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Background: The CRADLE Vital Signs Alert intervention (an accurate easy-to-use device that measures blood pressure and pulse with inbuilt traffic-light early warning system, and focused training package) was associated with reduced rates of eclampsia and maternal death when trialled in urban areas in Sierra Leone. Subsequently, implementation was successfully piloted as evidenced by measures of fidelity, feasibility and adoption. The CRADLE-5 trial will examine whether national scale-up, including in the most rural areas, will reduce a composite outcome of maternal and fetal mortality and maternal morbidity and will evaluate how the CRADLE package can be embedded sustainably into routine clinical pathways., Methods: CRADLE-5 is a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care across eight rural districts in Sierra Leone (Bonthe, Falaba, Karene, Kailahun, Koinadugu, Kono, Moyamba, Tonkolili). Each district will cross from control to intervention at six-weekly intervals over the course of 1 year (May 2022 to June 2023). All women identified as pregnant or within six-weeks postpartum presenting for maternity care in the district are included. Primary outcome data (composite rate of maternal death, stillbirth, eclampsia and emergency hysterectomy) will be collected. A mixed-methods process and scale-up evaluation (informed by Medical Research Council guidance for complex interventions and the World Health Organization ExpandNet tools) will explore implementation outcomes of fidelity, adoption, adaptation and scale-up outcomes of reach, maintenance, sustainability and integration. Mechanisms of change and contextual factors (barriers and facilitators) will be assessed. A concurrent cost-effectiveness analysis will be undertaken., Discussion: International guidance recommends that all pregnant and postpartum women have regular blood pressure assessment, and healthcare staff are adequately trained to respond to abnormalities. Clinical effectiveness to improve maternal and perinatal health in more rural areas, and ease of integration and sustainability of the CRADLE intervention at scale has yet to be investigated. This trial will explore whether national scale-up of the CRADLE intervention reduces maternal and fetal mortality and severe maternal adverse outcomes and understand the strategies for adoption, integration and sustainability in low-resource settings. If successful, the aim is to develop an adaptable, evidence-based scale-up roadmap to improve maternal and infant outcomes., Trial Registration: ISRCTN 94429427. Registered on 20 April 2022., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Access to training and education in novel surgical and medical techniques is challenging in low-and- middle income settings where the burden of maternal morbidity and mortality is highest. Video-based education tools are cost effective and sustainable, and enable clinicians, even those based in rural, remote settings, to develop new skills, to improve the quality of care delivered to their patients. This is illustrated by the case of a clinician in Tanzania who successfully performed a transabdominal cerclage on two patients, after studying a video our team developed describing the technique. Both women who underwent the procedure had successful pregnancy outcomes, despite poor obstetric histories. Video is a versatile medium for delivery of training and education to medical students and doctors, and should be further integrated into surgical training curricula globally., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Bidibidi Refugee Settlement's 223,000 refugees are vulnerable to malaria due to crowded conditions and limited healthcare access. Early identification and referral of suspected cases is key to reduce morbidity and mortality. We evaluated the shock index (heart rate/ systolic blood pressure) for detection of abnormal vital signs, calculated by the CRADLE Vital Signs Alert device, which can be used in routine patient blood pressure and heart rate assessment by non-medically trained Voluntary Health Team workers. The single most frequent diagnosis causing shock was malaria, and thus the device was useful to detect severe cases (as well as discovering other cases), after calculating appropriate shock indices.

Background: Preterm delivery (before 37 weeks of gestation) is the single most important contributor to neonatal death and morbidity, with lifelong repercussions. However, the majority of women who present with preterm labour (PTL) symptoms do not deliver imminently. Accurate prediction of PTL is needed in order ensure correct management of those most at risk of preterm birth (PTB) and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the majority. The QUantitative Innovation in Predicting Preterm birth (QUIPP) app aims to support clinical decision-making about women in threatened preterm labour (TPTL) by combining quantitative fetal fibronectin (qfFN) values, cervical length (CL), and significant PTB risk factors to create an individualised percentage risk of delivery., Methods and Findings: EQUIPTT was a multi-centre cluster randomised controlled trial (RCT) involving 13 maternity units in South and Eastern England (United Kingdom) between March 2018 and February 2019. Pregnant women (n = 1,872) between 23+0 and 34+6 weeks' gestation with symptoms of PTL in the analysis period were assigned to either the intervention (762) or control (1,111). The mean age of the study population was 30.2 (+/- SD 5.93). A total of 56.0% were white, 19.6% were black, 14.2% were Asian, and 10.2% were of other ethnicities. The intervention was the use of the QUiPP app with admission, antenatal corticosteroids (ACSs), and transfer advised for women with a QUiPP risk of delivery >5% within 7 days. Control sites continued with their conventional management of TPTL. Unnecessary management for TPTL was a composite primary outcome defined by the sum of unnecessary admission decisions (admitted and delivery interval >7 days or not admitted and delivery interval ≤7 days) and the number of unnecessary in utero transfer (IUT) decisions/actions (IUT that occurred or were attempted >7 days prior to delivery) and ex utero transfers (EUTs) that should have been in utero (attempted and not attempted). Unnecessary management of TPTL was 11.3% (84/741) at the intervention sites versus 11.5% (126/1094) at control sites (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.66-1.42, p = 0.883). Control sites frequently used qfFN and did not follow UK national guidance, which recommends routine treatment below 30 weeks without testing. Unnecessary management largely consisted of unnecessary admissions which were similar at intervention and control sites (10.7% versus 10.8% of all visits). In terms of adverse outcomes for women in TPTL <36 weeks, 4 women from the intervention sites and 12 from the control sites did not receive recommended management. If the QUiPP percentage risk was used as per protocol, unnecessary management would have been 7.4% (43/578) versus 9.9% (134/1,351) (OR 0.72, 95% CI 0.45-1.16). Our external validation of the QUiPP app confirmed that it was highly predictive of delivery in 7 days; receiver operating curve area was 0.90 (95% CI 0.85-0.95) for symptomatic women. Study limitations included a lack of compliance with national guidance at the control sites and difficulties in implementation of the QUiPP app., Conclusions: This cluster randomised trial did not demonstrate that the use of the QUiPP app reduced unnecessary management of TPTL compared to current management but would safely improve the management recommended by the National Institute for Health and Care Excellence (NICE). Interpretation of qfFN, with or without the QUiPP app, is a safe and accurate method for identifying women most likely to benefit from PTL interventions., Trial Registration: ISRCTN Registry ISRCTN17846337., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. AS is Principal Investigator on Hologic funded science grants, which are paid directly to institute. NC received financial assistance to cover expenses only, paid directly to institution, to provide educational talks and an article on preterm birth from Hologic, USA. The other authors report no conflicts of interest.

Introduction: To evaluate cervicovaginal fluid quantitative fetal fibronectin, measured by a bedside analyzer, to predict spontaneous preterm birth in twin pregnancy before 30 weeks of gestation., Material and Methods: In a prospective cohort study, we studied the accuracy of quantitative fetal fibronectin measured between 18 and 27 +6 weeks of gestation in high-risk asymptomatic women with twin pregnancies, to predict spontaneous preterm birth before 30 weeks of gestation. Predefined fetal fibronectin thresholds were ≥10, ≥50 and ≥200 ng/mL. Predictive statistics were also calculated to evaluate accuracy of "early" tests, performed between 18 and 21 +6 weeks and "standard" tests performed between 22 +0 and 27 +6 weeks of gestation in the same cohort. Subgroup analysis was performed according to cervical length measurement. In addition, we compared accuracy of prediction with quantitative fetal fibronectin measured during the standard test period in asymptomatic twin pregnancy with no additional risk factors, to twin pregnancies with one or more additional risk factors for spontaneous preterm birth., Results: Of 130 eligible women identified with quantitative fetal fibronectin tests undertaken during the standard testing period, 9% delivered before 30 weeks of gestation. Quantitative fetal fibronectin was significantly related to outcome before 30/40 (ROC curves of 0.8 [95% CI 0.7-1]). Early tests were not significantly predictive; ROC area 0.53 (95% CI 0.29-0.81). There was a trend towards better predictive accuracy when one or more additional risk factors for spontaneous preterm birth or cervical length were considered., Conclusions: Quantitative fetal fibronectin measured from 22 to 27 +6 weeks of gestation accurately predicts spontaneous preterm birth at <30 weeks of gestation. Tests undertaken earlier are of limited value. Consideration of cervical length or prior history in addition to quantitative fetal fibronectin strengthens prediction., (© 2020 King's College London. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Accurate diagnosis of preterm labour is needed to ensure correct management of those most at risk of preterm birth and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the large majority of women, who do not deliver within a week of presentation. Intervention "just-in-case" results in many avoidable admissions, women being transferred out of their local hospital unnecessarily and most women receiving unwarranted drugs, such as steroids and tocolytics. It also precludes appropriate transfers for others as neonatal cots are blocked pre-emptively, resulting in more dangerous ex-utero transfers. We have developed the QUiPP App which is a clinical decision-making aid based on previous outcomes of women, quantitative fetal fibronectin (qfFN) values and cervical length. It is hypothesised that using the QUiPP app will reduce inappropriate admissions and transfers., Methods: A multi-site cluster randomised trial will evaluate whether the QUiPP app reduces inappropriate management for threatened preterm labour. The 13 participating centres will be randomly allocated to receive either intervention or control. If the QUiPP app calculates risk of delivery within 7 days to be is less than 5%, clinicians are advised that interventions may be withheld. Women's experience of threatened preterm labour assessment will be explored using self-completed questionnaires, with a subset of participants being invited to semi-structured interview. A health economics analysis is also planned., Discussion: We hypothesise that the QUiPP app will improve identification of the most appropriate women for admission and transfer and ensure that therapies known to reduce risk of preterm neonatal morbidities are offered to those who need them. We will determine which women do not require these therapies, thereby reducing over-medicalisation and the associated maternal and fetal risks for these women. The findings will inform future national guidelines on threatened preterm labour. Beyond obstetrics, evaluating the impact of an app in an emergency setting, and our emphasis on balancing harms of over-treatment as well as under-treatment, make EQUIPTT a valuable contribution to translational medicine., Trial Registration: The EQUIPTT trial was prospectively registered on 16th January 2018 with the ISRCTN registry (no. 17846337 ).

Background: Increasingly, women of reproductive age participate in recreational running, but its impact on pregnancy outcome is unknown. We investigated whether running affects gestational age at delivery and birth weight as indicators of cervical integrity and placental function, respectively., Methods: 1293 female participants were recruited from parkrun, which organises weekly runs involving 1.25 million runners across 450 parks worldwide. Those under 16 or unable to provide outcome data were excluded. Women were categorised according to whether they continued to run during pregnancy or not. Those who continued were further stratified dependent on average weekly kilometres, and which trimester they ran until. Retrospectively collected primary outcomes were gestational age at delivery and birthweight centile. Other outcomes included assisted vaginal delivery rate and prematurity at clinically important gestations., Results: There was no significant difference in gestational age at delivery: 279.0 vs 279.6 days (mean difference 0.6 days, CI -1.3 to 2.4 days; P=0.55) or birthweight centile: 46.9%vs 44.9% (mean difference 2.0%, CI -1.3% to -5.3%; P=0.22) in women who stopped running and those who continued, respectively. Assisted vaginal delivery rate was increased in women who ran: 195/714 (27%) vs 128/579 (22%) (OR 1.32; CI 1.02 to 1.71; P=0.03)., Conclusion: Continuing to run during pregnancy does not appear to affect gestational age or birthweight centile, regardless of mean weekly distance or stage of pregnancy. Assisted vaginal delivery rates were higher in women who ran, possibly due to increased pelvic floor muscle tone. Randomised prospective analysis is necessary to further explore these findings., Competing Interests: Competing interests: None declared.

Objective: Spontaneous preterm birth is the leading cause of neonatal morbidity and mortality. Cervicovaginal fetal fibronectin (fFN) has enhanced prediction of preterm birth and, more recently, quantified results have become available so that management can planned more effectively and targeted to individual women. Manufacture guidelines stipulate that fetal fibronectin (fFN) samples should be discarded in the presence of moderate to heavy vaginal bleeding but there hasn't yet been any formal investigation into the effect of blood staining on fetal fibronectin concentration and subsequent preterm birth prediction. The objective for this study was to determine the impact of blood stained swabs on quantitative fetal fibronectin (qfFN) concentration and prediction of spontaneous preterm birth (sPTB) in asymptomatic high-risk women., Study Design: Predefined blinded sub-analysis of a larger prospective study of qfFN in asymptomatic women at high-risk of preterm labour. Women with and without blood stained swabs were matched for gestational age at testing and delivery, risk factors and cervical length measurement., Results: Median fFN concentration in blood stained swabs (n=58) was 66ng/ml vs. 7.5ng/ml in the controls (n=58) (p<0.0001). At ≥50ng/ml threshold the false positive ratio (FPR) in blood stained was 25/33 (75.8%) vs. 8/15 (53%) in controls, (risk difference 22.4; -6.8 to 51.6, p=0.18). At ≥50ng/ml threshold the false-negative ratio (FNR) in blood stained was 2/25 (8.0%) vs. 1/43 (2.3%) in controls (risk difference -5.7; -17.2 to 5.9, p=0.55). At each threshold 10, 50 and 200ng/ml blood stained swabs had higher sensitivity but lower specificity for predicting preterm birth. Receiver Operating Characteristic (ROC) curve, the strongest global measure of test performance, for prediction of delivery at <34 weeks gestation was similar in blood stained vs. control groups. (0.78 vs. 0.84) in blood stained vs. control groups respectively., Conclusion: Blood stained swabs have elevated qfFN concentrations but may still have predictive value, and clinical utility. Very low fFN values (<10ng/ml) are especially reassuring and indicate lower risk of delivery than non-blood stained swabs. The higher false positive rate must be noted and explained to the patient., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objective: Accurate prediction of spontaneous preterm birth (sPTB) is essential to target interventions. Fetal fibronectin (fFN) is a leading predictor. A quantitative fFN (qfFN) test has improved prediction, based on high vaginal swabs (HVS). It is not known how endocervical (ECS) fFN levels compare, or which has the best predictive value. Our principal aim was to determine the difference in fFN concentration between HVS and ECS and compare their ability to predict sPTB., Methods: Asymptomatic high risk women (18(+0)-30(+0) weeks gestation) had secretions sampled from the endocervix (ECS) and vaginal fornix (HVS), analyzed by the quantitative fFN analyzer (Hologic). Mean concentrations were compared; ROC curves were calculated using area under the curve (AUC) for prediction of delivery <30 and 37 weeks., Results: Mean HVS value was lower than ECS (80 ng/ml (SD142) versus 217 (SD 212) (p < 0.05). Predictive ability was similar: AUC of 0.92 and 0.94, respectively, for prediction of sPTB < 37 and 0.84 and 0.82 for <30 weeks., Conclusions: Endocervical qfFN is higher than HVS and clinicians should avoid ECS if using traditional thresholds. ECS and HVS are both useful predictors, but require different threshold values. Further work is needed to determine whether ECS is a better and safe test to justify the difficulty in sampling.

The 12th Annual International Generic Pharmaceutical Alliance conference, held in Montreal, included topics covering changes and developments in the generic industry. This conference report highlights selected presentations on the state of the generics industry, prospects for follow-on biological products, and developments in IP and emerging generic markets.

The 12th Annual International Generic Pharmaceutical Alliance conference, held in Montreal, Canada, included several preconference workshops covering changes and developments in the generic industry. This conference report highlights discussions from a selection of workshops that included topics such as the US generic industry, recent issues with active pharmaceutical ingredients and follow-on biological products.