Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic review of the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE, CINAHL, SCOPUS, BIOSIS, and Web of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review. A total of 44 globally representative group members met in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR''s

'Ring' your future, without changing diaper - Can preventing teenage pregnancy address child marriage in Zambia?

Teenage pregnancy and child marriage are prevalent in Zambia and are complexly interrelated issues with common causes and effects. The aim of this study was to explore factors in the social and cultural environment shaping young people's sexual behaviour, with specific attention to teenage pregnancy and child marriage in Eastern Zambia. The study was conducted in selected wards in Petauke, Chadiza and Katete districts, using an exploratory mixed-method design including a household survey, focus group discussions and in-depth interviews. The participants included 1,434 young females and males aged 15 to 24, female and male parents and caregivers; grandmothers; traditional leaders; teachers; health and social workers; representatives from youth associations, community-based and non-governmental organizations; and district level policy makers. Qualitative data were analysed using thematic content analysis and NVivo was used to manage the data, while survey data were analysed using Stata. The study revealed a high prevalence rate of teenage pregnancy (48%) and child marriage (13%) among young women. The mean age at first pregnancy or fatherhood was lower among female (17) than male respondents (20). A clear interlinkage between teenage pregnancy and child marriage was found, the two issues were mutually reinforcing. While teenage pregnancy appeared both as a cause and consequence of child marriage, marriage was mostly a common response to pregnancy. Early sexual debut, limited knowledge and use of contraception, poverty and limited future perspectives as well as sexual and gender norms were identified as the main causative factors of teenage pregnancy and therefore, child marriage. Based on the findings, a conceptual model to explain the interrelationships between young people's sexual behaviour, teenage pregnancy and child marriage is discussed. To address teenage pregnancy and child marriage in Eastern Zambia, there is a need to look into the realities and needs of young people regarding sex and relationships

FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.

BACKGROUND & AIMS Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria. MATERIALS Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl4. Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine. RESULTS Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl4-induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the inner mucus layer and pathological translocation of GFP-E. coli through the ileal epithelium. GVB is profoundly altered in BDL and CCl4-mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran, but only slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli. CONCLUSIONS Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route. LAY SUMMARY For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis

Coronagraph Design Survey for Future Exoplanet Direct Imaging Space Missions: Interim Update

NASA is about to embark on an ambitious program to develop a Habitable Worlds Observatory (HWO) flagship mission to directly image ~25 potentially Earth-like planets and spectroscopically characterize them for signs of life, as recommended by the Astro2020 decadal survey. In addition, Astro2020 recommended a new approach for flagship formulation, which involves increasing the scope and depth of early, pre-phase A trades and technology maturation, as part of the new Great Observatories Maturation Program (GOMAP). The critical capability of the HWO mission is starlight suppression. To inform future architecture trades, it is necessary to survey a wide range of technologies, from the relatively mature ones such as the ones described in the LUVOIR and HabEx reports, to the relatively new and emerging ones, which may lead to breakthrough performance. In this paper, we present an interim update on a new effort, initiated by NASA’s Exoplanet Exploration Program (ExEP), to survey coronagraph design options for HWO. We present a preliminary summary of the survey, including: (1) a current list of coronagraph design options; (2) proposed evaluation criteria, such as expected mission yields and feasibility of maturing to TRL5 by 2029; and (3) tools and methods which we are using to quantify evaluations of different designs. While not charged to down-select or prioritize the different coronagraph designs, this survey is expected to be valuable in informing future mission teams of coronagraph design options. All interested coronagraph researchers are welcome to participate in this survey by contacting the first two authors of this paper. © 2023 SPIE.Immediate accessThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis

Background & Aims: Decompensated cirrhosis (DC) is associated with high mortality, mainly owing to the development of acute-on-chronic liver failure (ACLF). Identifying the patients with DC who are at high risk of mortality and ACLF development is an unmet clinical need. Liver fatty acid-binding protein (L-FABP) is expressed in several organs and correlates with liver and systemic inflammation. Herein, we aimed to assess the prognostic value of L-FABP in patients with DC. Methods: A prospective series of 444 patients hospitalized for DC was divided into 2 cohorts: study cohort (305 patients) and validation cohort (139 patients). L-FABP was measured in urine and plasma samples collected at admission. Neutrophil gelatinase-associated lipocalin (NGAL) was also measured in urine samples for comparison. Results: Urine but not plasma L-FABP correlated with 3-month survival on univariate analysis. On multivariate analysis, urine L-FABP and model for end-stage liver disease (MELD)-Na were the only independent predictors of prognosis. Urine L-FABP levels were higher in patients with ACLF than in those without and also predicted the development of ACLF, together with MELD-Na, during follow-up. In patients with ACLF, urine L-FABP correlated with liver, coagulation, and circulatory failure. Urine L-FABP levels were also increased in patients with acute kidney injury, particularly in those with acute tubular necrosis. The ability of urinary L-FABP to predict survival and ACLF development was confirmed in the validation cohort. Urine NGAL predicted outcome on univariate but not multivariate analysis. Conclusions: Urinary L-FABP levels are independently associated with the 3-month clinical course in patients with DC, in terms of mortality and ACLF development. Urinary L-FABP is a promising prognostic biomarker for patients with DC. Lay summary: Increased levels of liver fatty acid-binding protein (L-FABP), a protein related to lipid metabolism, have been associated with liver-related diseases. The present study analyzed urinary L-FABP levels in 2 independent groups of patients with decompensated cirrhosis and showed that higher urinary L-FABP levels correlated with increased mortality and risk of acute-on-chronic liver failure development. Therefore, urinary L-FABP levels could be useful as a new tool to predict complications in patients with decompensated cirrhosis

Integrated photonic-based coronagraphic systems for future space telescopes

The detection and characterization of Earth-like exoplanets around Sun-like stars is a primary science motivation for the Habitable Worlds Observatory. However, the current best technology is not yet advanced enough to reach the 10−10 contrasts at close angular separations and at the same time remain insensitive to low-order aberrations, as would be required to achieve high-contrast imaging of exo-Earths. Photonic technologies could fill this gap, potentially doubling exo-Earth yield. We review current work on photonic coronagraphs and investigate the potential of hybridized designs which combine both classical coronagraph designs and photonic technologies into a single optical system. We present two possible systems. First, a hybrid solution which splits the field of view spatially such that the photonics handle light within the inner working angle and a conventional coronagraph that suppresses starlight outside it. Second, a hybrid solution where the conventional coronagraph and photonics operate in series, complementing each other and thereby loosening requirements on each subsystem. As photonic technologies continue to advance, a hybrid or fully photonic coronagraph holds great potential for future exoplanet imaging from space. © 2023 SPIE.Immediate accessThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]