Internet access market and one set of actors, Internet Service Provides (ISPs). ISPs provide Internet access for most of the households and business users in the country (NTIA, 1999), usually for a fee or, more recently, in exchange for advertising. Depending on the user facilities, whether it is a business or personal residence, access can involve dial-up to a local number or 1-800 number at different speeds, or direct access to the user's server employing one of several high-speed access technologies. The largest ISP in the United States today is America-On-Line, to which approximately half the households in the US subscribe. There also are many national ISPs with recognizable names, such as AT&T Worldnet, MCI WorldCom/UUNet, Mindspring/Earthlink, and PSINet, as well as thousands of smaller regional ISPs. The Internet access market is a good case to examine. Facilities for similar activity existed prior to commercialization, but there was reason to expect a problematic migration into commercial use. This activity 2 appeared to possess idiosyncratic technical features and uneconomic operational procedures which made it unsuitable in other settings. The Internet's exclusive use by academics and researchers fostered cautious predictions that unanticipated problems would abound and commercial demand might not materialize. In sharp contrast to cautious expectations, however, the ISP market displayed three extraordinary features. For one, this market grew rapidly, attracting thousands of entrants and many users, quickly achieving mass-market status. Second, firms offering this service became nearly geographically pervasive, a diffusion pattern rarely found in new infrastructure markets. And third, firms did not settle on a standard menu of services to offer, indicative of new commercial opportunities and also a lack of consensus about the optimal business model for this opportunity. Aside from defying expectations, all three traits --rapid growth, geographic pervasiveness and the absence of settlement --do not inherently go together in most markets. The presence of restructuring should have interfered with rapid growth and geographic expansion. So explaining this market experience is also interesting in its own right. What happened to make commercialization go so well? This paper's examination reveals four themes. First, commercialization did not give rise to many of the anticipated technical and operational challenges. Entrepreneurs quickly learned that the Internet access business was commercially feasible. This happened for a variety of economic reasons. ISPs began offering commercial service after making only incremental changes to familiar operating procedures borrowed from the academic setting. It was technically easy to collect revenue at what used to be the gateway functions of academic modem pools. Moreover, the academic model of Internet access migrated into commercial operation without any additional new equipment suppliers. Second, Internet access was malleable as a technology and as an economic unit. This is because the foundation for Internet inter-connectivity, TCP/IP, is not a single invention, diffusing across time and space without changing form. Instead, it is embedded in equipment which uses a suite of communication technologies, protocols and standards for networking between computers. This technology obtains economic value in combination with complementary invention, investment and equipment. While commercialization did 3 give rise to restructuring of Internet access to suit commercial users, the restructuring did not stand in the way of diffusion, nor interfere with the initial growth of demand. Third, privatizing Internet access fostered customizing Internet access technology to a wide variety of locations, circumstances and users. As it turned out, the predominant business model was feasible at small scale and, thus, at low levels of demand. This meant that the technology was commercially viable at low densities of population, whether or not it was part of a national branded service or a local geographically Fourth, and not trivially, the NSF was lucky in a particular sense of the word. It enabled the commercialization of the Internet access industry at a propitious moment, at the same time as the growth of an enormous new technological opportunity, the World Wide Web. This invention motivated further experimentation to take advantage of the new opportunity, which, as it turned out, thrived under marketoriented and decentralized decision making. The paper first develop these themes. Then it describes recent experience. It ends by discussing how these themes continue to resonate today. Challenges during technology transfer: an overview Conventional approaches to technological development led most observers in 1992 to be cautious about the commercialization of the Internet. To understand how this prediction went awry, it is important to understand its foundations. For example, military users frequently require electronic components to meet specifications that suit 6 the component to battle conditions. Extensive technical progress is needed to tailor a product design to meet these requirements. Yet, and this is difficult to anticipate prior to commercialization, an additional amount of invention is often needed to bring such a product design and to bring its manufacturing to a price/point with features that meet more cost-conscious or less technically stringent commercial requirements. Commercial challenges arise when commercial markets require substantial adaptation of operation and business processes in order to put technologies into use. In other words, government users or users in a research environment often tolerate operational processes that do not translate profitably to commercial environments. After a technology transfers out of government sponsorship, it may not be clear how to balance costs and revenues for technologies that had developed under settings with substantial subsidies underwriting losses, and research goals justifying expenditures. Hence, many government managed technologies require considerable experimentation with business models before they begin to grow, if they grow at all. For example, the supersonic transport actually met its engineering targets, but still failed to satisfy basic operational economics in most settings. Being technically sleek was insufficient to attract enough interest to generate the revenue which covered operating costs on any but a small set of routes. No amount of operational innovations and marketing campaigns were able to overcome these commercial problems. New technologies are also vulnerable to structural challenges that impede pathways to commercialization. Commercial and structural challenges are not necessarily distinct, though the latter are typically more complex. Structural challenges are those which require change to the bundle of services offered, change to the boundary of the firms offering or using the new technology, or dramatic change to the operational structure of the service organization. These challenges arise because technologies developed under government auspices may presume implementation at a particular scale or with a set of technical standards, but require a different set of organizational arrangements to support commercial applications. For example, while many organizations provided the technical advances necessary for scientific 7 computing in academic settings during the 1950s, very few of these same firms migrated into supporting large customer bases among business users. As it turned out, the required changes were too dramatic for many companies to make. The structure of the support and sales organization were very different, and so too were the product designs. Of course, the few who successfully made the transition to commercial users, such as IBM, did quite well, but doing so required overcoming considerable obstacles. In summary, conventional analysis forecasts that migrating Internet access into commercial use would engender technical, commercial and structural challenges. Why did the migration proceed so different than expected? The absence of challenge in the Internet Access industry An ISP is a commercial firm who provides access, maintains it for a fee and develop related applications as users require. While sometimes this is all they do, with business users they often do much more. Sometimes ISPs do simple things such as filtering. Sometimes it involves managing and designing email accounts, data-bases and web pages. Some ISPs label this activity consulting and charge for it separately; others do not consider it distinct from the normal operation of the Internet access services. On the surface the record of achievement for ISPs is quite remarkable. Most recent surveys show that no more than 10 percent of US households get their Internet access from university-sponsored Internet access providers, the predominant provider of such access prior to commercialization. Today almost all users go to a commercial providers By the end of the century the ISP market had obtained a remarkable structure. One firm, America On-line, provided access to close to half the households in the US market, while several score of other ISPs provided access to millions of households and businesses on a nationwide basis. Thousands of ISPs also 8 provided access for limited geographic areas, such as one city or region. Such small ISPs accounted for roughly a quarter of household use and another fraction of business use. Technical challenges did not get in the way The Internet access market did suffer from some technical challenges, but not enough to prevent rapid diffusion. Commercialization induced considerable technical innovation in complementary inventive activities. Much of this innovative activity became associated with developing new applications for existing users and new users. It is often forgotten that when the electronic commerce first developed based on TCP/IP standards, it was relatively mature in some applications, such as e-mail and file transfers, which were the most popular applications (these programs continue to be the most popular today, NTIA [1999]). To be sure, TCP/IP based programs were weak in others areas, such as commercial data base and software applications for business use, but those uses did not necessarily have to come immediately. The invention of the World Wide Web in the early 1990s further stretched the possibilities for potential applications and highlighted these weaknesses. More important for the initial diffusion, little technical invention was required for commercial vendors to put this technology into initial mainstream use. Academic modem pools and computing centers tended to use technologies similar to their civilian counterparts --such as bulletin board operators --while buying most equipment from commercial suppliers. Moving this activity into the mainstream commercial sector did not necessitate building a whole new Internet equipment industry; it was already there, supplying goods and services to the universities and to home PC users. Similarly, much of the software continued to be usefuli.e., Unix systems, the gate-keeping software, and the basic communication protocols. Indeed, every version of Unix software had been TPC/IP compatible for many years due to Department of Defense requirements. A simple commercial operation only needed to add a billing component to the gate-keeping software to turn an academic modem pool into a rudimentary commercial operation. 9 Technical information about these operations was easy to obtain if one had sufficient technical background; a BA in basic electrical engineering or computer science was far more than adequate. Many IS

Experience with a hybrid recruitment approach of patient-facing web portal screening and subsequent phone and medical record review for a neurosurgical intervention trial for chronic ischemic stroke disability (PISCES III)

Background: Recruitment of participants is the greatest risk to completion of most clinical trials, with 20–40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier 1), followed by phone screening and medical records review (tier 2) prior to a final in-person visit to confirm eligibility and consent. Methods: Two tiers of screening were established: an initial screen of general eligibility using a patient-facing web portal (tier 1), followed by a more detailed screen that included phone survey and medical record review (tier 2). If potential participants passed the tier 2 screen, they were referred directly to visit 1 at a study site, where final in-person screening and consent were performed. Rates of screening were tracked during the period of trial recruitment and sources of referrals were noted. Results: The approach to screening and recruitment resulted in 6125 tier 1 screens, leading to 1121 referrals to tier 2. The tier 2 screening resulted in 224 medical record requests and identification of 86 qualifying participants for referral to sites. The study attained a viable recruitment rate of 6 enrolled per month prior to being disrupted by COVID 19. Conclusions: A tiered approach to eligibility screening using a hybrid of web-based portals to self-identify and screen for general eligibility followed by a more detailed phone and medical record review allowed the study to use fewer sites and reduce cost. Despite the difficult and narrow population of patients suffering moderate chronic disability from stroke, this strategy produced a viable recruitment rate for this invasive study of intracranially injected neural stem cells

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Methodological considerations in PISCES 3: a randomized, placebo-controlled study of intracerebral stem cells in subjects with disability following an ischemic stroke

Background and hypothesis: At present, there are no medical interventions proven to improve functional recovery in patients with subacute stroke. We hypothesize that the intraparenchymal administration of CTX0E03, a conditionally immortalized neural stem cell line, linked with a standardized rehabilitation therapy regimen for the upper limb, would improve functional outcomes in patients 6–12 months after an index ischemic stroke. Study design: PISCES III was designed as a multicenter prospective, sham-controlled, outcome-blinded randomized clinical trial. Eligibility required a qualifying ischemic stroke 6–12 months prior to surgical intervention. Patients must be between 35 and 75 years of age and have residual moderate or moderately severe disability (mRS 3 or 4), with the preservation of some residual upper limb movement. All patients received a standardized regimen of home physical therapy following the intervention. Study outcomes: The primary outcome measure is improvement in the modified Rankin Scale (mRS) of disability at 6 months post treatment. Secondary outcomes include assessment of activities of daily living (Barthel Index), functional mobility (Timed Up and Go; Fugl Meyer Assessment), neurological impairment (NIHSS), upper limb function (Chedoke Arm and Hand Inventory), as well as patient related quality of life and global rating scales. Discussion: PISCES III was designed as a randomized trial directly comparing the effects of intraparenchymal injection of a conditional stem cell line vs. sham procedure in patients with subacute stroke. This is one of the first studies of this type to include a standardized minimum rehabilitation protocol. As there are a limited number of studies evaluating invasive stem cell administration in the chronic setting of CNS injury, study design considerations are discussed

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.KLG is supported by the Victorian Cancer Agency (MCRF15013) and the Australian National Health and Medical Research Council (APP1045783 and #628434). This study was supported by the Peter MacCallum Cancer Foundation. CS is supported by a University of Melbourne Postgraduate Scholarship. DDB is supported by National Health and Medical Research Council of Australia (NHMRC) grants APP1092856 and APP1117044 and by the US National Cancer Institute U54 programme (U54CA209978-04). ELG and SHK are supported through P50 CA136393-10. The following cohorts that contributed to the GAMuT study were supported as follows: CASCADE: Supported by the Peter MacCallum Cancer Foundation AOCS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID400413 and ID400281). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in these research programs. OVCARE receives core funding from The BC Cancer Foundation and the VGH and UBC Hospital Foundation. The Gynaecological Oncology Biobank at Westmead is a member of the Australasian Biospecimen Network-Oncology group, which was funded by the National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. COEUR: This study uses resources provided by the Canadian Ovarian Cancer Research Consortium’s - COEUR biobank funded by the Terry Fox Research Institute and managed and supervised by the Centre hospitalier de l’Université de Montréal (CRCHUM). The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see http://www.tfri.ca/en/research/translational-research/coeur/coeur_biobanks.aspx). The following cohorts that contributed to OTTA were supported as follows: AOV: Canadian Institutes of Health Research (MOP-86727), Cancer Research Society (19319). BAV: ELAN Funds of the University of Erlangen-Nuremberg; DOV: NCI/NIH R01CA168758. Huntsman Cancer Foundation and the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014. HAW: U.S. National 19 Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; SEA: SEARCH team: Mitul Shah, Jennifer Alsopp, Mercedes Jiminez-Linan SEARCH funding: Cancer Research UK (C490/A16561), the Cancer Research UK Cambridge Cancer Centre and the National Institute for Health Research Cambridge Biomedical Research Centres. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. JBD: Cancer Research UK Institute Group Award UK A22905 and A15601; STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and årKampMotCancer foundation; TVA: Canadian Institutes of Health Research grant (MOP-86727) and NIH/NCI 1 R01CA160669- 01A1; VAN: M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. The Vancouver study cohort (TVAN) is supported by BC’s Ovarian Cancer Research team (OVCARE), the BC Cancer Foundation and The VGH+UBC Hospital Foundation. WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16