Multiplatform characterization of dynamic changes in breast milk during lactation

The multicomponent analysis of human breast milk (BM) by metabolic profiling is a new area of study applied to determining milk composition, and is capable of associating BM composition with maternal characteristics, and subsequent infant health outcomes. A multiplatform approach combining HPLC‐MS and ultra‐performance LC‐MS, GC‐MS, CE‐MS, and 1H NMR spectroscopy was used to comprehensively characterize metabolic profiles from seventy BM samples. A total of 710 metabolites spanning multiple molecular classes were defined. The utility of the individual and combined analytical platforms was explored in relation to numbers of metabolites identified, as well as the reproducibility of the methods. The greatest number of metabolites was identified by the single phase HPLC‐MS method, while CE‐MS uniquely profiled amino acids in detail and NMR was the most reproducible, whereas GC‐MS targeted volatile compounds and short chain fatty acids. Dynamic changes in BM composition were characterized over the first 3 months of lactation. Metabolites identified as altering in abundance over lactation included fucose, di‐ and triacylglycerols, and short chain fatty acids, known to be important for infant immunological, neurological, and gastrointestinal development, as well as being an important source of energy. This extensive metabolic coverage of the dynamic BM metabolome provides a baseline for investigating the impact of maternal characteristics, as well as establishing the impact of environmental and dietary factors on the composition of BM, with a focus on the downstream health consequences this may have for infants

Assessing the climate resilience of community-managed water supplies in Ethiopia and Nepal

Understanding the resilience of water supplies to climate change is becoming an urgent priority to ensure health targets are met. Addressing systemic issues and building the resilience of community-managed supplies, which serve millions of people in rural LMIC settings, will be critical to improve access to safe drinking water. The How Tough is WASH (HTIW) framework to assess resilience was applied to community-managed water supplies in Ethiopia and Nepal to assess the effectiveness of this framework in field conditions. The resilience of these water supplies was measured along six domains—the environment, infrastructure, management, institutional support, community governance and supply chains—that can affect how they respond to climate change effects. We found that the HTIW framework provided an objective measure of resilience and could be used to rank water supplies in order of priority for action. We also found that systemic issues could be identified. The tools and methods used in the framework were easy to deploy by field research teams. The water supplies studied in Ethiopia and Nepal had low to moderate resilience to climate change. Service management and institutional support were weak in both countries. The data from Ethiopia and Nepal suggests that many water supplies in rural and small-town communities are unlikely to be resilient to future climate change without increased investment and support. The use of simple frameworks such as HTIW will be important in supporting decisions around such investments by identifying priority communities and actions

Sustainable Healthcare Elective in Nursing: A futures-thinking approach

Worldwide, despite over two decades of literature focusing on the climate emergency and its impact on public health, action on sustainable healthcare remains relatively neglected in nursing curricula. The UK government (Department for International Development) (Agenda 2030) pledged support for the United Nations 17 Global Goals for Sustainable Development, including action on climate change (Goal 13) (DfID, 2015). The NHS Sustainable Development Unit’ suggested ‘a sustainable health and care system is achieved by delivering high quality care and improved public health without exhausting natural resources or causing severe ecological damage’. Application of sustainability principles to medical and dental practice demonstrates cost savings, carbon reduction and lean thinking, particularly in respiratory medicine and nephrology/dialysis (Centre for Sustainable Healthcare, 2018)

Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)

ACKNOWLEDGMENTS The work was supported by National Institutes of Health grants DA027113 and EY024717 to G.A.T. and DA09158 to A.M. A portion of this work was submitted in 2011 by A. Kulkarni in partial fulfillment of M.S. degree requirements from Northeastern University, Boston, MA.Peer reviewedPublisher PD

Migration, Multiple Sexual Partnerships, and Sexual Concurrency in the Garífuna Population of Honduras

The Garífuna, an ethnic minority group in Honduras, have been disproportionately affected by HIV. Previous research suggests that migration and high rates of multiple sexual partnerships are major drivers of the epidemic. Using data from a 2012 population-based survey, we assessed whether temporary migration was associated with 1) multiple sexual partnerships and 2) sexual concurrency among Garífuna men and women in Honduras. Among both men and women, temporary migration in the last year was associated with an increased likelihood of multiple sexual partnerships and with concurrency, though only the association between migration and multiple sexual partnerships among men was statistically significant (Adjusted Prevalence Ratio 1.7, 95% CI 1.2-2.4). Migration may contribute to HIV/STI vulnerability among Garífuna men and women via increases in these sexual risk behaviors. Research conducted among men and women at elevated risk of HIV should continue to incorporate measures of mobility, including history of internal migration

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination

Background KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. Methods Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. Results Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. Conclusions We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors

Cationic tantalum oxide nanoparticle contrast agent for micro computed tomography reveals articular cartilage proteoglycan distribution and collagen architecture alterations

Objective: Cationic tantalum oxide nanoparticles (Ta2O5-cNPs), as a newly introduced contrast agent for computed tomography of cartilage, offer quantitative evaluation of proteoglycan (PG) content and biomechanical properties. However, knowledge on the depth-wise impact of cartilage constituents on nanoparticle diffusion, particularly the influence of the collagen network, is lacking. In this study, we aim to establish the depth-dependent relationship between Ta2O5-cNP diffusion and cartilage constituents (PG content, collagen content and network architecture). Methods: Osteochondral samples (n = 30) were harvested from healthy equine stifle joints (N = 15) and the diffusion of 2.55 nm diameter cationic Ta2O5-cNPs into the cartilage was followed with micro computed tomography (µCT) imaging for up to 96 hours. The diffusion-related parameters, Ta2O5-cNP maximum partition (Pmax) and diffusion time constant, were compared against biomechanical and depth-wise structural properties. Biomechanics were assessed using stress-relaxation and sinusoidal loading protocols, whereas PG content, collagen content and collagen network architecture were determined using digital densitometry, Fourier-transform infrared spectroscopy and polarized light microscopy, respectively. Results: The Pmax correlates with the depth-wise distribution of PGs (bulk Spearman's ρ = 0.87, p < 0.001). More open collagen network architecture at the superficial zone enhances intake of Ta2O5-cNPs, but collagen content overall decreases the intake. The Pmax values correlate with the equilibrium modulus (ρ = 0.80, p < 0.001) of articular cartilage. Conclusion: This study establishes the feasibility of Ta2O5-cNPs for the precise and comprehensive identification of biomechanical and structural changes in articular cartilage via contrast-enhanced µCT