Powder Epoxy for One-Shot Cure, Out-of-Autoclave Applications: Lap Shear Strength and Z-Pinning Study

Large composite structures manufactured out-of-autoclave require the assembly and bonding of multiple parts. A one-shot cure manufacturing method is demonstrated using powder epoxy. Lap shear plates were manufactured from powder epoxy and glass fiber-reinforced plastic with four different bonding cases were assessed: secondary bonding using standard adhesive film, secondary bonding using powder epoxy, co-curing, and co-curing plus a novel Z-pinning method. This work investigates the lap shear strength of the four cases in accordance with ISO 4587:2003. Damage mechanisms and fracture behavior were explored using digital image correlation (DIC) and scanning electron microscopy (SEM), respectively. VTFA400 adhesive had a load at break 24.8% lower than secondary bonding using powder epoxy. Co-curing increased the load at break by 7.8% compared to powder epoxy secondary bonding, with the co-cured and pinned joint resulting in a 45.4% increase. In the co-cured and co-cured plus pinned cases, DIC indicated premature failure due to resin spew. SEM indicated shear failure of resin areas and a large amount of fiber pullout in both these cases, with pinning delaying fracture phenomena resulting in increased lap joint strength. This highlights the potential of powder epoxy for the co-curing of large composite structures out-of-autoclave

Different Fumaric Acid Esters Elicit Distinct Pharmacologic Responses.

OBJECTIVE To test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS. METHODS In rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36). RESULTS In rodents and cynomolgus monkeys, monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited higher brain penetration, whereas MEF was preferentially partitioned into the kidney. In mice, transcriptional profiling for DMF and MEF alone identified both common and distinct pharmacodynamic responses, with almost no overlap between DMF- and MEF-induced differentially expressed gene profiles in immune tissues. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated oxidative stress response pathway was exclusively regulated by DMF, whereas apoptosis pathways were activated by MEF. DMF/MEF treatment demonstrated that DMF and MEF functionally interact to modify DMF- and MEF-specific responses in unpredictable ways. In patients with MS, DMF/MEF treatment led to early and pronounced suppression of lymphocytes, predominantly CD8+ T cells. In a multivariate regression analysis, the absolute lymphocyte count (ALC) was associated with age at therapy start, baseline ALC, and DMF/MEF dosage but not with previous immunosuppressive medication and sex. Furthermore, the ALC increased in a small cohort of patients with MS (n = 6/7) after switching from DMF/MEF to DMF monotherapy. CONCLUSIONS Fumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF

Sensorineural hearing loss after neonatal meningitis: a single-centre retrospective study

Babies in intensive care are at higher risk for meningitis and sensorineural hearing loss (SNHL). We reviewed the rate of SNHL among definite cases of bacterial/fungal meningitis in our neonatal intensive care unit over a 16-year period (2006–2021). We identified 16 confirmed meningitis cases among 16 070 admissions: 8 of 10 surviving infants with available diagnostic audiology had normal/satisfactory hearing while 2 of 10 had SNHL. Both infants with permanent hearing loss had been born extremely preterm and received potentially ototoxic antimicrobials. Larger studies are needed to clarify whether SNHL occurs mainly due to meningitis itself or to its antimicrobial drug treatment

Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes

We thank Polaris Pharmaceuticals and Bio-Cancer Treatment for providing drugs and reagents. This work was supported by the Cancer Prevention Research Trust, with assistance from the Wellcome Trust Institutional Strategic Support Fund [097828/z/11/B], and Cancer Research UK in conjunction with the Department of Health as part of an Experimental Cancer Medicine Centre grant [C325/A15575]. C.A. was funded by a PhD fellowship from the Cancer Prevention Research Trust, S.S.A. was funded by a studentship from the Iraqi Government. We are thankful to John Bomalaski and Sara Galavotti for their critical reading of the manuscript and insightful suggestions. Finally, we are profoundly indebted to Professor Andreas Gescher for his constant support during the execution of this project and the writing of this manuscript.Peer reviewedPublisher PD

Human Papillomavirus Drives Tumor Development Throughout the Head and Neck: Improved Prognosis Is Associated With an Immune Response Largely Restricted to the Oropharynx

Purpose In squamous cell carcinomas of the head and neck (HNSCC), the increasing incidence of oropharyngeal squamous cell carcinomas (OPSCCs) is attributable to human papillomavirus (HPV) infection. Despite commonly presenting at late stage, HPV-driven OPSCCs are associated with improved prognosis compared with HPV-negative disease. HPV DNA is also detectable in nonoropharyngeal (non-OPSCC), but its pathogenic role and clinical significance are unclear. The objectives of this study were to determine whether HPV plays a causal role in non-OPSCC and to investigate whether HPV confers a survival benefit in these tumors. Methods Meta-analysis was used to build a cross-tissue gene-expression signature for HPV-driven cancer. Classifiers trained by machine-learning approaches were used to predict the HPV status of 520 HNSCCs profiled by The Cancer Genome Atlas project. DNA methylation data were similarly used to classify 464 HNSCCs and these analyses were integrated with genomic, histopathology, and survival data to permit a comprehensive comparison of HPV transcript-positive OPSCC and non-OPSCC. Results HPV-driven tumors accounted for 4.1% of non-OPSCCs. Regardless of anatomic site, HPV+ HNSCCs shared highly similar gene expression and DNA methylation profiles; nonkeratinizing, basaloid histopathological features; and lack of TP53 or CDKN2A alterations. Improved overall survival, however, was largely restricted to HPV-driven OPSCCs, which were associated with increased levels of tumor-infiltrating lymphocytes compared with HPV-driven non-OPSCCs. Conclusion Our analysis identified a causal role for HPV in transcript-positive non-OPSCCs throughout the head and neck. Notably, however, HPV-driven non-OPSCCs display a distinct immune microenvironment and clinical behavior compared with HPV-driven OPSCCs

Relevance of Rheological Properties of Sodium Alginate in Solution to Calcium Alginate Gel Properties

Abstract. The purpose of this study is to determine whether sodium alginate solutions' rheological parameters are meaningful relative to sodium alginate's use in the formulation of calcium alginate gels. Calcium alginate gels were prepared from six different grades of sodium alginate (FMC Biopolymer), one of which was available in ten batches. Cylindrical gel samples were prepared from each of the gels and subjected to compression to fracture on an Instron Universal Testing Machine, equipped with a 1-kN load cell, at a cross-head speed of 120 mm/min. Among the grades with similar % G, (grades 1, 3, and 4), there is a significant correlation between deformation work (L E ) and apparent viscosity (η app ). However, the results for the partial correlation analysis for all six grades of sodium alginate show that L E is significantly correlated with % G, but not with the rheological properties of the sodium alginate solutions. Studies of the ten batches of one grade of sodium alginate show that η app of their solutions did not correlate with L E while tan δ was significantly, but minimally, correlated to L E . These results suggest that other factors-polydispersity and the randomness of guluronic acid sequencing-are likely to influence the mechanical properties of the resultant gels. In summary, the rheological properties of solutions for different grades of sodium alginate are not indicative of the resultant gel properties. Interbatch differences in the rheological behavior for one specific grade of sodium alginate were insufficient to predict the corresponding calcium alginate gel's mechanical properties

A Comparative Assessment of Non-Laboratory-Based versus Commonly Used Laboratory-Based Cardiovascular Disease Risk Scores in the NHANES III Population

National and international primary CVD risk screening guidelines focus on using total CVD risk scores. Recently, we developed a non-laboratory-based CVD risk score (inputs: age, sex, smoking, diabetes, systolic blood pressure, treatment of hypertension, body-mass index), which can assess risk faster and at lower costs compared to laboratory-based scores (inputs include cholesterol values). We aimed to assess the exchangeability of the non-laboratory-based risk score to four commonly used laboratory-based scores (Framingham CVD [2008, 1991 versions], and Systematic COronary Risk Evaluation [SCORE] for low and high risk settings) in an external validation population.Analyses were based on individual-level, score-specific rankings of risk for adults in the Third National Health and Nutrition Examination Survey (NHANES III) aged 25–74 years, without history of CVD or cancer (n = 5,999). Risk characterization agreement was based on overlap in dichotomous risk characterization (thresholds of 10-year risk >10–20%) and Spearman rank correlation. Risk discrimination was assessed using receiver operator characteristic curve analysis (10-year CVD death outcome). Risk characterization agreement ranged from 91.9–95.7% and 94.2–95.1% with Spearman correlation ranges of 0.957–0.980 and 0.946–0.970 for men and women, respectively. In men, c-statistics for the non-laboratory-based, Framingham (2008, 1991), and SCORE (high, low) functions were 0.782, 0.776, 0.781, 0.785, and 0.785, with p-values for differences relative to the non-laboratory-based score of 0.44, 0.89, 0.68 and 0.65, respectively. In women, the corresponding c-statistics were 0.809, 0.834, 0.821, 0.792, and 0.792, with corresponding p-values of 0.04, 0.34, 0.11 and 0.09, respectively.Every score discriminated risk of CVD death well, and there was high agreement in risk characterization between non-laboratory-based and laboratory-based risk scores, which suggests that the non-laboratory-based score can be a useful proxy for Framingham or SCORE functions in resource-limited settings. Future external validation studies can assess whether the sex-specific risk discrimination results hold in other populations

Comparative assessment of absolute cardiovascular disease risk characterization from non-laboratory-based risk assessment in South African populations

Background: All rigorous primary cardiovascular disease (CVD) prevention guidelines recommend absolute CVD risk scores to identify high- and low-risk patients, but laboratory testing can be impractical in low- and middle-income countries. The purpose of this study was to compare the ranking performance of a simple, non-laboratory-based risk score to laboratory-based scores in various South African populations. Methods: We calculated and compared 10-year CVD (or coronary heart disease (CHD)) risk for 14,772 adults from thirteen cross-sectional South African populations (data collected from 1987 to 2009). Risk characterization performance for the non-laboratory-based score was assessed by comparing rankings of risk with six laboratory-based scores (three versions of Framingham risk, SCORE for high- and low-risk countries, and CUORE) using Spearman rank correlation and percent of population equivalently characterized as ‘high’ or ‘low’ risk. Total 10-year non-laboratory-based risk of CVD death was also calculated for a representative cross-section from the 1998 South African Demographic Health Survey (DHS, n = 9,379) to estimate the national burden of CVD mortality risk. Results: Spearman correlation coefficients for the non-laboratory-based score with the laboratory-based scores ranged from 0.88 to 0.986. Using conventional thresholds for CVD risk (10% to 20% 10-year CVD risk), 90% to 92% of men and 94% to 97% of women were equivalently characterized as ‘high’ or ‘low’ risk using the non-laboratory-based and Framingham (2008) CVD risk score. These results were robust across the six risk scores evaluated and the thirteen cross-sectional datasets, with few exceptions (lower agreement between the non-laboratory-based and Framingham (1991) CHD risk scores). Approximately 18% of adults in the DHS population were characterized as ‘high CVD risk’ (10-year CVD death risk >20%) using the non-laboratory-based score. Conclusions: We found a high level of correlation between a simple, non-laboratory-based CVD risk score and commonly-used laboratory-based risk scores. The burden of CVD mortality risk was high for men and women in South Africa. The policy and clinical implications are that fast, low-cost screening tools can lead to similar risk assessment results compared to time- and resource-intensive approaches. Until setting-specific cohort studies can derive and validate country-specific risk scores, non-laboratory-based CVD risk assessment could be an effective and efficient primary CVD screening approach in South Africa

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London