Digital Clock Drawing as an Alzheimer's Disease Susceptibility Biomarker: Associations with Genetic Risk Score and APOE in Older Adults.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until significant neuronal loss has likely occurred along with a decline in cognition. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. OBJECTIVE: We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker. DESIGN: We used two primary independent variables, Apolipoprotein E (APOE) ε4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures. SETTING: We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. PARTICIPANTS: The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White). MEASUREMENTS: PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). RESULTS: Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed (both command and copy conditions) and Drawing Efficiency (command condition) were significantly associated with higher PRS levels and more copies of APOE ε4. APOE and PRS associations displayed similar effect sizes in both men and women. CONCLUSIONS: Our results indicate that higher AD genetic risk is associated with poorer DCTclockTM performance in older adults without dementia. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

Self-care barriers and facilitators in older adults with T1D during a time of sudden isolation.

Older adults with type 1 diabetes (T1D) have unique challenges and needs. In this mixed-methods study, we explored the impact of isolation during a pandemic on diabetes management and overall quality of life in this population. Older adults (age ≥ 65 years) with T1D receiving care at a tertiary care diabetes center participated in semi-structured interviews during COVID-19 pandemic isolation between June and August 2020. A multi-disciplinary team coded transcripts and conducted thematic analysis. Thirty-four older adults (age 71 ± 5 years, 97% non-Hispanic white, diabetes duration of 38 ± 7 years, A1C of 7.4 ± 0.9% (57.3 ± 10.1 mmol/mol) were recruited. Three themes related to diabetes self-care emerged regarding impact of isolation on: (1) diabetes management and self-care behaviors (how isolation prompted changes in physical activity and dietary habits); (2) emotional stress and anxiety (related to isolation and lack of support system, economic concerns); and (3) concerns regarding the COVID-19 pandemic (impact on timely medical care and access to information). Our findings identify modifiable barriers and challenges faced by older adults with T1D during isolation. As this population has a higher risk of decline in physical and psychosocial support even during non-pandemic times, clinicians will benefit from understanding these issues to improve care of this population.

Revising human-systems engineering principles for embedded AI applications.

The recent shift from predominantly hardware-based systems in complex settings to systems that heavily leverage non-deterministic artificial intelligence (AI) reasoning means that typical systems engineering processes must also adapt, especially when humans are direct or indirect users. Systems with embedded AI rely on probabilistic reasoning, which can fail in unexpected ways, and any overestimation of AI capabilities can result in systems with latent functionality gaps. This is especially true when humans oversee such systems, and such oversight has the potential to be deadly, but there is little-to-no consensus on how such system should be tested to ensure they can gracefully fail. To this end, this work outlines a roadmap for emerging research areas for complex human-centric systems with embedded AI. Fourteen new functional and tasks requirement considerations are proposed that highlight the interconnectedness between uncertainty and AI, as well as the role humans might need to play in the supervision and secure operation of such systems. In addition, 11 new and modified non-functional requirements, i.e., "ilities," are provided and two new "ilities," auditability and passive vulnerability, are also introduced. Ten problem areas with AI test, evaluation, verification and validation are noted, along with the need to determine reasonable risk estimates and acceptable thresholds for system performance. Lastly, multidisciplinary teams are needed for the design of effective and safe systems with embedded AI, and a new AI maintenance workforce should be developed for quality assurance of both underlying data and models.

Understanding unidentified human remains investigations through the United States census data.

Each year, thousands of unidentified human remains (UHR) cases are reported in the U.S. Technological advances have greatly enhanced the forensic community's capacity and capability to solve UHR cases, but little is known about the extent to which these resources are used by medical examiners and coroners (MECs). Using public datasets, the study purpose is to describe the current state MEC system with respect to UHR cases, the resources used to investigate these cases, and the evidence retention polices in place. There was an overall decline in UHR cases reported between 2004 and 2018. Less than half of MECs in both study years reported having established written final disposition and evidence retention policies for UHR cases. National missing persons databases were underused. This study provides an important window into the present state of UHRs being handled by our Nation's MEC offices and the resources available to solve these difficult cases.

In situ measurements of reef squid polarization patterns using two-dimensional polarization data mapped onto three-dimensional tessellated surfaces.

Reef squids belong to a group reputed for polarization sensitivity, yet polarization patterns of reef squid have not been quantified in situ. To quantify polarization patterns from video polarimetric data, we developed a protocol to map two-dimensional polarization data onto squid-shaped three-dimensional tessellated surfaces. This protocol provided a robust data container used to investigate three-dimensional regions-of-interest, producing data lineouts derived from the squid's geometry. This protocol also extracted polarimeter and squid body orientations and the solar heading from polarization images. When averaged over the solar heading, the ventral midline gave a low degree of polarization (2.4 ± 5.3%), and the area between the ventral and flank midlines had higher values (9.0 ± 5.3%). These averaged data had a large discontinuity in the angle of polarization (AoP) at the mantle's ventral midline (64 ± 55°), with larger discontinuities measured on individual squid. Ray-tracing calculations demonstrated that the AoP pattern was not related to the squid's surface-normal geometry. However, the AoP followed virtual striation axes on the squid's surface oriented 24° to the squid's long axis, similar in angle (27°) to the striations of birefringent collagen fibres documented in other squid species' skin.

Targeting the tumour microenvironment in platinum-resistant ovarian cancer.

Ovarian cancer typically presents at an advanced stage, and although the majority of cases initially respond well to platinum-based therapies, chemoresistance almost always occurs leading to a poor long-term prognosis. While various cellular autonomous mechanisms contribute to intrinsic or acquired platinum resistance, the tumour microenvironment (TME) plays a central role in resistance to therapy and disease progression by providing cancer stem cell niches, promoting tumour cell metabolic reprogramming, reducing chemotherapy drug perfusion and promoting an immunosuppressive environment. As such, the TME is an attractive therapeutic target which has been the focus of intense research in recent years. This review provides an overview of the unique ovarian cancer TME and its role in disease progression and therapy resistance, highlighting some of the latest preclinical and clinical data on TME-targeted therapies. In particular, it focuses on strategies targeting cancer-associated fibroblasts, tumour-associated macrophages, cancer stem cells and cancer cell metabolic vulnerabilities.

Gut microbiome alteration in MORDOR I: a community-randomized trial of mass azithromycin distribution.

The MORDOR I trial1, conducted in Niger, Malawi and Tanzania, demonstrated that mass azithromycin distribution to preschool children reduced childhood mortality1. However, the large but simple trial design precluded determination of the mechanisms involved. Here we examined the gut microbiome of preschool children from 30 Nigerien communities randomized to either biannual azithromycin or placebo. Gut microbiome γ-diversity was not significantly altered (P = 0.08), but the relative abundances of two Campylobacter species, along with another 33 gut bacteria, were significantly reduced in children treated with azithromycin at the 24-month follow-up. Metagenomic analysis revealed functional differences in gut bacteria between treatment groups. Resistome analysis showed an increase in macrolide resistance gene expression in gut microbiota in communities treated with azithromycin (P = 0.004). These results suggest that prolonged mass azithromycin distribution to reduce childhood mortality reduces certain gut bacteria, including known pathogens, while selecting for antibiotic resistance.

Unbiased Pathogen Detection and Host Gene Profiling for Conjunctivitis.

PURPOSE: The etiology of conjunctivitis is often misdiagnosed. An ideal diagnostic test would identify all possible infectious causes. In this study, we apply unbiased metagenomic RNA deep sequencing (MDS) to identify pathogens causing conjunctivitis. DESIGN: Molecular study of prospectively collected conjunctival swabs from patients with presumed infectious conjunctivitis. PARTICIPANTS: Patients with presumed acute infectious conjunctivitis. METHODS: Conjunctival swabs were collected from patients presenting with acute conjunctivitis. Swabs were processed for MDS. Pathogens were identified using a rapid computational pipeline to analyze the nonhost sequences obtained from MDS. Differential gene expression analysis was performed to evaluate for host transcriptome signatures for infectious types. Clinical samples were deidentified, and laboratory personnel handling the samples and interpreting the data were masked. MAIN OUTCOME MEASURES: Pathogens and differential transcripts identified by MDS. RESULTS: Metagenomic RNA deep sequencing detected pathogens in 86% (12/14) of the patients tested. Swabs from 10 of 14 patients were positive for human adenovirus (HAdV) while swabs from 2 of 14 patients were positive for Vittaforma corneae (a parasitic fungal species of the microsporidia group). Samples positive for HAdV by RNA-seq were independently verified in a CLIA-certified laboratory. Pathogen-directed polymerase chain reaction confirmed the presence of V. corneae genome in the samples positive by RNA-seq. Local host transcriptome analysis identified 12 differentially expressed genes that provided distinct expression signatures for patients infected with HAdV compared with V. corneae. CONCLUSIONS: Metagenomic RNA deep sequencing can reliably detect and quantify common and rare pathogens causing conjunctivitis, and identify strains. The unbiased nature of metagenomic RNA deep sequencing allowed an expanded scope of pathogen detection, including fungal species not commonly associated with acute conjunctivitis. In addition, the identification of infection type-specific local host transcriptome signatures may allow for pathogen detection even when the pathogen load is too low for direct identification.

Achieving quality primary care data: a description of the Canadian Primary Care Sentinel Surveillance Network data capture, extraction, and processing in Alberta.

INTRODUCTION: Electronic medical record (EMR) databases have become increasingly popular for secondary purposes, such as health research. The Canadian Primary Care Sentinel Surveillance Network (CPCSSN) is the first and only pan-Canadian primary care EMR data repository, with de-identified health information for almost two million Canadians. Comprehensive and freely available documentation describing the data 'lifecycle' is important for assessing potential data quality issues and appropriate interpretation of research findings. Here, we describe the flow and transformation of CPCSSN data in the province of Alberta. APPROACH: In Alberta, the data originate from 54 publicly-funded primary care settings, including one community pediatric clinic, with 318 providers contributing de-identified EMR data for 410,951 patients (as of December 2018). Data extraction methods have been developed for five different EMR systems, and include both backend and automated frontend extractions. The raw EMR data are transformed according to specific rules, including trimming implausible values, converting values and free text to standard terminologies or classification systems, and structuring the data into a common CPCSSN format. Following local data extraction and processing, the data are transferred to a central repository and made available for research and disease surveillance. CONCLUSION: This paper aims to provide important contextual information to future CPCSSN data users.

Characteristics of insulin-Naïve people with type 2 diabetes who successfully respond to insulin glargine U100 after 24 weeks of treatment: a meta-analysis of individual participant data from 3 randomized clinical trials.

BACKGROUND: To identify baseline/clinical characteristics associated with clinically meaningful responses to insulin glargine 100 U/mL (IGlar) in insulin-naive people with type 2 diabetes mellitus (T2DM). METHODS: Individual participant data were pooled from 3 randomized trials to compare baseline characteristics and clinical outcomes associated with 24-week response to IGlar in combination with non-insulin antihyperglycemic agents in participants with T2DM. Responders were defined as achieving endpoint HbA1c target < 53 mmol/mol (< 7%) and/or ≥ 11 mmol/mol (≥ 1%) HbA1c reduction from baseline. RESULTS: Differences in baseline characteristics for responders versus nonresponders were higher HbA1c (99 vs 91 mmol/mol [9.1 vs 8.3%]; P < 0.001), higher fasting blood glucose (FBG; 10.4 vs 8.8 mmol/L [187 vs 159 mg/dL; P < 0.001), and fewer participants (94% vs 98%; P = 0.006) taking oral medications targeting postprandial blood glucose (BG). Most participants (80%) achieved one or both components of composite endpoint. 12-week response was a strong predictor of subsequent 24-week response (sensitivity, 85.9%; predictive positive value, 91.4%). At both 12 and 24 weeks, < 40% of responders and nonresponders reached target FBG ≤ 5.6 mmol/L (≤ 100 mg/dL). Responders at 24 weeks had higher incidence of hypoglycemia (total, 82.5% vs 70.4%; P < 0.001; nocturnal, 60.3% vs 50.5%; P = 0.002; documented symptomatic, 65.8% vs 55.6%; P < 0.001) than nonresponders. CONCLUSIONS: Baseline characteristics associated with response were identified. The strong predictability of 12-week response suggests that the magnitude of early HbA1c reduction should be considered when assessing response to IGlar. More aggressive IGlar titration may be reasonable for nonresponders and responders who have not reached FBG and HbA1c targets, taking into account other BG timepoints.

A retrospective observational study of people with Type 1 diabetes with self-reported severe hypoglycaemia reveals high level of ambulance attendance but low levels of therapy change and specialist intervention.

AIM: To evaluate the impact of severe hypoglycaemia on NHS resources and overall glycaemic control in adults with Type 1 diabetes. METHODS: An observational, retrospective study of adults (aged ≥ 18 years) with Type 1 diabetes reporting one or more episodes of severe hypoglycaemia during the preceding 24 months in 10 NHS hospital diabetes centres in England and Wales. The primary outcome was healthcare resource utilization associated with severe hypoglycaemia. Secondary outcomes included demographic and clinical characteristics, diabetes control and pathway of care. RESULTS: Some 140 episodes of severe hypoglycaemia were reported by 85 people during the 2-year observation period. Ambulances were called in 99 of 140 (71%) episodes and Accident and Emergency attendance occurred in 26 of 140 (19%) episodes, whereas 29 of 140 (21%) episode required no immediate help from healthcare providers. Participants attended a median of 5 (range 0-58) diabetes clinic consultations during the observation period; 13% (70 of 552) of all consultations were severe hypoglycaemia-related. Of the HbA1c measurements recorded closest prior to severe hypoglycaemia (n = 119), only 7 of 119 measurements were < 48 mmol/mol (< 6.5%) and mean HbA1c was 70 (sd 19) mmol/mol (8.5%, sd 1.7%). Some 119 changes to diabetes treatment were recorded during the observation period (median/person 0;, range 0-11), of which 52 of 119 changes (44%) followed severe hypoglycaemic events. CONCLUSIONS: We observed a high level of ambulance service intervention but surprisingly low levels of hypoglycaemia follow-up, therapy change and specialist intervention in people self-reporting severe hypoglycaemia. These results suggest there may be important gaps in care pathways for people with Type 1 diabetes self-reporting severe hypoglycaemia.

Technical proficiency in cytopathology: assessment through external quality assurance.

OBJECTIVE: To assess both the feasibility and value of conducting an external quality assurance programme concerning technical aspects of cytopathology laboratory practice, and the interest by laboratories in enrolling in such a programme. METHODS: Six technical surveys, comprising staining exercises and questionnaires relating to laboratory practice, were distributed over a 4-year period to the approximately 220 laboratories enrolled in the RCPAQAP Cytopathology slide survey modules. Staining exercises using the Papanicolaou and Romanowsky techniques, the preparation of urine and body fluid specimens and immunocytochemistry on the cell block material were assessed. Accompanying relevant questionnaires were included, and one survey comprised a questionnaire alone concerning the collection of urinary tract and body fluid samples. RESULTS: Provision of an external cytopathology technical module was feasible for the RCPAQAP and participation rates (maximum of 87% per survey; average 68% for stained slides and 66% for questionnaires) were commendable, particularly considering these were optional undertakings with some exercises not applicable to all laboratories. The great majority of submitted slides were scored as satisfactory, and there was an especially high standard for the immunocytochemical staining exercise with 95% considered satisfactory, including 50.6% with a perfect score. Reasons for suboptimal scores were provided for potential quality improvement for interested laboratories. A wealth of information relating to laboratory practice was provided to the RCPAQAP which was collated and summarised for laboratory use. CONCLUSIONS: The provision of a technical module in cytopathology is both a feasible and valuable undertaking of interest to laboratories which should become standard practice for cytopathology external quality assurance providers.

Distribution of Central Line-Associated Bloodstream Infections Determined From Washington State's Annual Reporting Validation Program, 2009-2013.

Healthcare-associated infection reporting validation is essential because this information is increasingly used in public healthcare quality assurances and care reimbursement. Washington State's validation of central line-associated bloodstream infection reporting applies credible quality sciences methods to ensure that hospital reporting accuracy is maintained. This paper details findings and costs from our experience. Infect Control Hosp Epidemiol 2017;38:489-492.

The sixth vital sign: HIV status assessment and severe illness triage in Uganda.

Setting: Four in-patient health facilities in western Uganda. Objective: To determine the impact of an innovative multi-modal quality improvement program on human immunodeficiency virus (HIV) status assessment and the impact of HIV status on severe illness conditions and mortality. Design: This was a staggered, pre-post quasi-experimental study designed to assess a multi-modal intervention (collaborative improvement meetings, audit and feedback, clinical mentoring) for improving quality of care following formal training in the management of severe illness in low-income settings. Results: From August 2014 to May 2015, 5759 patients were hospitalized, of whom 2451 (42.6%) had their HIV status assessed; 395 (16.1%) were HIV-infected. HIV-infected patients were significantly more likely to meet criteria for shock (27.5% vs. 15.1%, risk ratio [RR] 1.8, 95% confidence interval [CI] 1.7-1.9, P < 0.001) and severe respiratory distress (6.7% vs. 4.3%, RR 1.5, 95%CI 1.2-2.0, P < 0.001), and were significantly more likely to die in hospital (12.0% vs. 2.9%, RR 4.1, 95%CI 3.2-5.4, P < 0.001). There was no evidence of improved HIV status assessment during the intervention period (36.5% vs. 44.8%, +8.3%, 95%CI -8.3 to 24.8, P = 0.33). Conclusions: Hospitalized HIV-infected patients in western Uganda are at high risk for severe illness and death. Novel quality improvement strategies are needed to enhance hospital-based HIV testing in high-burden settings.

Contexte : Quatre structures de santé hospitalières dans l'ouest de l'Ouganda.Objectif : Déterminer l'impact d'un programme innovant multimodal d'amélioration de la qualité sur l'évaluation du statut du virus de l'immunodéficience humaine (VIH) et l'impact du statut VIH sur les états de maladie grave et la mortalité.Schéma : Une étude échelonnée, pré-post et quasi-expérimentale conçue pour évaluer une intervention multimodale (réunions d'amélioration concertée, audit et rétro-information, tutorat clinique) pour améliorer la qualité des soins après la formation initiale sur la prise en charge de maladies graves dans un contexte de faibles ressources.Résultats : Entre août 2014 et mai 2015, 5759 patients ont été hospitalisés : 2451 (42,6%) ont eu une évaluation de leur statut VIH et 395 (16,1%) se sont avérés infectés par le VIH. Ces derniers ont été significativement plus susceptibles de répondre à des critères de choc (27,5% contre 15,1% ; rapport de risque [RR] 1,8 ; intervalle de confiance [IC] 95% 1,7­1,9 ; P < 0,001) et de détresse respiratoire grave (6,7% contre 4,3 ; RR 1,5 ; IC95% 1,2­2,0 ; P < 0,001), et ont été significativement plus susceptibles de décéder à l'hôpital (12,0% contre 2,9% ; RR 4,1 ; IC95% 3,2­5,4 ; P < 0,001). Il n'y a pas eu d'éléments en faveur d'une amélioration de l'évaluation du statut VIH pendant la période d'intervention (36,5% contre 44,8% ; +8,3% ; IC95% −8,3 à 24,8 ; P = 0,33).Conclusions : Les patients infectés par le VIH hospitalisés dans l'ouest de l'Ouganda ont un risque élevé de maladie grave et de décès. De nouvelles stratégies d'amélioration de qualité sont requises afin d'augmenter les tests VIH en hôpital dans les contextes à fardeau élevé de maladie.

Marco de referencia: Cuatro establecimientos hospitalarios en la zona occidental de Uganda.Objetivo: Determinar la repercusión de un programa innovador multimodal de mejora de la calidad sobre la evaluación de la situación frente al virus de la inmunodeficiencia humana (VIH) y la repercusión del estado frente al VIH en materia de enfermedades graves y mortalidad.Método: Se realizó un estudio semi-experimental escalonado pre y post con el fin de evaluar una intervención multimodal (reuniones de colaboración para mejorar de la calidad, auditorías y retroalimentación, tutoría clínica) encaminada a mejorar la calidad de la atención, tras una capacitación formal sobre el manejo de las enfermedades graves en entornos con bajos ingresos.Resultados: De agosto del 2014 a mayo del 2015 se hospitalizaron 5759 pacientes; en 2451 se examinó su situación frente al VIH (42,6%) y 395 presentaban infección por el VIH (16,1%). Los pacientes afectados por el VIH exhibieron una probabilidad significativamente mayor de cumplir con los criterios diagnósticos de choque (27,5% contra 15,1%; cociente de riesgos [RR] 1,8; intervalo de confianza [IC] del 95% 1,7­1,9; P < 0,001) y de insuficiencia respiratoria grave (6,7% contra 4,3%, RR 1,5; IC95% 1,2­2,0; P < 0,001) y la probabilidad de morir en el hospital fue significativamente más alta en estos pacientes (12,0% contra 2,9%, RR 4,1; IC95% 3,2­5,4; P < 0,001). No se encontraron pruebas en favor de una mejor evaluación de la situación frente al VIH durante el período de la intervención (36,5% contra 44,8%; +8,3%; IC95% −8,3 hasta 24,8; P = 0,33).Conclusión: Los pacientes hospitalizados aquejados de infección por el VIH en Uganda occidental son muy susceptibles de sufrir una enfermedad grave o la muerte. Se precisan nuevas estrategias de mejora de la calidad que refuercen la práctica de las pruebas diagnósticas de infección por el VIH en los entornos con alta carga de morbilidad.

Inverting the pyramid: increasing awareness of mycobacterial sepsis in sub-Saharan Africa.

Disseminated Mycobacterium tuberculosis is a leading cause of bloodstream infection and severe sepsis in sub-Saharan African settings with a high burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. Despite the high prevalence of M. tuberculosis bacteremia in these settings it is under-recognized. This is in part because timely diagnosis of M. tuberculosis bacteremia is difficult using traditional TB diagnostics. Novel triage algorithms and rapid diagnostic tests are needed to expedite the identification and treatment of patients with severe sepsis due to M. tuberculosis bacteremia. In this article, we emphasize the importance of M. tuberculosis bacteremia as an under-recognized etiology of severe sepsis, and discuss the potential role of two emerging rapid diagnostic tests in the triage and prognostication of critically ill patients with advanced HIV infection and suspected disseminated M. tuberculosis. We conclude with the recommendation that clinicians in high TB-HIV burden settings strongly consider empiric anti-tuberculosis treatment in patients with advanced HIV infection and severe sepsis in the appropriate clinical context. Future studies are needed to assess diagnostic and prognostic algorithms for severe sepsis caused by disseminated M. tuberculosis in these settings, and the safety, efficacy, and duration of empiric anti-tuberculosis treatment.

Preoperative neutrophil:lymphocyte and platelet:lymphocyte ratios predict endometrial cancer survival.

BACKGROUND: Variations in systemic inflammatory response biomarker levels have been associated with adverse clinical outcome in various malignancies. This study determined the prognostic significance of preoperative neutrophil:lymphocyte (NLR), platelet:lymphocyte (PLR) and monocyte:lymphocyte (MLR) ratios in endometrial cancer. METHODS: Clinicopathological and 5-year follow-up data were obtained for a retrospective series of surgically treated endometrial cancer patients (n=605). Prognostic significance was determined for overall (OS) and cancer-specific survival (CSS) using Cox proportional hazards models and Kaplan-Meier analysis. Receiver-operator characteristic and log-rank functions were used to optimise cut-offs. NLR, PLR and MLR associations with clinicopathological variables were determined using non-parametric tests. RESULTS: Applying cut-offs of ⩾2.4 (NLR), ⩾240 (PLR) and ⩾0.19 (MLR), NLR and PLR (but not MLR) had independent prognostic significance. Combining NLR and PLR scores stratified patients into low (NLR-low and PLR-low), intermediate (NLR-high or PLR-high) and high risk (NLR-high and PLR-high) groups: multivariable hazard ratio (HR) 2.51; P<0.001 (OS); HR 2.26; P<0.01 (CSS) for high vs low risk patients. Increased NLR and PLR were most strongly associated with advanced stage (P<0.001), whereas increased MLR was strongly associated with older age (P<0.001). CONCLUSION: Both NLR and PLR are independent prognostic indicators for endometrial cancer, which can be combined to provide additional patient stratification.

Epithelial and stromal-specific immune pathway activation in the murine endometrium post-coitum.

The endometrium is a dynamic tissue, demonstrating cyclical growth/remodelling in preparation for implantation. In mice, seminal constituents trigger mechanisms to prepare the endometrium, a process dubbed 'seminal priming' that modifies immune system components and mediates endometrial remodelling in preparation for pregnancy. An array of cytokines has been reported to mediate this interaction, although much of the literature relates to in vitro studies on isolated endometrial epithelial cells. This study measured changes in immune-related gene expression in endometrial epithelial and stromal cells in vivo following natural mating. CD1 mice were naturally mated and sacrificed over the first 4 days post-coitum (n=3 each day). Endometrial epithelial and stromal compartments were isolated by laser capture microdissection. Labelled cRNA was generated and hybridised to genome-wide expression microarrays. Pathway analysis identified several immune-related pathways active within epithelial and stromal compartments, in particular relating to cytokine networks, matrix metalloproteinases and prostaglandin synthesis. Cluster analysis demonstrated that the expression of factors involved in immunomodulation/endometrial remodelling differed between the epithelial and stromal compartments in a temporal fashion. This study is the first to examine the disparate responses of the endometrial epithelial and stromal compartments to seminal plasma in vivo in mice, and demonstrates the complexity of the interactions between these two compartments needed to create a permissive environment for implantation.