Summary Background Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the ...fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. Methods We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. Findings 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 5% within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84–0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. Interpretation The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. Funding Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.
Maternal deaths from preeclampsia primarily result in cases with eclampsia, uncontrolled hypertension, or progressing HELLP syndrome. Delivery is the only cure for preeclampsia. Management strategies ...involve determination of risk factors to predict which pregnancies are at high risk for adverse maternal outcomes. Previous attempts to develop risk assessment models that could identify potential predictive risk factors for adverse outcomes occurring at any time after admission with preeclampsia have been unsuccessful.The aim of this prospective multicenter study was to develop and internally validate a preeclampsia outcome prediction model—the fullPIERS (Preeclampsia Integrated Estimate of RiSk) model that could identify serious or fatal complications in women with preeclampsia or who developed the disorder within 48 hours of hospital admission.Between 2003 and 2010, data for 2023 women from 8 international sites were entered into the fullPIERS database. The primary study outcome was maternal mortality or other serious complications of preeclampsia. A stepwise backward elimination logistic regression model incorporating routinely reported and informative variables was used to predict adverse maternal outcome. Standard methods were used to calculate the area under the curve (AUC) of the receiver operating characteristic (ROC).Of the 2023 women with preeclampsia, 261 (13%) had adverse outcomes at any time after hospital admission and 106 (5%) had adverse outcomes within 48 hours of admission. Predictors in the fullPIERS model associated with adverse maternal outcome included gestational age at eligibility, chest pain or dyspnea, oxygen saturation, creatinine, platelet counts, and aspartate transaminase. Analysis of the fullPIERS model showed that the model predicted adverse maternal outcomes within the first 48 hours of eligibility; the AUC ROC was 0.88, with a 95% confidence interval, 0.84–0.92. Additionally, fullPIERS was also predictive of adverse maternal outcomes up to 7 days after eligibility (AUC ROC >0.7).Identification of women at high risk of preeclampsia complications at 48 hours to 7 days after admission may help guide clinical care and management of these women. Over time this may lead to development of new treatments and interventions that may reduce the risk of life-altering or life-ending complications such as stroke or end-organ damage.
Affecting 2–4% of pregnancies, pre-eclampsia is a leading cause of maternal death and morbidity worldwide. Using routinely available data, we aimed to develop and validate a novel machine ...learning-based and clinical setting-responsive time-of-disease model to rule out and rule in adverse maternal outcomes in women presenting with pre-eclampsia.
We used health system, demographic, and clinical data from the day of first assessment with pre-eclampsia to predict a Delphi-derived composite outcome of maternal mortality or severe morbidity within 2 days. Machine learning methods, multiple imputation, and ten-fold cross-validation were used to fit models on a development dataset (75% of combined published data of 8843 patients from 11 low-income, middle-income, and high-income countries). Validation was undertaken on the unseen 25%, and an additional external validation was performed in 2901 inpatient women admitted with pre-eclampsia to two hospitals in south-east England. Predictive risk accuracy was determined by area-under-the-receiver-operator characteristic (AUROC), and risk categories were data-driven and defined by negative (–LR) and positive (+LR) likelihood ratios.
Of 8843 participants, 590 (6·7%) developed the composite adverse maternal outcome within 2 days, 813 (9·2%) within 7 days, and 1083 (12·2%) at any time. An 18-variable random forest-based prediction model, PIERS-ML, was accurate (AUROC 0·80 95% CI 0·76–0·84 vs the currently used logistic regression model, fullPIERS: AUROC 0·68 0·63–0·74) and categorised women into very low risk (–LR <0·1; eight 0·7% of 1103 women), low risk (–LR 0·1 to 0·2; 321 29·1% women), moderate risk (–LR >0·2 and +LR <5·0; 676 61·3% women), high risk (+LR 5·0 to 10·0, 87 7·9% women), and very high risk (+LR >10·0; 11 1·0% women). Adverse maternal event rates were 0% for very low risk, 2% for low risk, 5% for moderate risk, 26% for high risk, and 91% for very high risk within 48 h. The 2901 women in the external validation dataset were accurately classified as being at very low risk (0% with outcomes), low risk (1%), moderate risk (4%), high risk (33%), or very high risk (67%).
The PIERS-ML model improves identification of women with pre-eclampsia who are at lowest and greatest risk of severe adverse maternal outcomes within 2 days of assessment, and can support provision of accurate guidance to women, their families, and their maternity care providers.
University of Strathclyde Diversity in Data Linkage Centre for Doctoral Training, the Fetal Medicine Foundation, The Canadian Institutes of Health Research, and the Bill & Melinda Gates Foundation.
Abstract Objectives To evaluate whether (1) the absolute magnitude of liver function test values, (2) the percentage change in liver function test values over time, or (3) the rate of change in liver ...function test values over time predicts adverse maternal outcomes in women with preeclampsia. Methods We used data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) study, a prospective multicentre cohort study assessing predictors of adverse maternal outcomes in women with preeclampsia. Women with at least one liver function test performed at the time of hospital admission were included. Liver functions were tested by serum concentrations of aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), albumin, total bilirubin, and the international normalized prothrombin time ratio. Parameters investigated were absolute levels, change within 48 hours of hospital admission, change from admission to delivery or outcome, and rate of change from admission to delivery or outcome of each liver function test. The ability of these parameters to predict adverse outcomes was assessed using logistic regression analyses and by calculating the receiver operating characteristic (ROC) area under the curve (AUC). Results Of the 2008 women, 1056 (53%) had at least one abnormal liver function test result. The odds of having an adverse maternal outcome were higher in women with any abnormal liver function test than in women with normal results. When test results were stratified into quartiles, women with results in the highest quartile (lowest quartile for albumin) were at higher risk of adverse outcomes than women in the lowest quartile for all parameters (highest for albumin). The absolute magnitude of AST, ALT, and LDH predicted adverse maternal outcomes (AST: ROC AUC 0.73 95% CI 0.67 to 0.97; ALT: ROC AUC 0.73 95% CI 0.67 to 0.79; LDH: ROC AUC 0.74 95% CI 0.68 to 0.81). Neither change of liver function test results, within 48 hours of admission or from admission to delivery or outcome, nor rate of change were predictive. Conclusion We found abnormal liver function test results to be associated with an increased risk for adverse maternal outcomes. Levels of AST, ALT, and LDH were found to be modestly predictive of these outcomes.
Abstract Objective We sought to determine the role of respiratory assessment by cardiorespiratory symptoms and/or oxygen saturation by pulse oximetry (SpO2 ) in predicting adverse maternal outcomes ...in women admitted to hospital with preeclampsia. Methods These data derive from an international, prospective multicentre cohort study, PIERS (Pre-eclampsia Integrated Estimate of RiSk), which assesses predictors of adverse outcomes in women admitted to tertiary perinatal units with preeclampsia. Univariate and multivariate analyses of cardiorespiratory symptoms and pulse oximetry were performed to assess their ability to predict a combined adverse maternal outcome developed through international Delphi consensus. Results SpO2 successfully predicted adverse maternal outcomes; the area under the receiver-operator characteristic curve (AUC ROC) was 0.71 (95% CI 0.65 to 0.77). Combining the symptoms of chest pain and/or dyspnea with pulse oximetry improved this predictive ability (AUC ROC 0.73; 95% CI 0.67 to 0.78). When SpO2 was stratified into risk groups using inflection points on the ROC curve, the highest risk group (SpO2 90% to 93%) had an odds ratio of 18.1 (95% CI 8.2 to 40.2) for all outcomes within 48 hours when compared with the baseline group (SpO2 98% to 100%). Conclusion Assessing SpO2 aids in the assessment of maternal risk in women admitted to hospital with preeclampsia. An SpO2 value of ≤ 93% confers particular risk. The symptom complex of chest pain and/or dyspnea adds to the association.
Abstract Objectives To optimize the management of adnexal masses and to assist primary care physicians and gynaecologists determine which patients presenting with an ovarian mass with a significant ...risk of malignancy should be considered for gynaecologic oncology referral and management. Options Laparoscopic evaluation, comprehensive surgical staging for early ovarian cancer, or tumour debulking for advanced stage ovarian cancer. Outcomes To optimize conservative versus operative management of women with possible ovarian malignancy and to optimize the involvement of gynaecologic oncologists in planning and delivery of treatment. Evidence Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and the Cochrane Library, using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified by searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Recommendations 1. Primary care physicians and gynaecologists should always consider the possibility of an underlying ovarian cancer in patients in any age group who present with an adnexal or ovarian mass. (II-2B) 2. Appropriate workup of a perimenopausal or postmenopausal woman presenting with an adnexal mass should include evaluation of symptoms and signs suggestive of malignancy, such as persistent pelvic/abdominal pain, urinary urgency/frequency, increased abdominal size/bloating, and difficulty eating. In addition, CA125 measurement should be considered. (II-2B) 3. Transvaginal or transabdominal ultrasound examination is recommended as part of the initial workup of a complex adnexal/ovarian mass. (II-2B) 4. Ultrasound reports should be standardized to include size and unilateral/bilateral location of the adnexal mass and its possible origin, thickness of septations, presence of excrescences and internal solid components, vascular flow distribution pattern, and presence or absence of ascites. This information is essential for calculating the risk of malignancy index II score to identify pelvic mass with high malignant potential. (IIIC) 5. Patients deemed to have a high risk of an underlying malignancy should be reviewed in consultation with a gynaecologic oncologist for assessment and optimal surgical management. (II-2B)
Troxacitabine is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Significant differences in troxacitabine toxicity ...between mice, rats, monkeys, and humans were observed during preclinical and clinical evaluations. To better understand the different toxicity and efficacy results observed between the human xenograft mouse tumor models used for preclinical assessment and the clinical study results, the pharmacodynamics and pharmacokinetics of troxacitabine were reassessed in murine and human models.
Clonal and thymidine incorporation assays were used to investigate the in vitro antiproliferative activity of troxacitabine on a selected panel of mouse and human tumor cell lines and normal hemapoietic cells. Analysis of the intracellular metabolites of 14Ctroxacitabine was determined in mouse and human T-lymphocytes obtained from peripheral blood. The antitumor efficacy of troxacitabine administered either as single or repeated high-dose bolus administrations or as low-dose continuous infusions was evaluated in the human colon HT-29 xenograft model. We also determined plasma concentrations of troxacitabine using the different administration schedules.
Five to nine hundred-fold lower concentrations of troxacitabine were required to inhibit cell growth in human compared with murine tumor and normal hemapoietic cell lines. Furthermore, the sensitivity of cells of both species to troxacitabine was strongly time dependent, requiring >24 hours exposure for maximum activity. Analysis of the intracellular metabolites of 14Ctroxacitabine in T-lymphocytes obtained from peripheral blood revealed subsequently higher levels of mono-, di-, and triphosphates in human compared with mouse. Antitumor efficacy studies revealed that prolonged exposure schedules (up to 6 days) showed equivalent efficacy to repeated high-dose bolus administrations. Five-day continuous infusion of 20 mg/mL troxacitabine via subcutaneous implanted mini-osmotic pump maintained systemic concentrations of 262 ng/mL (1.2 micromol/L) for the duration of administration, which are clinically achievable plasma concentrations, and led to significant antitumor activity treated versus control (T/C) of 27% and tumor regression during treatment.
These studies support the hypothesis that troxacitabine infusions might be the administration regimen with the greatest likelihood of fully exploiting clinically the potent preclinical antitumor activity of troxacitabine.
Résumé Objectifs Optimiser la prise en charge des masses annexielles et aider les médecins de premier recours et les gynécologues à identifier les patientes présentant une masse ovarienne qui ...s’accompagne d’un risque considérable de malignité pour lesquelles une orientation et une prise en charge en oncologie gynécologique devraient être envisagées Options Évaluation laparoscopique, stadification par chirurgie exhaustive (pour ce qui est du cancer de l’ovaire précoce) ou chirurgie de réduction tumorale (pour ce qui est du cancer de l’ovaire de stade avancé). Issues Optimiser la prise en charge conservatrice (par comparaison avec la prise en charge opératoire) des femmes présentant une possible malignité ovarienne et optimiser la participation des gynécologues oncologues à la planification et à la mise en oeuvre du traitement. Résultats La littérature publiée a été localisée par l’intermédiaire de recherches menées dans PubMed ou MEDLINE, CINAHL et la Cochrane Library, au moyen d’un vocabulaire contrôlé approprié et de mots clés. Les résultats ont été limités aux analyses systématiques, aux essais comparatifs randomisés / cliniques et aux études observationnelles. La littérature grise (non publiée) a été identifiée par l’intermédiaire de recherches menées dans les sites Web d’organismes du domaine de l’évaluation des technologies de santé, les collections de directives cliniques, les registres d’essais cliniques et les sites Web de sociétés de spécialité médicale nationales et internationales. Recommandations 1. Les médecins de premier recours et les gynécologues devraient toujours envisager la possibilité d’un cancer de l’ovaire sous-jacent chez toute patiente, quel qu’en soit l’âge, qui présente une masse annexielle ou ovarienne. (II-2B) 2. Le bilan approprié d’une femme périménopausée ou postménopausée présentant une masse annexielle devrait comprendre une évaluation des symptômes évoquant une affection maligne, tels que la douleur pelvienne / abdominale persistante, la miction impérieuse / la pollakiurie, l’accroissement de la taille de l’abdomen / le ballonnement et la difficulté de manger. De plus, la détermination du taux de CA125 devrait être envisagée. (II-2B) 3. La tenue d’une échographie transvaginale ou transabdominale est recommandée dans le cadre du bilan initial d’une masse annexielle / ovarienne complexe. (II-2B) 4. Les rapports d’échographie devraient être standardisés de façon à inclure la taille et l’emplacement (unilatéral / bilatéral) de la masse annexielle et son origine possible, l’épaisseur des cloisons, la présence d’excroissances et de composants internes solides, la distribution du débit vasculaire et la présence ou l’absence d’ascites. Ces données sont essentielles pour le calcul du score de l’indice du risque de malignité II servant à identifier les masses pelviennes qui présentent un fort potentiel malin. (IIIC) 5. Les patientes qui semblent courir un risque élevé de présenter une affection maligne sous-jacente devraient faire l’objet d’un examen, mené avec le concours d’un gynécologue oncologue, aux fins de l’évaluation de la situation et de la mise en oeuvre d’une prise en charge chirurgicale optimale. (II-2B)
Troxacitabine (BCH-4556, l-(-)-OddC, Troxatyl) is a novel beta- l-nucleoside analogue with potent antineoplastic activity both in vitro and in several tumor models in vivo, and is presently in phase ...II clinical trials. The combination of the cytosine analogues troxacitabine and araC (1-beta- d-arabinofuranosylcytosine, cytarabine) has shown promising activity in patients with acute myelogenous leukemia. To further examine the interactions between these two analogues, we investigated the in vitro and in vivo effects of their combination against a human leukemia cell line, CCRF-CEM.
. The in vitro cytotoxic effect of the combination of troxacitabine and araC on the survival of CCRF-CEM cells was measured using a standard MTT assay and combination indices were generated with the CalcuSyn software. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on survival of CCRF-CEM tumor-bearing animals. Mechanistic studies addressed recovery of DNA synthesis, intracellular levels of araC metabolites, feedback inhibition by triphosphate species and pharmacokinetics of both drugs.
The combination of troxacitabine and araC in vitro was synergistic with combination indices between 0.1 and 0.7. This appeared to be related to the impact of the combination on DNA synthesis recovery, which was significantly delayed following exposure to the combination of troxacitabine and araC compared to either agent alone. Analysis of the effect of troxacitabine on the intracellular metabolites of araC revealed that troxacitabine did not inhibit araC deamination and caused a slight decrease in the overall intracellular accumulation of araCTP. The lower accumulation of araCTP could not be attributed to feedback inhibition caused by troxacitabine triphosphate on dCK. Furthermore, our in vivo experiments demonstrated that the combination of araC and troxacitabine was better at slowing down the progression of leukemia in SCID mice than either agent used alone without additive toxicities. Injections of 10 mg/kg troxacitabine i.p. daily for 5 days in combination with araC at 10 mg/kg led to an increase in median survival time of 58 days compared to 49.5 and 53.5 days for araC and troxacitabine, respectively, given as single agents. This represents an increase in life span of 17%, respectively when compared to araC alone. A pharmacokinetic study revealed that troxacitabine did not influence the disposition of araC when coadministered.
Overall, our results show that the antileukemic activity of troxacitabine and araC is complementary when the two nucleoside analogues are combined in vivo. These effects appear to be related to their interaction at the level of DNA repair rather than to pharmacokinetic interactions. These results encourage the use of troxacitabine and araC in combination in patients with acute leukemia.
xxe-xxie siècles Entretien avec Bill Viola sur l’histoire de l’art ; Giacometti ; l’urbanisme des villes d’Europe centrale ; publications récentes sur la couleur au cinéma et dans la photographie, le ...postmodernisme, les archives d’art contemporain et les revues d’art. Le Canada Développement et pratiques actuelles de la discipline : de l’histoire de l’art aux études d’intermédialité, le rôle des musées et de la muséographie ; Ancien et Nouveau Mondes ; chroniques sur art et cinéma, les revues, le patrimoine…
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