Identification of Components of the Host Type IA Phosphoinositide 3-Kinase Pathway That Promote Internalization of Listeria monocytogenes

The bacterial pathogen Listeria monocytogenes causes food-borne illnesses resulting in gastroenteritis, meningitis, or abortion. Listeria promotes its internalization into some human cells through binding of the bacterial surface protein InlB to the host receptor tyrosine kinase Met. The interaction of InlB with the Met receptor stimulates host signaling pathways that promote cell surface changes driving bacterial uptake. One human signaling protein that plays a critical role in Listeria entry is type IA phosphoinositide 3-kinase (PI 3-kinase). The molecular mechanism by which PI 3-kinase promotes bacterial internalization is not understood. Here we perform an RNA interference (RNAi)-based screen to identify components of the type IA PI 3-kinase pathway that control the entry of Listeria into the human cell line HeLa. The 64 genes targeted encode known upstream regulators or downstream effectors of type IA PI 3-kinase. The results of this screen indicate that at least 9 members of the PI 3-kinase pathway play important roles in Listeria uptake. These 9 human proteins include a Rab5 GTPase, several regulators of Arf or Rac1 GTPases, and the serine/threonine kinases phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTor), and protein kinase C-zeta. These findings represent a key first step toward understanding the mechanism by which type IA PI 3-kinase controls bacterial internalization

Countdown to 2030 : tracking progress towards universal coverage for reproductive, maternal, newborn, and child health

Building upon the successes of Countdown to 2015, Countdown to 2030 aims to support the monitoring and measurement of women's, children's, and adolescents' health in the 81 countries that account for 95% of maternal and 90% of all child deaths worldwide. To achieve the Sustainable Development Goals by 2030, the rate of decline in prevalence of maternal and child mortality, stillbirths, and stunting among children younger than 5 years of age needs to accelerate considerably compared with progress since 2000. Such accelerations are only possible with a rapid scale-up of effective interventions to all population groups within countries (particularly in countries with the highest mortality and in those affected by conflict), supported by improvements in underlying socioeconomic conditions, including women's empowerment. Three main conclusions emerge from our analysis of intervention coverage, equity, and drivers of reproductive, maternal, newborn, and child health (RMNCH) in the 81 Countdown countries. First, even though strong progress was made in the coverage of many essential RMNCH interventions during the past decade, many countries are still a long way from universal coverage for most essential interventions. Furthermore, a growing body of evidence suggests that available services in many countries are of poor quality, limiting the potential effect on RMNCH outcomes. Second, within-country inequalities in intervention coverage are reducing in most countries (and are now almost non-existent in a few countries), but the pace is too slow. Third, health-sector (eg, weak country health systems) and non-health-sector drivers (eg, conflict settings) are major impediments to delivering high-quality services to all populations. Although more data for RMNCH interventions are available now, major data gaps still preclude the use of evidence to drive decision making and accountability. Countdown to 2030 is investing in improvements in measurement in several areas, such as quality of care and effective coverage, nutrition programmes, adolescent health, early childhood development, and evidence for conflict settings, and is prioritising its regional networks to enhance local analytic capacity and evidence for RMNCH

Policies and clinical practices relating to the management of gestational diabetes mellitus in the public health sector, South Africa – a qualitative study

BACKGROUND: Women with a prior gestational diabetes have an increased lifetime risk of developing type 2 diabetes. Although post-partum follow-up for GDM women is essential to prevent progression to type 2 diabetes, it is poorly attended. The need for health systems interventions to support postpartum follow-up for GDM women is evident, but there is little knowledge of actual current practice. The aim of this study was to explore current policies and clinical practices relating to antenatal and post-natal care for women with GDM in South Africa, as well as health sector stakeholders’ perspectives on the barriers to – and opportunities for – delivering an integrated mother - baby health service that extends beyond the first week post-partum, to the infant’s first year of life. METHODS: Following a document review of policy and clinical practice guidelines, in-depth interviews were conducted with 11 key informants who were key policy makers, health service managers and clinicians working in the public health services in South Africa’s two major cities (Johannesburg and Cape Town). Data were analysed using qualitative content analysis procedures. RESULTS: The document review and interviews established that it is policy that health services adhere to international guidelines for GDM diagnosis and management, in addition to locally developed guidelines and protocols for clinical practice. All key informants confirmed that lack of postpartum follow-up for GDM women is a significant problem. Health systems barriers include fragmentation of care and the absence of standardised postnatal care for post-GDM women. Key informants also raised patient - related challenges including lack of perceived future risk of developing type 2 diabetes and non-attendance for postpartum follow up, as barriers to postnatal care for GDM women. All participants supported integrated primary health services but cautioned against overloading health workers. CONCLUSION: Although there is alignment between international guidelines, local policy and reported clinical practice in the management of GDM, there is a gap in continuation of care in the postpartum period. Health systems interventions that support and facilitate active follow-up for women with prior GDM are needed if high rates of progression to type 2 diabetes are to be avoided

Can multi-criteria decision analysis (MCDA) be implemented into real-world drug decision-making processes? A Canadian provincial experience.

OBJECTIVE:To describe the implementation of multi-criteria decision analysis (MCDA) into a Canadian public drug reimbursement decision-making process, identifying the aspects of the MCDA approach, and the context that promoted uptake. METHODS:Narrative summary of case study describing the how, when, and why of implementing MCDA. RESULTS:Faced with a fixed budget, a pipeline of expensive but potentially valuable drugs, and potential delays to drug decision making, the Ministry of Health (i.e., decision makers) and its independent expert advisory committee (IAB) sought alternative values-based decision processes. MCDA was considered highly compatible with current processes, but the ability as a stand-alone intervention to address issues of opportunity cost was unclear. The IAB nevertheless collaboratively voted to implement an externally developed MCDA with support from decision makers. After several months of engagement and piloting, implementation was rapid and leveraged strong pre-existing formal and informal communication networks. The IAB as a whole rates new submissions which serves as an input into the deliberative process. CONCLUSIONS:MCDA can be a highly adaptable approach that can be implemented into a functioning drug reimbursement setting when facilitated by (i) a truly limited budget; (ii) a shared vision for change by end-users and decision makers; (iii) using pre-existing deliberative processes; and (iv) viewing the approach as a decision framework rather than the decision (when appropriate). Given the current limitations of MCDA, implementing an academically imperfect tool first and evaluating later reflects a practical solution to real-time fiscal constraints and impending delays to drug approvals that may be faced by decision makers

The Influence of Branched-Chain Amino Acid Supplementation on Fatigue and Tryptophan Metabolism After Acute and Chronic Exercise in Older Adults: Protocol for a Pilot Randomized Controlled Trial

BackgroundFatigue is a strong predictor of negative health outcomes in older adults. Kynurenine, a metabolite of tryptophan, is strongly associated with fatigue. Reductions in fatigue are observed with exercise; however, exercise training does not completely alleviate symptoms. Branched-chain amino acids (BCAAs) have been shown to have advantageous effects on exercise performance and compete with kynurenine for transport into the central nervous system. Thus, the combination of BCAA and exercise may exert synergized effects of mental and physical fatigue. Therefore, we hypothesize that BCAA added to exercise will shift kynurenine metabolism toward enhanced synthesis of kynurenic acid, thereby reducing fatigue. ObjectiveThis randomized, double-blind, placebo-controlled trial aims to compare the effects of acute (approximately 45 min) and chronic (8 wk) exercise with and without BCAA supplementation on mental and physical fatigue and assess whether the hypothesized outcomes are modulated by changes in kynurenine metabolism in 30 older adults (n=15, 50% per group). MethodsOlder adults (aged 60-80 y) who do not exercise >2 days per week and self-report fatigue (≥3 on a scale of 1-10) will be recruited. Participants will be randomized to either the exercise+BCAA group or exercise+placebo group. Participants will engage in high-volume, moderate-intensity, whole-body exercise training (aerobic and resistance exercise; either in-person or web-based sessions) 3 times per week for 8 weeks. In addition, participants will consume daily either 100 mg/kg body weight of BCAA (2:1:1 leucine:isoleucine:valine) or placebo (maltodextrin) throughout the 8-week intervention. BCAA and placebo powders will be identical in color and dissolved in 400 mL of water and 2.5 g of a calorie-free water flavor enhancer. Muscle biopsies will be collected before and after the intervention after a 12-hour fast to examine changes in the biomarkers of tryptophan metabolism and inflammation. Our primary outcomes include changes in mental and physical fatigue and metabolism after the 8-week exercise training between the 2 groups. Mental and physical fatigue will be measured before and after the intervention. Mental fatigue will be subjectively assessed through the completion of validated questionnaires. Physical fatigue will be measured by isometric handgrip, 1-repetition maximum, chair rise, 400-meter walk, and cardiopulmonary exercise tests. ResultsThe study was funded in March 2022, with an anticipated projected data collection period lasting from January 2023 through December 2023. ConclusionsThe discovery that kynurenine concentrations are associated with fatigue and are responsive to BCAA supplementation during exercise training could have important implications for the development of future interventions, both lifestyle and pharmacologic, to treat fatigue in older adults. Trial RegistrationClinicalTrials.gov NCT05484661; https://www.clinicaltrials.gov/study/NCT05484661 International Registered Report Identifier (IRRID)DERR1-10.2196/5219