Binding of Pentagalloyl Glucose to Aortic Wall Proteins: Insights from Peptide Mapping and Simulated Docking Studies.

Pentagalloyl glucose (PGG) is currently being investigated as a non-surgical treatment for abdominal aortic aneurysms (AAAs); however, the molecular mechanisms of action of PGG on the AAA matrix components and the intra-luminal thrombus (ILT) still need to be better understood. To assess these interactions, we utilized peptide fingerprinting and molecular docking simulations to predict the binding of PGG to vascular proteins in normal and aneurysmal aorta, including matrix metalloproteinases (MMPs), cytokines, and fibrin. We performed PGG diffusion studies in pure fibrin gels and human ILT samples. PGG was predicted to bind with high affinity to most vascular proteins, the active sites of MMPs, and several cytokines known to be present in AAAs. Finally, despite potential binding to fibrin, PGG was shown to diffuse readily through thrombus at physiologic pressures. In conclusion, PGG can bind to all the normal and aneurysmal aorta protein components with high affinity, potentially protecting the tissue from degradation and exerting anti-inflammatory activities. Diffusion studies showed that thrombus presence in AAAs is not a barrier to endovascular treatment. Together, these results provide a deeper understanding of the clinical potential of PGG as a non-surgical treatment of AAAs.

COVID-19: lessons and experiences from South Africa's first surge.

On 5 March 2020, South Africa recorded its first case of imported COVID-19. Since then, cases in South Africa have increased exponentially with significant community transmission. A multisectoral approach to containing and mitigating the spread of SARS-CoV-2 was instituted, led by the South African National Department of Health. A National COVID-19 Command Council was established to take government-wide decisions. An adapted World Health Organiszion (WHO) COVID-19 strategy for containing and mitigating the spread of the virus was implemented by the National Department of Health. The strategy included the creation of national and provincial incident management teams (IMTs), which comprised of a variety of work streams, namely, governance and leadership; medical supplies; port and environmental health; epidemiology and response; facility readiness and case management; emergency medical services; information systems; risk communication and community engagement; occupational health and safety and human resources. The following were the most salient lessons learnt between March and September 2020: strengthened command and control were achieved through both centralised and decentralised IMTs; swift evidenced-based decision-making from the highest political levels for instituting lockdowns to buy time to prepare the health system; the stringent lockdown enabled the health sector to increase its healthcare capacity. Despite these successes, the stringent lockdown measures resulted in economic hardship particularly for the most vulnerable sections of the population.

Proteasome Inhibition in Brassica napus Roots Increases Amino Acid Synthesis to Offset Reduced Proteolysis.

Cellular homeostasis is maintained by the proteasomal degradation of regulatory and misfolded proteins, which sustains the amino acid pool. Although proteasomes alleviate stress by removing damaged proteins, mounting evidence indicates that severe stress caused by salt, metal(oids), and some pathogens can impair the proteasome. However, the consequences of proteasome inhibition in plants are not well understood and even less is known about how its malfunctioning alters metabolic activities. Lethality causes by proteasome inhibition in non-photosynthetic organisms stem from amino acid depletion, and we hypothesized that plants respond to proteasome inhibition by increasing amino acid biosynthesis. To address these questions, the short-term effects of proteasome inhibition were monitored for 3, 8 and 48 h in the roots of Brassica napus treated with the proteasome inhibitor MG132. Proteasome inhibition did not affect the pool of free amino acids after 48 h, which was attributed to elevated de novo amino acid synthesis; these observations coincided with increased levels of sulfite reductase and nitrate reductase activities at earlier time points. However, elevated amino acid synthesis failed to fully restore protein synthesis. In addition, transcriptome analysis points to perturbed abscisic acid signaling and decreased sugar metabolism after 8 h of proteasome inhibition. Proteasome inhibition increased the levels of alternative oxidase but decreased aconitase activity, most sugars and tricarboxylic acid metabolites in root tissue after 48 h. These metabolic responses occurred before we observed an accumulation of reactive oxygen species. We discuss how the metabolic response to proteasome inhibition and abiotic stress partially overlap in plants.

Rationale for Using Irreversible Epidermal Growth Factor Receptor Inhibitors in Combination with Phosphatidylinositol 3-Kinase Inhibitors for Advanced Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a common and debilitating form of cancer characterized by poor patient outcomes and low survival rates. In HNSCC, genetic aberrations in phosphatidylinositol 3-kinase (PI3K) and epidermal growth factor receptor (EGFR) pathway genes are common, and small molecules targeting these pathways have shown modest effects as monotherapies in patients. Whereas emerging preclinical data support the combined use of PI3K and EGFR inhibitors in HNSCC, in-human studies have displayed limited clinical success so far. Here, we examined the responses of a large panel of patient-derived HNSCC cell lines to various combinations of PI3K and EGFR inhibitors, including EGFR agents with varying specificity and mechanistic characteristics. We confirmed the efficacy of PI3K and EGFR combination therapies, observing synergy with α isoform-selective PI3K inhibitor HS-173 and irreversible EGFR/ERBB2 dual inhibitor afatinib in most models tested. Surprisingly, however, our results demonstrated only modest improvement in response to HS-173 with reversible EGFR inhibitor gefitinib. This difference in efficacy was not explained by differences in ERBB target selectivity between afatinib and gefitinib; despite effectively disrupting ERBB2 phosphorylation, the addition of ERBB2 inhibitor CP-724714 failed to enhance the effect of HS-173 gefitinib dual therapy. Accordingly, although irreversible ERBB inhibitors showed strong synergistic activity with HS-173 in our models, none of the reversible ERBB inhibitors were synergistic in our study. Therefore, our results suggest that the ERBB inhibitor mechanism of action may be critical for enhanced synergy with PI3K inhibitors in HNSCC patients and motivate further preclinical studies for ERBB and PI3K combination therapies.

Prevalence of Childhood Permanent Hearing Loss after Early Complex Cardiac Surgery.

OBJECTIVES: To estimate the prevalence of childhood permanent hearing loss (PHL) after early cardiac surgery. STUDY DESIGN: This prospective observational (1996-2015) study after complex cardiac surgery with cardiopulmonary bypass at ≤6 weeks of life reports audiology follow-up by registered pediatric-experienced audiologists at 6-8 months postsurgery, age 2 years, and as required throughout and thereafter to complete diagnoses. PHL at any frequency (500-4000 Hz) is defined as responses of >25-decibel hearing level in either ear. PHL was evaluated by type (conductive or sensorineural), pattern (flat or sloping), and severity (mild to profound). RESULTS: Survival rate was 83.4% (706 of 841 children) with a 97.9% follow-up rate (691 children); 41 children had PHL, 5.9% (95% CI 4.3%, 8.0%). By cardiac defect, prevalence was biventricular, 4.0% (95%CI 2.5%, 6.1%); single ventricle, 10.8% (95%CI 6.8%, 16.1%). Eighty-seven (12.6%) of 691 had syndromes/genetic abnormalities with known association with PHL; of these, 17 (41.5%) had PHL. Of 41 children, 4 had permanent conductive, moderate to severe loss (1 bilateral); 37 had moderate to profound sensorineural loss (29 bilateral with 20 sloping and 9 flat), 6 with cochlear implant done or recommended. CONCLUSIONS: Infants surviving complex cardiac surgery are at high risk for PHL. Over 40% with PHL have known syndromes/genetic abnormalities, but others do not have easily identifiable risk indicators. Early cardiac surgery should be considered a risk indicator for PHL.

Cardiovascular Disease in Women.

Cardiovascular disease in women as a distinct disease entity is underappreciated relative to other female-specific diseases. A perception that cardiovascular disease affects men more commonly and a lack of understanding about the underlying pathophysiology of cardiovascular disease in women contribute to this phenomenon. Hormonal changes, pregnancy-related conditions, and cancer therapies have an impact on endothelial function, vascular anatomy, and myocardial contractility. Women with heart disease often present later, receive care not consistent with accepted guidelines, and have less access to diagnostic and therapeutic resources. Understanding the differences and challenges of treating cardiovascular disease in women is essential to improving population health.

Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC.

OBJECTIVE: Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite the frequency of activating genomic alterations in PIK3CA (the gene encoding the catalytic subunit of PI3K, targeted inhibitors of PI3K have not shown clinical efficacy as monotherapies. We hypothesized that co-dependent pathways, including the Ras-MEK-ERK pathway, may still be functional in the presence of PI3K inhibitors and might serve as mediators of this resistance. METHODS: We assessed the hypothesis using resazurin cell viability and trypan blue exclusion assays. We also used Western blot to characterize Ras-MEK-ERK pathway activity. STUDY DESIGN: We evaluated this hypothesis in six PIK3CA-amplified, PI3K inhibitor-resistant HNSCC cell lines following treatment with pan and alpha-isoform selective PI3K inhibitors (BKM120 and HS-173 respectively). We also tested the effect of combination treatment with PI3K inhibitor HS-173 and MEK inhibitor trametinib or EGFR inhibitor gefitinib. RESULTS: Our results displayed maintenance of Ras-MEK-ERK pathway activity in 4 of 6 HNSCC cell lines after PI3K inhibitor treatment. We also found that UM-SCC-69 and UM-SCC-108 cells display synergistic responses to dual therapy. CONCLUSION: This study suggests that inhibition of the PI3K and Ras-MEK-ERK pathways might be effective in some HNSCC patients; however, it also prompts the study of additional resistance mechanisms to identify synergistic combination therapies for tumors resistant to these di-therapies.

Use of AUDIT-C as a tool to identify hazardous alcohol consumption in admitted trauma patients.

INTRODUCTION: Alcohol use is an important contributor to injuries. Simple bedside tools to identify trauma patients with potentially harmful drinking may assist in brief intervention efforts in clinical practice. The objective of the study was to determine and compare the accuracy of alcohol use disorders identification test (AUDIT) and an abbreviated version of this test, in the detection of hazardous drinking. METHODS: A cross-sectional study of a convenience sample of admitted trauma patients at a single Australian major trauma centre. Eligible patients completed the AUDIT. AUDIT survey responses were scored in two ways, using the full form scale and secondly an abbreviated (AUDIT C) scale which uses only the first 3 questions. AUDIT and AUDIT-C scores were then evaluated with respect to the primary study measure; the detection of hazardous alcohol consumption based on a full alcohol consumption history. Sensitivities for each relevant score were calculated and receiver operator characteristic (ROC) curve analysis was used to determine test accuracy. RESULTS: During the study period, 523 trauma admissions were identified and of these 146 (28%) were screened. The optimum cut off scores for AUDIT and AUDIT-C were 8 and 5 respectively corresponding to sensitivities of 88% and 91% and both tests had excellent overall accuracy for the detection of hazardous alcohol consumption. There was no significant difference between AUDIT-C and AUDIT performance (p=0.395) (AUDIT-C AUROC 0.96 95%CI 0.93, 0.99). CONCLUSION: AUDIT-C appears to be a potentially useful screening tool for use trauma centres, but that further research with larger samples is required.

Are Australian and New Zealand trauma service resources reflective of the Australasian Trauma Verification Model Resource Criteria?

INTRODUCTION: The Australasian Trauma Verification Program was developed in 2000 to improve the quality of care provided at services in Australia and New Zealand. The programme outlines resources required for differing levels of trauma services. This study compares the human resources in Australia and New Zealand trauma services with those recommended by the Australasian College of Surgeons Trauma Verification Program. METHODS: In September 2011, all trauma nurse coordinators in Australia and New Zealand were invited to participate in an electronic survey endorsed by the Australasian Trauma Society. This study expands on previous bi-national research and aimed to identify demographic and trauma service human resource levels. RESULTS: Fifty-three surveys (78%) were completed and all 27 Level 1 trauma centres represented. Of the Level 1 trauma centres, a trauma director and fellow were available at 16 (51.8%) and 14 (40.7%) centres, respectively. The majority (93%) had a full-time trauma coordinator although a trauma case manager was only available at 14 (48.1%) of Level 1 trauma centres. Despite the large amount of data collection and extraction required, trauma services had limited access to a data manager (50.9%) or clerical staff (36.9%). CONCLUSION: Human resources in Australian and NZ trauma services are not reflective of those recommended by the Australasian Trauma Verification Program. This impacts on the ability to coordinate trauma monitoring and performance improvement. Review of the Australasian Trauma Verification Model Resource Criteria is required. Injury surveillance in Australia and NZ is hampered by insufficient trauma registry resources.

Meta-analysis as a tool for evidence-based practice: an example using the Rice meta-analysis of smoking cessation interventions.

Enhanced quality of patient care and the prevention of errors are emphasized greatly in today's health care settings. Nurses are now held accountable for the care they provide and, as a result, nurses are responsible for incorporating solid scientific evidence into their practice. Published meta-analyses represent one source of such evidence. Meta-analyses offer statistical summarizations of all studies conducted about a particular phenomenon and more objective evaluation of the research often results. This article examines seven basic processes for evaluating meta-analyses and determining the value of their results for use in nursing practice.