Associations between vision impairment and vision-related interventions on crash risk and driving cessation: systematic review and meta-analysis.

OBJECTIVES: To systematically investigate the associations between vision impairment and risk of motor vehicle crash (MVC) involvement, and evaluate vision-related interventions to reduce MVCs. DESIGN: Medline (Ovid), EMBASE and Global Health electronic databases were systematically searched from inception to March 2022 for observational and interventional English-language studies. Screening, data extraction and appraisals using the Joanna Briggs Institute appraisal tools were completed by two reviewers independently. Where appropriate, measures of association were converted into risk ratios (RRs) or ORs for meta-analysis. PARTICIPANTS: Drivers of four-wheeled vehicles of all ages with no cognitive declines. PRIMARY AND SECONDARY OUTCOMES: MVC involvement (primary) and driving cessation (secondary). RESULTS: 101 studies (n=778 052) were included after full-text review. 57 studies only involved older drivers (≥65 years) and 85 were in high-income settings. Heterogeneity in the data meant that most meta-analyses were underpowered as only 25 studies, further split into different groups of eye diseases and measures of vision, could be meta-analysed. The limited evidence from the meta-analyses suggests that visual field defects (four studies; RR 1.51 (95% CI 1.23, 1.85); p<0.001; I2=46.79%), and contrast sensitivity (two studies; RR 1.40 (95% CI 1.08, 1.80); p=0.01, I2=0.11%) and visual acuity loss (five studies; RR 1.21 (95% CI 1.02, 1.43); p=0.03, I2=28.49%) may increase crash risk. The results are more inconclusive for available evidence for associations of glaucoma (five studies, RR 1.27 (95% CI 0.67, 2.42); p=0.47; I2=93.48%) and cataract (two studies RR 1.15 (95% CI 0.97, 1.36); p=0.11; I2=3.96%) with crashes. Driving cessation may also be linked with glaucoma (two studies; RR 1.62 (95% CI 1.20, 2.19); p<0.001, I2=22.45%), age-related macular degeneration (AMD) (three studies; RR 2.21 (95% CI 1.47, 3.31); p<0.001, I2=75.11%) and reduced contrast sensitivity (three studies; RR 1.30 (95% CI 1.05, 1.61); p=0.02; I2=63.19%). Cataract surgery halved MVC risk (three studies; RR 0.55 (95% CI 0.34, 0.92); p=0.02; I2=97.10). Ranibizumab injections (four randomised controlled trials) prolonged driving in persons with AMD. CONCLUSION: Impaired vision identified through a variety of measures is associated with both increased MVC involvement and cessation. Cataract surgery can reduce MVC risk. Despite literature being highly heterogeneous, this review shows that detection of vision problems and appropriate treatment are critical to road safety. PROSPERO REGISTRATION NUMBER: CRD42020172153.

Prevalence and impact of combined vision and hearing (dual sensory) impairment: A scoping review.

Hearing and vision impairments are common globally. They are often considered separately in research, and in planning and delivering services. However, they can occur concurrently, termed dual sensory impairment (DSI). The prevalence and impact of hearing and vision impairment have been well-examined, but there has been much less consideration of DSI. The aim of this scoping review was to determine the nature and extent of the evidence on prevalence and impact of DSI. Three databases were searched: MEDLINE, Embase and Global Health (April 2022). We included primary studies and systematic reviews reporting the prevalence or impact of DSI. No limits were placed on age, publication dates, or country. Only studies where the full text was available in English were included. Two reviewers independently screened titles, abstract, full texts. Data were charted by two reviewers independently using a pre-piloted form. The review identified 183 reports of 153 unique primary studies and 14 review articles. Most evidence came from high-income countries (86% of reports). Prevalence varied across reports, as did age groups of participants and definitions used. The prevalence of DSI increased with age. Impact was examined across three broad groups of outcomes-psychosocial, participation, and physical health. There was a strong trend towards poorer outcomes for people with DSI across all categories compared to people with one or neither impairment, including activities of daily living (worse for people with DSI in 78% of reports) and depression (68%). This scoping review highlights that DSI is a relatively common condition with substantial impact, particularly among older adults. There is a gap in evidence from low and middle-income countries. There is a pressing need for a consensus position on the definition(s) of DSI and standardisation of reporting age groups to enable reliable estimates to be ascertained and compared and responsive services developed.

A Systematic Review of Clinical Practice Guidelines for Cataract: Evidence to Support the Development of the WHO Package of Eye Care Interventions.

The World Health Organization (WHO) is developing a Package of Eye Care Interventions (PECI) to facilitate the integration of eye care into Universal Health Coverage. This paper presents the results of a systematic review of clinical practice guidelines for cataract in adults, to help inform PECI development. We searched academic and guideline databases, and websites of professional associations, for guidelines published between January 2010 and April 2020. Guidelines were excluded if there was commercial funding or unmanaged conflicts of interest. Quality appraisal was conducted using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. We identified 3778 reports, 35 related to cataract guidelines, four of which met the inclusion criteria (United Kingdom: 2, United States: 1, Iran: 1). The recommendations across the four guidelines covered pre-operative (43%), intra-operative (37%), and post-operative interventions (20%). Most 'strong' recommendations were supported by good quality evidence. Differences in recommendations across guidelines may be attributable to time of publication or regional differences in surgical practice. Few guidelines met the quality criteria, and only three countries were represented. The results of this step of the PECI development process will inform subsequent phases for development of the WHO's package of evidence-based eye care interventions for cataract.

The economics of vision impairment and its leading causes: A systematic review.

Vision impairment (VI) can have wide ranging economic impact on individuals, households, and health systems. The aim of this systematic review was to describe and summarise the costs associated with VI and its major causes. We searched MEDLINE (16 November 2019), National Health Service Economic Evaluation Database, the Database of Abstracts of Reviews of Effects and the Health Technology Assessment database (12 December 2019) for partial or full economic evaluation studies, published between 1 January 2000 and the search dates, reporting cost data for participants with VI due to an unspecified cause or one of the seven leading causes globally: cataract, uncorrected refractive error, diabetic retinopathy, glaucoma, age-related macular degeneration, corneal opacity, trachoma. The search was repeated on 20 January 2022 to identify studies published since our initial search. Included studies were quality appraised using the British Medical Journal Checklist for economic submissions adapted for cost of illness studies. Results were synthesized in a structured narrative. Of the 138 included studies, 38 reported cost estimates for VI due to an unspecified cause and 100 reported costs for one of the leading causes. These 138 studies provided 155 regional cost estimates. Fourteen studies reported global data; 103/155 (66%) regional estimates were from high-income countries. Costs were most commonly reported using a societal (n = 48) or healthcare system perspective (n = 25). Most studies included only a limited number of cost components. Large variations in methodology and reporting across studies meant cost estimates varied considerably. The average quality assessment score was 78% (range 35-100%); the most common weaknesses were the lack of sensitivity analysis and insufficient disaggregation of costs. There was substantial variation across studies in average treatment costs per patient for most conditions, including refractive error correction (range $12-$201 ppp), cataract surgery (range $54-$3654 ppp), glaucoma (range $351-$1354 ppp) and AMD (range $2209-$7524 ppp). Future cost estimates of the economic burden of VI and its major causes will be improved by the development and adoption of a reference case for eye health. This could then be used in regular studies, particularly in countries with data gaps, including low- and middle-income countries in Asia, Eastern Europe, Oceania, Latin America and sub-Saharan Africa.

Advancing the Sustainable Development Goals through improving eye health: a scoping review.

UN member states have committed to achieving the Sustainable Development Goals (SDGs) by 2030. This Review examines the published evidence on how improving eye health can contribute to advancing the SDGs (beyond SDG 3). We identified 29 studies that showed direct benefits from providing eye health services on SDGs related to one or more of poverty (SDGs 1, 2, and 8), education (SDG 4), equality (SDGs 5 and 10), and sustainable cities (SDG 11). The eye health services included cataract surgery, free cataract screening, provision of spectacles, trichiasis surgery, rehabilitation services, and rural community eye health volunteers. These findings provide a comprehensive perspective on the direct links between eye health services and advancing the SDGs. In addition, eye health services likely have indirect effects on multiple SDGs, mediated through one of the direct effects. Finally, there are additional plausible links to other SDGs, for which evidence has not yet been established.

How can we improve the quality of cataract services for all? A global scoping review.

BACKGROUND: Cataract is a leading cause of blindness and vision impairment globally. Cataract surgery is one of the most frequently performed operations worldwide, but good quality services are not universally available. This scoping review aims to summarise the nature and extent of published literature on interventions to improve the quality of services for age-related cataract globally. METHODS: We used the dimensions of quality adopted by WHO-effectiveness, safety, people-centredness, timeliness, equity, integration and efficiency-to which we added planetary health. On 17 November 2019, we searched MEDLINE, Embase and Global Health for manuscripts published since 1990, without language or geographic restrictions. We included studies that reported quality-relevant interventions and excluded studies focused on technical aspects of surgery or that only involved children (younger than 18 years). Screening of titles/abstracts, full-text review and data extraction were performed by two reviewers independently. Studies were grouped thematically and results synthesised narratively. RESULTS: Most of the 143 included studies were undertaken in high-income countries (n = 93, 65%); 29 intervention groups were identified, most commonly preoperative education (n = 17, 12%) and pain/anxiety management (n = 16, 11%). Efficiency was the quality element most often assessed (n = 58, 41%) followed by people-centredness (n = 40, 28%), while integration (n = 4) and timeliness (n = 3) were infrequently reported, and no study reported outcomes related to planetary health. CONCLUSION: Evidence on interventions to improve quality of cataract services shows unequal regional distribution. There is an urgent need for more evidence relevant to low- and middle-income countries as well as across all quality elements, including planetary health.

Global economic productivity losses from vision impairment and blindness.

BACKGROUND: In the absence of accessible, good quality eye health services and inclusive environments, vision loss can impact individuals, households and communities in many ways, including through increased poverty, reduced quality of life and reduced employment. We aimed to estimate the annual potential productivity losses associated with reduced employment due to blindness and moderate and severe vision impairment (MSVI) at a regional and global level. METHODS: We constructed a model using the most recent economic, demographic (2018) and prevalence (2020) data. Calculations were limited to the working age population (15-64 years) and presented in 2018 US Dollars purchasing power parity (ppp). Two separate models, using Gross Domestic Product (GDP) and Gross National Income (GNI), were calculated to maximise comparability with previous estimates. FINDINGS: We found that 160.7 million people with MSVI or blindness were within the working age and estimated that the overall relative reduction in employment by people with vision loss was 30.2%. Globally, using GDP we estimated that the annual cost of potential productivity losses of MSVI and blindness was $410.7 billion ppp (range $322.1 - $518.7 billion), or 0.3% of GDP. Using GNI, overall productivity losses were estimated at $408.5 billion ppp (range $320.4 - $515.9 billion), 0.5% lower than estimates using GDP. INTERPRETATION: These findings support the view that blindness and MSVI are associated with a large economic impact worldwide. Reducing and preventing vision loss and developing and implementing strategies to help visually impaired people to find and keep employment may result in significant productivity gains. FUNDING: MJB is supported by the Wellcome Trust (207472/Z/17/Z). JR's appointment at the University of Auckland is funded by the Buchanan Charitable Foundation, New Zealand. The Lancet Global Health Commission on Global Eye Health was supported by grants from The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity (GR001061), NIHR Moorfields Biomedical Research Centre, The Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The SEVA Foundation, The British Council for the Prevention of Blindness and Christian Blind Mission. The funders had no role in the design, conduct, data analysis of the study, or writing of the manuscript.

Gender and ethnic diversity in global ophthalmology and optometry association leadership: a time for change.

PURPOSE: To assess the diversity of leadership bodies of member organisations of the International Council of Ophthalmology (ICO) and the World Council of Optometry (WCO) in terms of: (1) the proportion who are women in all world regions, and (2) the proportion who are ethnic minority women and men in Eurocentric high-income regions. METHODS: We undertook a cross-sectional study of board members and chairs of ICO and WCO member organisations using a desk-based assessment of member organisation websites during February and March 2020. Gender and ethnicity of board members and chairs were collected using a combination of validated algorithmic software and manual assessment, based on names and photographs where available. Gender proportions were calculated across Global Burden of Disease super-regions, and gender and ethnicity proportions in the high-income regions of Australasia, North America and Western Europe. RESULTS: Globally, approximately one in three board members were women for both ICO (34%) and WCO (35%) members, and one in three ICO (32%) and one in five WCO (22%) chairpersons were women. Women held at least 50% of posts in only three of the 26 (12%) leadership structures assessed; these were based in Latin America and the Caribbean (59% of WCO board positions held by women, and 56% of WCO chairs), and Southeast Asia, East Asia and Oceania (55% of ICO chairs). In the Eurocentric high-income regions, white men held more than half of all board (56%) and chair (58%) positions and white women held a further quarter of positions (26% of board and 27% of chair positions). Ethnic minority women held the fewest number of board (6%) and chair (7%) positions. CONCLUSIONS: Improvements in gender parity are needed in member organisations of the WCO and ICO across all world regions. In high-income regions, efforts to address inequity at the intersection of gender and ethnicity are also needed. Potential strategies to enable inclusive leadership must be centred on structurally enabled diversity and inclusion goals to support the professional progression of women, and people from ethnic minorities in global optometry and ophthalmology.

Association between vision impairment and mortality: a systematic review and meta-analysis.

BACKGROUND: The number of individuals with vision impairment worldwide is increasing because of an ageing population. We aimed to systematically identify studies describing the association between vision impairment and mortality, and to assess the association between vision impairment and all-cause mortality. METHODS: For this systematic review and meta-analysis, we searched MEDLINE (Ovid), Embase, and Global Health database on Feb 1, 2020, for studies published in English between database inception and Feb 1, 2020. We included prospective and retrospective cohort studies that measured the association between vision impairment and all-cause mortality in people aged 40 years or older who were followed up for 1 year or more. In a protocol amendment, we also included randomised controlled trials that met the same criteria as for cohort studies, in which the association between visual impairment and mortality was independent of the study intervention. Studies that did not report age-adjusted mortality data, or that focused only on populations with specific health conditions were excluded. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. We graded the overall certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations framework. We did a random-effects meta-analysis to calculate pooled maximally adjusted hazard ratios (HRs) for all-cause mortality for individuals with a visual acuity of <6/12 versus those with ≥6/12; <6/18 versus those with ≥6/18; <6/60 versus those with ≥6/18; and <6/60 versus those with ≥6/60. FINDINGS: Our searches identified 3845 articles, of which 28 studies, representing 30 cohorts (446 088 participants) from 12 countries, were included in the systematic review. The meta-analysis included 17 studies, representing 18 cohorts (47 998 participants). There was variability in the methods used to assess and report vision impairment. Pooled HRs for all-cause mortality were 1·29 (95% CI 1·20-1·39) for visual acuity <6/12 versus ≥6/12, with low heterogeneity between studies (n=15; τ2=0·01, I2=31·46%); 1·43 (1·22-1·68) for visual acuity <6/18 versus ≥6/18, with low heterogeneity between studies (n=2; τ2=0·0, I2=0·0%); 1·89 (1·45-2·47) for visual acuity <6/60 versus ≥6/18 (n=1); and 1·02 (0·79-1·32) for visual acuity <6/60 versus ≥6/60 (n=2; τ2=0·02, I2=25·04%). Three studies received an assessment of low risk of bias across all six domains, and six studies had a high risk of bias in one or more domains. Effect sizes were greater for studies that used best-corrected visual acuity compared with those that used presenting visual acuity as the vision assessment method (p=0·0055), but the effect sizes did not vary in terms of risk of bias, study design, or participant-level factors (ie, age). We judged the evidence to be of moderate certainty. INTERPRETATION: The hazard for all-cause mortality was higher in people with vision impairment compared with those that had normal vision or mild vision impairment, and the magnitude of this effect increased with more severe vision impairment. These findings have implications for promoting healthy longevity and achieving the Sustainable Development Goals. FUNDING: Wellcome Trust, Commonwealth Scholarship Commission, National Institutes of Health, Research to Prevent Blindness, the Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research, Moorfields Biomedical Research Centre, Sightsavers, the Fred Hollows Foundation, the Seva Foundation, the British Council for the Prevention of Blindness, and Christian Blind Mission.

Associations between vision impairment and driving and the effectiveness of vision-related interventions: protocol for a systematic review and meta-analysis.

INTRODUCTION: Driving is one of the main modes of transport with safe driving requiring a combination of visual, cognitive and physical skills. With population ageing, the number of people living with vision impairment is set to increase in the decades ahead. Vision impairment may negatively impact an individual's ability to safely drive. The association between vision impairment and motor vehicle crash involvement or driving participation has yet to be systematically investigated. Further, the evidence for the effectiveness of vision-related interventions aimed at decreasing crashes and driving errors has not been synthesised. METHODS AND ANALYSIS: A search will be conducted for relevant studies on Medline (Ovid), EMBASE and Global Health from their inception to March 2020 without date or geographical restrictions. Two investigators will independently screen abstracts and full texts using Covidence software with conflicts resolved by a third investigator. Data extraction will be conducted on all included studies, and their quality assessed to determine the risk of bias using the Joanna Briggs Institute Critical Appraisal Tools. Outcome measures include crash risk, driving cessation and surrogate measures of driving safety (eg, driving errors and performance). The results of this review will be reported using the Preferred Reporting Items for Systematic Review and Meta-Analysis guideline. Meta-analysis will be undertaken for outcomes with sufficient data and reported following the Meta-analyses of Observational Studies in Epidemiology guideline. Where statistical pooling is not feasible or appropriate, narrative summaries will be presented following the Synthesis Without Meta-analysis in systematic reviews guideline. ETHICS AND DISSEMINATION: This review will only report on published data thus no ethics approval is required. Results will be included in the Lancet Global Health Commission on Global Eye Health, published in a peer-reviewed journal and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42020172153.

Estimating the global cost of vision impairment and its major causes: protocol for a systematic review.

INTRODUCTION: Vision impairment (VI) places a burden on individuals, health systems and society in general. In order to support the case for investing in eye health services, an updated cost of illness study that measures the global impact of VI is necessary. To perform such a study, a systematic review of the literature is needed. Here we outline the protocol for a systematic review to describe and summarise the costs associated with VI and its major causes. METHODS AND ANALYSIS: We will systematically search in Medline (Ovid) and the Centre for Reviews and Dissemination database which includes the National Health Service Economics Evaluation Database. No language or geographical restriction will be applied. Additional literature will be identified by reviewing the references in the included studies and by contacting field experts. Grey literature will be considered. The review will include any study published from 1 January 2000 to November 2019 that provides information about costs of illness, burden of disease and/or loss of well-being in participants with VI due to an unspecified cause or due to one of the seven leading causes globally.Two reviewers will independently screen studies and extract relevant data from included studies. Methodological quality of economic studies will be assessed based on the British Medical Journal checklist for economic submissions adapted to costs of illness studies. This protocol has been prepared following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols and has been published prospectively in Open Science Framework. ETHICS AND DISSEMINATION: Formal ethical approval is not required, as primary data will not be collected in this review. The findings of this study will be disseminated through peer-reviewed publications, stakeholder meetings and inclusion in the ongoing Lancet Global Health Commission on Global Eye Health. REGISTRATION DETAILS: https://osf.io/9au3w (DOI 10.17605/OSF.IO/6F8VM).

Are we advancing universal health coverage through cataract services? Protocol for a scoping review.

INTRODUCTION: Universal health coverage (UHC) includes the dimensions of equity in access, quality services that improve health and protection against financial hardship. Cataract continues to be the leading cause of blindness globally, despite cataract surgery being an efficacious intervention. The aim of this scoping review is to map the nature, extent and global distribution of data on cataract services for UHC in terms of equity, access, quality and financial protection. METHODS AND ANALYSIS: The search will be constructed by an Information Specialist and undertaken in MEDLINE, Embase and Global Health databases. We will include all published non-interventional primary research studies and systematic reviews that report a quantitative assessment of access, equity, quality or financial protection of cataract surgical services for adults at the subnational, national, regional or global level from population-based surveys or routinely collected health service data since 1 January 2000 and published through to February 2020.Screening and data charting will be undertaken using Covidence systematic review software. Titles and abstracts of identified studies will be screened by two authors independently. Full-text articles of potentially relevant studies will be obtained and reviewed independently by two authors against the inclusion criteria. Any discrepancies between the authors will be resolved by discussion, and with a third author as necessary. A data charting form will be developed and piloted on three studies by three authors and amendments made as necessary. Data will be extracted by two reviewers independently and summarised narratively and using maps. ETHICS AND DISSEMINATION: Ethical approval was not sought as the scoping review will only use published and publicly accessible data. The review will be published in an open access peer-reviewed journal. A summary of the results will be developed for website posting, stakeholder meetings and inclusion in the ongoing Lancet Global Health Commission on Global Eye Health.

Association between vision impairment and mortality: protocol for a systematic review and meta-analysis.

INTRODUCTION: Due to growth and ageing of the world's population, the number of individuals worldwide with vision impairment (VI) and blindness is projected to increase rapidly over the coming decades. VI and blindness are an important cause of years lived with disability. However, the association of VI and blindness with mortality, including the risk of bias in published studies and certainty of the evidence, has not been adequately studied in an up-to-date systematic review and meta-analysis. METHODS AND ANALYSIS: The planned systematic review and meta-analysis will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Databases, including MEDLINE Ovid, Embase Ovid and Global Health, will be searched for relevant studies. Two reviewers will then screen studies and review full texts to identify studies for inclusion. Data extraction will be performed, and for included studies, the risk of bias and certainty of the evidence will be assessed using the Grades of Recommendation, Assessment, Development and Evaluation approach. The prognostic factor in this study is visual function, which must have been measured using a standard objective ophthalmic clinical or research instrument. We will use standard criteria from WHO to categorise VI and blindness. All-cause mortality may be assessed by any method one or more years after baseline assessment of vision. Results from included studies will be meta-analysed according to relevant sections of the Meta-analysis Of Observational Studies in Epidemiology checklist. ETHICS AND DISSEMINATION: This review will only include published data; therefore, ethics approval will not be sought. The findings of this review and meta-analysis will be published in an open-access, peer-reviewed journal and will be included in the ongoing Lancet Global Health Commission on Global Eye Health.

Global eye health and the sustainable development goals: protocol for a scoping review.

INTRODUCTION: In 2015, most governments of the world committed to achieving 17 sustainable development goals (SDGs) by the year 2030. Efforts to improve eye health contribute to the advancement of several SDGs, including those not exclusively health-related. This scoping review will summarise the nature and extent of the published literature that demonstrates a link between improved eye health and advancement of the SDGs. METHODS AND ANALYSIS: Searches will be conducted in MEDLINE, Embase and Global Health for published, peer-reviewed manuscripts, with no time period, language or geographic limits. All intervention and observational studies will be included if they report a link between a change in eye health and (1) an outcome related to one of the SDGs or (2) an element on a pathway between eye health and an SDG (eg, productivity). Two investigators will independently screen titles and abstracts, followed by full-text screening of potentially relevant articles. Reference lists of all included articles will be examined to identify further potentially relevant studies. Conflicts between the two independent investigators will be discussed and resolved with a third investigator. For included articles, data regarding publication characteristics, study details and SDG-related outcomes will be extracted. Results will be synthesised by mapping the extracted data to a logic model, which will be refined through an iterative process during data synthesis. ETHICS AND DISSEMINATION: As this scoping review will only include published data, ethics approval will not be sought. The findings of the review will be published in an open-access, peer-reviewed journal. A summary of the results will be developed for website posting, stakeholder meetings and inclusion in the ongoing Lancet Global Health Commission on Global Eye Health.

C-reactive protein and pentraxin-3 binding of factor H-like protein 1 differs from complement factor H: implications for retinal inflammation.

Retinal inflammation plays a key role in the progression of age-related macular degeneration (AMD), a condition that leads to loss of central vision. The deposition of the acute phase pentraxin C-reactive protein (CRP) in the macula activates the complement system, thereby contributing to dysregulated inflammation. The complement protein factor H (FH) can bind CRP and down-regulate an inflammatory response. However, it is not known whether a truncated form of FH, called factor H-like protein 1 (FHL-1), which plays a significant regulatory role in the eye, also interacts with CRP. Here, we compare the binding properties of FHL-1 and FH to both CRP and the related protein pentraxin-3 (PTX3). We find that, unlike FH, FHL-1 can bind pro-inflammatory monomeric CRP (mCRP) as well as the circulating pentameric form. Furthermore, the four-amino acid C-terminal tail of FHL-1 (not present in FH) plays a role in mediating its binding to mCRP. PTX3 was found to be present in the macula of donor eyes and the AMD-associated Y402H polymorphism altered the binding of FHL-1 to PTX3. Our findings reveal that the binding characteristics of FHL-1 differ from those of FH, likely underpinning independent immune regulatory functions in the context of the human retina.

Characterizing Factors Associated With Differences in FGF19 Blood Levels and Synthesis in Patients With Primary Bile Acid Diarrhea.

OBJECTIVES: Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD. METHODS: Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR. RESULTS: FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01). CONCLUSIONS: These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids.

Fibroblast growth factor 19 (FGF19) is proposed to be a negative feedback regulator of hepatic bile acid (BA) synthesis. We aimed to clarify the distribution of FGF19 expression in human intestine and to investigate induction in a novel explant system. Ileal and colonic mucosal biopsies were obtained at endoscopy and analyzed for FGF19 transcript expression. Primary explants were incubated with physiological concentrations of various BA for up to 6 h, and expression of FGF19 and other genes was determined. FGF19 transcripts were detected in ileum but were unquantifiable in colon. No loss of FGF19 mRNA occurred as a consequence of the explant system. Ileal FGF19 transcript expression was induced 350-fold by 50 µM chenodeoxycholate (CDCA, n = 24, P < 0.0001) and 161-fold by 50 µM glycochenodeoxycholate (GCDCA, n = 12, P = 0.0005). The responses of other genes to CDCA or GCDCA (50 µM) were smaller: median increases of ileal bile acid binding protein, organic solute transporter-α and -ß, and short heterodimer partner were 2.4- to 4.0-fold; apical membrane sodium bile acid transporter and farnesoid X receptor (FXR) showed little change. The EC50 for FGF19 transcript induction by CDCA was 20 µM. FGF19 protein concentrations were significantly higher in the culture fluid from BA-stimulated explants. FGF19 induction with cholate was 81% of that found with CDCA, but deoxycholate (40%) and lithocholate (4%) were significantly less potent. The synthetic FXR agonist obeticholic acid was much more potent than CDCA with a 70-fold FGF19 stimulation at 1 µM. We concluded that FGF19 expression in human ileum is very highly responsive to BA. Changes in FGF19 induction are a potential mechanism involved in disorders of BA homeostasis.