Search

ObjectivesAccess to reproductive information and contraception (RIC) continues to be a critical unmet need in Tanzania and impedes the realisation of reproductive health rights. This study examined key sources of RIC and the factors influencing their uptake by women in Mbeya region of Tanzania.SettingThis qualitative study was undertaken in a rural ward in a district in the south of the Mbeya regionParticipantsIn-depth interviews were undertaken with 48 women users and 2 nurses working in a public health facility, and focus group discussions with 16 home-based care workers in the district. Participants were recruited through a local non-governmental organisation (NGO) in the region, and via snowball sampling. All interactions were recorded, translated and transcribed and sought to identify the available resources and barriers in using them.ResultsParticipants reported six main sources of reproductive information and contraceptives: public health facilities, NGO mobile clinics, other women, Mganga wa Asili (witchdoctors/traditional doctors) and Duka la Dawa (pharmacy). Women users and healthcare workers identified a range of individual (age, marital status and geography) and health system-wide factors shaping women’s reproductive choices and preventing uptake of contraceptives. The study also revealed structural factors such as gender, ethnicity, indigeneity as key determinants of access and health seeking, placing women from Sukuma and Maasai communities is the most disadvantageous position. Historical social disadvantage, patriarchal social controls and the pressure to preserve sociocultural traditions that women experience in the Maasai and Sukuma tribes underpin their disconnect from mainstream services.ConclusionWomen’s reproductive choices and their uptake of contraceptives are shaped by the interaction of a range of individual, household, institutional and structural factors. An intersectional lens enables examination of the ways in which these factors interact and mutually constitute disadvantage and privilege.

Activin receptor-like kinase 2 (ALK2) has been implicated as a key target in multiple rare diseases. Herein, we describe the design of a novel bicyclic lactam series of potent and selective ALK2 inhibitors. This manuscript details an improvement in potency of two orders of magnitude from the initial bicyclic structure as well as a two-fold improvement in cellular potency from the original monocyclic inhibitor. Furthermore, we provide a detailed strategy for progressing this project in the future.

With the growing salience of ideas and reforms concerning women’s human rights and gender equality, violence against women (VAW) has received heightened policy attention. Recent global calls for ending VAW identify health care systems as having a crucial role in a multisector response to tackle this social injustice. Scholars emphasize the transformative potential of such response in its ability to not only address the varied health consequences but also prevent future recurrence by enabling wider access to support and justice. This wider consensus on the role of health systems, however, demands stronger empirical basis. This article reports findings from an exploratory research developed around the core question: What are the perceived strengths and challenges confronting health systems in offering a comprehensive response to VAW in India? Drawing on site visits, observations, and interviews with front-line staff and program managers of an integrated intervention to tackle violence in Kerala and nongovernment organisation staff in Delhi and Mumbai, the article presents its historical context and key barriers to effective implementation. While promising in terms of outreach and incremental changes in attitudes, barriers include deficits in infrastructure and institutional practices that reinforce inequities in gender–power relations, hostile attitudes, and limited capacities of health workforce to tackle the complex and diverse needs of women experiencing abuse. Locating these experiences in relation to other models rooted in feminist approach, I argue how conventional intervention models of provisioning fail to challenge institutional contexts and structural inequalities that underpin violence and compound vulnerabilities experienced by women, thereby serving a functional response. Health systems are social institutions embedded in prevailing gender norms and power relations that must be tackled alongside addressing imminent needs of women victims of abuse. To this end, feminist approaches to counselling and relational perspectives to social justice can strengthen responsiveness (and transformative potential) of integrated sector-wide interventions.

The identification of lattice multiphases in TiO2 nanocrystals is studied by high resolution transmission electron microscope and electron diffraction patterns. Based on the spectroscopic analysis using soft x-ray absorption and resonant inelastic soft x-ray scattering, it is believed that the oxygen vacancies at the interface exhibit structural distortion of the TiO68− cluster around the defect site as for the multiphase lattice. We elucidate that the extra 3d electrons nearby induce the inelastic scattering features with the excitation energy dependence owing to different energy relaxation processes, a characteristic of the electron-phonon coupling or the nature of the electron-hole pair at the intermediate state. The manifold dd excitations driven by the strong interaction between Ti-3d and O-2p electrons are noticeably rich, coexisting on both Ti and O sites. This sophisticated experiment can advance the perspective of nanocomposite TiO2 for various interactions of surface Ti3+ in applications of future devices.

BackgroundBlocking the PD-L1 immune checkpoint axis with therapeutic antibodies against either the ligand or PD-1 has proven to be an effective treatment modality for multiple cancer histologies. Small molecules targeting the PD-L1/PD-1 axis represent an alternate modality of blocking this pathway. INCB090244 is a small molecule that blocks the PD-L1/PD-1 interaction and restores T cell function similar to the clinical stage PD-L1 inhibitor INCB086550.MethodsMDA-MB-231 or CHO cells overexpressing PD-L1 were used to investigate effects of INCB090244 on PD-L1 dimerization, and intracellular trafficking. In vivo, CD34+ humanized mice harboring MDA-MB-231 tumors or C57Bl/6 mice bearing GL261 subcutaneous or orthotopic tumors were used to investigate the efficacy, biodistribution, and pharmacodynamic effects of INCB090244. Human specific gene expression changes in tumors from MDA-MB-231 bearing humanized mice were analyzed by RNA sequencing.ResultsIn vitro, INCB090244 potently disrupted the PD-L1:PD-1 interaction, induced PD-L1 dimerization, and inhibited PD-1-mediated negative signaling, resulting in enhanced IFN gamma and IL-2 production in primary human immune cells. Following dimerization, INCB090244 induced internalization of PD-L1 resulting in co-localization with the Golgi apparatus and partial localization in the nucleus. After cell treatment and washing, full restoration of PD-L1 at the cell surface was observed after 5 days of culture in vitro. In vivo, INCB090244 reduced tumor growth in CD34+ humanized mice bearing MDA-MB-231 tumors, to similar levels as atezolizumab. Antitumor activity was completely abrogated in immunodeficient mice, confirming the pharmacologic dependency on a competent immune system. RNA sequencing analysis on tumors from these mice demonstrated similar T cell activation gene signatures as clinical checkpoint blockade antibodies. Biodistribution studies in mice bearing both subcutaneous and orthotopically implanted GL261 glioma tumors demonstrated higher accumulation of INCB090244 in tumor tissue compared to PD-L1 antibodies.ConclusionsINCB090244 effectively disrupted the PD-L1/PD-1 interaction, induced dimerization and internalization of PD-L1, restored immunity in in vitro and in vivo tumor models, and is a suitable surrogate for the clinical candidate INCB086550. RNA sequencing demonstrated T cell activation signatures similar to those observed in patients receiving checkpoint blockade antibodies. Biodistribution studies demonstrated higher subcutaneous and brain tumor penetration by INCB090244 compared to PD-L1 antibodies, suggesting a potential advantage of small molecule PD-L1 inhibitors in accessing intratumoral regions. These data further support the clinical evaluation of small molecule PD-L1 inhibitors as an alternative approach to immune therapy.

Recent advances in synchrotron based x-ray spectroscopy enable materials scientists to emanate fingerprints on important materials properties, e.g., electronic, optical, structural, and magnetic properties, in real-time and under nearly real-world conditions. This characterization in combination with optimized materials synthesis routes and tailored morphological properties could contribute greatly to the advances in solid-state electronics and renewable energy technologies. In connection to this, such perspective reflects the current materials research in the space of emerging energy technologies, namely photocatalysis, with a focus on transition metal oxides, mainly on the Fe2O3- and TiO2-based materials.

Transition state stabilization is essential for rate acceleration of enzymatic reactions. Despite extensive studies on various transition state structures of enzymes, an intriguing puzzle is whether an enzyme can accommodate multiple transition states (TS) to catalyze a chemical reaction. It is experimentally challenging to interrogate this proposition in terms of the choices of suitable enzymes and the feasibility to distinguish multiple TS. As a paradigm with the protein lysine methyltransferase (PKMT) SET7/9 paired with its physiological substrates H3 and p53, their TS were solved with experimental kinetic isotope effects as computational constraints. Remarkably, SET7/9 adopts two structurally distinct TS---a nearly symmetric S(N)2 and an extremely early S(N)2---for H3K4 and p53K372 methylation, respectively. The two TS are also different from those previously revealed for other PKMTs. The setting of multiple TS is expected to be essential for SET7/9 and likely other PKMTs to act on broad substrates with high efficiency.

Global Health Security and Universal Health Coverage have been frequently considered as “two sides of the same coin”. Yet, greater analysis is required as to whether and where these two ideals converge and what important differences exist. A consequence of ignoring their individual characteristics is to distort global and local health priorities in an effort to streamline policymaking and funding activities. This paper examines the areas of convergence and divergence between global health security and universal health coverage, both conceptually and empirically. We consider analytical concepts of risk and human rights as fundamental to both goals, but also identify differences in priorities between the two ideals. We support the argument that the process of Health System Strengthening provides the most promising mechanism of benefiting both goals.

The Fourth Global Symposium on Health Systems Research was themed around 'Resilient and responsive health systems for a changing world.' This commentary is the outcome of a panel discussion at the symposium in which the resilience discourse and its use in health systems development was critically interrogated. The 2014-15 Ebola outbreak in West-Africa added momentum for the wider adoption of resilient health systems as a crucial element to prepare for and effectively respond to crisis. The growing salience of resilience in development and health systems debates can be attributed in part to development actors and philanthropies such as the Rockefeller Foundation. Three concerns regarding the application of resilience to health systems development are discussed: (1) the resilience narrative overrules certain democratic procedures and priority setting in public health agendas by 'claiming' an exceptional policy space; (2) resilience compels accepting and maintaining the status quo and excludes alternative imaginations of just and equitable health systems including the socio-political struggles required to attain those; and (3) an empirical case study from Gaza makes the case that resilience and vulnerability are symbiotic with each other rather than providing a solution for developing a strong health system. In conclusion, if the normative aim of health policies is to build sustainable, universally accessible, health systems then resilience is not the answer. The current threats that health systems face demand us to imagine beyond and explore possibilities for global solidarity and justice in health. [Abstract copyright: © The Author 2017; all rights reserved. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.]

© 2018 Elsevier Ltd The observation of a spontaneous electron enrichment at the apexes of bismuth vanadate (BiVO4) nanopyramidal arrays is achieved by performing synchrotron-based angular dependent X-ray absorption spectroscopy. In accordance with density function theory calculations, the formation of (112) facets enriched apexes is proposed. Such intrinsically electron-enriched (112) facets at the apexes produce a potential facilitating the diffusion of photoexcited holes, which not only mitigates the recombination with the photoexcited electrons, but also provide an active reaction site for the photoassisted selective growth of cobalt phosphate (CoPi), a well known and highly active co-catalyst for water oxidation at the apex of BiVO4nanopyramids. Benefiting from the element-resolved properties of synchrotron-based X-ray spectroscopy, 3d electrons on the vanadium site are directly resolved by resonant inelastic X-ray scattering measurements. Due to this unique morphology, the charge at the apex is expected to induce a strong interaction with CoPi, as a result of the metal-to-ligand charge transfer spectroscopy feature observed from the cobalt site. Substantial evidences are collected by means of comprehensive soft X-ray spectroscopy techniques with high spectral resolution revealing the atomic-scale origin and the nature of the synergy as well as the strong correlation between its unique structural properties and the electronic structure of this novel highly-ordered hybrid photocatalyst and its significantly improved photoelectrochemical performance.