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Objective Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. Conclusions The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. (c) 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Objective: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at risk can guide decisions on closer surveillance or timing of birth to prevent fetal death.Prognostic models have been developed to predict the risk of stillbirth, but none have yet been externally validated. We externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods: We searched Medline, EMBASE, DH-DATA and AMED databases from inception to December 2020 to identify stillbirth prediction models. We included studies that developed or updated prediction models for stillbirth for use at any time during pregnancy. IPD from cohorts within the International Prediction of Pregnancy Complication (IPPIC) Network were used to externally validate the identified prediction models whose individual variables were available in the IPD. We assessed the risk of bias of the models and IPD using PROBAST, and reported discriminative performance using the C-statistic, and calibration performance using calibration plots, calibration slopeand calibration-in-the-large. We estimated performance measures separately in each study, and then summarised across studies using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results: We identified 17 studies reporting the development of 40 prognostic models for stillbirth. None of the models were previously externally validated, and only a fifth (20%, 8/40) reported the full model equation. We were able to validate three of these models using the IPD from 19 cohort studies (491,201 pregnant women) within the IPPIC Network database. Based on evaluating their development studies, all three models had an overall high risk of bias according to PROBAST. In our IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65; summary calibration slopes of 0.40to 0.88, and generally with observed risks predictions that were too extreme compared to observed risks; and little to no clinical utility as assessed by net benefit. However, there remained uncertainty in performance for some models due to small available sample sizes. Conclusion: The three validated models generally showed poor and uncertain predictive performancein new data, with limited evidence to support their clinical application. Findings suggest methodological shortcomings in their development including overfitting of models. Further research is needed to further validate these and other models, identify stronger prognostic factors, and to develop more robust prediction models

Imogen Tyler: Stigma. The Machinery of Inequality. Zed Books 2020.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. Design: This was an individual participant data meta-analysis of cohort studies. Setting: Source data from secondary and tertiary care. Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey. Primary outcomes: Early-onset (delivery at < 34 weeks’ gestation), late-onset (delivery at ≥ 34 weeks’ gestation) and any-onset pre-eclampsia. Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration.We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and 2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. © 2020, NIHR Journals Library. All rights reserved.

no abstract

In order to find out whether the response rate and survival in epithelial ovarian cancer can be improved by aid of sensitivity testing with the subrenal capsule assay (SRCA), 196 patients with FIGO Stage II-IV epithelial ovarian cancer were randomized to be treated with either cyclophosphamide-doxorubicin-cisplatin (CAP) or SRCA-guided chemotherapy. The drug combinations tested with the SRCA were (1) cyclophosphamide-doxorubicin-carboplatin (CACAR), (2) CAP, (3) carboquone-methotrexate-tegafur (CQ-MTX-TEG), (4) cisplatin-etoposide-hexamethyl-melamine (P-VP-HXM), and (5) bleomycin-epirubicin-cisplatin (BEP). A total of 132 patients (CAP, 69; SRCA, 63) were eligible for efficacy analysis based on relaparotomy findings. The overall response rate was 59% in the CAP arm and 62% in the SRCA arm. In the SRCA arm, 16 patients were treated with CACAR, 24 with CAP, 10 with CQ-MTX-TEG, 11 with P-VP-HXM, and 2 with BEP. The response rate to CACAR was 63% and to SRCA-CAP was 75%. The number of complete responses was higher when CAP was given as guided by the assay than when given at random (14/24 vs 23/69; P = 0.03, Pearson chi 2). Survival curves as estimated by Kaplan-Meier method gave a median survival of 24 (SE = 4) months to the SRCA arm and 28 (SE = 5) for the CAP arm (P = 0.7; log-rank test). Because no survival benefit was achieved, the SRCA obviously needs further development before it can be routinely recommended in the choice of first-line chemotherapy for patients with ovarian cancer.

Summary Twenty-seven deaths in premature infants weighing less than 1 250 g who were treated with intermittent positive pressure respiration are reported. The major pulmonary abnormalities were hyaline membrane formation, infection, and hemorrhage occurring‘ alone or in combination with intraverticular hemorrhage. Hyaline membranes were associated with severe clinical features of respiratory distress, whereas infection was not. Prolonged treatment resulted in “bronchopulmonary dysplasia” in only 1 case where severe clinical respiratory distress was associated with the finding of hyaline membranes at post mortem.

Baroreflex activity was assessed in 10 fetal lambs at 85-145 days of gestation. ECG leads sewn to the fetal chest wall, vinyl catheters in brachial artery and femoral vein, and a balloon catheter in the descending aorta were exteriorized through the ewe's flank. After at least 36 hours, the reflex bradycardia, in response to increased blood pressure by balloon inflation, was measured. Baroreflex sensitivity was expressed as the slope of the beat-to-beat relationship between systolic (S.P.) or pulse (P.P.) pressure and the subsequent R-R interval or instantaneous heart rate (H.R.). Baroreflex activity was considered absent if the slope did not differ significantly from zero or if the correlation coefficient was less than 0.7. Throughout gestation baroreceptors could respond to pressure elevation, but the proportion of positive responses increased with age. Baroreflex sensitivity increased up to term when either S.P. or P.P. were plotted against the next R-R interval. Regression analysis of S.P. or P.P. vs. R-R interval, or of P.P. vs. H.R showed increasing baroreflex sensitivity with maturation Analysis of S.P. vs. H.R. showed no significant increase in response with advancing gestation; however, this type of analysis does not take into account the slower resting heart rates of older animals.

Summary Clinical findings and results of treatment in a series of 49 premature infants with birth weights between 850 and 1250 g are presented. The “intensive care” included nursing in incubators with high environmental humidity maintaining skin temperature at 36.5°C, umbilical catheterisation (both arterial and venous), intravenous glucose infusions, correction of metabolic acidosis by rapid sodium bicarbonate infusions, oxygen therapy and finally endotracheal intubation and mechanical ventilation. The series was divided into 3 categories according to the severity of respiratory symptoms. There was only one survivor out of 12 cases in the category of severe RD, whereas 14 of 21 with moderate RD and 9 of 16 with slight or no RD survived. The overall survival rate was 45%. The correlation between clinical findings, arterial blood gases and pH, chest X-rays, response to treatment and outcome in each of the 3 categories is discussed. The preliminary data from our follow-up studies indicate that there are only a few cases showing signs of permanent brain injury at the age of two years.

Baroreceptor response have been observed in exteriorized fetal lambs, but ther have been no quantitative studies of changes with maturation in fetuses in utero. In 9 fetal and 3 newborn lambs an inflatable balloon catheter was passed from the femoral artery into the descending aorta. In 7 other fetuses inflatable balloons were placed around the pulmonary artery (PA) or the aortic isthmus. Vinyl catheters were positioned in a brachial or carotid artery, and catheters and ECG leads were exteriorized. Arterial pH, PCO2 and PO2 were normal in all studies. Reflex bradycardia in response to blood pressure elevation by balloon inflation was measured repeatedly for several weeks. Baroreceptor sensitivity was expressed as the regression coefficient of the beat-to-beat relationship between systolic (SP) and pulse (PP) pressure, and the subsequent R-R interval (R-R) or heart rate (HR). In over 100 observations we found: (1) elevation of systemic but not main PA pressure elicits reflex bradycardia; (2) reflex bradycardia could be elicite in all animals but was frequently absent in fetuses less than 120 days gestation; (3) reflex bradycardia was blocked by atropine but not influenced by propranolol; (4) in fetuse the regression coefficients of SP or PP vs. R-R increased with gestational age, but not when SP or PP was correlated with HR because of the lower initial HR in older fetuses; (5) lambs had significantly higher regression coefficients for all correlations than fetuses. We have not yet evaluated if baroreceptor response depend on gestational age and initial HR in combination.

Sympathetic and parasympathetic activity have been studied in exteriorized fetal lambs but not in intact fetuses in utero. We placed vinyl catheters in a systemic artery and hindlimb vein in 20 fetuses from 92 days of gestation to term and also in 3 newborn lambs. The animals were allowed to recover from surgery for 2–3 days and then studied daily for several weeks. Maternal and fetal pH, PCO2 and PO2 were normal in all experiments. The blood pressure (BP) and heart rate (HR) responses to selective intravenous injection of propranolol (1 mg/kg), practolol (1–2 mg/kg), atropine (1.0 mg/kg), phentolamine (0.1 mg/kg), phenoxybenzamine (5 mg/kg) and tyramine (0.25 mg/kg) were recorded. The adequacy of autonomic blockade was confirmed by absence of response to acetylcholine (5–15 μg/kg), isoproterenol (0.1 μg/kg) or methoxamine (50 μg/kg). Change in HR from resting levels without significant BP change were observed as follows: propranolol 5–25% decrease, practolol 8–22% decrease and atropine 0–64% increase. Response to beta-adrenergic blockade did not vary significantly with gestational age. Phentolamine and phenoxybenzamine decreased systolic BP 2-14 and diastolic BP 2-12 mm Hg in 19/21 animals and tyramine increased systolic BP 7-60 and diastolic BP 10-46 mm Hg in 7/7 animals. No significant difference in sympathetic responses were observed in fetal and newborn lambs, indicating HR and BP to be under similar autonomic control at all ages studied.

Kirja-arvio Casares, Julio: Introducción a la lexicografía moderna

Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. Methods IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. Results Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model’s calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. Conclusions The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.