Evidence for a Role of the Multifunctional Calcium/Calmodulin-Dependent Protein Kinase II in Insulin Secretion

Calcium/calmodulin-dependent protein kinase II (CaM kinase II) is demonstrated to exist in the ß-cell and immunopecipitation. Glucose and potassium significantly stimulate the rapid autophosphorylation of CaM kinase II and proportionally induce autonomous activity of the kinase in a dose-dependent manner that parallels insulin secretion. The activation of CaM kinase II, alloxan, KN-62 and KN-93, suggest that the enzyme is an integral component of insulin secretion and/or related processes in the β-cell

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer

Endometrial cancer; Metastatic; RecurrentCàncer d'endometri; Metastàtic; RecurrentCáncer endometrial; Metastásico; RecurrenteObjective This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. Methods Patients with histologic diagnosis of endometrial cancer (1–2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2–4, 9–11, 16–18, and 23–25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1–3, 8–10, 15–17, and 22–24. Results Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58–1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43–1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. Conclusions Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. Trial registration: ClinicalTrials.gov number, NCT02725268Takeda Development Center Americas, Inc., Lexington, MA, USA. This work was supported by funding from Takeda Development Center Americas, Inc. The study was designed by the authors in conjunction with the sponsors. Data were gathered and analyzed by the investigator and the sponsor; all the authors had access to the data. The authors received medical writing support for drafting the manuscript, which was funded by Takeda Pharmaceuticals USA, Inc. Manuscript drafts were reviewed by all authors and the sponsor and all the authors made the decision to submit the manuscript for publication

Mapping regional cooperation of state actors for health research systems in Africa:: a social network analysis

Regional bodies can potentially play an important role in improving health research in Africa. This study analyses the network of African state-based regional organisations for health research and assesses their potential relationship with national health research performance metrics. After cataloguing organisations and their membership, we conducted a social network analysis to determine key network attributes of national governments’ connections via regional organisations supporting functions of health research systems. This data was used to test the hypothesis that state actors with more connections to other actors via regional organisations would have higher levels of health research performance across indicators. With 21 unique regional organisations, the African continent is densely networked around health research systems issues. In general, the regional network for health research is inclusive. No single actor serves as a nexus. However, when statistics are grouped by African Union regions, influential poles emerge, with the most predominate spheres of influence in East and West Africa. Further, when connectivity data was analysed against national health research performance, there were no statistically significant relationships between increased connectivity and higher performance of key health research metrics. The inclusive and dense network dynamics of African regional organisations for health research strengthening present key opportunities for knowledge diffusion and cooperation to improve research capacity on the continent. Further reflection is needed on appropriate and meaningful ways to assess the role of regionalism and evaluate the influence of regional organisations in strengthening health research systems in Africa

Self-Swabbing for Virological Confirmation of Influenza-Like Illness Among an Internet-Based Cohort in the UK During the 2014-2015 Flu Season: Pilot Study

BACKGROUND: Routine influenza surveillance, based on laboratory confirmation of viral infection, often fails to estimate the true burden of influenza-like illness (ILI) in the community because those with ILI often manage their own symptoms without visiting a health professional. Internet-based surveillance can complement this traditional surveillance by measuring symptoms and health behavior of a population with minimal time delay. Flusurvey, the UK's largest crowd-sourced platform for surveillance of influenza, collects routine data on more than 6000 voluntary participants and offers real-time estimates of ILI circulation. However, one criticism of this method of surveillance is that it is only able to assess ILI, rather than virologically confirmed influenza. OBJECTIVE: We designed a pilot study to see if it was feasible to ask individuals from the Flusurvey platform to perform a self-swabbing task and to assess whether they were able to collect samples with a suitable viral content to detect an influenza virus in the laboratory. METHODS: Virological swabbing kits were sent to pilot study participants, who then monitored their ILI symptoms over the influenza season (2014-2015) through the Flusurvey platform. If they reported ILI, they were asked to undertake self-swabbing and return the swabs to a Public Health England laboratory for multiplex respiratory virus polymerase chain reaction testing. RESULTS: A total of 700 swab kits were distributed at the start of the study; from these, 66 participants met the definition for ILI and were asked to return samples. In all, 51 samples were received in the laboratory, 18 of which tested positive for a viral cause of ILI (35%). CONCLUSIONS: This demonstrated proof of concept that it is possible to apply self-swabbing for virological laboratory testing to an online cohort study. This pilot does not have significant numbers to validate whether Flusurvey surveillance accurately reflects influenza infection in the community, but highlights that the methodology is feasible. Self-swabbing could be expanded to larger online surveillance activities, such as during the initial stages of a pandemic, to understand community transmission or to better assess interseasonal activity

Beyond the metrics of health research performance in African countries

While it is important to be able to evaluate and measure a country’s performance in health research (HR), HR systems are complex and multifaceted in nature. As such, attempts at measurement can suffer several limitations which risk leading to inadequate indices or representations. In this study, we critically review common indicators of HR capacity and performance and explore their strengths and limitations. The paper is informed by review of data sources and documents, combined with interviews and peer-to-peer learning activities conducted with officials working in health and education ministries in a set of nine African countries. We find that many metrics that can assess HR performance have gaps in the conceptualisation or fail to address local contextual realities, which makes it a challenge to interpret them in relation to other theoretical constructs. Our study identified several concepts that are excluded from current definitions of indicators and systems of metrics for HR performance. These omissions may be particularly important for interpreting HR performance within the context and processes of HR in African countries, and thus challenging the relevance, utility, appropriateness and acceptability of universal measures of HR in the region. We discuss the challenges that scholars may find in conceptualising such a complex phenomenon—including the different and competing viewpoints of stakeholders, in setting objectives of HR measurement work, and in navigating the realities of empirical measurement where missing or partial data may necessitate that proxies or alternative indicators may be chosen. These findings are important to ensure that the global health community does not rely on over-simplistic evaluations of HR when analysing and planning for improvements in low-income and middle-income countries

Measuring health science research and development in Africa: mapping the available data

Background: In recent years there have been calls to strengthen health sciences research capacity in African countries. This capacity can contribute to improvements in health, social welfare and poverty reduction through domestic application of research findings; it is increasingly seen as critical to pandemic preparedness and response. Developing research infrastructure and performance may reduce national economies’ reliance on primary commodity and agricultural production, as countries strive to develop knowledge-based economies to help drive macroeconomic growth. Yet efforts to date to understand health sciences research capacity are limited to output metrics of journal citations and publications, failing to reflect the complexity of the health sciences research landscape in many settings. Methods: We map and assess current capacity for health sciences research across all 54 countries of Africa by collecting a range of available data. This included structural indicators (research institutions and research funding), process indicators (clinical trial infrastructures, intellectual property rights and regulatory capacities) and output indicators (publications and citations). Results: While there are some countries which perform well across the range of indicators used, for most countries the results are varied—suggesting high relative performance in some indicators, but lower in others. Missing data for key measures of capacity or performance is also a key concern. Taken as a whole, existing data suggest a nuanced view of the current health sciences research landscape on the African continent. Conclusion: Mapping existing data may enable governments and international organizations to identify where gaps in health sciences research capacity lie, particularly in comparison to other countries in the region. It also highlights gaps where more data are needed. These data can help to inform investment priorities and future system needs

Governance of health research in four Eastern and Southern African countries

BACKGROUND: Health research governance is an essential function of national health research systems. Yet many African countries have not developed strong health research governance structures and processes. This paper presents a comparative analysis of national health research governance in Botswana, Kenya, Uganda and Zambia, where health sciences research production is well established relative to some others in the region and continues to grow. The paper aims to examine progress made and challenges faced in strengthening health research governance in these countries. METHODS: We collected data through document review and key informant interviews with a total of 80 participants including decision-makers, researchers and funders across stakeholder institutions in the four countries. Data on health research governance were thematically coded for policies, legislation, regulation and institutions and analysed comparatively across the four national health research systems. RESULTS: All countries were found to be moving from using a research governance framework set by national science, technology and innovation policies to one that is more anchored in health research structures and policies within the health sectors. Kenya and Zambia have adopted health research legislation and policies, while Botswana and Uganda are in the process of developing the same. National-level health research coordination and regulation is hampered by inadequate financial and human resource capacities, which present challenges for building strong health research governance institutions. CONCLUSION: Building health research governance as a key pillar of national health research systems involves developing stronger governance institutions, strengthening health research legislation, increasing financing for governance processes and improving human resource capacity in health research governance and management

Synovial incorporation of polyacrylamide hydrogel after injection into normal and osteoarthritic animal joints

Polyacrylamide hydrogel (PAAG) is a non-toxic, non-degradable synthetic product, used for years in the augmentation of soft tissues. Preliminary results in animals and humans have suggested long-lasting beneficial effects on symptoms of osteoarthritis (OA). The aim of this histopathological study was to investigate whether intra-articular injection of PAAG is integrated into synovial tissue in normal and OA animal joints, and if this integration is sustained.(A) A prospective, controlled, longitudinal study of normal knee joints injected with PAAG was performed in 10 rabbits, following the animals up to 1 year, and (B) a post mortem examination was carried out up to 2 years post-injection on 18 horse joints which had previously been treated with 1-2 injections of 2 ml PAAG for clinically and radiologically diagnosed OA.Integration of the injected gel was evident at day 10 in the rabbit and by day 14 in the horse, with proliferation and invasion of synovial cells into the gel. By day 90 in rabbit joints and day 30 in horse joints, the gel had formed a sub-synovial layer, which was traversed by thin strands of connective tissue with vessels and covered by a synovial lining facing the joint cavity. This histological appearance persisted up to 2 years post-injection in horse joints.Intra-articular injection of PAAG results in a stable, long-lasting sub-synovial layer of gel traversed with thin strands of connective tissue. Further studies to explore potential effects on synovial inflammation and pain are warranted