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Islet amyloid polypeptide (IAPP) fibrillation induces β-cell dysfunction and toxicity in patients with type 2 diabetes. Cytotoxicity is caused by the ability of IAPP fibrils and fibrillar intermediates to permeate the cellular membrane of pancreatic β-cells, trigger endoplasmic reticular stress, induce reactive oxygen species production, and upregulate apoptosis-related genes. Thus, inhibition of IAPP fibrillation is of great interest for preventing associated cytotoxicity. In this study, the cellular protective effects of three anti-fibrillation tetrapeptides, YMSV, MANT, and TNGQ, against IAPP fibrillation-induced membrane leakage in giant unilamellar vesicles (GUVs) and toxicity in RIN-m cells were evaluated. The anti-fibrillation activity of TNGQ translated to cytoprotective effects as it resulted in a 69.0 ± 7.9% decrease in calcein release in GUVs and a significant increase in cell viability from 6.4 ± 6.4% with IAPP to 47.5 ± 3.8% with the addition of TNGQ. MANT slightly inhibited IAPP-induced GUV leakage and increased cell viability. In contrast, the protective effect of YMSV against IAPP fibrillation-induced membrane damage in GUVs was completely diminished in β-cells. Molecular docking of pentameric IAPP showed that Asn21 and Asn22 of IAPP are important for inhibitor binding, which, coupled with the cross-domain binding interactions of TNGQ, explains its stronger anti-fibrillation and cytoprotective effects than MANT and YMSV. These findings provide insights into the functional significance of peptide-IAPP binding interactions in mitigating fibrillation and IAPP fibrillation-induced cytotoxicity.

This research work explores the physicochemical characteristics and biological functions of polysaccharides extracted from four selected green seaweed species: Ulva lactuca (UL), Halimeda opuntia (HO), Caulerpa racemosa (CR), and Chaetomorpha antennina (CA). The extracts were investigated for cell-based bio-activities (i.e., cytotoxicity, cell proliferation and migration) using three cell lines (HDF, HaCaT, RAW264.7) reflecting cell models involved in wound healing, as well as anticoagulant activity. Ulvans from UL significantly increased HaCaT (at 0.06 μg/μL) and HDF (at 0.5 μg/μL) cell proliferation. In addition, extracts from CA showed the highest cell migration ability using HDF and HaCaT cells. UL (all fractions), HO-2A, CR-1B, CA-1A and CA-2B fractions improved phagocytosis. Furthermore, RAW264.7 cells treated with fraction CA-1A produced significantly more intracellular NO (pro-inflammatory) within 24 h compared to control (LPs). Green seaweed extracts CA-2A and UL-1A resulted in lower expression of the pro-inflammatory cytokine TNF-α in skin cells (HDF, HaCaT). Caulerpa cold-extracted polysaccharides possessed higher anticoagulant properties. The Ulva (1,4-linked α-l-rhamnose, β-d-glucuronic acid, l-iduronic acid) and CA extracts are promising sources of bioactive therapeutic agents. Our data provide useful insights into the possible biomedical benefits of selected polysaccharides mixtures (i.e., ulvan, sulfated or/and pyruvylated β-d-galactans, sulfated xyloarabinogalactan) for food, pharmaceutical, and biotechnological applications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Corneal blindness affects over 10 million patients worldwide. Due to the limited supply of donor corneas and frequent graft failure, bioengineered alternatives are crucial. To overcome drawbacks associated with corneal substitutes from synthetic biomaterials, fabrication from plant-derived biomaterials is a potential alternative. Herein, soy protein and glutenin in combination with different crosslinkers were evaluated for fabrication of corneal substitutes. Optical, mechanical, and biochemical properties of fabricated constructs and control rabbit corneas were evaluated in vitro. Soy protein crosslinked with peroxidase/H 2 0 2 possessed transparency and mechanical properties comparable to controls, although their water content and biocompatibility were inferior. In contrast, soy protein crosslinked with tannic acid showed similar water content, tensile strength, and biocompatibility as rabbit corneas; however, these constructs displayed significantly lower transparency and higher strain to failure. Finally, glutenin cross-linked using formaldehyde showed excellent transparency, strain to failure, and biocompatibility, however; they exhibited significantly lower water content and tensile strength than controls. This study is the first to establish CIELAB color values for the rabbit cornea, allowing quantitative optical evaluation of tissue-engineered substitutes. Thus, a crosslinking strategy utilizing plant-derived proteins for fabrication of constructs with properties comparable to rabbit corneas is a promising direction for development of tissue-engineered corneal substitutes., (© 2024 Wiley Periodicals LLC.)

In this study, we aimed to develop a protective probiotic coculture to inhibit the growth of Salmonella enterica serovar Typhimurium in the simulated chicken gut environment. Bacterial strains were isolated from the digestive mucosa of broilers and screened in vitro against Salmonella Typhimurium ATCC 14028. A biocompatibility coculture test was performed, which identified two biocompatible strains, Ligilactobacillus salivarius UO.C109 and Ligilactobacillus saerimneri UO.C121 with high inhibitory activity against Salmonella. The cell-free supernatant (CFS) of the selected isolates exhibited dose-dependent effects, and the inhibitory agents were confirmed to be proteinaceous by enzymatic and thermal treatments. Proteome and genome analyses revealed the presence of known bacteriocins in the CFS of L. salivarius UO.C109, but unknown for L. saerimneri UO.C121. The addition of these selected probiotic candidates altered the bacterial community structure, increased the diversity of the chicken gut microbiota challenged with Salmonella, and significantly reduced the abundances of Enterobacteriaceae, Parasutterlla, Phascolarctobacterium, Enterococcus, and Megamonas. It also modulated microbiome production of short-chain fatty acids (SCFAs) with increased levels of acetic and propionic acids after 12 and 24 h of incubation compared to the microbiome challenged with S. Typhimurium. Furthermore, the selected probiotic candidates reduced the adhesion and invasion of Salmonella to Caco-2 cells by 37-39% and 51%, respectively, after 3 h of incubation, compared to the control. These results suggest that the developed coculture probiotic strains has protective activity and could be an effective strategy to control Salmonella infections in poultry., Competing Interests: Declarations Conflict of Interest The authors declare no competing interests., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The immunomodulatory properties of the polysaccharides (carrageenan, xylan) from Chondrus crispus (CC), Ahnfeltiopsis devoniensis (AD), Sarcodiotheca gaudichaudii (SG) and Palmaria palmata (PP) algal species were studied. Using RAW264.7 macrophages, we investigated the proliferation and migration capacity of different extracts along with their immunomodulatory activities, including nitric oxide (NO) production, phagocytosis, and secretion of pro-inflammatory cytokines. Polysaccharides from C. crispus and S. gaudichaudii effectively mitigated inflammation and improved scratch-wound healing. Polysaccharide fractions extracted under cold conditions (25 °C), including CC-1A, SG-1A and SG-1B stimulated cell proliferation, while fractions extracted under hot conditions (95 °C), including CC-3A, CC-2B and A. devoniensis (AD-3A), inhibited cell proliferation after 48 h. Furthermore, RAW264.7 cells treated with the fractions CC-3A, AD-1A, and SG-2A significantly reduced LPS-stimulated NO secretion over 24 h. Phagocytosis was significantly improved by treatment with C. crispus (CC-2B, CC-3B) and A. devoniensis (AD-3A) fractions. RAW264.7 cells treated with the CC-2A and SG-1A fractions showed elevated TGF-β1 expression without affecting TNF-α expression at 24 h. Polysaccharide fractions of A. devoniensis (ι/κ hybrid carrageenan; AD-2A, AD-3A) showed the highest anti-coagulation activity. CC-2A and SG-1A fractions enhanced various bioactivities, suggesting they are candidates for skin-health applications. The carrageenan fractions (CC-3A: λ-, μ-carrageenan, SG-2A: ν-, ι-carrageenan) tested herein showed great potential for developing anti-inflammatory and upscaled skin-health applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To analyze the associations between pain and physical performance in different aging contexts., Methods: Data from 1725 older adults from Canada, Brazil, Colombia, and Albania from the 2014 wave of the IMIAS were used to assess the associations between Back Pain (BP) or Lower Limb Pain (LLP) and physical performance by the Short Physical Performance Battery (SPPB). Three binary logistic regression models adjusted for sex, age, study site, education, income sufficiency, BMI, depressive symptoms, and chronic conditions were used to estimate the associations between LLP or BP and SPPB. The SPPB was classified into good performance (8 points or more) and poor physical performance (< 8 points)., Results: The mean age of the older men was 71.2 (± 3.0) and the mean age of the women was 71.2 (± 2.8) years. Older men (72.8%, p < 0.05) and women (86.1%, p-value < 0.05) from Albania had the highest frequencies of self-reported general pain. Older women in Colombia had the highest frequencies of LLP or BP (33.5%, p-value < 0.05). In the fully adjusted logistic regression model, LLP or BP was significantly associated with poor SPPB (OR = 0.48, 0.35 to 0.66 95% CI, p < 0.01)., Conclusions: Pain symptoms are associated with reduced physical performance in older people, even when adjusted for other clinical and sociodemographic factors. Protocols for aiming to increase the level of physical activity to manage pain should be incorporated into health care strategies., (© 2023. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

This study describes the development and characterization of novel composite scaffolds, made of an alginate-chitosan hydrogel matrix containing eggshell (ES) particles, for bone tissue engineering applications. Scaffolds with ES particles, either untreated or treated with phosphoric acid to create a nanotextured particle surface, were compared to scaffolds without particles. Results indicate that the nanotexturing process exposed occluded ES proteins orthologous to those in human bone extracellular matrix. Scaffolds with ES or nanotextured ES (NTES) particles had a higher porosity (81 ± 4% and 89 ± 5%, respectively) than scaffolds without particles (59 ± 5%) (p = .002 and p < .001, respectively). Scaffolds with NTES particles had a larger median pore size (113 μm [interquartile range [IQ]: 88-140 μm]) than scaffolds with ES particles (94 μm [IQ: 75-112 μm]) and scaffolds without particles (99 μm [IQ: 74-135 μm]) (p < .001 and p = .011, respectively). The compressive modulus of the scaffolds with ES or NTES particles remained low (3.69 ± 0.70 and 3.14 ± 0.62 kPa, respectively), but these scaffolds were more resistant to deformation following maximum compression than those without particles. Finally, scaffolds with ES or NTES particles allowed better retention of human mesenchymal stem cells during seeding (53 ± 12% and 57 ± 8%, respectively, vs. 17 ± 5% for scaffolds without particles; p < .001 in both cases), as well as higher cell viability up to 21 days of culture (67 ± 17% and 61 ± 11%, respectively, vs. 15 ± 7% for scaffolds without particles; p < .001 in both cases). In addition, alkaline phosphatase (ALP) activity increased up to 558 ± 164% on day 21 in the scaffolds with ES particles, and up to 567 ± 217% on day 14 in the scaffolds with NTES particles (p = .006 and p = .002, respectively, relative to day 0). Overall, this study shows that the physicochemical properties of the alginate-chitosan hydrogel scaffolds with ES or NTES particles are similar to those of cancellous bone. In addition, scaffolds with particles supported early osteogenic differentiation and therefore represent a promising new bone substitute, especially for non-load bearing applications., (© 2023 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals LLC.)

Objective: This study aimed to evaluate the association between Allostatic Load (AL) and physical performance scores in older adults from four cities in North and South America., Methods: In this cross-sectional study, data from 1101 volunteers from three countries (Canada, Brazil, and Colombia) from the International Mobility in Aging Study (IMIAS) were used to evaluate the association between AL index and Short Physical Performance Battery (SPPB) scores. Three multiple linear regression models adjusted by age, Socioeconomic Status (SES), chronic conditions, depression symptoms, and Leganés Cognitive Test (LCT) were developed to estimate the independent association between SPPB and AL. Mediation analysis with 2012 LA data and covariates was performed to access the total, direct, and indirect effects of mediation on SPPB scores from 2016., Results: AL and SPPB were inversely associated, with older adults with high allostatic load scoring lower on SPPB (β: -0.234, Std: 0.033, p-value: <0.001).  Indirect effects were evidenced between age, SES and chronic conditions with AL and SPPB scores. Chronic conditions also had a total effect on SPPB scores and were also mediated by AL. However, indirect effects of depressive symptoms and LCT on SPPB scores mediated by AL were not observed., Conclusions: Findings from this study support that increased AL index determines worse physical performance states after full adjustments. AL has a mediator role between the number of chronic diseases, depressive symptoms, cognitive status and physical performance. Socioeconomic status also influenced physical scores mediated by the AL index., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Keratoconus (KC) is easily recognized by its unique topographic pattern, but it can be difficult to distinguish subclinical form of the disease from the normal cornea. Optovue anterior segment optical coherence tomography (AS-OCT) helps diagnose KC., Aim of the Work: To assess and the level of agreement of Keratometry-readings (K), Central Corneal Thickness (CCT) and Thinnest Corneal Thickness (TCT) measurements obtained by Optovue AS-OCT and Wavelight Oculyzer Pentacam HR in two groups: KC eyes and normal eyes., Patients and Methods: This is a prospective clinical observational study. The study included 110 eyes divided into two groups. The study group included 62 eyes with topographic evidence of KC. The control group included 48 eyes of normal subjects with no topographic evidence of KC. All of the participants underwent full cycloplegic refraction, spectacle best-corrected distance visual acuity, comprehensive slit-lamp biomicroscopy and fundoscopy. All participants underwent corneal topography by Pentacam HR and AS-OCT., Results: There were highly significant differences between the studied groups as regarding BCVA, intraocular pressure and CCT measurements which were found to be lower among KC group compared to the control one. There were highly significant differences between the studied groups regarding TCT measurement detected by Pentacam HR and AS-OCT which was found to be lower among the keratoconus group compared to the control one (470.9, 455.7 versus 541.9 and 518.7 respectively)., Conclusion: Both Scheimpflug-based imaging and AS-OCT provide comparable readings with a good agreement regarding corneal pachymetry in keratoconus group with accurate identification of KC eyes and healthy ones. However, there was a significant difference in K readings between both devices in Keratoconus and control group., (© 2023. The Author(s).)

Objectives: To investigate the association between anemia and depression and whether the treatment of anemia modifies the effect of the association between anemia and depression., Methods: This secondary data analysis is based on data from the Enquête sur la santé des aînés (ESA)-Services study conducted in 2011-2013 on community-dwelling older adults recruited in primary care and have given access to their medico-administrative data (n = 1447). The presence of anemia was self-reported, as was depression (major and minor) aligned with symptoms of the DSM-5. Treated anemia was based on the presence of medications delivered to participants. Cross-sectional associations were analyzed using multivariable logistic regression, controlling for confounders., Results: The prevalence of self-reported anemia in our sample was estimated at 6.7%. Self-reported anemia was associated with increased odds of depression. Individuals with untreated anemia had a 2.6-fold increased odds of depression compared to those with no anemia. In contrast, the odds of depression in individuals with treated anemia were not different from individuals with no anemia., Conclusion: The findings underline the importance of treating anemia in older adults. Future longitudinal studies are needed to replicate the findings and further explore the role of treating anemia on symptoms of depression., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objective: This study aimed to assess the longitudinal predictions between glycated hemoglobin A1c (HbA1c) and physical performance scores in different epidemiological contexts of aging., Material and Methods: Longitudinal data of 1,337 older people from three countries (Canada, Brazil and Colombia) of the International Mobility in Aging Study (IMIAS) were used to assess the relationship between HbA1c and Short Physical Performance Battery (SPPB) scores between 2012 and 2016. Linear Mixed Models grouped by sex and adjusted by Age, Study site, Chronic Conditions, Anthropometric Measures, and Inflammatory Level were used to estimate the influence of HbA1c and covariates on SPPB scores., Results: At the IMIAS baseline, Latin American (LA) cities had higher HbA1c averages compared to Canadian cities, with Natal (Brazil) being the city with the highest HbA1c averages in men and women (6.32 ± 1.49; 6,56 ± 1.70 respectively). SPPB scores were significantly lower in LA cities, and older people in Natal had lower SPPB averages in men (9.67 ± 2.38; p-value < 0.05) and women (8.52 ± 2.33; p-value <0.05). In the multivariate mixed linear models of longitudinal analyses, HbA1c was significantly associated with lower SPPB scores in men (β = -0.25, 95% CI: -0.39 to -0.12, p-value = 0.02) but not in women., Conclusion: High HbA1c levels at baseline were longitudinally associated in older adults from different countries, and this association was observed only in men and not in women. This study highlights a possible influence of gender on this relationship., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: The gastrointestinal tract plays a major role in regulating glucose homeostasis and gut endocrine function. The current study examines the effects of Roux-en-Y gastric bypass (RYGB) on intestinal GLP-1, glucose transporter expression and function in the obese Zucker rat (ZR)., Methods: Two groups of ZRs were studied: RYGB and sham surgery pair-fed (PF) fed rats. Body weight and food intake were measured daily. On post-operative day (POD) 21, an oral glucose test (OGT) was performed, basal and 30-minute plasma, portal venous glucose and glucagon-like peptide-1 (GLP-1) levels were measured. In separate ZRs, the biliopancreatic, Roux limb (Roux) and common channel (CC) intestinal segments were harvested on POD 21., Results: Body weight was decreased in the RYGB group. Basal and 30-minute OGT plasma and portal glucose levels were decreased after RYGB. Basal plasma GLP-1 levels were similar, while a 4.5-fold increase in GLP-1 level was observed in 30-minute after RYGB (vs. PF). The increase in basal and 30-minute portal venous GLP-1 levels after RYGB were accompanied by increased mRNA expressions of proglucagon and PC 1/3, GPR119 protein in the Roux and CC segments. mRNA and protein levels of FFAR2/3 were increased in Roux segment. RYGB decreased brush border glucose transport, transporter proteins (SGLT1 and GLUT2) and mRNA levels of Tas1R1/Tas1R3 and α-gustducin in the Roux and CC segments., Conclusions: Reductions in intestinal glucose transport and enhanced post-prandial GLP-1 release were associated with increases in GRP119 and FFAR2/3 after RYGB in the ZR model. Post-RYGB reductions in the regulation of intestinal glucose transport and L cell receptors regulating GLP-1 secretion represent potential mechanisms for improved glycemic control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Meng, Culnan, Ahmed, Sun and Cooney.)

In oviparous animals, the egg contains all resources required for embryonic development. The chorioallantoic membrane (CAM) is a placenta-like structure produced by the embryo for acid-base balance, respiration, and calcium solubilization from the eggshell for bone mineralization. The CAM is a valuable in vivo model in cancer research for development of drug delivery systems and has been used to study tissue grafts, tumor metastasis, toxicology, angiogenesis, and assessment of bacterial invasion. However, the protein constituents involved in different CAM functions are poorly understood. Therefore, we have characterized the CAM proteome at two stages of development (ED12 and ED19) and assessed the contribution of the embryonic blood serum (EBS) proteome to identify CAM-unique proteins. LC/MS/MS-based proteomics allowed the identification of 1470, 1445, and 791 proteins in CAM (ED12), CAM (ED19), and EBS, respectively. In total, 1796 unique proteins were identified. Of these, 175 (ED12), 177 (ED19), and 105 (EBS) were specific to these stages/compartments. This study attributed specific CAM protein constituents to functions such as calcium ion transport, gas exchange, vasculature development, and chemical protection against invading pathogens. Defining the complex nature of the CAM proteome provides a crucial basis to expand its biomedical applications for pharmaceutical and cancer research., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Tamer A. E. Ahmed et al.)

A new easily separable core-shell Fe 3 O 4 /PVP/ZIF-8 nanostructure adsorbent was synthesized and then examined for removal of Fosfomycin antibiotic from synthetic pharmaceutical wastewater. The removal process of Fosfomycin was expressed through testing the total phosphorus (TP). A response surface model (RSM) for Fosfomycin adsorption (as mg-P L -1 ) was used by carrying out the experiments using a central composite design. The adsorption model showed that Fosfomycin adsorption is directly proportional to core-shell Fe 3 O 4 /PVP/ZIF-8 nanostructure adsorbent dosage and time, and indirectly to initial Fosfomycin concentration. The removal increased by decreasing the pH to 2. The Fosfomycin removal was done at room temperature under an orbital agitation speed of 250 rpm. The adsorption capacity of core-shell Fe 3 O 4 /PVP/ZIF-8 nanostructure adsorbent reached around 1200 mg-P g -1 , which is significantly higher than other MOF adsorbents reported in the literature. The maximum Langmuir adsorption capacity of the adsorbent for Fosfomycin was 126.58 mg g -1 and Fosfomycin adsorption behavior followed the Freundlich isotherm ( R 2 = 0.9505) in the present study. The kinetics was best fitted by the pseudo-second-order model ( R 2 = 0.9764). The RSM model was used for the adsorption process in different target modes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background and Objectives: There is an urgent need to better understand frailty and its predisposing factors. Although numerous cross-sectional studies have identified various risk and protective factors of frailty, there is a limited understanding of longitudinal frailty progression. Furthermore, discrepancies in the methodologies of these studies hamper comparability of results. Here, we use a coordinated analytical approach in 5 independent cohorts to evaluate longitudinal trajectories of frailty and the effect of 3 previously identified critical risk factors: sex, age, and education., Research Design and Methods: We derived a frailty index (FI) for 5 cohorts based on the accumulation of deficits approach. Four linear and quadratic growth curve models were fit in each cohort independently. Models were adjusted for sex/gender, age, years of education, and a sex/gender-by-age interaction term., Results: Models describing linear progression of frailty best fit the data. Annual increases in FI ranged from 0.002 in the Invecchiare in Chianti cohort to 0.009 in the Longitudinal Aging Study Amsterdam (LASA). Women had consistently higher levels of frailty than men in all cohorts, ranging from an increase in the mean FI in women from 0.014 in the Health and Retirement Study cohort to 0.046 in the LASA cohort. However, the associations between sex/gender and rate of frailty progression were mixed. There was significant heterogeneity in within-person trajectories of frailty about the mean curves., Discussion and Implications: Our findings of linear longitudinal increases in frailty highlight important avenues for future research. Specifically, we encourage further research to identify potential effect modifiers or groups that would benefit from targeted or personalized interventions., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Inflammatory bowel diseases (IBD) are chronic medical disorders characterized by recurrent gastrointestinal inflammation. While the etiology of IBD is still unknown, the pathogenesis of the disease results from perturbations in both gut microbiota and the host immune system. Gut microbiota dysbiosis in IBD is characterized by depleted diversity, reduced abundance of short chain fatty acids (SCFAs) producers and enriched proinflammatory microbes such as adherent/invasive E. coli and H 2 S producers. This dysbiosis may contribute to the inflammation through affecting either the immune system or a metabolic pathway. The immune responses to gut microbiota in IBD are extensively discussed. In this review, we highlight the main metabolic pathways that regulate the host-microbiota interaction. We also discuss the reported findings indicating that the microbial dysbiosis during IBD has a potential metabolic impact on colonocytes and this may underlie the disease progression. Moreover, we present the host metabolic defectiveness that adds to the impact of symbiont dysbiosis on the disease progression. This will raise the possibility that gut microbiota dysbiosis associated with IBD results in functional perturbations of host-microbiota interactions, and consequently modulates the disease development. Finally, we shed light on the possible therapeutic approaches of IBD through targeting gut microbiome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sultan, El-Mowafy, Elgaml, Ahmed, Hassan and Mottawea.)

The eggshell (ES) provides protection against pathogenic and physical insults while supplying essential metabolic and nutritional needs for the growing avian embryo. It is constituted mainly of calcium carbonate arranged as calcite crystals. The global chicken egg production in 2018 was over 76.7 million metric tons. In industrialized countries, about 30% of eggs are processed at breaker plants that produce liquid egg products and large quantities of solid ES waste. ES waste is utilized for a variety of low-value applications, or alternatively is disposed in landfill with associated economic and environmental burdens. The number of patents pertaining to ES applications has increased dramatically in recent years; of 673 patents granted in the last century, 536 (80%) were published in the last two decades. This review provides a snapshot of the most recent patents published between 2015 and 2020, with emphasis on different biotechnological applications of ES waste, and summarizes applications for biomedical, chemical, engineering, and environmental technologies. Biomedical technologies include the production of calcium lactate, calcium phosphate, and health-promoting products, while chemical technologies include plant growth promoters, food processing and production, and biodiesel oil catalysis along with active calcium, carbon, soluble proteins, organic calcium, and ultrafine calcium carbonate sources. Engineering technologies address material engineering and nanoparticle production, while environmental technologies pertain to production of biomass, solubilization of sludge as well as production of magnetic ES adsorbents and adsorption of heavy metals, organics, total nitrogen and fluoride, soil pollutants, and radioactive compounds. Although the number of ES-based patents has exponentially increased in the last decade, exploration of innovative top-down approaches and ES development as a physical platform are new endeavors that are expected to further increase the upscaling of ES waste exploitation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ahmed, Wu, Younes and Hincke.)

Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF) but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Molecular dynamic simulations reveal restriction of the movement of the BRAF αC-helix as the basis of inhibitor selectivity. Combination of inhibitors based on their conformation selectivity (mBRAF- plus dBRAF-selective plus the most potent BRAF-MEK disruptor MEK inhibitor) promoted suppression of tumor growth in BRAF V600E therapy-resistant models. Strikingly, the triple combination showed no toxicities, whereas dBRAF-selective plus MEK inhibitor treatment caused weight loss in mice. Finally, the triple combination achieved durable response and improved clinical well-being in a patient with stage IV colorectal cancer. Thus, exploiting allosteric properties of RAF and MEK inhibitors enables the design of effective and well-tolerated therapies for BRAF V600E tumors. SIGNIFICANCE: This work identifies a new class of RAFi that are selective for dBRAF over mBRAF and determines the basis of their selectivity. A rationally designed combination of RAF and MEK inhibitors based on their conformation selectivity achieved increased efficacy and a high therapeutic index when used to target BRAF V600E tumors. See related commentary by Zhang and Bollag, p. 1620 . This article is highlighted in the In This Issue feature, p. 1601 ., (©2021 American Association for Cancer Research.)

Chronic neutrophilic leukaemia is a very rare disease with diagnosis based on persistent leucocytosis >25×10 3 /μl and monocytes <1×10 3 /μl. The revised WHO criteria 2016 included CSF3R gene mutations as a diagnostic finding. We report the case of a 77-year-old man who was found to have asymptomatic persistent mature neutrophilic leucocytosis with monocytosis. Molecular study confirmed the presence of a CSF3R gene mutation in the absence of morphological or genetic features of myelodysplasia or other forms of myelodysplastic syndrome. The patient's medical history was significant for coronary artery disease, hypertension, chronic obstructive pulmonary disease, bilateral cystic bronchiectasis, moderate pulmonary hypertension, tuberculosis treated 27 years previously, hypothyroidism, and a thyroid nodule. He had hepatosplenomegaly but no lymphadenopathy, and no other malignancy was seen on computed tomography (CT) scanning. At the time of evaluation, he was free of symptoms and had no evidence of infection or drug-induced leucocytosis. The patient was referred to an oncology centre and treated with hydroxyurea and subsequently azacitidine. However, he developed pancytopenia with bone marrow aplasia. He died with neutropenia sepsis. The presence of persistent monocytosis in this case created a diagnostic dilemma as to whether the disease was a variant of chronic neutrophilic leukaemia or was reactive monocytosis., Learning Points: The presence of a CSF3R gene mutation is diagnostic for chronic neutrophilic leukaemia (CNL).The monocytosis in this patient might have been a new variant of CNL., Competing Interests: Conflicts of Interests: The authors declare there are no competing interests., (© EFIM 2021.)

The chicken egg is a well-known complete food of human daily consumption which serves as a cost-effective, high-quality nutrient resource. About 30% of table eggs are directed to breaker plants in developed countries, leading to the generation of substantial eggshell (ES) waste, which is increasingly explored for potential value-added applications. The number of patents describing ES-based applications has increased dramatically in recent years. This review provides insight into the most recent patents published between 2015 and 2020, with focus on different engineering technologies for the screening, separation, and processing of ES. Screening technologies include detection of ES surface spots and glossiness, ES cracks, and mechanical properties, along with identification of chicken breed and enumeration of surface bacterial count. Collection and separation technologies describe separation strategies of ES from egg white (EW), egg yolk (EY), liquid egg, eggshell membrane (ESM), hatchlings, and cooked egg. Separation of ES from liquid eggs utilizes gravity, rotational forces, or air pressure. Processing of ES involves washing and sterilization along with cutting, crushing, and pulverization technologies that enable the collection of ES suitable for value-added applications. In addition, ES carving (mechanical and laser) opens up the realm of artwork and decoration. Furthermore, intact ES can be utilized for food serving. The exponential increase in innovative screening, separation, collection, and processing technologies reflects industrial interest to upscale low-value ES waste material, and is a first crucial step in the emergence of advanced technologies that exploit the biomedical, chemical, engineering, and environmental applications for ES., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ahmed, Younes, Wu and Hincke.)

Objectives: To examine the relationship between anemia and depression and whether sex and global cognition modify this relationship over a 4-year follow-up., Design: Longitudinal analysis of an international cohort study SETTINGS AND PARTICIPANTS: Older adults from the International Mobility in Aging Study (IMIAS) aged between 65 and 74 years at baseline., Methods: Participants were recruited in Natal (Brazil), Manizales (Colombia), Kingston (Ontario, Canada), and Saint-Hyacinthe (Quebec, Canada). The study outcome was depression, defined by a score of ≥16 in the Center for Epidemiologic Studies Depression Scale. Longitudinal associations over a 4-year follow-up were examined using generalized estimating equations. Cognition was ascertained with the Leganes Cognitive Test with scores ≤ 22 indicating poor cognition. Models were also adjusted for research sites, marital status, alcohol drinking status, body mass index, chronic conditions, activities of daily life disabilities, and polypharmacy., Results: Anemia and poor cognition at baseline were associated with an increased risk of depression at follow-up (OR = 5.73, 95% CI: 1.58-20.78). Global cognition was also an effect modifier of the longitudinal association between the severity of anemia and depression., Conclusions: In international samples of older adults, anemia, as well as the severity of anemia, were independent risk factors for depression, and the effect of these associations was modified by global cognition. The findings highlight an important issue as to whether depression in old age may be at least partially preventable through public health interventions to correct low Hb levels., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

Objective: To explore the impact of the implementation of eCTAS, a real-time electronic decision-support tool, on hospital admission, rate of left without being seen, and time from triage to physician initial assessment., Methods: We conducted a cohort study using population-based administrative data from all Ontario emergency departments (EDs) that had implemented eCTAS for 9 months. We compared 6 months post-eCTAS data to the same 6 months the previous year (pre-eCTAS). We included triage encounters of adult (≥ 18 years) patients if they had one of 16 pre-specified, high-volume presenting complaints. Multivariable logistic regression and quantile regression models informed the effect of eCTAS on outcomes., Results: We included data from 354,176 triage encounters from 31 EDs. There was a change in the distribution of triage scores post-eCTAS, with fewer patients classified as CTAS 2 and CTAS 3, and more patients classified as CTAS 1 and CTAS 4. Overall, hospital admission decreased post-eCTAS (adjusted OR: 0.98; 95% CI: 0.97 to 1.00), with fewer CTAS 2 and more CTAS 3 and CTAS 4 patients admitted post-eCTAS. The rate of left without being seen increased (2.8% vs. 3.0%; adjusted OR: 1.07; 95% CI: 1.03 to 1.11) post-eCTAS, while time to physician initial assessment proved similar pre and post-eCTAS., Conclusions: eCTAS implementation had little impact on admission, rate of left without being seen and time to physician initial assessment. eCTAS appears to reclassify patients from higher to lower acuity scores, resulting in higher admission rates for CTAS 3 and CTAS 4 patients. It remains unknown if this reclassification is appropriate.

Objectives: To investigate a 4-year longitudinal relationship between falls, recurrent falls, and injurious falls, according to different levels of life-space mobility (LSM)., Methods: Longitudinal analysis of an international cohort study. The participants were older adults from the International Mobility in Aging Study (IMIAS) aged between 65 and 74 years at baseline. Three waves of data (2012, 2014, 2016) were used. Fall history during the past year was recorded. Recurrent fallers were identified as those who fell at least twice and injurious fallers as participants who required medical attention. LSM measurements included Total Life-Space (LS-C), Maximal Life-Space (LS-M), Assisted Life-Space (LS-A), Independent Life-Space (LS-I) and Restricted Life-space (LS-ID) scores. Generalized estimation equation (GEE) models were used to determine whether life-space mobility measures and their change over time differed between recurrence of falls and injurious falls., Results: At baseline, the prevalence of falls in the last year was 28%. 11.8% reported recurrent falls and 2.6% had serious injurious falls in the last year preceding the assessments. Recurrent fallers were more likely to be female, with insufficient income and, with comorbidities. GEE models showed that life-space mobility was lower among those with recurrent falls or serious injurious falls compared to those who never fell, but the rate of change did not differ over the 4-year follow-up except for the LS-A and LS-I scores, where some improvements were observed over time., Conclusions and Implications: Falls were independently associated with a decrease in LSM over 4 years. Targeting older adults with recurrent and injurious falls with appropriate interventions may improve community mobility and social participation.

The gut-liver-axis is a bidirectional coordination between the gut, including microbial residents, the gut microbiota, from one side and the liver on the other side. Any disturbance in this crosstalk may lead to a disease status that impacts the functionality of both the gut and the liver. A major cause of liver disorders is hepatitis C virus (HCV) infection that has been illustrated to be associated with gut microbiota dysbiosis at different stages of the disease progression. This dysbiosis may start a cycle of inflammation and metabolic disturbance that impacts the gut and liver health and contributes to the disease progression. This review discusses the latest literature addressing this interplay between the gut microbiota and the liver in HCV infection from both directions. Additionally, we highlight the contribution of gut microbiota to the metabolism of antivirals used in HCV treatment regimens and the impact of these medications on the microbiota composition. This review shed light on the potential of the gut microbiota manipulation as an alternative therapeutic approach to control the liver complications post HCV infection., Competing Interests: The authors declare no conflict of interest.

In the present work, modified embedded atom potential and large-scale molecular dynamics' simulations were used to explore the effect of grain boundary (GB) segregated foreign interstitials on the deformation behavior of nanocrystalline (nc) iron. As a case study, carbon and nitrogen (about 2.5 at.%) were added to (nc) iron. The tensile test results showed that, at the onset of plasticity, grain boundary sliding mediated was dominated, whereas both dislocations and twinning were prevailing deformation mechanisms at high strain. Adding C/N into GBs reduces the free excess volume and consequently increases resistance to GB sliding. In agreement with experiments, the flow stress increased due to the presence of carbon or nitrogen and carbon had the stronger impact. Additionally, the simulation results revealed that GB reduction and suppressing GBs' dislocation were the primary cause for GB strengthening. Moreover, we also found that the stress required for both intragranular dislocation and twinning nucleation were strongly dependent on the solute type.

The eggshell membrane (ESM) is a natural bioactive material, which is increasingly utilized for various biomedical applications. However, the poor solubility of ESM limits the bioavailability of its constituents and reduces the expression of their potential bioactivity. In this study, we utilized an innovative green strategy to separate ESM from shell, and processed ESM for size reduction by cryo-grinding and homogenization to produce particalized eggshell membrane (PEM) approaching submicron dimensions, with enhanced anti-inflammatory activity and increased antimicrobial activity against skin associated pathogens. Gram-positive Staphylococcus aureus (log 10 reduction = 4.5 ± 0.3) was more sensitive to PEM as compared to Gram-negative Pseudomonas aeruginosa (log 10 reduction = 2.1 ± 0.3). PEM elicited a dose-dependent reduction in NO accumulation in LPS-induced RAW 264.7 macrophages, suggesting an anti-inflammatory response to ESM particles. These findings suggest that processed PEM possesses great potential as a topical ingredient in skincare applications to maintain skin health by reducing bacterial infections and inflammation.

Objective: eCTAS is a real-time electronic decision-support tool designed to standardize the application of the Canadian Triage and Acuity Scale (CTAS). This study addresses the variability of CTAS score distributions across institutions pre- and post-eCTAS implementation., Methods: We used population-based administrative data from 2016-2018 from all emergency departments (EDs) that had implemented eCTAS for 9 months. Following a 3-month stabilization period, we compared 6 months post-eCTAS data to the same 6 months the previous year (pre-eCTAS). We included triage encounters of adult (≥17 years) patients who presented with 1 of 16 pre-specified, high-volume complaints. For each ED, consistency was calculated as the absolute difference in CTAS distribution compared to the average of all included EDs for each presenting complaint. Pre-eCTAS and post-eCTAS change scores were compared using a paired-samples t-test . We also assessed if eCTAS modifiers were associated with triage consistency., Results: There were 363,214 (183,231 pre-eCTAS, 179,983 post-eCTAS) triage encounters included from 35 EDs. Triage scores were more consistent ( P  < 0.05) post-eCTAS for 6 (37.5%) presenting complaints: chest pain (cardiac features), extremity weakness/symptoms of cerebrovascular accident, fever, shortness of breath, syncope, and hyperglycemia. Triage consistency was similar pre- and post-eCTAS for altered level of consciousness, anxiety/situational crisis, confusion, depression/suicidal/deliberate self-harm, general weakness, head injury, palpitations, seizure, substance misuse/intoxication, and vertigo. Use of eCTAS modifiers was associated with increased triage consistency., Conclusions: eCTAS increased triage consistency across many, but not all, high-volume presenting complaints. Modifier use was associated with increased triage consistency, particularly for non-specific complaints such as fever and general weakness., Competing Interests: At the time of the study, SS, TA, JM, BF and NM were paid employees of Ontario Health (Cancer Care Ontario). HO is a paid advisor to the Ministry of Health of Ontario and in that capacity has provided leadership to the eCTAS project. SLM, CT, BB, LT, KG, AW, TA, MB and GG state no conflict of interest and have received no payment in preparation of this manuscript., (© 2020 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of the American College of Emergency Physicians.)

Study Objective: The electronic Canadian Triage and Acuity Scale (eCTAS) is a real-time electronic triage decision-support tool designed to improve patient safety and quality of care by standardizing the application of the Canadian Triage and Acuity Scale (CTAS). The objective of this study is to determine interrater agreement of triage scores pre- and post-implementation of eCTAS., Methods: This was a prospective, observational study conducted in 7 emergency departments (EDs), selected to represent a mix of triage documentation practices, hospital types, and patient volumes. A provincial CTAS auditor observed triage nurses in the ED pre- and post-implementation of eCTAS and assigned an independent CTAS score in real time. Research assistants independently recorded triage time. Interrater agreement was estimated with κ statistics with 95% confidence intervals (CIs)., Results: A total of 1,491 individual triage assessments (752 pre-eCTAS, 739 post-implementation) were audited during 42 7-hour triage shifts (21 pre-eCTAS, 21 post-implementation). Exact modal agreement was achieved for 567 patients (75.4%) pre-eCTAS compared with 685 patients (92.7%) triaged with eCTAS. With the auditor's CTAS score as the reference, eCTAS significantly reduced the number of patients over-triaged (12.0% versus 5.1%; Δ 6.9; 95% CI 4.0 to 9.7) and under-triaged (12.6% versus 2.2%; Δ 10.4; 95% CI 7.9 to 13.2). Interrater agreement was higher with eCTAS (unweighted κ 0.89 versus 0.63; quadratic-weighted κ 0.93 versus 0.79). Median triage time was 312 seconds (n=3,808 patients) pre-eCTAS and 347 seconds (n=3,489 patients) with eCTAS (Δ 35 seconds; 95% CI 29 to 40 seconds)., Conclusion: A standardized, electronic approach to performing triage assessments improves both interrater agreement and data accuracy without substantially increasing triage time., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the relationship between gender roles and self-rated health in older men and women from different contexts., Methods: 2002 community-dwelling older adults from the International Mobility in Aging Study were recruited from 5 research sites. Gender role was measured with the 12-item Bem Sex Role Inventory, which categorized study participants into four gender roles: Masculine, Feminine, Androgynous, and Undifferentiated. Self-rated health was collapsed into a dichotomous variable (Very Good/Good and Fair/Poor/Very Poor). Prevalence risk ratios (PRR) of self-rated health relative to gender roles were estimated with Poisson regression models adjusted for all relevant confounders., Results: After complete adjustment, feminine (PRR 1.22 (95 % CI 1.01-1.49)) and undifferentiated (PRR 1.25 (95 % CI 1.05-1.50)) gender roles were associated with poorer relative self-rated health., Discussion: Gender roles confer independent risks and benefits for self-rated health in older adults., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: The efficacy of many therapeutics techniques for treatment of branch retinal vein occlusion (BRVO) has been the subject of many investigations. The aim of the present work is to evaluate the transluminal Nd: YAG laser thrombolysis as a new therapeutic approach used for treatment of BRVO in rabbits as an experimental model. Methods: Four rabbits were considered as a control (n=8 eyes); occlusion of the branch retinal veins was performed by using a dye enhancing thrombus formation in right eyes of 10 rabbits (n=10 eyes). Thrombi in the retinal veins were induced by intravenous injection of rose bengal solution as a photosensitizer immediately before the argon laser application with a power of 1200 mW, a spot size of 100 µm, and a duration of 20 ms. One week later, transluminal Nd: YAG laser thrombolysis (30 mJ, 3 pulses/4 ns) was employed to the site of occluded veins, until the thrombi were partially or completely shattered. The rabbits were followed up after 4 days, 1 week and 2 weeks for slit lamp fundus examination and the treated retinas were isolated for histopathological examination. Results: Argon laser photothrombosis induced complete BRVO with some vitreous hemorrhage, destruction, and necrosis in the surrounding retinal layers. Moreover, one week later, Nd: YAG laser thrombolysis showed complete venous flow, minimal vitreous hemorrhage, reperfused retina, complete veins improvement. Follow up after 2 weeks revealed more improvement of all retinal layers. Conclusion: Treatment with transluminal Nd: YAG laser thrombolysis represented a novel therapeutic modality in BRVO.

An optimization-simulation strategy has been applied by coupling a commercial process simulator (Aspen HYSYS®) with a programming tool (MATLAB®) to produce a precise steady state simulation-based optimization of a whole green-field saturated gas plant as a real case study. The plant has more than 100-components and comprises interacting three-phase fractionation towers, pumps, compressors and exchangers. The literature predominantly uses this coupling to optimize individual units at small scales, while paying more attention to optimizing discrete design decisions. However, bridging the gap to scalable continuous design variables is indispensable for industry. The strategy adopted is a merge between sensitivity analysis and constrained bounding of the variables along with stochastic optimization algorithms from MATLAB® such as genetic algorithm (GA) and particle swarm optimization (PSO) techniques. The benefits and shortcomings of each optimization technique have been investigated in terms of defined inputs, performance, and finally the elapsed time for such highly complex case study. Although, both GA and PSO were satisfactory for the optimization, the GA provided greater confidence in optimization with wider ranges of constrained bounds. The implemented strategy precisely reached the best operating conditions, within the range covered, by minimizing the total annual cost while maintaining at least 92% butane recovery as a process guarantee for the whole plant. The optimization-simulation strategy applied in the current work is recommended to be used in brownfields to optimize the operating conditions since they are susceptible to continuous changes in feedstock conditions., Competing Interests: The authors have declared no conflict of interest., (© 2020 THE AUTHORS. Published by Elsevier BV on behalf of Cairo University.)

Background: In patients with distal malignant biliary obstruction (MBO), endoscopic biliary drainage using the conventional self-expandable metal stent (SEMS) is the gold standard method for palliative treatment. However, there are limited data on the role of the antireflux valve metal stent (ARVMS). The aim of this study was to compare the safety and efficacy of ARVMS and SEMS in patients with distal MBO., Methods: We searched PubMed, Ovid, Embase and the Cochrane Library from inception until April 2019 for relevant randomized controlled trials (RCTs). The selected studies provided data regarding technical and clinical success rates, adverse events, and stent dysfunction. Data were meta-analyzed using RevMan software., Results: Three RCTs were selected, enrolling 293 patients (147 ARVMS and 146 SEMS). The rates of technical success were 95.23% and 99.31% for ARVMS and SEMS groups, respectively (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.01-1.06; P=0.06). The clinical success rates were 91.57% and 89.36% for ARVMS and SEMS groups, respectively (OR 1.30, 95%CI 0.48-3.51; P=0.61). There was no significant difference between the ARVMS and SEMS groups in terms of adverse events (OR 0.61, 95%CI 0.35-1.05; P=0.07) or stent dysfunction (OR 0.77, 95%CI 0.31-1.95; P=0.58), while the incidence of stent occlusion was significantly lower in the ARVMS group (OR 0.44, 95%CI 0.26-0.76; P=0.003)., Conclusion: Our study showed that ARVMS and SEMS had similar technical and clinical success rates. Adverse events were comparable between the 2 arms; however, ARVMS was associated with a lower risk of stent occlusion. Larger RCTs are required to verify the benefit of ARVMS in distal MBO patients., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Objectives: We examined the lower extremity function trajectories of older men and women over 4 years and baseline predictors of these trajectories., Design: Longitudinal analysis of an international cohort study., Settings and Participants: Older adults from the International Mobility in Aging Study (IMIAS) aged between 65 and 74 years at baseline., Measures: Physical performance of the lower extremities was measured in 2012, with follow-ups in 2014 and in 2016, using the Short Physical Performance Battery (SPPB). Group-based trajectory analysis of physical performance by gender was performed. Multinomial logistic regression was used to derive relative risk ratios with 95% confidence intervals between the physical performance trajectories and the potential baseline predictors in men and women separately., Results: Three physical performance trajectories were identified in men and women: high-stable (30.0% vs 35.5%), gradual functional decline (63.1% vs 54.3%), and rapid functional decline (6.9% vs 10.2%). Common baseline characteristics associated with memberships in the gradual functional decline and rapid functional decline trajectory groups in men and women were age, single marital status, and multiple chronic conditions (>3). Among men, depression was a strong predictor of the membership in the rapid functional decline trajectory group. Women in the rapid functional decline trajectory group were more likely to be obese, with feminine and undifferentiated gender roles, and have poor self-rated health at baseline., Conclusions/implications: There are gender differences in the physical performance trajectories and related factors among older adults. Programs aiming at preventing or slowing functional decline in old age should be sensitive to gender., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Eggshell (ES) and eggshell membrane (ESM) is a significant byproduct of the egg producing industry (Ahmed et al., 2019). Many studies have been undertaken to utilize ES waste for potential value added applications (Cordeiro and Hincke, 2011). Described here are the datasets from our evaluation of processed eggshell membrane powder (PEP) as a wound healing product using the mouse excisional wound splinting model (Ahmed et al., 2019). PEP biomaterial was characterized by proteomics using various extraction and solubilization strategies including moderate (lithium dodecyl sulphate (LDS) and urea/ammonium bicarbonate) and harsh conditions (3-mercaptopropionic acid (3-MPA) and NaOH/dimethylsulfoxide) in order to progressively overcome its stable, insoluble nature (Ahmed et al., 2019, Ahmed et al., 2017). Analysis of proteomic data allowed the relative abundance of the main PEP protein constituents to be determined. The efficacy of PEP for promotion of wound healing was assessed using the mouse excisional wound splinting model, and well-established semi-quantitative histological scoring. (More details about the PEP biomaterial characterization and its in vivo evaluation can be found in the related research article (Ahmed et al., 2019))., (© 2019 The Authors.)

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide. HCC is a complex process that is associated with several etiological factors, which in turn result in aberrant activation of different cellular and molecular pathways and the disruption of balance between activation and inactivation of protooncogenes and tumor suppressor genes, respectively. Since HCC most often occurs in the setting of a diseased or cirrhotic liver and most of the patients are diagnosed at the late stage of disease, prognosis is generally poor. At present, limited treatment options with marginal clinical benefits are available. Systemic therapy, particularly in the form of conventional cytotoxic drugs, are generally ineffective. In recent years, molecular-targeted therapies have been clinically used to treat various cancers, including liver cancer. This approach inhibits the growth of tumor cells by interfering with molecules that are involved in carcinogenesis, which makes it more selective and specific than cytotoxic chemotherapy. Many clinical trials have been carried out while using molecular targeted drugs in advanced HCC with many more in progress. The clinical trials in HCC to date have evaluated a single-targeted therapy alone, or two or more targeted therapies in parallel. The aim of this review is to provide insight of various molecular mechanisms, leading to HCC development and progression, and also the range of experimental therapeutics for patients with advanced HCC. The review will summarize different clinical trials data the successes and failures of these treatments, as well as the most effective and approved drugs designed against HCC., Competing Interests: The authors declare no conflict of interest.

Objectives: To examine differences in incidence of functional disability between older women and men., Methods: 2002 participants (65-74 years) were recruited in 2012 from Canada, Brazil, Colombia, and Albania, and re-assessed in 2016. Three measures of functional disability were used (1) Difficulty in any of five mobility-related Activities of Daily Living (ADL disability); (2) Self-reported difficulty climbing a flight of stairs or walking 400 m (mobility disability); and (3) Poor physical performance. We estimated the adjusted gender-specific incidence risk ratios (IRR) for each outcome in 2016., Results: In 2016, 1506 participants (52% women) were re-examined, 80% of the surviving cohort. Among those not disabled in 2012, seventy-four (12.9%) men developed ADL disability, while 105 (19.2%) developed mobility disability, and 97 (16.1%) developed poor physical performance. For women, numbers were higher 120 (21.4%) developed ADL disability, 117 (26.5%) developed mobility disability, and 140 (23.0%) developed poor physical performance. Compared to men, women had a higher adjusted incidence of self-reported ADL disability (IRR 1.4; 95% CI 1.04-1.88) and mobility disability (IRR 1.4; 95% CI 1.06-1.77), but not of poor physical performance (IRR 1.03; 95% CI 0.88-1.32)., Conclusions: Although women have a higher self-reported incidence of ADL and mobility disability than men, there was no significant difference in poor physical performance. Reasons for this discrepancy between self-reported and performance-based measures require further investigation. Understanding gender differences in functional disabilities can provide the basis for interventions to prevent mobility loss and minimize any gender gap., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Non-healing wounds are a major health problem worldwide and a significant cause of morbidity and mortality. Effective treatments for acute and chronic skin wounds are the focus of intensive research. Eggshell membrane (ESM) is a natural proteinaceous by-product of the food industry and is suitable for biomedical applications. The objective of this study was to evaluate processed eggshell membrane powder (PEP) for the promotion of skin wound healing. PEP was characterized using proteomics and bioinformatics. Proteomic analysis of PEP identified 110 proteins, including structural proteins such as collagen and cysteine-rich eggshell membrane proteins (CREMPs) that together constitute about 40% of PEP. Functional annotation clustering showed various predicted functionalities related to wound healing including response to external stimulus, defense response, inflammatory response, and cell-substrate adhesion. The impact of PEP on wound healing was determined using the mouse excisional wound splinting model with a subsequent assessment by histopathology. PEP was found to significantly accelerate wound closure at days 3, 7, and 10. Histological assessment showed significantly thicker granulation tissue in wounds treated with PEP than non-treated controls at days 10 and 17. In addition, histological scoring showed higher levels of collagen deposition at day 10 in wounds treated with PEP, with limited inflammatory reaction. Therefore, PEP is a biocompatible and non-cytotoxic biomaterial that has great potential for development into a cost-effective wound healing product., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to ERK signaling inhibition. The strategy was broadly effective in TNBC models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. In addition, we identified a subset of BRAF(V600E) tumors that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Thus, we identify molecular determinants of response to combined ERK signaling and SHP2 inhibition in ERK-dependent tumors., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The application of antimicrobial peptides (AMPs) in food preservation presents a promising alternative and offers many benefits, such as reducing the use of chemical preservatives, reducing food losses due to spoilage, and development of health-promoting food supplements. The biological activity of AMPs largely dependent on several physicochemical features including charge, the degree of helicity, hydrophobicity, and sequence. The present review provides an overview of the structural classification of AMPs emphasizing the importance of their structural features for biological activity, followed by the description of some antimicrobial mechanism of action. Despite the several hurdles that must be overcome for the exploitation of food-derived AMPs in drug discovery and food systems, the developments discussed in this review offer a taste of future trends in food and pharmaceutical applications of these intriguing molecules. PRACTICAL APPLICATIONS: Numerous AMPs have been reported in recent years as naturally present or released from food proteins upon enzymatic digestion during food processing, fermentation, or gastrointestinal transit. Particularly, food-released AMPs is a promising alternative to satisfy consumer demands for safe, ready-to-eat, extended shelf-life, fresh-tasting, and minimally processed foods, without chemical additives. The potential of several AMPs to inhibit foodborne pathogens is increasingly studied in various food matrices including dairy products, meat, fruits, and beverages. Although extensive progress has been made with respect to our understanding of AMPs structure/function, additional thorough investigation of the factors influencing peptide activity is required. The time has now come for the development of nutraceuticals and pharmaceutical products containing food-derived AMPs. Despite the several hurdles that must be overcome for the exploitation of AMPs, the features and developments discussed in this review offer a taste of future trends in food and pharmaceutical applications of these intriguing molecules., (© 2018 Wiley Periodicals, Inc.)

Objectives: The objectives of this study were to explore the perspectives of older adults about the most important domains of aging well and to identify the social determinants of a person-centered index capturing these domains., Methods: We conducted a mixed-methods study of 40 semi-structured interviews and epidemiological data from 670 older adults participating in the International Mobility in Aging Study (IMIAS) in Saint-Hyacinthe and Kingston. A composite index capturing the domains of aging well was constructed on the basis of findings from qualitative content analysis. Bivariate and multivariate regressions were carried out to examine the determinants of aging well, including economic determinants, health behaviours, health services, and the social environment., Results: The qualitative results confirm the importance of symptomatic health conditions and psychosocial components. The index was computed as a continuous score (0 to 100) containing health components (ADL disability, mobility disability, pain, self-rated health, and cognitive function), and psychosocial components (mood, productive activities, social relations, life satisfaction, and self-mastery). Mean scores were 81 among Canadian older adults, and 83 and 79 for men and women respectively. Being male, having sufficient income, doing leisure physical activity, and feeling safe in one's neighbourhood were all significantly associated with a higher score on the aging well index., Conclusion: The composite index highlights important aspects of health and psychosocial well-being that could be augmented according to older adults themselves. Modifiable social determinants of aging well could guide social and health policies to maximize well-being in this population.

Avian eggshell membrane (ESM) is a natural biomaterial that has been used as an alternative natural bandage to cure wounds, and is available in large quantities from egg industries. We have previously demonstrated that processed eggshell membrane powder (PEP), aiming to be used in a low cost wound healing product, possesses anti-inflammatory properties. In this study, we further investigated effects of PEP on MMP activities in vitro (a dermal fibroblast cell culture system) and in vivo (a mouse skin wound healing model). Three days incubation with PEP in cell culture led to rearrangement of the actin-cytoskeleton and vinculin in focal adhesions and increased syndecan-4 shedding. In addition, we observed increased matrix metalloproteinase type 2 (MMP-2) enzyme activation, without effects on protein levels of MMP-2 or its regulators (membrane type 1 (MT1)-MMP and tissue inhibitor of matrix metalloproteinase type 2 (TIMP-2). Longer incubation (10 days) led to increased protein levels of MMP-2 and its regulators. We also observed an increased alpha-smooth muscle actin (α-SMA) production, suggesting an effect of PEP on myofibroblast differentiation. In vivo, using the mouse skin wound healing model, PEP treatment (3 days) increased MMP activity at the wound edges, along with increased MMP-2 and MMP-9 protein levels, and increased keratinocyte cell proliferation. Altogether, our data suggest PEP stimulates MMP activity, and with a positive effect on early cellular events during wound healing., Competing Interests: The authors have the following financial competing interests: The author HPS is employed by Biovotec AS, a biotech company aiming to develop wound treatment products. Biovotec has filed a patent on the use of micronized eggshell (WO2016066718: Micronized eggshell membrane particles and the use thereof to promote the healing of wounds). Micronized eggshell membrane was provided from Biovotec to Nofima for its research activities. Micronized eggshell particles are not commercialized and is today used for research purposes only. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: We estimated the 2-year incidence of poor physical performance according to gender roles and examined mediating pathways related to health behaviors and chronic conditions., Method: Data are from the International Mobility in Aging Study ( n = 1,676). The Bem Sex Role Inventory was used to classify participants into four gender roles as "masculine," "feminine," "androgynous," and "undifferentiated.", Results: We found a higher incidence of poor physical performance among participants endorsing the feminine (adjusted incidence rate ratio [IRR] = 2.36, 95% confidence interval (CI) = [1.55, 3.60]) or the undifferentiated role (adjusted IRR = 2.19, 95% CI = [1.45, 3.30]) compared with the androgynous role. Smoking, physical activity, the number of chronic conditions, high body mass index, and depression were mediators of this association but not alcohol consumption., Discussion: This study provides evidence that gender roles are independently associated with physical performance. Health behaviors and chronic conditions are mediators of the relationship between gender roles and lower extremity physical function.

The purpose of this study was to develop and validate a new instrument to assess social networks and social support (IMIAS-SNSS) for different types of social ties in an international sample of older adults. The study sample included n = 1995 community dwelling older people aged between 65 and 74 years from the baseline of the longitudinal International Mobility in Aging Study (IMIAS). In order to measure social networks for each type of social tie, participants were asked about the number of contacts, the number of contacts they see at least once a month or have a very good relationship with, or speak with at least once a month. For social support, participants had to rate the level of social support provided by the four types of contacts for five Likert scale items. Confirmatory Factor Analysis was conducted to determine the goodness of fit of the measurement models. Satisfactory goodness-of-fit indices confirmed the satisfactory factorial structure of the IMIAS-SNSS instrument. Reliability coefficients were 0.80, 0.81, 0.85, and 0.88 for friends, children, family, and partner models, respectively. The models were confirmed by CFA for each type of social tie. Moreover, IMIAS-SNSS detected gender differences in the older adult populations of IMIAS. These results provide evidence supporting that IMIAS-SNSS is a psychometrically sound instrument and of its validity and reliability for international populations of older adults.