Progression of the first stage of spontaneous labour: A prospective cohort study in two sub-Saharan African countries.

BACKGROUND: Escalation in the global rates of labour interventions, particularly cesarean section and oxytocin augmentation, has renewed interest in a better understanding of natural labour progression. Methodological advancements in statistical and computational techniques addressing the limitations of pioneer studies have led to novel findings and triggered a re-evaluation of current labour practices. As part of the World Health Organization's Better Outcomes in Labour Difficulty (BOLD) project, which aimed to develop a new labour monitoring-to-action tool, we examined the patterns of labour progression as depicted by cervical dilatation over time in a cohort of women in Nigeria and Uganda who gave birth vaginally following a spontaneous labour onset. METHODS AND FINDINGS: This was a prospective, multicentre, cohort study of 5,606 women with singleton, vertex, term gestation who presented at ≤ 6 cm of cervical dilatation following a spontaneous labour onset that resulted in a vaginal birth with no adverse birth outcomes in 13 hospitals across Nigeria and Uganda. We independently applied survival analysis and multistate Markov models to estimate the duration of labour centimetre by centimetre until 10 cm and the cumulative duration of labour from the cervical dilatation at admission through 10 cm. Multistate Markov and nonlinear mixed models were separately used to construct average labour curves. All analyses were conducted according to three parity groups: parity = 0 (n = 2,166), parity = 1 (n = 1,488), and parity = 2+ (n = 1,952). We performed sensitivity analyses to assess the impact of oxytocin augmentation on labour progression by re-examining the progression patterns after excluding women with augmented labours. Labour was augmented with oxytocin in 40% of nulliparous and 28% of multiparous women. The median time to advance by 1 cm exceeded 1 hour until 5 cm was reached in both nulliparous and multiparous women. Based on a 95th percentile threshold, nulliparous women may take up to 7 hours to progress from 4 to 5 cm and over 3 hours to progress from 5 to 6 cm. Median cumulative duration of labour indicates that nulliparous women admitted at 4 cm, 5 cm, and 6 cm reached 10 cm within an expected time frame if the dilatation rate was ≥ 1 cm/hour, but their corresponding 95th percentiles show that labour could last up to 14, 11, and 9 hours, respectively. Substantial differences exist between actual plots of labour progression of individual women and the 'average labour curves' derived from study population-level data. Exclusion of women with augmented labours from the study population resulted in slightly faster labour progression patterns. CONCLUSIONS: Cervical dilatation during labour in the slowest-yet-normal women can progress more slowly than the widely accepted benchmark of 1 cm/hour, irrespective of parity. Interventions to expedite labour to conform to a cervical dilatation threshold of 1 cm/hour may be inappropriate, especially when applied before 5 cm in nulliparous and multiparous women. Averaged labour curves may not truly reflect the variability associated with labour progression, and their use for decision-making in labour management should be de-emphasized.

Realizing the promise of The Partnership for Maternal, Newborn and Child Health.

Reflecting on Storeng and Béhague ("Lives in the balance": the politics of integration in the Partnership for Maternal, Newborn and Child Health. Health Policy and Planning Storeng and Béhague (2016).) historical ethnography of the Partnership for Maternal, Newborn and Child Health (PMNCH), this commentary provides a more current account of PMNCH's trajectory since its inception in 2005. It highlights PMNCH's distinct characteristics and how it is positioned to play an instrumental role in the current global health landscape.

Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors.

Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting ß-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.

Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study.

BACKGROUND: We report the main findings of the WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS), which aimed to assess the burden of complications related to pregnancy, the coverage of key maternal health interventions, and use of the maternal severity index (MSI) in a global network of health facilities. METHODS: In our cross-sectional study, we included women attending health facilities in Africa, Asia, Latin America, and the Middle East that dealt with at least 1000 childbirths per year and had the capacity to provide caesarean section. We obtained data from analysis of hospital records for all women giving birth and all women who had a severe maternal outcome (SMO; ie, maternal death or maternal near miss). We regarded coverage of key maternal health interventions as the proportion of the target population who received an indicated intervention (eg, the proportion of women with eclampsia who received magnesium sulphate). We used areas under the receiver operator characteristic curves (AUROC) with 95% CI to externally validate a previously reported MSI as an indicator of severity. We assessed the overall performance of care (ie, the ability to produce a positive effect on health outcomes) through standardised mortality ratios. RESULTS: From May 1, 2010, to Dec 31, 2011, we included 314,623 women attending 357 health facilities in 29 countries (2538 had a maternal near miss and 486 maternal deaths occurred). The mean period of data collection in each health facility was 89 days (SD 21). 23,015 (7.3%) women had potentially life-threatening disorders and 3024 (1.0%) developed an SMO. 808 (26.7%) women with an SMO had post-partum haemorrhage and 784 (25.9%) had pre-eclampsia or eclampsia. Cardiovascular, respiratory, and coagulation dysfunctions were the most frequent organ dysfunctions in women who had an SMO. Reported mortality in countries with a high or very high maternal mortality ratio was two-to-three-times higher than that expected for the assessed severity despite a high coverage of essential interventions. The MSI had good accuracy for maternal death prediction in women with markers of organ dysfunction (AUROC 0.826 [95% CI 0.802-0.851]). INTERPRETATION: High coverage of essential interventions did not imply reduced maternal mortality in the health-care facilities we studied. If substantial reductions in maternal mortality are to be achieved, universal coverage of life-saving interventions need to be matched with comprehensive emergency care and overall improvements in the quality of maternal health care. The MSI could be used to assess the performance of health facilities providing care to women with complications related to pregnancy. FUNDING: UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP); WHO; USAID; Ministry of Health, Labour and Welfare of Japan; Gynuity Health Projects.

Uterine bacterial isolates from mares and their resistance to antimicrobials: 8,296 cases (2003-2008).

OBJECTIVE: To describe bacteria isolated from reproductive tracts of mares and to examine the extent and patterns of resistance to antimicrobials commonly used for treatment of endometritis. DESIGN: Retrospective case series. SAMPLE: 8,296 uterine swab, lavage, or biopsy samples obtained between January 2003 and December 2008 from 7,665 horses in central Florida. PROCEDURES: Results of bacterial culture and antimicrobial susceptibility testing were obtained for uterine swab, lavage, and biopsy samples collected from mares undergoing a routine breeding examination or examined because of a reproductive disorder. Bacterial organisms were identified by means of standard techniques, and proportions of samples resistant to various antimicrobials were determined. RESULTS: At least 95% of samples (n = 1,451) were collected with uterine swabs. Potentially pathogenic organisms were cultured from 2,576 (31%) samples, with Escherichia coli (n = 729 [29%]) and ß-hemolytic Streptococcus equi subsp zooepidemicus (733 [28%]) being most common. Resistance to antimicrobials changed over time for E coli, S equi subsp zooepidemicus, and Enterobacteriaceae isolates. Overall, E coli was most resistant to trimethoprim-sulfonamide and ampicillin and least to amikacin and enrofloxacin. For S equi subsp zooepidemicus, resistance was greatest to oxytetracycline and enrofloxacin and least to ceftiofur and ticarcillin with or without clavulanic acid. Inflammatory response was greater for S equi subsp zooepidemicus. CONCLUSIONS AND CLINICAL RELEVANCE: E coli and S equi subsp zooepidemicus were the most common pathogens recovered from uterine samples, with S equi subsp zooepidemicus more commonly associated with inflammation. Antimicrobials most commonly used empirically to treat endometritis are appropriate on the basis of these data. However, as antimicrobial resistance changes over time, susceptibility assays should aid antimicrobial selection.

High-throughput 96-well solvent mediated sonic blending synthesis and on-plate solid/solution stability characterization of pharmaceutical cocrystals.

A 96-well high-throughput cocrystal screening workflow has been developed consisting of solvent-mediated sonic blending synthesis and on-plate solid/solution stability characterization by XRPD. A strategy of cocrystallization screening in selected blend solvents including water mixtures is proposed to not only manipulate solubility of the cocrystal components but also differentiate physical stability of the cocrystal products. Caffeine-oxalic acid and theophylline-oxalic acid cocrystals were prepared and evaluated in relation to saturation levels of the cocrystal components and stability of the cocrystal products in anhydrous and hydrous solvents. AMG 517 was screened with a number of coformers, and solid/solution stability of the resulting cocrystals on the 96-well plate was investigated. A stability trend was observed and confirmed that cocrystals comprised of lower aqueous solubility coformers tended to be more stable in water. Furthermore, cocrystals which could be isolated under hydrous solvent blending condition exhibited superior physical stability to those which could only be obtained under anhydrous condition. This integrated HTS workflow provides an efficient route in an API-sparing approach to screen and identify cocrystal candidates with proper solubility and solid/solution stability properties.

Investigating financial incentives for maternal health: an introduction.

Projection of current trends in maternal and neonatal mortality reduction shows that many countries will fall short of the UN Millennium Development Goal 4 and 5. Underutilization of maternal health services contributes to this poor progress toward reducing maternal and neonatal morbidity and mortality. Moreover, the quality of services continues to lag in many countries, with a negative effect on the health of women and their babies, including deterring women from seeking care. To enhance the use and provision of quality maternal care, countries and donors are increasingly using financial incentives. This paper introduces the JHPN Supplement, in which each paper reviews the evidence of the effectiveness of a specific financial incentive instrument with the aim of improving the use and quality of maternal healthcare and impact. The US Agency for International Development and the US National Institutes of Health convened a US Government Evidence Summit on Enhancing Provision and Use of Maternal Health Services through Financial Incentives on 24-25 April 2012 in Washington, DC. The Summit brought together leading global experts in finance, maternal health, and health systems from governments, academia, development organizations, and foundations to assess the evidence on whether financial incentives significantly and substantially increase provision, use and quality of maternal health services, and the contextual factors that impact the effectiveness of these incentives. Evidence review teams evaluated the multidisciplinary evidence of various financial mechanisms, including supply-side incentives (e.g. performance-based financing, user fees, and various insurance mechanisms) and demand-side incentives (e.g. conditional cash transfers, vouchers, user fee exemptions, and subsidies for care-seeking). At the Summit, the teams presented a synthesis of evidence and initial recommendations on practice, policy, and research for discussion. The Summit enabled structured feedback on recommendations which the teams included in their final papers appearing in this Supplement. Papers in this Supplement review the evidence for a specific financial incentive mechanism (e.g. pay for performance, conditional cash transfer) to improve the use and quality of maternal healthcare and makes recommendations for programmes and future research. While data on programmes using financial incentives for improved use and indications of the quality of maternal health services support specific conclusions and recommendations, including those for future research, data linking the use of financial incentives with improved health outcomes are minimal.

Financial incentives and maternal health: where do we go from here?

Health financing strategies that incorporate financial incentives are being applied in many low- and middle-income countries, and improving maternal and neonatal health is often a central goal. As yet, there have been few reviews of such programmes and their impact on maternal health. The US Government Evidence Summit on Enhancing Provision and use of Maternal Health Services through Financial Incentives was convened on 24-25 April 2012 to address this gap. This article, the final in a series assessing the effects of financial incentives--performance-based incentives (PBIs), insurance, user fee exemption programmes, conditional cash transfers, and vouchers--summarizes the evidence and discusses issues of context, programme design and implementation, cost-effectiveness, and sustainability. We suggest key areas to consider when designing and implementing financial incentive programmes for enhancing maternal health and highlight gaps in evidence that could benefit from additional research. Although the methodological rigor of studies varies, the evidence, overall, suggests that financial incentives can enhance demand for and improve the supply of maternal health services. Definitive evidence demonstrating a link between incentives and improved health outcomes is lacking; however, the evidence suggests that financial incentives can increase the quantity and quality of maternal health services and address health systems and financial barriers that prevent women from accessing and providers from delivering quality, lifesaving maternal healthcare.

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial.

BACKGROUND: Active management of the third stage of labour reduces the risk of post-partum haemorrhage. We aimed to assess whether controlled cord traction can be omitted from active management of this stage without increasing the risk of severe haemorrhage. METHODS: We did a multicentre, non-inferiority, randomised controlled trial in 16 hospitals and two primary health-care centres in Argentina, Egypt, India, Kenya, the Philippines, South Africa, Thailand, and Uganda. Women expecting to deliver singleton babies vaginally (ie, not planned caesarean section) were randomly assigned (in a 1:1 ratio) with a centrally generated allocation sequence, stratified by country, to placental delivery with gravity and maternal effort (simplified package) or controlled cord traction applied immediately after uterine contraction and cord clamping (full package). After randomisation, allocation could not be concealed from investigators, participants, or assessors. Oxytocin 10 IU was administered immediately after birth with cord clamping after 1-3 min. Uterine massage was done after placental delivery according to local policy. The primary (non-inferiority) outcome was blood loss of 1000 mL or more (severe haemorrhage). The non-inferiority margin for the risk ratio was 1·3. Analysis was by modified intention-to-treat, excluding women who had emergency caesarean sections. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN 12608000434392. FINDINGS: Between June 1, 2009, and Oct 30, 2010, 12,227 women were randomly assigned to the simplified package group and 12,163 to the full package group. After exclusion of women who had emergency caesarean sections, 11,861 were in the simplified package group and 11,820 were in the full package group. The primary outcome of blood loss of 1000 mL or more had a risk ratio of 1·09 (95% CI 0·91-1·31) and the upper 95% CI limit crossed the pre-stated non-inferiority margin. One case of uterine inversion occurred in the full package group. Other adverse events were haemorrhage-related. INTERPRETATION: Although the hypothesis of non-inferiority was not met, omission of controlled cord traction has very little effect on the risk of severe haemorrhage. Scaling up of haemorrhage prevention programmes for non-hospital settings can safely focus on use of oxytocin. FUNDING: United States Agency for International Development and UN Development Programme/UN Population Fund/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research.

Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.

mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 µM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.

Improved pharmacokinetics of AMG 517 through co-crystallization part 2: analysis of 12 carboxylic acid co-crystals.

Intrinsic dissolution, powder dissolution, and the pharmacokinetics (PK) of 12 carboxylic acid co-crystals of AMG 517 were determined and compared. Dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). A control dissolution experiment was conducted with the free base in FaSIF plus sorbic acid to compare with the AMG 517 sorbic acid co-crystal (SRA). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. All co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF as well as higher area under the concentration-time curves (AUC) in rat PK investigations compared with the free base. The control dissolution experiment indicates that the increase in dissolution rate of SRA over the free base is not due to the presence of sorbic acid in the dissolution medium. Linear correlation of dissolution rate and AUC among the 12 co-crystals was moderate, indicating that in vitro dissolution is a valuable method to predict whether a co-crystal will improve the exposure of a poorly soluble pharmaceutical ingredient; however, in vivo testing may be required to determine the extent.

Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines.

In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.

Improved pharmacokinetics of AMG 517 through co-crystallization. Part 1: comparison of two acids with corresponding amide co-crystals.

The dissolution and pharmacokinetics (PK) of two carboxylic acid co-crystals (cinnamic acid and benzoic acid) with the corresponding amide co-crystals (cinnamamide and benzamide) of AMG 517 were investigated. Powder and intrinsic dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. The four co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF than the free base. This correlated with a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations. When contrasting the acid to its corresponding amide co-crystal, cinnamamide shows improvement over cinnamic acid, while benzamide and benzoic acid perform similarly.