<jats:title>Abstract</jats:title><jats:p>Epigenetic modifications on chromatin play important roles in regulating gene expression. While chromatin states are often governed by multi-layered structure, how individual pathways contribute to gene expression remains poorly understood. For example, DNA methylation is known to regulate transcription factor binding but also to recruit methyl-CpG binding proteins that affect chromatin structure through the activity of histone deacetylase complexes (HDACs). Both of these mechanisms can potentially affect gene expression, but the importance of each, and whether these activities are integrated to achieve appropriate gene regulation, remains largely unknown. To address this important question, we measured gene expression, chromatin accessibility, and transcription factor occupancy in wild-type or DNA methylation-deficient mouse embryonic stem cells following HDAC inhibition. Interestingly, we observe widespread increases in chromatin accessibility at repeat elements when HDACs are inhibited, and this is magnified when cells also lack DNA methylation. A subset of these elements have elevated binding of the YY1 and GABPA transcription factors and increased expression. The pronounced additive effect of HDAC inhibition in DNA methylation deficient cells demonstrate that DNA methylation and histone deacetylation act largely independently to suppress transcription factor binding and gene expression.</jats:p>
\n \n\n \n \n<jats:sec><jats:title>Introduction</jats:title><jats:p>This paper maps the evidence published between 2000 and 2018 on the use of mobile technologies to train community health workers (CHWs) in low- and middle-income countries (LMICs) across nine areas of global healthcare, including the neglected areas of disability and mental health.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used an evidence mapping methodology, based on systematic review guidelines, to systematically and transparently assess the available evidence-base. We searched eight scientific databases and 54 grey literature sources, developed explicit inclusion criteria, and coded all included studies at full text for key variables. The included evidence-base was visualised and made accessible through heat mapping and the development of an online interactive evidence interface.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The systematic search for evidence identified a total of 2530 citations of which 88 met the full inclusion criteria. Results illustrate overall gaps and clusters of evidence. While the evidence map shows a positive shift away from information dissemination towards approaches that use more interactive learner-centred pedagogies, including supervision and peer learning, this was not seen across all areas of global health. Areas of neglect remain; no studies of trauma, disability, nutrition or mental health that use information dissemination, peer learning or supervision for training CHWs in LMICs were found.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The evidence map shows significant gaps in the use of mobile technologies for training, particularly in the currently neglected areas of global health. Significant work will be needed to improve the evidence-base, including assessing the quality of mobile-based training programmes.</jats:p></jats:sec>
\n \n\n \n \n<sec>\n <title>BACKGROUND</title>\n <p>The Kenyan government, working with international partners and local organizations, has developed an eHealth strategy, specified standards, and guidelines for electronic health record adoption in public hospitals and implemented two major health information technology projects: District Health Information Software Version 2, for collating national health care indicators and a rollout of the KenyaEMR and International Quality Care Health Management Information Systems, for managing 600 HIV clinics across the country. Following these projects, a modified version of the Open Medical Record System electronic health record was specified and developed to fulfill the clinical and administrative requirements of health care facilities operated by devolved counties in Kenya and to automate the process of collating health care indicators and entering them into the District Health Information Software Version 2 system.</p>\n </sec>\n <sec>\n <title>OBJECTIVE</title>\n <p>We aimed to present a descriptive case study of the implementation of an open source electronic health record system in public health care facilities in Kenya.</p>\n </sec>\n <sec>\n <title>METHODS</title>\n <p>We conducted a landscape review of existing literature concerning eHealth policies and electronic health record development in Kenya. Following initial discussions with the Ministry of Health, the World Health Organization, and implementing partners, we conducted a series of visits to implementing sites to conduct semistructured individual interviews and group discussions with stakeholders to produce a historical case study of the implementation.</p>\n </sec>\n <sec>\n <title>RESULTS</title>\n <p>This case study describes how consultants based in Kenya, working with developers in India and project stakeholders, implemented the new system into several public hospitals in a county in rural Kenya. The implementation process included upgrading the hospital information technology infrastructure, training users, and attempting to garner administrative and clinical buy-in for adoption of the system. The initial deployment was ultimately scaled back due to a complex mix of sociotechnical and administrative issues. Learning from these early challenges, the system is now being redesigned and prepared for deployment in 6 new counties across Kenya.</p>\n </sec>\n <sec>\n <title>CONCLUSIONS</title>\n <p>Implementing electronic health record systems is a challenging process in high-income settings. In low-income settings, such as Kenya, open source software may offer some respite from the high costs of software licensing, but the familiar challenges of clinical and administration buy-in, the need to adequately train users, and the need for the provision of ongoing technical support are common across the North-South divide. Strategies such as creating local support teams, using local development resources, ensuring end user buy-in, and rolling out in smaller facilities before larger hospitals are being incorporated into the project. These are positive developments to help maintain momentum as the project continues. Further integration with existing open source communities could help ongoing development and implementations of the project. We hope this case study will provide some lessons and guidance for other challenging implementations of electronic health record systems as they continue across Africa.</p>\n </sec>
\n \n\n \n \n<sec>\n <title>BACKGROUND</title>\n <p>As healthcare facilities in Low- and Middle-Income Countries (LMICs) such as Kenya adopt Electronic Health Record (EHR) systems to improve hospital administration and patient care, it is important to understand the adoption process, identify the key stakeholders, and assess the capabilities of the systems in use.</p>\n </sec>\n <sec>\n <title>OBJECTIVE</title>\n <p>To describe the level of adoption of Electronic Health Records systems in public hospitals and understand the process of adoption from Health Management Information System (HMIS) system vendors and system users.</p>\n </sec>\n <sec>\n <title>METHODS</title>\n <p>We conducted a survey of County Health Records Information Officers (CHRIOs) in Kenya to determine the level of adoption of Electronic Health Records systems in public hospitals. We conducted site visits to hospitals to view systems in use and to interview hospital administrators and end users. We also interviewed Health Management Information System (HMIS) system vendors to understand the adoption process from their perspective.</p>\n </sec>\n <sec>\n <title>RESULTS</title>\n <p>From the survey of CHRIOs, all facilities mentioned had adopted some form of EHR. Hospitals commonly purchased systems for patient administration and hospital billing functions. Radiology and laboratory management systems were commonly standalone systems. There were varying levels of interoperability within facilities that had more than one system in operation. We only saw one in-patient EHR system in use although many vendors and hospital administrators we interviewed were planning to adopt or support such systems. From the user perspective, issues such as system usability, adequate training, availability of adequate infrastructure and system support emerged. From the vendor perspective, a wide range of services was available to the hospital though constrained by funding and the need to computerise service areas that were deemed as priority. Additionally, vendors were unable to implement some data sharing modules linking to national HMIS due to lack of appropriate policies to facilitate this and users\u2019 lack of confidence in new technologies such as cloud services.</p>\n </sec>\n <sec>\n <title>CONCLUSIONS</title>\n <p>EHR adoption in Kenya has been underway for some years, particularly in comprehensive care clinics, and hospitals are increasing purchasing systems to support administrative functions. Considerable support from government, donors and regional health informatics organisations will be required to enable hospitals to move to full EHR adoption for in-patient care.</p>\n </sec>
\n \n\n \n \nThe growth hormone secretagogue receptor type\u20051a (GHS-R1a) is a class\u2005A rhodopsin-like G\u2005protein coupled receptor (GPCR) that is expressed in a variety of human tissues and is differentially expressed in benign and malignant prostate cancer. Previously, the peptidomimetic [1-Nal4 ,Lys5 (4-fluorobenzoyl)]G-7039 was designed as a molecular imaging tool for positron emission tomography (PET). However, this candidate was a poor binder (IC50 =69\u2005nm), required a lengthy four-step radiosynthesis, and had a cLogP above 8. To address these challenges, we now report on changes targeted at the 4th position of G-7039. A 2-fluoropropionic acid (2-FPA) group was added on to Lys5 to determine the potential binding affinity of the [18 F]-2-FP radiolabeled analogue, which could be prepared by simplified radiochemistry. Lead candidate [Tyr4 ,Lys5 (2-fluoropropionyl)]G-7039 exhibited an IC50 of 0.28\u2005nm and low picomolar activity toward GHS-R1a. Molecular docking revealed a molecular basis for this picomolar affinity.
\n \n\n \n \nMost studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.
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