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Background: Debates exist as to whether, as overall population health improves, the absolute and relative magnitude of income- and race/ethnicity-related health disparities necessarily increase-or decrease. We accordingly decided to test the hypothesis that health inequities widen-or shrink-in a context of declining mortality rates, by examining annual US mortality data over a 42 year period.Methods and Findings: Using US county mortality data from 1960-2002 and county median family income data from the 1960-2000 decennial censuses, we analyzed the rates of premature mortality (deaths among persons under age 65) and infant death (deaths among persons under age 1) by quintiles of county median family income weighted by county population size. Between 1960 and 2002, as US premature mortality and infant death rates declined in all county income quintiles, socioeconomic and racial/ethnic inequities in premature mortality and infant death (both relative and absolute) shrank between 1966 and 1980, especially for US populations of color; thereafter, the relative health inequities widened and the absolute differences barely changed in magnitude. Had all persons experienced the same yearly age-specific premature mortality rates as the white population living in the highest income quintile, between 1960 and 2002, 14% of the white premature deaths and 30% of the premature deaths among populations of color would not have occurred.Conclusions: The observed trends refute arguments that health inequities inevitably widen-or shrink-as population health improves. Instead, the magnitude of health inequalities can fall or rise; it is our job to understand why. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has had intense, heterogeneous impacts on different communities and geographies in the United States. We explore county-level associations between COVID-19 attributed deaths and social, demographic, vulnerability, and political variables to develop a better understanding of the evolving roles these variables have played in relation to mortality. We focus on the role of political variables, as captured by support for either the Republican or Democratic presidential candidates in the 2020 elections and the stringency of state-wide governor mandates, during three non-overlapping time periods between February 2020 and February 2021. We find that during the first three months of the pandemic, Democratic-leaning and internationally-connected urban counties were affected. During subsequent months (between May and September 2020), Republican counties with high percentages of Hispanic and Black populations were most hardly hit. In the third time period -between October 2020 and February 2021- we find that Republican-leaning counties with loose mask mandates experienced up to 3 times higher death rates than Democratic-leaning counties, even after controlling for multiple social vulnerability factors. Some of these deaths could perhaps have been avoided given that the effectiveness of non-pharmaceutical interventions in preventing uncontrolled disease transmission, such as social distancing and wearing masks indoors, had been well-established at this point in time., Competing Interests: WPH declares compensation for expert witness testimony during the pandemic, and is a member of the Scientific Advisory Board of Biobot Analytics., (Copyright: © 2022 Kaashoek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Antecedent factors which influence adult engagement with nature are underexplored given the human health benefits strongly associated with nature exposure. Formative pathways and impediments to nature contact merit understanding as they may contribute to later-life health disparities. We probed experiential pathways and attitudes toward nature engagement among adults purposefully sampled across U.S. regions, age, race/ethnicity, and urbanicity through semi-structured focus group discussions. The research aims were to explore entryways and barriers to experiencing nature and learn how natured and built environments compete in influencing human-nature relationships. Sessions were recorded, transcribed, and analyzed following Braun and Clarke's phases of thematic analysis. Qualitative content analysis of discussions identified three principal themes: 1) formative influences promoting adult nature engagement (i.e., persons/organizations and places of origin), 2) detractors from nature engagement (i.e., perceptual, material, and physical barriers), and 3) role of current setting (i.e., natural and built environments) shaping nature-seeking relationships. We found experiential factors that included early life exposures outdoors, personal mentorship, and organizational affiliation to be highly influential in socializing individuals to nature and in soldering attachment to nature which manifests into adulthood. In contrast, changing demographics and childhood, inequity, social dynamics, metropolitan growth, urban renewal explained alienation from nature. These findings emphasize the importance of efforts to expand opportunities for nature contact, especially for youth living in economically challenged urban areas, which go beyond increasing greenspace to encompass mentoring partnerships for gaining skills and comfort outdoors and redesign of safe natured spaces within cities for hands-on learning and discovery., Competing Interests: The authors have declared that no competing interests exist.

Proliferative vitreoretinopathy (PVR) progression is associated with TGF-β2-induced epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells. In cancer cells, miR-4516 downregulates orthodenticle homeobox 1 (OTX1)-mediated cell invasion. Moreover, OTX1 is shown to be involved in invasion and EMT. The purpose of this study was to assess whether microRNA (miR-4516) suppresses EMT in RPE cells. EMT features were assessed using Western blotting, immunocytochemical staining, scratch-wound healing, modified Boyden chamber assay, and collagen gel contraction assay. For in vivo testing, a rabbit model was used, which involved induction of PVR by injection of transfected spontaneously arising RPE (ARPE) cells into the vitreous chamber. The putative target of miR-4516 was identified by luciferase reporter assay. Results showed that TGF-β2-induced transdifferentiation and migration of RPE cells was inhibited by miR-4516 delivery. Overexpression of miR-4516 led to upregulation of zonula occludens-1, downregulation of α-smooth muscle actin and vimentin, and cell contractility-all EMT features-in the TGF-β2-treated ARPE-19 cells. MiR-4516 regulated OTX1 expression negatively by binding to its 3'-UTR. TGF-β2-induced phosphorylated ERK was inhibited in miR-4516-overexpressing ARPE-19 cells. MiR-4516 suppressed experimental PVR in vitro and in vivo. In conclusion, the overexpression of miR-4516 suppresses TGF-β2-induced EMT in a PVR model, and its role in PVR depends on OTX1/ERK. Further research is needed to develop a feasible treatment method to prevent and treat PVR., Competing Interests: The authors declare that they have no competing interests.

Background: Increasing both the frequency and quality of social interactions within treatments for anxiety and depressive disorders in older adults may improve their mental health outcomes and quality of life. This study aims to evaluate the clinical efficacy and cost utility of an enhanced cognitive behavioural therapy (CBT) plus social participation program in a sample of older adults with depression and/or anxiety., Methods: A total of 172 community-dwelling adults aged 65 years or older with an anxiety and/or depressive disorder will be randomly allocated to either an enhanced CBT plus social participation program (n = 86) or standard CBT (n = 86). Both treatments will be delivered during 12 weekly individual sessions utilising structured manuals and workbooks. Participants will be assessed at pre-treatment, post-treatment, and 12-month follow-up. The primary outcome evaluates mean change in clinician-rated diagnostic severity of anxiety and depressive disorders from baseline to post-treatment (primary endpoint) based on a semi-structured diagnostic interview. Secondary outcomes evaluate changes in symptomatology on self-report anxiety and depression measures, as well as changes in social/community participation, social network, and perceived social support, loneliness, quality of life, and use of health services. Economic benefits will be evaluated using a cost-utility analysis to derive the incremental cost utility ratios for the enhanced CBT program., Discussion: Outcomes from this study will provide support for the establishment of improved psychosocial treatment for older adults with anxiety and/or depression. Study outcomes will also provide health systems with a clear means to reduce the impact of poor emotional health in older age and its associated economic burden. In addition to the empirical validation of a novel treatment, the current study will contribute to the current understanding of the role of social participation in older adult wellbeing., Trial Registration: Prospectively registered on the Australian New Zealand Clinical Trials Registry (ID: ACTRN12619000242123; registered 19th February 2019) and the ISRCTN registry (ID: ISRCTN78951376; registered 10th July 2019)., Competing Interests: The authors have declared that no competing interests exist.

H5N1 virus (H5N1V) is highly contagious among birds and it was first detected in humans in 1997 during a poultry outbreak in Hong Kong. As the mechanism of its pathogenesis inside the host is still lacking, in this in-silico study we hypothesized that H5N1V might create miRNAs, which could target the genes associated with host cellular regulatory pathways, thus provide persistent refuge to the virus. Using bioinformatics approaches, several H5N1V produced putative miRNAs as well as the host genes targeted by these miRNAs were found. Functional enrichment analysis of targeted genes revealed their involvement in many biological pathways that facilitate their host pathogenesis. Eventually, the microarray dataset (GSE28166) was analyzed to validate the altered expression level of target genes and found the genes involved in protein binding and adaptive immune responses. This study presents novel miRNAs and their targeted genes, which upon experimental validation could facilitate in developing new therapeutics against H5N1V infection., Competing Interests: The authors have declared that no competing interests exist.

The purpose of this study was to assess whether microRNA (miR)-1285 can suppress the epithelial-mesenchymal transition (EMT) in retinal pigment epithelial cells. Expression of miR-1285 was evaluated using quantitative real-time polymerase chain reaction (RT-qPCR). The features of EMT were assessed using Western blotting, immunocytochemical staining, scratch wound healing tests, modified Boyden chamber assay, and collagen gel contraction assay. A rabbit model of proliferative vitreoretinopathy (PVR) was used for in vivo testing, which involved the induction of PVR by injection of transfected ARPE cells into the vitreous chamber. Luciferase reporter assay was performed to identify the putative target of miR-1285. The expression of miR-1285 was downregulated in ARPE-19 cells treated with transforming growth factor (TGF)-β. Overexpression of miR-1285 led to upregulation of zonula occludens-1, downregulation of α-smooth muscle actin and vimentin, cell migration and cell contractility-all EMT features-in the TGF-β2-treated ARPE-19 cells. The reporter assay indicated that the 3' untranslated region of Smad4 was the direct target of miR1285. PVR progression was alleviated in the miR-1285 transfected rabbits. In conclusion, overexpression of miR-1285 attenuates TGF-β2-induced EMT in a rabbit model of PVR, and the effect of miR-1285 in PVR is dependent on Smad4. Further research is warranted to develop a feasible therapeutic approach for the prevention and treatment of PVR., Competing Interests: The authors have declared that no competing interests exist.

Extramammary Paget's disease (EMPD) is an intra-epidermal adenocarcinoma. Till now, the mechanisms underlying the pathogenesis of scrotal EMPD is poorly known. This present study aims to explore the knowledge of molecular mechanism of scrotal EMPD by identifying the hub genes and candidate drugs using integrated bioinformatics approaches. Firstly, the microarray datasets (GSE117285) were downloaded from the GEO database and then analyzed using GEO2R in order to obtain differentially expressed genes (DEGs). Moreover, hub genes were identified on the basis of their degree of connectivity using Cytohubba plugin of cytoscape tool. Finally, GEPIA and DGIdb were used for the survival analysis and selection of therapeutic candidates, respectively. A total of 786 DEGs were identified, of which 10 genes were considered as hub genes on the basis of the highest degree of connectivity. After the survival analysis of ten hub genes, a total of 5 genes were found to be altered in EMPD patients. Furthermore, 14 drugs of CHEK1, CCNA2, and CDK1 were found to have therapeutic potential against EMPD. This study updates the information and yields a new perspective in the context of understanding the pathogenesis of EMPD. In future, hub genes and candidate drugs might be capable of improving the personalized detection and therapies for EMPD., Competing Interests: The authors have declared that no competing interests exist.

We evaluated the clinical utility of ultra-widefield imaging as an adjunctive tool for training resident ophthalmologists in the detection of retinal breaks. This was a prospective study conducted at a secondary health care center (Tri-Service General Hospital) in Taiwan. Participants were 44 patients (53 eyes) who were referred to our hospital after being diagnosed with retinal breaks. Patients first underwent an indirect ophthalmoscopy examination of the total fundus without scleral depression by our junior (first and second year) or senior (third and fourth year) resident ophthalmologist and then underwent an ultra-widefield imaging examination with a central image and four gaze-steered (up, down, nasal, and temporal) images to determine the number of retinal breaks in the total fundus and the four quadrants. Of the total 53 eyes, 31 were examined by junior residents and 22 were examined by senior residents. In the group of junior residents, ultra-widefield imaging was significantly better at detecting retinal breaks of the total fundus (49 vs. 33 retinal breaks, p < 0.001) and the temporal quadrant (17 vs. 10 retinal breaks, p = 0.018) than indirect ophthalmoscopy. In the group of senior residents, there was no significant difference in the ability to detect retinal breaks in the total fundus or each of the four quadrants with ultra-widefield imaging or indirect ophthalmoscopy. Our results indicate that, compared to indirect ophthalmoscopy, ultra-widefield imaging with a central image and four gaze-steered images has a better performance and is a useful adjunct tool for the detection of retinal breaks in junior resident training. Additionally, it could be a useful method for teaching indirect ophthalmoscopy examination to junior residents., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To analyze the association between glucosamine (GlcN) use and the risk of age-related macular degeneration (AMD) using claims data from the National Health Insurance Research Database (NHIRD)., Methods: A retrospective, population-based study was conducted with NHIRD data from a 14-year period (2000-2013). Chi-squared and Student's t-tests were used to evaluate differences between the study and comparison cohorts for categorical and continuous variables, respectively. Risk factors for disease development were examined by the adjusted hazard ratio (aHR) with 95% confidence interval. Kaplan-Meier analysis was performed to compare the cumulative risk of AMD between the two cohorts., Results: In total, 1,344 patients with GlcN treatment were enrolled in the study cohort and 5,376 patients without GlcN use were enrolled in the comparison cohort. The incidence rate of AMD was lower with GlcN use (3.65%) than without GlcN use (5.26%) (P = 0.014). GlcN use was associated with a lower risk of developing AMD among patients with hyperlipidemia, coronary artery disease, chronic obstructive pulmonary disease, stroke, other neurological disorders, or degenerative arthritis. Although the incidence of wet type AMD did not significantly differ (P = 0.91), the incidence of dry type AMD was lower in patients with GlcN use (2.9%) than those without GlcN use (4.84%) (P = 0.003). Kaplan-Meier analysis similarly revealed a lower rate of dry type AMD in patients with GlcN use compared to those without GlcN use (log-rank P = 0.004)., Conclusions: GlcN treatment can decrease the risk of developing dry type AMD. Further prospective controlled studies are needed to determine the effectiveness of GlcN treatment in patients with AMD and the associated mechanism., Competing Interests: The authors have declared that no competing interests exist.

Many phytochemicals can affect the growth and development of plants and insects which can be used as biological control agents. In this study, different concentrations of crude, hexane, chloroform, butanol, and aqueous extracts of Euphorbia nivulia Buch.-Ham., an endemic plant of the Cholistan desert in South Punjab of Pakistan, were analysed for their chemical constituents. Their various concentrations were also tested for their phytotoxic and insecticidal potential against duckweed, Lemna minor L., and the dusky cotton bug, Oxycarenus hyalinipennis Costa. various polyphenols, i.e., quercetin, gallic acid, caffeic acid, syringic acid, coumaric acid, ferulic acid, and cinnamic acid were detected in different concentrations with different solvents during the phytochemical screening of E. nivulia. In the phytotoxicity test, except for 100 μg/mL of the butanol extract gave 4.5% growth regulation, no phytotoxic lethality could be found at 10 and 100 μg/mL of all the extracts. The highest concentration, 1000 μg/mL, of the chloroform, crude, and butanol extracts showed 100, 63.1, and 27.1% of growth inhibition in duckweed, respectively. In the insecticidal bioassay, the highest O. hyalinipennis mortalities (87 and 75%) were recorded at 15% concentration of the chloroform and butanol extracts of E. nivulia. In contrast, the lower concentrations of the E. nivulia extracts caused the lower mortalities. Altogether, these findings revealed that E. nivulia chloroform extracts showed significant phytotoxicity while all the extracts showed insecticidal potential. This potential can be, further, refined to be developed for bio-control agents., Competing Interests: The authors have declared that no competing interests exist.

Wheat is one of the best-domesticated cereal crops and one of the vital sources of nutrition for humans. An investigation was undertaken to reveal the potential of novel bio-inoculants enriching micronutrients in shoot and grains of wheat crop to eliminate the hazards of malnutrition. Sole as well as consortia inoculation of bio-inoculants significantly enhanced mineral nutrients including zinc (Zn) and iron (Fe) concentrations in shoot and grains of wheat. Various treatments of bio-inoculants increase Zn and Fe content up to 1-15% and 3-13%, respectively. Sole inoculation of Bacillus aryabhattai (S10) impressively improves the nutritious of wheat. However, the maximum increase in minerals contents of wheat was recorded by consortia inoculation of Paenibacillus polymyxa ZM27, Bacillus subtilis ZM63 and Bacillus aryabhattai S10. This treatment also showed a maximum bacterial population (18 × 104 cfu mL-1) in the rhizosphere. The consortium application of these strains showed up to a 17% increase in yield. It is evident from the results that the consortium application was more effective than sole and co-inoculation. A healthy positive correlation was found between growth, yield, and the accessibility of micronutrients to wheat crops at the harvesting stage. The present investigations revealed the significance of novel bacterial strains in improving the nutritional status of wheat crops. These strains could be used as bio-inoculants for the biofortification of wheat to combat hidden hunger in developing countries., Competing Interests: The authors have declared that no competing interests exist.

Background: In the United States, non-Hispanic Black (NHB), Hispanic, and non-Hispanic American Indian/Alaska Native (NHAIAN) populations experience excess COVID-19 mortality, compared to the non-Hispanic White (NHW) population, but racial/ethnic differences in age at death are not known. The release of national COVID-19 death data by racial/ethnic group now permits analysis of age-specific mortality rates for these groups and the non-Hispanic Asian or Pacific Islander (NHAPI) population. Our objectives were to examine variation in age-specific COVID-19 mortality rates by racial/ethnicity and to calculate the impact of this mortality using years of potential life lost (YPLL)., Methods and Findings: This cross-sectional study used the recently publicly available data on US COVID-19 deaths with reported race/ethnicity, for the time period February 1, 2020, to July 22, 2020. Population data were drawn from the US Census. As of July 22, 2020, the number of COVID-19 deaths equaled 68,377 for NHW, 29,476 for NHB, 23,256 for Hispanic, 1,143 for NHAIAN, and 6,468 for NHAPI populations; the corresponding population sizes were 186.4 million, 40.6 million, 2.6 million, 19.5 million, and 57.7 million. Age-standardized rate ratios relative to NHW were 3.6 (95% CI 3.5, 3.8; p < 0.001) for NHB, 2.8 (95% CI 2.7, 3.0; p < 0.001) for Hispanic, 2.2 (95% CI 1.8, 2.6; p < 0.001) for NHAIAN, and 1.6 (95% CI 1.4, 1.7; p < 0.001) for NHAP populations. By contrast, NHB rate ratios relative to NHW were 7.1 (95% CI 5.8, 8.7; p < 0.001) for persons aged 25-34 years, 9.0 (95% CI 7.9, 10.2; p < 0.001) for persons aged 35-44 years, and 7.4 (95% CI 6.9, 7.9; p < 0.001) for persons aged 45-54 years. Even at older ages, NHB rate ratios were between 2.0 and 5.7. Similarly, rate ratios for the Hispanic versus NHW population were 7.0 (95% CI 5.8, 8.7; p < 0.001), 8.8 (95% CI 7.8, 9.9; p < 0.001), and 7.0 (95% CI 6.6, 7.5; p < 0.001) for the corresponding age strata above, with remaining rate ratios ranging from 1.4 to 5.0. Rate ratios for NHAIAN were similarly high through age 74 years. Among NHAPI persons, rate ratios ranged from 2.0 to 2.8 for persons aged 25-74 years and were 1.6 and 1.2 for persons aged 75-84 and 85+ years, respectively. As a consequence, more YPLL before age 65 were experienced by the NHB and Hispanic populations than the NHW population-despite the fact that the NHW population is larger-with a ratio of 4.6:1 and 3.2:1, respectively, for NHB and Hispanic persons. Study limitations include likely lag time in receipt of completed death certificates received by the Centers for Disease Control and Prevention for transmission to NCHS, with consequent lag in capturing the total number of deaths compared to data reported on state dashboards., Conclusions: In this study, we observed racial variation in age-specific mortality rates not fully captured with examination of age-standardized rates alone. These findings suggest the importance of examining age-specific mortality rates and underscores how age standardization can obscure extreme variations within age strata. To avoid overlooking such variation, data that permit age-specific analyses should be routinely publicly available., Competing Interests: The authors have declared no competing interests exist.

Purpose: We assessed whether mitomycin-C (MMC) has different antifibrotic mechanisms in trabeculectomy wound healing., Methods: We identified 2 concentrations of MMC as "low-dose" by using WST-1 assay, Lactic dehydrogenase assay, and fluorescence-activated cell sorting flow cytometry. Senescence-associated β-galactosidase (SA-β-gal) and fibrotic gene expression was examined through immunocytochemistry, flow cytometry, real-time quantitative reverse transcription polymerase chain reaction, Western blotting, zymography, and modified scratch assay in vitro. In vivo, 0.1 mL of MMC or normal saline was injected to Tenon's capsule before trabeculectomy in a rabbit model. SA-β-gal expression, apoptotic cell death, and collagen deposition in sites treated and not treated with MMC were evaluated using terminal dUTP nick end labeling assay and histochemical staining. Bleb function and intraocular pressure (IOP) levels were examined 3, 7, 14, 21, 28, and 35 days after trabeculectomy., Results: In vitro, human Tenon's fibroblast (HTF) senescence was confirmed by observing cell morphologic change, SA-β-gal accumulation, formation of senescence-associated heterochromatin, increased p16INK4a and p21CIP1/WAF1 expression, lower percentage of Ki-67-positive cells, and decreased COL1A1 release. Increased expression of α-SMA, COL1A1, and Smad2 signaling in TGF-β1-induced stress fibers were passivated in senescent HTFs. In addition, cellular migration enhanced by TGF-β1was inactivated. In vivo, histological examination indicated increased SA-β-gal accumulation, lower apoptosis ratios, and looser collagen deposition in sites treated with 0.2 μM MMC. Low-dose MMC-induced cellular senescence prolonged trabeculectomy bleb survival and reduced IOP levels in a rabbit model., Conclusion: Low-dose MMC-induced cellular senescence is involved in the antifibrotic mechanism of trabeculectomy wound healing., Competing Interests: The authors have declared that no competing interests exist.

Background: The entomopathogenic fungus Beauveria bassiana has been widely used to kill mosquito larvae and adults in the laboratory and field. However, its slow action of killing has hampered its widespread application. In our study, the B. bassiana fungus was genetically modified to express the Bacillus thuringiensis (Bt) toxin Cyt2Ba to improve its efficacy in killing mosquitoes., Methodology/principal Findings: The efficacy of the wild type (WT) of B. bassiana and a transgenic strain expressing Cyt2Ba toxin (Bb-Cyt2Ba) was evaluated against larval and adult Aedes mosquitoes (Aedes aegypti and Aedes albopictus) using insect bioassays. The Bb-Cyt2Ba displayed increased virulence against larval and adult Aedes mosquitoes compared with the WT: for Ae. aegypti adults, the median lethal time (LT50) was decreased by 33% at the concentration of 1× 108 conidia/ml, 19% at 1× 107 conidia/ml and 47% at 1× 106 conidia/ml. The LT50 for Ae. albopictus adults was reduced by 20%, 23% and 29% at the same concentrations, respectively. The LT50 for Ae. aegypti larvae was decreased by 42% at 1× 107 conidia/ml and 25% at 1× 106 conidia/ml, and that for Ae. albopictus larvae was reduced by 33% and 31% at the same concentrations, respectively. In addition, infection with Bb-Cyt2Ba resulted in a dramatic reduction in the fecundity of Aedes mosquitoes., Conclusions/significance: In conclusion, our study demonstrated that the virulence of B. bassiana against mosquitoes can be significantly improved by introducing the Bt toxin gene Cyt2Ba into the genome to express the exogenous toxin in the fungus. The transgenic strain Bb-Cyt2Ba significantly reduced the survival and fecundity of Ae. aegypti and Ae. albopictus compared with the WT strain, which suggested that this recombinant B. bassiana has great potential for use in mosquito control., Competing Interests: The authors have declared that no competing interests exist.

Ischemia-reperfusion (I/R) injury is associated with numerous retinal diseases, such as diabetic retinopathy, acute glaucoma, and other vascular retinopathies. Hypercapnic acidosis (HCA) has a protective effect on lung, myocardial, and central nervous system ischemic injury models. However, no study has evaluated its protective effects in an experimental retinal I/R injury model. In this study, retinal I/R injury was induced in Sprague Dawley rats by elevating the intraocular pressure to 110 mmHg for 60 minutes. HCA was induced before and after the injury. After 24 hours, the terminal dUTP nick end labeling assay was performed. Moreover, the ratios of cleaved caspase-3/total caspase-3, phosphorylated IκB/IκB, and phosphorylated p38 were measured through Western blotting. After 7 days, the rats' aqueous humor was analyzed. In addition, electroretinography and retinal thickness measurement were performed in the rats. Moreover, the retinal neural cell line RGC-5 was exposed to 500 μM H2O2 for 24 hours to induce a sustained oxidative stress in vitro. The effects of HCA were evaluated by comparing oxidative stress, MAPK signals, NF-κB signals, survival rates, and apoptosis rates in the RGC-5 cells before and after H2O2 exposure. We further investigated whether the potent I/R-protective heat shock protein (HSP) 32 contribute to protective effects of HCA. Our results indicated that HCA has protective effects against retinal I/R injury both in vivo and in vitro, at multiple levels, including antiapoptotic, anti-inflammatory, antioxidative, and functional retinal cell protection. Further research clarifying the role of HCA in retinal I/R injury prevention and treatment is warranted., Competing Interests: The authors have declared that no competing interests exist.

Uveitis, an intraocular inflammatory disease, occurs mostly in young people and can result in the loss of socioeconomic capabilities. Silibinin has been shown to exert anti-inflammatory effects in human retinal pigment epithelial (RPE) cells. The present study investigated the anti-inflammatory effect of silibinin pretreatment on endotoxin-induced uveitis (EIU) in rats and the mechanisms by which it exerts these effects. Uveitis was induced via injection of lipopolysaccharides (LPS) into Lewis rats. Twenty-four hours after the LPS injection, histological examination showed that silibinin decreased inflammatory cell infiltration in the anterior segment of the eyes of LPS-treated rats. Analyses of the aqueous humor showed that silibinin decreased cell infiltration, protein concentration, nitric oxide (NO), and prostaglandin (PG)-E2 production. Western blot analysis indicated that silibinin decreased the expression of inducible NO synthase (iNOS), cyclooxygenase (COX-2), and phosphorylated IkB in the iris-ciliary body (ICB). Immunohistochemistry showed that silibinin decreased intercellular adhesion molecule (ICAM-1) expression in the ICB. In addition, western blot analysis showed that silibinin attenuated the expression of iNOS, COX-2, ICAM-1, and nuclear p65 in LPS-treated RAW cells. In conclusion, silibinin pretreatment prevents EIU and the subsequent production of proinflammatory mediators and ICAM-1, at least in part, by blocking the NF-κB-dependent signaling pathway both in vivo and in vitro. These effects may contribute to the silibinin-mediated preventive effects on intraocular inflammatory diseases such as acute uveitis.

The objective of this study was to evaluate the effects of silibinin on cell proliferation in platelet-derived growth factor (PDGF)-treated human Tenon's fibroblasts (HTFs). The effect of silibinin on cell proliferation in PDGF-treated HTFs was determined by examining the expression of proliferating cell nuclear antigen (PCNA) and performing WST-1 assays. Cell cycle progression was evaluated using flow cytometry. The related cyclins and cyclin-dependent kinases (CDKs) were also analyzed using western blot. A modified rat trabeculectomy model was established to evaluate the effect of silibinin on cell proliferation in vivo. Western blot analysis was carried out to determine the effect of silibinin on the expression of PDGF receptor and on the downstream signaling pathways regulated by PDGF receptor. PDGF elevated the expression of PCNA in HTFs, and this elevation was inhibited by silibinin. The inhibitory effect of silibinin on cell proliferation was also confirmed via WST-1 assay. PDGF-stimulated cell cycle in HTFs was delayed by silibinin, and the related cyclin D1 and CDK4 were also suppressed by silibinin. In the rat model of trabeculectomy, silibinin reduced the expression of PCNA at the site of blebs in vivo. The effects of silibinin on PDGF-stimulated HTFs were mediated via the downregulation of PDGF receptor-regulated signaling pathways, such as ERKs and STATs, which may be partially caused by the downregulation of N-glycosylation of PDGF receptor beta (PDGFRβ). The effect of silibinin on modulation of N-glycosylation of PDGFRβ was mediated in a proteasome-dependent manner. Silibinin inhibited cell proliferation and delayed cell cycle progression in PDGF-treated HTFs in vitro. PDGF also modulated the process of N-glycosylation of the PDGFRβ in a proteasome-dependent manner. Our findings suggest that silibinin has potential therapeutic applications in glaucoma filtering surgery., Competing Interests: The authors have declared that no competing interests exist.

Nancy Krieger and colleagues argue that law-enforcement-related deaths in the United States should be treated as notifiable conditions, which would allow public health departments to report these data in real-time.

Background: Regular screening of transfusion-transmissible infections (TTIs), such as human immunodeficiency virus (HIV), hepatitis B and hepatitis C virus (HBV and HCV, respectively), and Treponema pallidum, in blood donors is essential to guaranteeing clinical transfusion safety. This study aimed to determine the seroprevalence of four TTIs among blood donors on Bioko Island, Equatorial Guinea (EG)., Methods: A retrospective survey of blood donors from January 2011 to April 2013 was conducted to assess the presence of HIV, HBV, HCV and T. pallidum. The medical records were analyzed to verify the seroprevalence of these TTIs among blood donations stratified by gender, age and geographical region., Results: Of the total 2937 consecutive blood donors, 1098 (37.39%) had a minimum of one TTI and 185 (6.29%) harbored co-infections. The general seroprevalence of HIV, HBV, HCV and T. pallidum were 7.83%, 10.01%, 3.71% and 21.51%, respectively. The most frequent TTI co-infections were HBV-T. pallidum 60 (2.04%) and HIV-T. pallidum 46 (1.57%). The seroprevalence of HIV, HBV, HCV and T. pallidum were highest among blood donors 38 to 47 years, 18 to 27 years and ≥ 48 years age, respectively (P<0.05). The seroprevalence of TTIs varied according to the population from which the blood was collected on Bioko Island., Conclusions: Our results firstly provide a comprehensive overview of TTIs among blood donors on Bioko Island. Strict screening of blood donors and improved hematological examinations using standard operating procedures are recommended.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobinopathies were the inherited conditions found mostly in African. However, few epidemiological data of these disorders was reported in Equatorial Guinea (EQG). This study aimed to assess the prevalence and healthy effects of G6PD deficiency and hemoglobinopathies among the people on malaria endemic Bioko Island, EQG., Materials and Methods: Blood samples from 4,144 unrelated subjects were analyzed for G6PD deficiency by fluorescence spot test (FST), high-resolution melting assay and PCR-DNA sequencing. In addition, 1,186 samples were randomly selected from the 4,144 subjects for detection of hemoglobin S (HbS), HbC, and α-thalassemia deletion by complete blood count, PCR-DNA sequencing and reverse dot blot (RDB)., Results: The prevalence of malaria and anemia was 12.6% (522/4,144) and 32.8% (389/1,186), respectively. Overall, 8.7% subjects (359/4,144) were G6PD-deficient by FST, including 9.0% (249/2,758) males and 7.9% (110/1,386) females. Among the 359 G6PD-deficient individuals molecularly studied, the G6PD A- (G202A/A376G) were detected in 356 cases (99.2%), G6PD Betica (T968C/A376G) in 3 cases. Among the 1,186 subjects, 201 cases were HbS heterozygotes, 35 cases were HbC heterozygotes, and 2 cases were HbCS double heterozygotes; 452 cases showed heterozygous α-thalassemia 3.7 kb deletion (-α3.7 kb deletion) and 85 homozygous - α3.7 kb deletion. The overall allele frequencies were HbS 17.1% (203/1186); HbC, 3.1% (37/1186); and -α3.7 kb deletion 52.4% (622/1186), respectively., Conclusions: High G6PD deficiency in this population indicate that diagnosis and management of G6PD deficiency is necessary on Bioko Island. Obligatory newborn screening, prenatal screening and counseling for these genetic disorders, especially HbS, are needed on the island.

Background: Alendronate (ALE) is a conventional drug used to treat osteoporosis. Low-magnitude whole-body vibration (WBV) exercise has been developed as a potential treatment for osteoporosis. The aim of this study was to investigate whether low-magnitude WBV could enhance the protective effect of ALE on bone properties in ovariectomized rats., Methods: A total of 128 Sprague-Dawley rats were randomly divided into five groups (SHAM, OVX+VEH, OVX+WBV, OVX + ALE, OVX+WBV+ALE). The level of WBV applied was 0.3 g at 45-55 Hz for 20 min/day, 5 day/week and for 3 months. ALE was administered in dose of 1 mg/Kg once a week. Every four weeks eight rats from each group were sacrificed and their blood and both tibiae were harvested. The expression of osteocalcin and CTX in serum was measured by enzyme-linked immunosorbent assay (ELISA) and the tibiae were subjected to metaphyseal three-point bending and μCT analysis., Results: Osteocalcin rose after ovariectomy and was not appreciably changed by either alendronate or WBV alone or in combination. Alendronate treatment significantly prevented an increase in CTX. WBV alone treatment did not alter this effect. Compared with the OVX+WBV group, nearly all tested indices such as the BV/TV, TV apparent, Tb.N, Tb.Th, and Conn.D were higher in the OVX+ALE group at week 12.Compared with the OVX+WBV group, certain tested indices such as BV/TV, TV apparent, Tb.N, and Con.D, were higher in the OVX+WBV+ALE group at week 12. At week 12, tibiae treated with WBV+ALE exhibited a significantly higher Fmax compared to the OVX+VEH group, and a significant difference was also found in energy absorption between the OVX+WBV+ALE and OVX+VEH groups., Conclusions: Compared with the WBV, ALE was more effective at preventing bone loss and improved the trabecular architecture. However, WBV enhanced the effect of alendronate in ovariectomized rats by inducing further improvements in trabecular architecture.

Objectives: To date, limited and inconsistent evidence exists regarding racial discrimination and risk of cardiovascular disease (CVD)., Methods: Cross-sectional observational study of 1005 US-born non-Hispanic black (n = 504) and white (n = 501) participants age 35-64 randomly selected from community health centers in Boston, MA (2008-2010; 82.4% response rate), using 3 racial discrimination measures: explicit self-report; implicit association test (IAT, a time reaction test for self and group as target vs. perpetrator of discrimination); and structural (Jim Crow status of state of birth, i.e. legal racial discrimination prior 1964)., Results: Black and white participants both had adverse cardiovascular and socioeconomic profiles, with black participants most highly exposed to racial discrimination. Positive crude associations among black participants occurred for Jim Crow birthplace and hypertension (odds ratio (OR) 1.92, 95% confidence interval (CI) 1.28, 2.89) and for explicit self-report and the Framingham 10 year CVD risk score (beta = 0.04; 95% CI 0.01, 0.07); among white participants, only negative crude associations existed (for IAT for self, for lower systolic blood pressure (SBP; beta = -4.86; 95% CI -9.08, -0.64) and lower Framingham CVD score (beta = -0.36, 95% CI -0.63, -0.08)). All of these associations were attenuated and all but the white IAT-Framingham risk score association were rendered null in analyses that controlled for lifetime socioeconomic position and additional covariates. Controlling for racial discrimination, socioeconomic position, and other covariates did not attenuate the crude black excess risk for SBP and hypertension and left unaffected the null excess risk for the Framingham CVD score., Conclusion: Despite worse exposures among the black participants, racial discrimination and socioeconomic position were not associated, in multivariable analyses, with risk of CVD. We interpret results in relation to constrained variability of exposures and outcomes and discuss implications for valid research on social determinants of health.

Background: To evaluate the outcomes of Descemet-stripping automated endothelial keratoplasty (DSAEK) with the use of continuous air pumping technique in Asian eyes with previous Ahmed glaucoma valve implantation., Methods: The DSAEK procedure was modified in that complete air retention of the anterior chamber was maintained for 10 min using continuous air pumping at 30 mm Hg. The primary outcome measurement was graft survival, and postoperative clinical features including, rate of graft detachment, endothelial cell count, intraocular pressure (IOP), surgical time and cup/disc ratio were also recorded., Results: A total of 13 eyes of 13 patients which underwent modified DSAEK and 6 eyes of 6 patients which underwent conventional DSAEK were included. There was a significant difference in graft survival curves between two groups (P = 0.029); the 1-year graft survival rates were estimated as 100% and 66.7% for patients with modified DSAEK and those with traditional DSAEK, respectively. The rate of graft detachment were 0% and 33.3% for the modified DSAEK and conventional DSAEK groups, respectively (P = 0.088). The significantly lowered surgical time for air tamponade was noted in the modified DSAEK group compared to that in the conventional DSAEK group [median (IQR): 10.0 (10.0, 10.0) min vs. 24.5 (22.0, 27.0) min; P<0.001] Postoperatively, patients in the modified DSAEK group had significantly lower IOP as compared to the conventional DSAEK group [12.0 (11.0, 15.0) mm Hg vs. 16.0 (15.0, 18.0) mm Hg; P = 0.047]. Modified DSAEK patients had higher endothelial cell counts as compared to conventional DSAEK patients [2148.0 (1964.0, 2218.0) vs. 1529.0 (713.0, 2014.0)], but the difference did not reach statistical significance (P = 0.072)., Conclusions: New continuous air pumping technique in DSAEK can be performed safely and effectively in patients with prior GDDs placement who have corneal failure.

Renal cell carcinoma (RCC) is a malignancy with poor prognosis. WNT/β-catenin signaling dysregulation, especially β-catenin overactivation and WNT antagonist silencing, is associated with RCC carcinogenesis and progression. However, the role of WNT ligands in RCC has not yet been determined. We screened 19 WNT ligands from normal kidney and RCC cell lines and tissues and found that WNT10A was significantly increased in RCC cell lines and tissues as compared to that in normal controls. The clinical significance of increase in WNT10A was evaluated by performing an immunohistochemical association study in a 19-year follow-up cohort comprising 284 RCC and 267 benign renal disease (BRD) patients. The results of this study showed that WNT10A was dramatically upregulated in RCC tissues as compared to that in BRD tissues. This result suggests that WNT10A, nuclear β-catenin, and nuclear cyclin D1 act as independent risk factors for RCC carcinogenesis and progression, with accumulative risk effects. Molecular validation of cell line models with gain- or loss-of-function designs showed that forced WNT10A expression induced RCC cell proliferation and aggressiveness, including higher chemoresistance, cell migration, invasiveness, and cell transformation, due to the activation of β-catenin-dependent signaling. Conversely, WNT10A siRNA knockdown decreased cell proliferation and aggressiveness of RCC cells. In conclusion, we showed that WNT10A acts as an autocrine oncogene both in RCC carcinogenesis and progression by activating WNT/β-catenin signaling.

Background: To evaluate the efficacy of Ahmed Glaucoma Valve (AGV) surgery and the optimal interval between penetrating keratoplasty (PKP) and AGV implantation in a population of Asian patients with preexisting glaucoma who underwent PKP., Methodology/principal Findings: In total, 45 eyes of 45 patients were included in this retrospective chart review. The final intraocular pressures (IOPs), graft survival rate, and changes in visual acuity were assessed to evaluate the outcomes of AGV implantations in eyes in which AGV implantation occurred within 1 month of post-PKP IOP elevation (Group 1) and in eyes in which AGV implantation took place more than 1 month after the post-PKP IOP evaluation (Group 2). Factors that were associated with graft failure were analyzed, and the overall patterns of complications were reviewed. By their final follow-up visits, 58% of the patients had been successfully treated for glaucoma. After the operation, there were no statistically significant differences between the groups with respect to graft survival (p = 0.98), but significant differences for IOP control (p = 0.049) and the maintenance of visual acuity (VA) (p<0.05) were observed. One year after surgery, the success rates of IOP control in Group 1 and Group 2 were 80% and 46.7%, respectively, and these rates fell to 70% and 37.3%, respectively, by 2 years. Factors that were associated with a high risk of AGV failure were a diagnosis of preexisting angle-closure glaucoma, a history of previous PKP, and a preoperative IOP that was >21 mm Hg. The most common surgical complication, aside from graft failure, was hyphema., Conclusions/significance: Early AGV implantation results in a higher probability of AGV survival and a better VA outcome without increasing the risk of corneal graft failure as a result of post-PKP glaucoma drainage tube implantation.

Background: To date, research on racial discrimination and health typically has employed explicit self-report measures, despite their potentially being affected by what people are able and willing to say. We accordingly employed an Implicit Association Test (IAT) for racial discrimination, first developed and used in two recent published studies, and measured associations of the explicit and implicit discrimination measures with each other, socioeconomic and psychosocial variables, and smoking., Methodology/principal Findings: Among the 504 black and 501 white US-born participants, age 35-64, randomly recruited in 2008-2010 from 4 community health centers in Boston, MA, black participants were over 1.5 times more likely (p<0.05) to be worse off economically (e.g., for poverty and low education) and have higher social desirability scores (43.8 vs. 28.2); their explicit discrimination exposure was also 2.5 to 3.7 times higher (p<0.05) depending on the measure used, with over 60% reporting exposure in 3 or more domains and within the last year. Higher IAT scores for target vs. perpetrator of discrimination occurred for the black versus white participants: for "black person vs. white person": 0.26 vs. 0.13; and for "me vs. them": 0.24 vs. 0.19. In both groups, only low non-significant correlations existed between the implicit and explicit discrimination measures; social desirability was significantly associated with the explicit but not implicit measures. Although neither the explicit nor implicit discrimination measures were associated with odds of being a current smoker, the excess risk for black participants (controlling for age and gender) rose in models that also controlled for the racial discrimination and psychosocial variables; additional control for socioeconomic position sharply reduced and rendered the association null., Conclusions: Implicit and explicit measures of racial discrimination are not equivalent and both warrant use in research on racial discrimination and health, along with data on socioeconomic position and social desirability.

Background: Important controversies exist about the extent to which people's health status as adults is shaped by their living conditions in early life compared to adulthood. These debates have important policy implications, and one obstacle to resolving them is the relative lack of sufficient high-quality data on childhood and adult socioeconomic position and adult health status. We accordingly compared the health status among monozygotic and dizygotic women twin pairs who lived together through childhood (until at least age 14) and subsequently were discordant or concordant on adult socioeconomic position. This comparison permitted us to ascertain the additional impact of adult experiences on adult health in a population matched on early life experiences., Methods and Findings: Our study employed data from a cross-sectional survey and physical examinations of twins in a population-based twin registry, the Kaiser Permanente Women Twins Study Examination II, conducted in 1989 to 1990 in Oakland, California, United States. The study population was composed of 308 women twin pairs (58% monozygotic, 42% dizygotic); data were obtained on childhood and adult socioeconomic position and on blood pressure, cholesterol, post-load glucose, body mass index, waist-to-hip ratio, physical activity, and self-rated health. Health outcomes among adult women twin pairs who lived together through childhood varied by their subsequent adult occupational class. Cardiovascular factors overall differed more among monozygotic twin pairs that were discordant compared to concordant on occupational class. Moreover, among the monozygotic twins discordant on adult occupational class, the working class twin fared worse and, compared to her professional twin, on average had significantly higher systolic blood pressure (mean matched difference = 4.54 mm Hg; 95% confidence interval [CI], 0.10-8.97), diastolic blood pressure (mean matched difference = 3.80 mm Hg; 95% CI, 0.44-7.17), and low-density lipoprotein cholesterol (mean matched difference = 7.82 mg/dl; 95% CI, 1.07-14.57). By contrast, no such differences were evident for analyses based on educational attainment, which does not capture post-education socioeconomic position., Conclusion: These results provide novel evidence that lifetime socioeconomic position influences adult health and highlight the utility of studying social plus biological aspects of twinship.