The Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials in Mozambique, Pakistan, and India: an individual participant-level meta-analysis.

BACKGROUND: To overcome the three delays in triage, transport and treatment that underlie adverse pregnancy outcomes, we aimed to reduce all-cause adverse outcomes with community-level interventions targeting women with pregnancy hypertension in three low-income countries. METHODS: In this individual participant-level meta-analysis, we de-identified and pooled data from the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trials in Mozambique, Pakistan, and India, which were run in 2014-17. Consenting pregnant women, aged 12-49 years, were recruited in their homes. Clusters, defined by local administrative units, were randomly assigned (1:1) to intervention or control groups. The control groups continued local standard of care. The intervention comprised community engagement and existing community health worker-led mobile health-supported early detection, initial treatment, and hospital referral of women with hypertension. For this meta-analysis, as for the original studies, the primary outcome was a composite of maternal or perinatal outcome (either maternal, fetal, or neonatal death, or severe morbidity for the mother or baby), assessed by unmasked trial surveillance personnel. For this analysis, we included all consenting participants who were followed up with completed pregnancies at trial end. We analysed the outcome data with multilevel modelling and present data with the summary statistic of adjusted odds ratios (ORs) with 95% CIs (fixed effects for maternal age, parity, maternal education, and random effects for country and cluster). This meta-analysis is registered with PROSPERO, CRD42018102564. FINDINGS: Overall, 44 clusters (69 330 pregnant women) were randomly assigned to intervention (22 clusters [36 008 pregnancies]) or control (22 clusters [33 322 pregnancies]) groups. 32 290 (89·7%) pregnancies in the intervention group and 29 698 (89·1%) in the control group were followed up successfully. Median maternal age of included women was 26 years (IQR 22-30). In the intervention clusters, 6990 group and 16 691 home-based community engagement sessions and 138 347 community health worker-led visits to 20 819 (57·8%) of 36 008 women (of whom 11 095 [53·3%] had a visit every 4 weeks) occurred. Blood pressure and dipstick proteinuria were assessed per protocol. Few women were eligible for methyldopa for severe hypertension (181 [1%] of 20 819) or intramuscular magnesium sulfate for pre-eclampsia (198 [1%]), of whom most accepted treatment (162 [89·5%] of 181 for severe hypertension and 133 [67·2%] of 198 for pre-eclampsia). 1255 (6%) were referred to a comprehensive emergency obstetric care facility, of whom 864 (82%) accepted the referral. The primary outcome was similar in the intervention (7871 [24%] of 32 290 pregnancies) and control clusters (6516 [22%] of 29 698; adjusted OR 1·17, 95% CI 0·90-1·51; p=0·24). No intervention-related serious adverse events occurred, and few adverse effects occurred after in-community treatment with methyldopa (one [2%] of 51; India only) and none occurred after in-community treatment with magnesium sulfate or during transport to facility. INTERPRETATION: The CLIP intervention did not reduce adverse pregnancy outcomes. Future community-level interventions should expand the community health worker workforce, assess general (rather than condition-specific) messaging, and include health system strengthening. FUNDING: University of British Columbia, a grantee of the Bill & Melinda Gates Foundation.

The incidence of pregnancy hypertension in India, Pakistan, Mozambique, and Nigeria: A prospective population-level analysis.

BACKGROUND: Most pregnancy hypertension estimates in less-developed countries are from cross-sectional hospital surveys and are considered overestimates. We estimated population-based rates by standardised methods in 27 intervention clusters of the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. METHODS AND FINDINGS: CLIP-eligible pregnant women identified in their homes or local primary health centres (2013-2017). Included here are women who had delivered by trial end and received a visit from a community health worker trained to provide supplementary hypertension-oriented care, including standardised blood pressure (BP) measurement. Hypertension (BP ≥ 140/90 mm Hg) was defined as chronic (first detected at <20 weeks gestation) or gestational (≥20 weeks); pre-eclampsia was gestational hypertension plus proteinuria or a pre-eclampsia-defining complication. A multi-level regression model compared hypertension rates and types between countries (p < 0.05 considered significant). In 28,420 pregnancies studied, women were usually young (median age 23-28 years), parous (53.7%-77.3%), with singletons (≥97.5%), and enrolled at a median gestational age of 10.4 (India) to 25.9 weeks (Mozambique). Basic education varied (22.8% in Pakistan to 57.9% in India). Pregnancy hypertension incidence was lower in Pakistan (9.3%) than India (10.3%), Mozambique (10.9%), or Nigeria (10.2%) (p = 0.001). Most hypertension was diastolic only (46.4% in India, 72.7% in Pakistan, 61.3% in Mozambique, and 63.3% in Nigeria). At first presentation with elevated BP, gestational hypertension was most common diagnosis (particularly in Mozambique [8.4%] versus India [6.9%], Pakistan [6.5%], and Nigeria [7.1%]; p < 0.001), followed by pre-eclampsia (India [3.8%], Nigeria [3.0%], Pakistan [2.4%], and Mozambique [2.3%]; p < 0.001) and chronic hypertension (especially in Mozambique [2.5%] and Nigeria [2.8%], compared with India [1.2%] and Pakistan [1.5%]; p < 0.001). Inclusion of additional diagnoses of hypertension and related complications, from household surveys or facility record review (unavailable in Nigeria), revealed higher hypertension incidence: 14.0% in India, 11.6% in Pakistan, and 16.8% in Mozambique; eclampsia was rare (<0.5%). CONCLUSIONS: Pregnancy hypertension is common in less-developed settings. Most women in this study presented with gestational hypertension amenable to surveillance and timed delivery to improve outcomes. TRIAL REGISTRATION: This study is a secondary analysis of a clinical trial - ClinicalTrials.gov registration number NCT01911494.

The feasibility of task-sharing the identification, emergency treatment, and referral for women with pre-eclampsia by community health workers in India.

BACKGROUND: Hypertensive disorders are the second highest direct obstetric cause of maternal death after haemorrhage, accounting for 14% of maternal deaths globally. Pregnancy hypertension contributes to maternal deaths, particularly in low- and middle-income countries, due to a scarcity of doctors providing evidence-based emergency obstetric care. Task-sharing some obstetric responsibilities may help to reduce the mortality rates. This study was conducted to assess acceptability by the community and other healthcare providers, for task-sharing by community health workers (CHW) in the identification and initial care in hypertensive disorders in pregnancy. METHODS: This study was conducted in two districts of Karnataka state in south India. A total of 14 focus group discussions were convened with various community representatives: women of reproductive age (N = 6), male decision-makers (N = 2), female decision-makers (N = 3), and community leaders (N = 3). One-to-one interviews were held with medical officers (N = 2), private healthcare OBGYN specialists (N = 2), senior health administrators (N = 2), Taluka (county) health officers (N = 2), and obstetricians (N = 4). All data collection was facilitated by local researchers familiar with the setting and language. Data were subsequently transcribed, translated and analysed thematically using NVivo 10 software. RESULTS: There was strong community support for home visits by CHW to measure the blood pressure of pregnant women; however, respondents were concerned about their knowledge, training and effectiveness. The treatment with oral antihypertensive agents and magnesium sulphate in emergencies was accepted by community representatives but medical practitioners and health administrators had reservations, and insisted on emergency transport to a higher facility. The most important barriers for task-sharing were concerns regarding insufficient training, limited availability of medications, the questionable validity of blood pressure devices, and the ability of CHW to correctly diagnose and intervene in cases of hypertensive disorders of pregnancy. CONCLUSION: Task-sharing to community-based health workers has potential to facilitate early diagnosis of the hypertensive disorders of pregnancy and assist in the provision of emergency care. We identified some facilitators and barriers for successful task-sharing of emergency obstetric care aimed at reducing mortality and morbidity due to hypertensive disorders of pregnancy.

Case 237: Renal Cell Carcinoma with Osseous Metaplasia.

History A 47-year-old man presented with palpitations and decreased exercise tolerance. A peripheral blood smear revealed anemia, thrombocytopenia, and blast cells, and a diagnosis of acute myeloid leukemia was made. Immunohistochemistry revealed positivity for cluster of differentiation (or CD) markers, which have been reported to be associated with an increased risk of extramedullary leukemic involvement. Thus, contrast material-enhanced computed tomography (CT) of the thorax, abdomen, and pelvis was requested to enable exclusion of any extramedullary extension of leukemia. Unenhanced and contrast-enhanced nephrographic phase CT was performed. Follow-up CT 3 months later showed minimal interval change in the lesion (images not shown).

Validating the Performance of the Modified Early Obstetric Warning System Multivariable Model to Predict Maternal Intensive Care Unit Admission.

OBJECTIVES: To evaluate the performance of the Modified Early Obstetric Warning System (MEOWS) to predict maternal ICU admission in an obstetric population. DESIGN: Case-control study. SETTING: Two maternity units in Vancouver, Canada, one with ICU facilities, between January 1, 2000, and December 31, 2011. PATIENTS: Pregnant or recently delivered (≤6 weeks) women admitted to the hospital for >24 hours. Three control patients were randomly selected per case and matched for year of admission. MEASUREMENTS AND MAIN RESULTS: Retrospective, observational, case-control validation study investigating the physiologic predictors of admission in the 24-hour period preceding either ICU admission >24 hours (cases) or following admission (control patients). Model performance was assessed based on sensitivity, specificity, and predictive values. Forty-six women were admitted to the ICU for >24 hours (0.51/1000 deliveries); the study included 138 randomly selected control patients. There were no maternal deaths in the cohort. MEOWS had high sensitivity (0.96) but low specificity (0.54) for ICU admission >24 hours, whereas ≥1 one red trigger maintained sensitivity (0.96) and improved specificity (0.73). CONCLUSION: Altering MEOWS trigger parameters may improve the accuracy of MEOWS in predicting ICU admission. Formal modelling of a MEOWS scoring system is required to support evidence-based care.

Maternal and perinatal outcomes of pregnancies delivered at 23 weeks' gestation.

OBJECTIVE: To evaluate the maternal and perinatal outcomes of pregnancies delivered at 23+0 to 23+6 weeks' gestation. METHODS: This prospective cohort study included women in the Canadian Perinatal Network who were admitted to one of 16 Canadian tertiary perinatal units between August 1, 2005, and March 31, 2011, and who delivered at 23+0 to 23+6 weeks' gestation. Women were included in the network if they were admitted with spontaneous preterm labour with contractions, a short cervix without contractions, prolapsing membranes with membranes at or beyond the external os or a dilated cervix, preterm premature rupture of membranes, intrauterine growth restriction, gestational hypertension, or antepartum hemorrhage. Maternal outcomes included Caesarean section, placental abruption, and serious complication. Perinatal outcomes were mortality and serious morbidity. RESULTS: A total of 248 women and 287 infants were included in the study. The rate of Caesarean section was 10.5% (26/248) and 40.3% of women (100/248) had a serious complication, the most common being chorioamnionitis (38.6%), followed by blood transfusion (4.5%). Of infants with known outcomes, perinatal mortality was 89.9% (223/248) (stillbirth 23.3% [67/287] and neonatal death 62.9% [156/248]). Of live born neonates with known outcomes (n = 181), 38.1% (69/181) were admitted to NICU. Of those admitted to NICU, neonatal death occurred in 63.8% (44/69). Among survivors at discharge, the rate of severe brain injury was 44.0% (11/25), of retinopathy of prematurity 58.3% (14/24), and of any serious neonatal morbidity 100% (25/25). Two subgroup analyses were performed: in one, antepartum stillbirths were excluded, and in the other only centres that indicated they offered fetal monitoring at 23 weeks' gestation were included and antepartum stillbirths were excluded. In each of these, perinatal outcomes similar to the overall group were found. CONCLUSION: Pregnant women delivering at 23 weeks' gestation are at risk of morbidity. Their infants have high rates of serious morbidity and mortality. Further research is needed to identify strategies and forms of management that not only increase perinatal survival but also reduce morbidities in these extremely low gestational age infants and reduce maternal morbidity.

Objectif : Évaluer les issues maternelles et périnatales des grossesses donnant lieu à un accouchement entre 23+0 et 23+6 semaines de gestation. Méthodes : Cette étude de cohorte prospective portait sur des femmes du Réseau périnatal canadien qui ont été admises à l'une des 16 unités périnatales tertiaires canadiennes participantes entre le 1er août 2005 et le 31 mars 2011, et qui ont accouché entre 23+0 et 23+6 semaines de gestation. Les femmes ont été admises dans le réseau si elles avaient été hospitalisées en raison d'un travail préterme spontané (s'accompagnant de contractions), d'un col court (sans contractions), d'un prolapsus des membranes (s'accompagnant d'une dilatation du col ou dans le cadre duquel les membranes se situaient au niveau de l'orifice externe ou faisaient saillie au-delà de ce dernier), d'une rupture prématurée des membranes préterme, d'un retard de croissance intra-utérin, d'une hypertension gestationnelle ou d'une hémorragie antepartum. Parmi les issues maternelles, on trouvait la césarienne, le décollement placentaire et la manifestation d'une complication grave. La morbidité grave et la mortalité constituaient les issues périnatales. Résultats : En tout, 248 femmes et 287 nouveau-nés ont été inclus dans l'étude. Le taux de césarienne était de 10,5 % (26/248) et 40,3 % des femmes (100/248) ont connu une complication grave (la plus courante étant la chorioamnionite [38,6 %], suivie de la transfusion sanguine [4,5 %]). Parmi les nouveau-nés pour lesquels les issues étaient connues, le taux de mortalité périnatale était de 89,9 % (223/248) (taux de mortinaissance : 23,3 % [67/287] et taux de décès néonatal : 62,9 % [156/248]). Une admission à l'UNSI a été requise pour 38,1 % (69/181) des enfants nés vivants pour lesquels les issues étaient connues (n = 181). Parmi ces enfants ayant dû être admis à l'UNSI, un décès néonatal a été constaté dans 63,8 % (44/69) des cas. Chez les survivants (au moment de l'obtention de leur congé de l'UNSI), le taux de lésion cérébrale grave était de 44,0 % (11/25), le taux de rétinopathie des prématurés était de 58,3 % (14/24) et le taux de quelque morbidité néonatale grave que ce soit était de 100 % (25/25). Deux analyses de sous-groupe ont été menées : dans le cadre de l'une d'entre elles, les mortinaissances pendant la période antepartum ont été exclues; dans le cadre de l'autre, seuls les centres ayant indiqué qu'ils offraient le monitorage fœtal à 23 semaines de gestation ont été inclus et les mortinaissances pendant la période antepartum ont également été exclues. Des issues périnatales semblables à celles du groupe général ont été constatées dans chacune de ces analyses. Conclusion : Les femmes enceintes qui accouchent à 23 semaines de gestation sont exposées à des risques de morbidité. Leurs nouveau-nés présentent des taux élevés de morbidité grave et de mortalité. La poursuite de la recherche s'avère requise pour permettre l'identification de stratégies et de formes de prise en charge qui entraînent non seulement une amélioration du taux de survie périnatale, mais également une baisse des taux de morbidité que connaissent ces nouveau-nés d'âge gestationnel extrêmement faible et les mères.

Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma.

In classical Hodgkin lymphoma (CHL), 20%-30% of patients experience relapse or progressive disease after initial treatment. The pathogenesis and biology of treatment failure are still poorly understood, in part because the molecular phenotype of the rare malignant Hodgkin Reed-Sternberg (HRS) cells is difficult to study. Here we examined microdissected HRS cells from 29 CHL patients and 5 CHL-derived cell lines by gene expression profiling. We found significant overlap of HL-specific gene expression in primary HRS cells and HL cell lines, but also differences, including surface receptor signaling pathways. Using integrative analysis tools, we identified target genes with expression levels that significantly correlated with genomic copy-number changes in primary HRS cells. Furthermore, we found a macrophage-like signature in HRS cells that significantly correlated with treatment failure. CSF1R is a representative of this signature, and its expression was significantly associated with progression-free and overall survival in an independent set of 132 patients assessed by mRNA in situ hybridization. A combined score of CSF1R in situ hybridization and CD68 immunohistochemistry was an independent predictor for progression-free survival in multivariate analysis. In summary, our data reveal novel insights into the pathobiology of treatment failure and suggest CSF1R as a drug target of at-risk CHL.

Triplet energy transfer from quantum dots increases Ln(iii) photoluminescence, enabling excitation at visible wavelengths.

Europium(iii) complexes are promising for bioimaging because of their long-lived, narrow emission. The photoluminescence (PL) from europium(iii) complexes is usually low. Thus, the effective utilization of low-energy light >400 nm and enhancement of PL are long-standing goals. Here, we show for the first time that 1-naphthoic acid triplet transmitter ligands bound to CdS quantum dots (QDs) and europium(iii) complexes create an energy transfer cascade that takes advantage of the strong QD absorption. This is confirmed by transient absorption spectroscopy, which shows hole mediated triplet energy transfer from QDs to 1-NCA, followed by triplet transfer from 1-NCA to europium(iii) complexes with an efficiency of 65.9 ± 7.7%. Smaller CdS QDs with a larger driving force lead to higher triplet transfer efficiency, with Eu(iii) PL intensity enhanced up to 21.4 times, the highest value ever reported. This hybrid QD system introduces an innovative approach to enhance the brightness of europium complexes.

Tumor-associated macrophages and survival in classic Hodgkin's lymphoma.

BACKGROUND: Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score. METHODS: Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis. RESULTS: Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies. CONCLUSIONS: An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification.

EGFR signaling promotes TGFß-dependent renal fibrosis.

The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGFß signaling and activates the EGF receptor (EGFR), but the relative contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFR-deficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGFß expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFR-dependent signaling for TGFß expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGFß-mediated fibrogenesis. We conclude that TGFß-mediated tissue fibrosis relies on a persistent feed-forward mechanism of EGFR/ERK activation through an unexpected signaling pathway, highlighting EGFR as a potential therapeutic target for modulating tissue fibrogenesis.

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model.

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.

Indications for, timing of, and modes of delivery in a national cohort of women admitted with antepartum hemorrhage at 22+0 to 28+6 weeks' gestation.

OBJECTIVE: Antepartum hemorrhage is associated with preterm birth and operative delivery. Since the Canadian Perinatal Network records obstetric interventions for women admitted to tertiary care hospitals with antepartum hemorrhage, our objective was to describe the delivery characteristics of this cohort. METHODS: Trained abstractors collected data by chart review from women admitted with antepartum hemorrhage between 22+0 and 28+6 weeks' gestation. We included all women with complete follow-up postpartum and used descriptive statistics to report the indications for, timing of, and modes of delivery. RESULTS: The study cohort included 806 women from 13 tertiary perinatal centres in six provinces. The most common causes of bleeding were placental abruption (n = 256) and placenta previa (n = 171). The median gestational age at delivery was 30 weeks, and 497 (61.7%) births occurred at less than 34 weeks. Over one half of the women began labour spontaneously, and 238 (29.5%) were delivered prior to the onset of labour. Overall, 370 (45.9%) women delivered vaginally, including 98 who had induction of labour. Of the 436 Caesarean sections (54.1%), 345 (79.1%) were emergencies. The most common indications for Caesarean section were placenta previa, abnormal fetal presentation, and placental abruption or vaginal bleeding. CONCLUSION: This inpatient cohort of women with antepartum hemorrhage had high rates of spontaneous labour, preterm birth, and emergency Caesarean section. These results can be used as current Canadian benchmark rates of preterm delivery, induction of labour, and Caesarean section in women admitted to tertiary care centres with antepartum hemorrhage between 22+0 and 28+6 weeks' gestation, and can aid in the counselling of similar women.

Halting the Canadian STRIDER randomised controlled trial of sildenafil for severe, early-onset fetal growth restriction: ethical, methodological, and pragmatic considerations.

OBJECTIVES: To determine the efficacy and safety of sildenafil citrate to improve outcomes in pregnancies complicated by early-onset, dismal prognosis, fetal growth restriction (FGR). Eligibility: women ≥ 18 years, singleton, 18 + 0-27 + 6 weeks' gestation, estimated fetal weight < 700 g, low PLFG, and ≥ 1 of (i) abdominal circumference < 10th percentile for gestational age (GA); or (ii) reduced growth velocity and either abnormal uterine artery Doppler or prior early-onset FGR with adverse outcome. Ineligibility criteria included: planned termination or reversed umbilical artery end-diastolic flow. Eligibility confirmed by placental growth factor (PLGF) < 5 th percentile for GA measured post randomization. Women randomly received (1:1) either sildenafil 25 mg three times daily or matched placebo until either delivery or 31 + 6 weeks. PRIMARY OUTCOME: delivery GA. The trial stopped early when Dutch STRIDER signalled potential harm; despite distinct eligibility criteria and IRB and DSMB support to continue, because of futility. NCT02442492 [registered 13/05/2015]. RESULTS: Between May 2017 and June 2018, 21 (90 planned) women were randomised [10 sildenafil; 11 placebo (1 withdrawal)]. Baseline characteristics, PLGF levels, maternal and perinatal outcomes, and adverse events did not differ. Delivery GA: 26 + 6 weeks (sildenafil) vs 29 + 2 weeks (placebo); p = 0.200. Data will contribute to an individual participant data meta-analysis.

The role of platelet counts in the assessment of inpatient women with preeclampsia.

OBJECTIVE: Platelet count has been proposed as a screening test for generalized coagulopathy in women with preeclampsia. We performed this study to determine the relationship between platelet counts and the risk of abnormal coagulation and adverse maternal outcomes in women with preeclampsia. METHODS: We used data from women in the PIERS (Pre-eclampsia Integrated Estimate of RiSk) database. Abnormal coagulation was defined as either an international normalized ratio result greater than and/or a serum fibrinogen level less than the BC Women's Hospital laboratory's pregnancy-specific normal range. The relationship between platelet counts and adverse maternal outcomes was explored using a logistic regression analysis. The sensitivity, specificity, positive predictive value, and negative predictive value of platelet counts in identifying abnormal coagulation or adverse maternal outcomes were calculated. RESULTS: Abnormal coagulation occurred in 105 of 1405 eligible women (7.5%). The odds of having abnormal coagulation were increased for women with platelet counts < 50 × 10(9)/L (OR 7.78; 95% CI 3.36 to 18.03) and between 50 and 99 × 10(9)/L (OR 2.69; 95% CI 1.44 to 5.01) compared with women who had platelet counts above 150 × 10(9)/L. Platelet counts < 100 × 10(9)/L were associated with significantly increased odds of adverse maternal outcomes, most specifically blood transfusion. A platelet count of < 100 × 10(9)/L had good specificity in identifying abnormal coagulation and adverse maternal outcomes (92% [95% CI 91% to 94%] and 92% [95% CI 91% to 94%], respectively), but poor sensitivity (22% [95% CI 15% to 31%] and 16% [95% CI 11% to 23%], respectively). CONCLUSION: A platelet count < 100 × 10(9)/L is associated with an increased risk of abnormal coagulation and maternal adverse outcomes in women with preeclampsia. However, the platelet count should not be used in isolation to guide care because of its poor sensitivity. Whether or not a platelet count is normal should not be used to determine whether further coagulation tests are needed.

Using clinical symptoms to predict adverse maternal and perinatal outcomes in women with preeclampsia: data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) study.

OBJECTIVES: Preeclampsia is a leading cause of maternal morbidity. The clinical challenge lies in predicting which women with preeclampsia will suffer adverse outcomes and would benefit from treatment, while minimizing potentially harmful interventions. Our aim was to determine the ability of maternal symptoms (i.e., severe nausea or vomiting, headache, visual disturbance, right upper quadrant pain or epigastric pain, abdominal pain or vaginal bleeding, and chest pain or dyspnea) to predict adverse maternal or perinatal outcomes. METHODS: We used data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) study, a multicentre, prospective cohort study designed to investigate the maternal risks associated with preeclampsia. Relative risks and receiver operating characteristic (ROC) curves were assessed for each preeclampsia symptom and outcome pair. RESULTS: Of 2023 women who underwent assessment, 52% experienced at least one preeclampsia symptom, with 5.2% and 5.3% respectively experiencing an adverse maternal or perinatal outcome. No symptom and outcome pair, in either of the maternal or perinatal groups, achieved an area under the ROC curve value > 0.7, which would be necessary to demonstrate a discriminatory predictive value. CONCLUSION: Maternal symptoms of preeclampsia are not independently valid predictors of maternal adverse outcome. Caution should be used when making clinical decisions on the basis of symptoms alone in the preeclamptic patient.

Oxygen saturation as a predictor of adverse maternal outcomes in women with preeclampsia.

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.

The Canadian Perinatal Network: a national network focused on threatened preterm birth at 22 to 28 weeks' gestation.

OBJECTIVE: The Canadian Perinatal Network (CPN) maintains an ongoing national database focused on threatened very preterm birth. The objective of the network is to facilitate between-hospital comparisons and other research that will lead to reductions in the burden of illness associated with very preterm birth. METHODS: Women were included in the database if they were admitted to a participating tertiary perinatal unit at 22+0 to 28+6 weeks' gestation with one or more conditions most commonly responsible for very preterm birth, including spontaneous preterm labour with contractions, incompetent cervix, prolapsing membranes, preterm prelabour rupture of membranes, gestational hypertension, intrauterine growth restriction, or antepartum hemorrhage. Data were collected by review of maternal and infant charts, entered directly into standardized electronic data forms and uploaded to the CPN via a secure network. RESULTS: Between 2005 and 2009, the CPN enrolled 2524 women from 14 hospitals including those with preterm labour and contractions (27.4%), short cervix without contractions (16.3%), prolapsing membranes (9.4%), antepartum hemorrhage (26.1%), and preterm prelabour rupture of membranes (23.0%). The mean gestational age at enrolment was 25.9 ± 1.9 weeks and the mean gestation age at delivery was 29.9 ± 5.1 weeks; 57.0% delivered at < 29 weeks and 75.4% at < 34 weeks. Complication rates were high and included serious maternal complications (26.7%), stillbirth (8.2%), neonatal death (16.3%), neonatal intensive care unit admission (60.7%), and serious neonatal morbidity (35.0%). CONCLUSION: This national dataset contains detailed information about women at risk of very preterm birth. It is available to clinicians and researchers who are working with one or more CPN collaborators and who are interested in studies relating processes of care to maternal or perinatal outcomes.

Targeted inactivation of EGF receptor inhibits renal collecting duct development and function.

The ureteric bud (UB) expresses high levels of the EGF receptor (EGFR) during kidney development, but its function in this setting is unclear. Here, Egfr mRNA was abundant in medullary portions of the UB trunk but absent from the branching UB tips during embryogenesis. Homozygous Egfr knockout did not affect the pattern of UB arborization, but renal papillae were hypoplastic and exhibited widespread apoptosis of tubular cells. Because these EGFR-deficient mice die within 1 week of life, we targeted Egfr inactivation to the renal collecting ducts using Cre-lox technology with a Hoxb7-Cre transgene. This targeted inactivation of Egfr led to a thin renal medulla, and at 7 weeks of age, the mice had moderate polyuria and reduced urine-concentrating ability. At 30 to 33 weeks, water deprivation demonstrated a continued urine-concentrating defect despite similar levels of vasopressin between knockout mice and littermate controls. Taken together, these results suggest that unlike other tyrosine kinases expressed at the UB tip, EGFR functions primarily to drive elongation of the emerging collecting ducts and to optimize urine-concentrating ability.

High resolution analysis of follicular lymphoma genomes reveals somatic recurrent sites of copy-neutral loss of heterozygosity and copy number alterations that target single genes.

A multiplatform approach, including conventional cytogenetic techniques, BAC array comparative genomic hybridization, and Affymetrix 500K SNP arrays, was applied to the study of the tumor genomes of 25 follicular lymphoma biopsy samples with paired normal DNA samples to characterize balanced translocations, copy number imbalances, and copy-neutral loss of heterozygosity (cnLOH). In addition to the t(14;18), eight unique balanced translocations were found. Commonly reported FL-associated copy number regions were revealed including losses of 1p32-36, 6q, and 10q, and gains of 1q, 6p, 7, 12, 18, and X. The most frequent regions affected by copy-neutral loss of heterozygosity were 1p36.33 (28%), 6p21.3 (20%), 12q21.2-q24.33 (16%), and 16p13.3 (24%). We also identified by SNP analysis, 45 aberrant regions that each affected one gene, including CDKN2A, CDKN2B, FHIT, KIT, PEX14, and PTPRD, which were associated with canonical pathways involved in tumor development. This study illustrates the power of using complementary high-resolution platforms on paired tumor/normal specimens and computational analysis to provide potential insights into the significance of single-gene somatic aberrations in FL tumorigenesis.