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Introduction: The formation of mesosiderites, a group of stony-iron meteorites, is complex; they are also historically understudied [1]. As a result, existing classification schemes have not been reexamined in several decades, despite the addition of numerous new mesosiderites to collections worldwide. Mesosiderites consist of roughly equal portions of Fe,Ni-metal and silicate material; however, current classification schemes are based on the plagioclase: pyroxene ratio and the degree of metamorphism or impact melting observed in their silicates [2,3], without consideration of the metal phase. The aim of this research is to: 1) increase the number of well characterized mesosiderites by examining a selection of understudied and/or unclassified examples, 2) establish whether metallography can be used to refine existing classification schemes to describe all portions of mesosiderites, and not only the silicates. Methodology: The Monnig Meteorite Collection database [4] was examined to identify mesosiderites that are either understudied (i.e., not present in published literature) and/or ungrouped (classified only as a mesosiderite but not into a petrologic or metamorphic type). Five mesosiderites were selected: North West Africa (NWA) 10882, NWA 2639, NWA 4230, NWA 1827, and Sahara (SAH) 98088. NWA 10882 (Fig. 1) only meets one of our criteria, as it has been classifed as an A2-type mesosiderite; however, as it has not been thoroughly characterized, the decision was made to still include it. Each sample was examined in hand specimen and thin section locations were chosen to include both silicate and metal portions of each mesosiderite, where possible. Two thin sections were made of each sample, with the exception of NWA 10882 where four sections were made. [ABSTRACT FROM AUTHOR]

Allergic bronchopulmonary aspergillosis is an allergic pulmonary condition caused by hypersensitivity to antigens of Aspergillus sp. found most commonly in patients with underlying asthma or cystic fibrosis. Host factors which alter the innate and adaptive immune responses to this abundant airborne fungus contribute to the development of chronic airway inflammation, bronchiectasis, and fibrosis. Traditionally, treatment has focussed on reducing fungal burden and immune response to fungal antigens. However, a significant proportion of patients continue to suffer recurrent exacerbations with progressive lung damage, and the side effect burden of existing treatments is high. New treatments including novel antifungal agents, monoclonal antibodies against aspects of the adaptive immune response as well as targeted immunotherapies may be better tolerated and achieve improved outcomes but have not yet been studied in large-scale randomised control trials., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AS reports grants from Vertex pharmaceuticals, Pfizer, and Gilead Sciences and speaker fees from Pfizer and Gilead Sciences., (© The Author(s), 2021.)

The arginyl-glycinyl-aspartic acid (RGD) integrin alpha-v beta-6 ( α v β 6) has been identified as playing a key role in the activation of transforming growth factor- β (TGF β ) that is hypothesized to be pivotal in the development of fibrosis and other diseases. In this study, α v β 6 small molecule inhibitors were characterized in a range of in vitro systems to determine affinity, kinetics, and duration of TGF β inhibition. High α v β 6 binding affinity was shown to be correlated with slow dissociation kinetics. Compound 1 (high α v β 6 affinity, slow dissociation) and SC-68448 (low α v β 6 affinity, fast dissociation) induced concentration- and time-dependent internalization of α v β 6 in normal human bronchial epithelial (NHBE) cells. After washout, the α v β 6 cell surface repopulation was faster for SC-68448 compared with compound 1 In addition, α v β 6-dependent release of active TGF β from NHBE cells was inhibited by compound 1 and SC-68448. After washout of SC-68448, release of active TGF β was restored, whereas after washout of compound 1 the inhibition of TGF β activation was maintained and only reversible in the presence of a lysosomal inhibitor (chloroquine). However, SC-68448 was able to reduce total levels of α v β 6 in NHBE cells if present continuously. These observations suggest α v β 6 can be degraded after high affinity RGD binding that sorts the integrin for lysosomal degradation after internalization, likely due to sustained engagement as a result of slow dissociation kinetics. In addition, the α v β 6 integrin can also be downregulated after sustained engagement of the RGD binding site with low affinity ligands that do not sort the integrin for immediate lysosomal degradation. SIGNIFICANCE STATEMENT: The fate of RGD integrin after ligand binding has not been widely investigated. Using the αvβ6 integrin as a case study, we have demonstrated that RGD-induced downregulation of αvβ6 is both affinity and time dependent. High affinity ligands induced downregulation via lysosomal degradation, likely due to slow dissociation, whereas sustained low affinity ligand engagement was only able to decrease αvβ6 expression over longer periods of time. Our study provides a potential unique mechanism for obtaining duration of action for drugs targeting integrins., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

Globally, in 2017 35 million people were living with HIV (PLHIV) and 257 million had chronic HBV infection (HBsAg positive). The extent of HIV-HBsAg co-infection is unknown. We undertook a systematic review to estimate the global burden of HBsAg co-infection in PLHIV. We searched MEDLINE, Embase and other databases for published studies (2002-2018) measuring prevalence of HBsAg among PLHIV. The review was registered with PROSPERO (#CRD42019123388). Populations were categorized by HIV-exposure category. The global burden of co-infection was estimated by applying regional co-infection prevalence estimates to UNAIDS estimates of PLHIV. We conducted a meta-analysis to estimate the odds of HBsAg among PLHIV compared to HIV-negative individuals. We identified 506 estimates (475 studies) of HIV-HBsAg co-infection prevalence from 80/195 (41.0%) countries. Globally, the prevalence of HIV-HBsAg co-infection is 7.6% (IQR 5.6%-12.1%) in PLHIV, or 2.7 million HIV-HBsAg co-infections (IQR 2.0-4.2). The greatest burden (69% of cases; 1.9 million) is in sub-Saharan Africa. Globally, there was little difference in prevalence of HIV-HBsAg co-infection by population group (approximately 6%-7%), but it was slightly higher among people who inject drugs (11.8% IQR 6.0%-16.9%). Odds of HBsAg infection were 1.4 times higher among PLHIV compared to HIV-negative individuals. There is therefore, a high global burden of HIV-HBsAg co-infection, especially in sub-Saharan Africa. Key prevention strategies include infant HBV vaccination, including a timely birth-dose. Findings also highlight the importance of targeting PLHIV, especially high-risk groups for testing, catch-up HBV vaccination and other preventative interventions. The global scale-up of antiretroviral therapy (ART) for PLHIV using a tenofovir-based ART regimen provides an opportunity to simultaneously treat those with HBV co-infection, and in pregnant women to also reduce mother-to-child transmission of HBV alongside HIV., (© 2019 World Health Organization; licensed by John Wiley & Sons Ltd.)

Background: Excessive extracellular matrix (ECM) deposition is a hallmark feature in fibrosis and tissue remodelling diseases. Typically, mesenchymal cells will produce collagens under standard 2D cell culture conditions, however these do not assemble into fibrils. Existing assays for measuring ECM production are often low throughput and not disease relevant. Here we describe a robust, high content, pseudo-3D phenotypic assay to quantify mature fibrillar collagen deposition which is both physiologically relevant and amenable to high throughput compound screening. Using pulmonary fibroblasts derived from patients with idiopathic pulmonary fibrosis (IPF), we developed the 'scar-in-a-jar' assay into a medium-throughput phenotypic assay to robustly quantify collagen type I deposition and other extracellular matrix (ECM) proteins over 72 h., Results: This assay utilises macromolecular crowding to induce an excluded volume effect and enhance enzyme activity, which in combination with TGF-β 1 stimulation significantly accelerates ECM production. Collagen type I is upregulated approximately 5-fold with a negligible effect on cell number. We demonstrate the robustness of the assay achieving a Z prime of approximately 0.5, and % coefficient of variance (CV) of < 5 for the assay controls SB-525334 (ALK5 inhibitor) and CZ415 (mTOR inhibitor). This assay has been used to confirm the potency of a number of potential anti-fibrotic agents. Active compounds from the 'scar-in-a-jar' assay can be further validated for other markers of ECM deposition and fibroblast activation such as collagen type IV and α-smooth muscle actin exhibiting a 4-fold and 3-fold assay window respectively., Conclusion: In conclusion, we have developed 'scar -in-a-jar is' into a robust disease-relevant medium-throughput in vitro assay to accurately quantify ECM deposition. This assay may enable iterative compound profiling for IPF and other fibroproliferative and tissue remodelling diseases., Competing Interests: Competing interestsR.B.G, J.D.E, E. G, G. B, A.D.B, C.B.N are employees and shareholders at GlaxoSmithKline., (© The Author(s) 2019.)

Telemedicine involves electronic communication between a physician in one location and a patient in another location to provide remote medical care. Ophthalmologists are increasingly employing telemedicine, particularly in retinal disease screening and monitoring. Telemedicine has been utilized to decrease barriers to care and yield greater patient satisfaction and lower costs, while maintaining high sensitivity and specificity. This review discusses common patient barriers to eye care, innovative approaches to retinal disease screening and monitoring using telemedicine, and eye care policy initiatives needed to enact large-scale telemedicine eye disease screening programs.

Background: At global level, there are 37 million people infected with HIV and 115 million people with antibodies to hepatitis C virus (HCV). Little is known about the extent of HIV-HCV co-infection. We sought to characterise the epidemiology and burden of HCV co-infection in people living with HIV., Methods: In this systematic review and meta-analysis we searched MEDLINE, Embase, CINAHL+, POPLINE, Africa-wide Information, Global Health, Web of Science, and the Cochrane Library and WHO databases for studies measuring prevalence of HCV and HIV, published between Jan 1, 2002, and Jan 28, 2015. We included studies in HIV population samples of more than 50 individuals and recruited patients based on HIV infection status or other behavioural characteristics. We excluded editorials or reviews containing no primary data, samples of HCV or HIV-HCV co-infected individuals, or samples relying on self-reported infection status. We also excluded samples drawn from populations with other comorbidities or undergoing interventions that put them at increased risk of co-infection. Populations were categorised according to HIV exposure, with the regional burden of co-infection being derived by applying co-infection prevalence estimates to published numbers of HIV-infected individuals. We did a meta-analysis to estimate the odds of HCV in HIV-infected individuals compared with their HIV-negative counterparts., Findings: From 31 767 citations identified, 783 studies met the inclusion criteria, resulting in 902 estimates of the prevalence of HIV-HCV co-infection. In HIV-infected individuals, HIV-HCV co-infection was 2·4% (IQR 0·8-5·8) within general population samples, 4·0% (1·2-8·4) within pregnant or heterosexually exposed samples, 6·4% (3·2-10·0) in men who have sex with men (MSM), and 82·4% (55·2-88·5) in people who inject drugs (PWID). Odds of HCV infection were six times higher in people living with HIV (5·8, 95% CI 4·5-7·4) than their HIV-negative counterparts. Worldwide, there are approximately 2 278 400 HIV-HCV co-infections (IQR 1 271 300-4 417 000) of which 1 362 700 (847 700-1 381 800) are in PWID, equalling an overall co-infection prevalence in HIV-infected individuals of 6·2% (3·4-11·9)., Interpretation: We noted a consistently higher HCV prevalence in HIV-infected individuals than HIV-negative individuals  across all risk groups and regions, but especially in PWID. This study highlights the importance of routine HCV testing in all HIV-infected individuals, but especially in PWID. There is also a need to improve country-level surveillance of HCV prevalence across different population groups in all regions., Funding: WHO., (Copyright © 2016 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk., Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index., Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14-1.57), and similar associations were observed for each histotype., Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes., Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114-24. ©2016 AACR., (©2016 American Association for Cancer Research.)

Introduction: Family members of critically ill patients in the intensive care unit face significant morbidity. It may be the decision-making process that plays a significant role in the psychological morbidity associated with being a surrogate in the ICU. We hypothesize that family members facing end-of-life decisions will have more decisional conflict and decisional regret than those facing non-end-of-life decisions., Methods: We enrolled a sample of adult patients and their surrogates in a tertiary care, academic medical intensive care unit. We queried the surrogates regarding decisions they had made on behalf of the patient and assessed decision conflict. We then contacted the family member again to assess decision regret., Results: Forty (95%) of 42 surrogates were able to identify at least 1 decision they had made on behalf of the patient. End-of-life decisions (defined as do not resuscitate [DNR]/do not intubate [DNI] or continuation of life support) accounted for 19 of 40 decisions (47.5%). Overall, the average Decision Conflict Scale (DCS) score was 21.9 of 100 (range 0-100, with 0 being little decisional conflict and 100 being great decisional conflict). The average DCS score for families facing end-of-life decisions was 25.5 compared with 18.7 for all other decisions. Those facing end-of-life decisions scored higher on the uncertainty subscale (subset of DCS questions that indicates level of certainty regarding decision) with a mean score of 43.4 compared with all other decisions with a mean score of 27.0. Overall, very few surrogates experienced decisional regret with an average DRS score of 13.4 of 100., Conclusions: Nearly all surrogates enrolled were faced with decision-making responsibilities on behalf of his or her critically ill family member. In our small pilot study, we found more decisional conflict in those surrogates facing end-of-life decisions, specifically on the subset of questions dealing with uncertainty. Surrogates report low levels of decisional regret., (Copyright © 2015 Elsevier Inc. All rights reserved.)

While substance use is one of the most consistent predictors of poor adherence to antiretroviral therapy (ART), few studies among people living with HIV (PLH) have utilized mobile phone-based assessment of these health behaviors. PLH were recruited from primary care clinics to report ART and substance use using a smartphone application (app) for 14 consecutive days. The app's feasibility as a data collection tool was evaluated quantitatively via surveys and qualitatively via in-depth interviews to assess daily report completion, compliance, and study satisfaction. Overall, 26 participants (M = 49.5 years, 76% male) completed 95.3% of time-based daily reports. Participants reported high satisfaction with the app and expressed future interest in using smartphones to report daily behaviors. High completion rates and participant acceptability suggest that smartphones are a feasible, acceptable method for collecting substance use and ART data among PLH. Potential areas of concern such as sufficient training and assistance for those with limited smartphone experience should be considered for future app-based research studies among PLH.

Background: Use of analgesics has been associated with lower risk of ovarian cancer, but, to date, very few studies have explored the association between analgesics and ovarian cancer survival., Methods: We examined the relationship between self-reported prediagnostic use of aspirin, ibuprofen, and acetaminophen and overall survival (OS), progression-free survival (PFS), ascites at the time of primary treatment, and persistence of disease after primary treatment among 699 women diagnosed with epithelial ovarian carcinoma. The associations between use of these medications and OS and PFS were estimated using Cox proportional hazards models. We utilized unconditional logistic regression models to estimate associations between medication use and presence of ascites and persistence of disease., Results: Prediagnostic intake of aspirin, both low-dose and regular-dose, ibuprofen, and acetaminophen was not associated with any of the outcomes of interest., Conclusions: Our results indicate a lack of association between prediagnostic intake of selected analgesics and OS, PFS, presence of ascites at the time of primary treatment, and persistence of disease after primary treatment., Impact: Prediagnostic intake of analgesics may not be associated with ovarian cancer outcomes., (©2015 American Association for Cancer Research.)

FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [(35)S]GTPγS-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues.