A research agenda to improve incidence and outcomes of assisted vaginal birth.

Access to emergency obstetric care, including assisted vaginal birth and caesarean birth, is crucial for improving maternal and childbirth outcomes. However, although the proportion of births by caesarean section has increased during the last few decades, the use of assisted vaginal birth has declined. This is particularly the case in low- and middle-income countries, despite an assisted vaginal birth often being less risky than caesarean birth. We therefore conducted a three-step process to identify a research agenda necessary to increase the use of, or reintroduce, assisted vaginal birth: after conducting an evidence synthesis, which informed a consultation with technical experts who proposed an initial research agenda, we sought and incorporated the views of women's representatives of this agenda. This process has allowed us to identify a comprehensive research agenda, with topics categorized as: (i) the need to understand women's perceptions of assisted vaginal birth, and provide appropriate and reliable information; (ii) the importance of training health-care providers in clinical skills but also in respectful care, effective communication, shared decision-making and informed consent; and (iii) the barriers to and facilitators of implementation and sustainability. From women's feedback, we learned of the urgent need to recognize labour, childbirth and postpartum experiences as inherently physiological and dignified human processes, in which interventions should only be implemented if necessary. The promotion and/or reintroduction of assisted vaginal birth in low-resource settings requires governments, policy-makers and hospital administrators to support skilled health-care providers who can, in turn, respectfully support women in labour and childbirth

Patient and provider determinants for receipt of three dimensions of respectful maternity care in Kigoma Region, Tanzania-April-July, 2016

Abstract Background Lack of respectful maternity care (RMC) is increasingly recognized as a human rights issue and a key deterrent to women seeking facility-based deliveries. Ensuring facility-based RMC is essential for improving maternal and neonatal health, especially in sub-Saharan African countries where mortality and non-skilled delivery care remain high. Few studies have attempted to quantitatively identify patient and delivery factors associated with RMC, and none has modeled the influence of provider characteristics on RMC. This study aims to help fill these gaps through collection and analysis of interviews linked between clients and providers, allowing for description of both patient and provider characteristics and their association with receipt of RMC. Methods We conducted cross-sectional surveys across 61 facilities in Kigoma Region, Tanzania, from April to July 2016. Measures of RMC were developed using 21-items in a Principal Components Analysis (PCA). We conducted multilevel, mixed effects generalized linear regression analyses on matched data from 249 providers and 935 post-delivery clients. The outcomes of interest included three dimensions of RMC—Friendliness/Comfort/Attention; Information/Consent; and Non-abuse/Kindness—developed from the first three components of PCA. Significance level was set at p < 0.05. Results Significant client-level determinants for perceived Friendliness/Comfort/Attention RMC included age (30–39 versus 15–19 years: Coefficient [Coef] 0.63; 40–49 versus 15–19 years: Coef 0.79) and self-reported complications (reported complications versus did not: Coef − 0.41). Significant provider-level determinants included perception of fair pay (Perceives fair pay versus unfair pay: Coef 0.46), cadre (Nurses/midwives versus Clinicians: Coef − 0.46), and number of deliveries in the last month (11–20 versus < 11 deliveries: Coef − 0.35). Significant client-level determinants for Information/Consent RMC included labor companionship (Companion versus none: Coef 0.37) and religiosity (Attends services at least weekly versus less often: Coef − 0.31). Significant provider-level determinants included perception of fair pay (Perceives fair pay versus unfair: Coef 0.37), weekly work hours (Coef 0.01), and age (30–39 versus 20–29 years: Coef − 0.34; 40–49 versus 20–29 years: Coef − 0.58). Significant provider-level determinants for Non-abuse/Kindness RMC included the predictors of age (age 50+ versus 20–29 years: Coef 0.34) and access to electronic mentoring (Access to two mentoring types versus none: Coef 0.37). Conclusions These findings illustrate the value of including both client and provider information in the analysis of RMC. Strategies that address provider-level determinants of RMC (such as equitable pay, work environment, access to mentoring platforms) may improve RMC and subsequently address uptake of facility delivery

Abstract 2350: Discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design.

Abstract Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Overexpression of Mcl-1 is also a resistance mechanism that prevents tumor cells from being effectively treated by existing chemotherapies. Thus, inhibition of Mcl-1 is a promising therapeutic strategy for the treatment of cancer. However, Mcl-1 exerts its effects through protein-protein interactions and is thought to be very challenging to target with small molecules. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. From an NMR-based screen of a large fragment library, over 130 hits were identified. Two distinct chemical hit series were found that bind to two different sites on Mcl-1 as revealed by NMR-derived model structures. Members of the two fragment classes were merged together to produce compounds that bind to Mcl-1 with greater than two orders of magnitude improved binding affinity. Structures of these compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition involved in small-molecule binding to Mcl-1. Lead compounds exhibited a dissociation constant of &amp;lt;100 nM, with selectivity for Mcl-1 over Bcl-xL and Bcl-2. These compounds represent useful starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers. Citation Format: Taekyu Lee, Anders Friberg, Dominico Vigil, Bin Zhao, R. Nathan Daniels, Jason P. Burke, Pedro M. Garcia-Barrantes, DeMarco Camper, Brian A. Chauder, Edward T. Olejniczak, Stephen W. Fesik. Discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2350. doi:10.1158/1538-7445.AM2013-2350</jats:p

The cannabinoid CB2 receptor: improvement of sleep or memory in rotenone model of Parkinson's disease

The impact of cannabinoid CB2 receptor modulation on the non-motor symptoms of Parkinson's disease remains unknown. We investigated the role of nigrostriatal CB2 receptors modulation in reversing alterations in sleep macrostructure, inter-hemispheric synchronization dynamics, and memory consolidation in the rotenone model of Parkinson's disease. Male Wistar rats (n = 65) underwent stereotaxic surgery for the administration of either rotenone (12 μg/μl) or dimethyl sulfoxide (vehicle, 10 % v/v) into the substantia nigra pars compacta. Seven days later, the rotenone-treated animals received intrastriatal injections of either dimethyl sulfoxide (vehicle, 10 % v/v), GW405833 (partial agonist of CB2 receptors, 10 μg/μl), or AM630 (antagonist/inverse agonist of CB2 receptors, 3 μg/μl). One group of animals underwent 6 h of sleep-wake recording, while another group performed object recognition and open field tests. Real-time polymerase chain reaction was conducted to determine striatal transcript levels of CB1 and CB2 receptors. Infusion of AM630 reversed the rotenone-induced alterations in sleep macrostructure and inter-hemispheric synchronization dynamics. This modulation led to increased sleep efficiency (p < 0.01), higher probability of shorter desynchronization events (p < 0.01), and reduced transition rate from synchronized to desynchronized states (p < 0.05). Conversely, GW405833, but not AM630, reversed the rotenone-induced impairment in object recognition memory (p < 0.01). No significant effects were observed on striatal cannabinoid receptors transcripts levels. These findings suggest that CB2 receptors modulation is associated with paradoxical outcomes in terms of non-motor signs of Parkinson's disease, indicating somewhat independent mechanisms underlying sleep and memory alterations in the rotenone model of the disease

Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design

Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers

Connectivity and complex systems: learning from a multi-disciplinary perspective

In recent years, parallel developments in disparate disciplines have focused on what has come to be termed connectivity; a concept used in understanding and describing complex systems. Conceptualisations and operationalisations of connectivity have evolved largely within their disciplinary boundaries, yet similarities in this concept and its application among disciplines are evident. However, any implementation of the concept of connectivity carries with it both ontological and epistemological constraints, which leads us to ask if there is one type or set of approach(es) to connectivity that might be applied to all disciplines. In this review we explore four ontological and epistemological challenges in using connectivity to understand complex systems from the standpoint of widely different disciplines. These are: (i) defining the fundamental unit for the study of connectivity; (ii) separating structural connectivity from functional connectivity; (iii) understanding emergent behaviour; and (iv) measuring connectivity. We draw upon discipline-specific insights from Computational Neuroscience, Ecology, Geomorphology, Neuroscience, Social Network Science and Systems Biology to explore the use of connectivity among these disciplines. We evaluate how a connectivity-based approach has generated new understanding of structural-functional relationships that characterise complex systems and propose a ‘common toolbox’ underpinned by network-based approaches that can advance connectivity studies by overcoming existing constraints