Artificial intelligence-supported diabetic retinopathy screening in Tanzania: rationale and design of a randomised controlled trial.

INTRODUCTION: Globally, diabetic retinopathy (DR) is a major cause of blindness. Sub-Saharan Africa is projected to see the largest proportionate increase in the number of people living with diabetes over the next two decades. Screening for DR is recommended to prevent sight loss; however, in many low and middle-income countries, because of a lack of specialist eye care staff, current screening services for DR are not optimal. The use of artificial intelligence (AI) for DR screening, which automates the grading of retinal photographs and provides a point-of-screening result, offers an innovative potential solution to improve DR screening in Tanzania. METHODS AND ANALYSIS: We will test the hypothesis that AI-supported DR screening increases the proportion of persons with true referable DR who attend the central ophthalmology clinic following referral after screening in a single-masked, parallel group, individually randomised controlled trial. Participants (2364) will be randomised (1:1 ratio) to either AI-supported or the standard of care DR screening pathway. Participants allocated to the AI-supported screening pathway will receive their result followed by point-of-screening counselling immediately after retinal image capture. Participants in the standard of care arm will receive their result and counselling by phone once the retinal images have been graded in the usual way (typically after 2-4 weeks). The primary outcome is the proportion of persons with true referable DR attending the central ophthalmology clinic within 8 weeks of screening. Secondary outcomes, by trial arm, include the proportion of persons attending the central ophthalmology clinic out of all those referred, sensitivity and specificity, number of false positive referrals, acceptability and fidelity of AI-supported screening. ETHICS AND DISSEMINATION: The London School of Hygiene & Tropical Medicine, Kilimanjaro Christian Medical Centre and Tanzanian National Institute of Medical Research ethics committees have approved the trial. The results will be submitted to peer-reviewed journals for publication. TRIAL REGISTRATION NUMBER: ISRCTN18317152.

Differentiating stages of functional vision loss from glaucoma using the Disc Damage Likelihood Scale and cup:disc ratio.

BACKGROUND: Glaucoma staging is critical for treatment planning but has rarely been tested in severe/end-stage disease. We compared the performance of the Disc Damage Likelihood Scale (DDLS) and cup:disc ratio (CDR) using a functional glaucoma staging system (GSS) as the reference standard. METHODS: Post hoc analysis of a randomised controlled trial at the Eye Department of Kilimanjaro Christian Medical Centre, Tanzania. Eligible participants (aged ≥18 years) with open-angle glaucoma, intraocular pressure (IOP) of >21 mm Hg, were randomised to timolol 0.5% eye drops or selective laser trabeculoplasty. Fundoscopy established vertical and horizontal CDRs and DDLS. Visual acuity and static visual fields were graded (GSS). The study used area under the receiver operating characteristic (AROC) curves and Spearman's rank correlation coefficients to compare staging systems. Logistic regression with generalised estimating equations determined risk factors of functional severe/end-stage glaucoma. RESULTS: 382 eyes (201 participants) were evaluated; 195 (51%) had severe or end-stage glaucoma; mean IOP was 26.7 (SD 6.9) mm Hg. DDLS yielded an AROC of 0.90 (95% CI 0.87 to 0.93), vertical cup:disc ratio (vCDR) of 0.88 (95% CI 0.85 to 0.91, p=0.048) for identifying severe/end-stage disease. Correlation coefficients comparing GSS to DDLS and vCDRs were 0.73 and 0.71, respectively. Advanced structural stages, vision impairment, higher IOP and less financial resources were risk factors of functional severe/end-stage glaucoma. CONCLUSION: This study indicates that both structural staging systems can differentiate severe/end-stage glaucoma from less severe disease, with a moderate advantage of DDLS over CDR. Clinical examination of the optic disc plays an important role in addition to functional assessment when managing severe/end-stage glaucoma.

Improvement studies for equitable and evidence-based innovation: an overview of the 'IM-SEEN' model.

BACKGROUND: Health inequalities are ubiquitous, and as countries seek to expand service coverage, they are at risk of exacerbating existing inequalities unless they adopt equity-focused approaches to service delivery. MAIN TEXT: Our team has developed an equity-focused continuous improvement model that reconciles prioritisation of disadvantaged groups with the expansion of service coverage. Our new approach is based on the foundations of routinely collecting sociodemographic data; identifying left-behind groups; engaging with these service users to elicit barriers and potential solutions; and then rigorously testing these solutions with pragmatic, embedded trials. This paper presents the rationale for the model, a holistic overview of how the different elements fit together, and potential applications. Future work will present findings as the model is operationalised in eye-health programmes in Botswana, India, Kenya, and Nepal. CONCLUSION: There is a real paucity of approaches for operationalising equity. By bringing a series of steps together that force programme managers to focus on groups that are being left behind, we present a model that can be used in any service delivery setting to build equity into routine practice.

The Basic VRS-Effect Study: Clinical Trial Outcomes and Cost-Effectiveness of Low Vision Rehabilitation in Portugal.

INTRODUCTION: The aim of this study was twofold: (1) to investigate the clinical impact of vision rehabilitation in patients with vision impairment and (2) to investigate the cost-effectiveness of a basic vision rehabilitation service in Portugal. METHODS: The trial recruited patients diagnosed with age-related macular degeneration or diabetic retinopathy (DR) and visual acuity in the range 0.4-1.0logMAR in the better-seeing eye. Participants were randomised to one of the study arms consisting of immediate intervention and delayed intervention. The intervention included: new refractive correction, optical reading aids, in-office training and advice about modifications at home. Visual ability, health-related quality of life and costs were measured. Economic analysis was performed to evaluate whether the intervention was cost-effective. The trial compared the outcomes 12 weeks after the start in both arms. RESULTS: Of the 46 participants, 34 (74%) were diagnosed with DR, 25 (54%) were female, and mean age was 70.08 years (SD = 8.74). In the immediate intervention arm visual ability increased a mean of 0.523 logits (SE = 0.11) (p < 0.001). Changes in the delayed intervention arm were not statistically significant (p = 0.95). Acuity in the better-seeing eye, near acuity and critical print size also improved during the study. The mean cost of the intervention was €118.79 (SD = 24.37). The incremental cost-effectiveness ratio using the EQ-5D-5L was 30,421€/QALY and 1186€/QALY when using near acuity. CONCLUSION: The current study gives evidence of positive clinical impact of a basic vision rehabilitation intervention and shows that a basic vision rehabilitation service is cost-effective. These findings are important to clinical and rehabilitation practices and for planning vision rehabilitation services. TRIAL REGISTRATION: Retrospectively registered, 21/01/2019. ISRCTN10894889, https://www.isrctn.com/ISRCTN10894889.

There is limited research addressing the actual impact of vision rehabilitation. The current trial compares the effect of a basic vision rehabilitation intervention with usual care on patients' functioning. The intervention was clinically impactful and cost-effective.

Untargeted Metabolomics Reveals Antidepressant Effects in a Marine Photosynthetic Organism: The Diatom Phaeodactylum tricornutum as a Case Study.

The increased use of antidepressants, along with their increased occurrence in aquatic environments, is of concern for marine organisms. Although these pharmaceutical compounds have been shown to negatively affect marine diatoms, their mode of action in these non-target, single-cell phototrophic organisms is yet unknown. Using a Fourier-transform ion cyclotron-resonance mass spectrometer (FT-ICR-MS) we evaluated the effects of fluoxetine in the metabolomics of the model diatom Phaeodactylum tricornutum, as well as the potential use of the identified metabolites as exposure biomarkers. Diatom growth was severely impaired after fluoxetine exposure, particularly in the highest dose tested, along with a down-regulation of photosynthetic and carbohydrate metabolisms. Notably, several mechanisms that are normally down-regulated by fluoxetine in mammal organisms were also down-regulated in diatoms (e.g., glycerolipid metabolism, phosphatidylinositol signalling pathway, vitamin metabolism, terpenoid backbone biosynthesis and serotonin remobilization metabolism). Additionally, the present work also identified a set of potential biomarkers of fluoxetine exposure that were up-regulated with increasing fluoxetine exposure concentration and are of high metabolic significance following the disclosed mode of action, reinforcing the use of metabolomics approaches in ecotoxicology.

Performance and Resource Requirements of In-Person, Voice Call, and Automated Telephone-Based Socioeconomic Data Collection Modalities for Community-Based Health Programs: A Systematic Review.

Importance: Gathering data on socioeconomic status (SES) is a prerequisite for health programs that aim to improve equity. There is a lack of evidence on which approaches offer the best combination of reliability, cost, and acceptability. Objective: To compare the performance of different approaches to gathering data on SES in community health programs. Data Sources: A search of the Cochrane Library, MEDLINE, Embase, Global Health, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and OpenGrey from 1999 to June 29, 2021, was conducted, with no language limits. Google Scholar was also searched and the reference lists of included articles were checked to identify further studies. The search was performed on June 29, 2021. Study Selection: Any empirical study design was eligible if it compared 2 or more modalities to elicit SES data from the following 3 categories: in-person, voice call, or automated telephone-based systems. Data Extraction and Synthesis: Two reviewers independently screened titles, abstracts, and full-text articles and extracted data. They also assessed the risk of bias using Cochrane tools and assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Findings were synthesized thematically without meta-analysis. Main Outcomes and Measures: Response rate, equivalence, time, costs, and acceptability to patients and health care professionals. Results: The searches returned 3943 records. The 11 included studies reported data on 14 036 individuals from 7 countries, collecting data on 11 socioeconomic domains using 2 or more of the following modes: in-person surveys, computer-assisted telephone interviews (CATIs), and 2 types of automated data collection: interactive voice response calls (IVRs) and web surveys. Response rates were greater than 80% for all modes except IVRs. Equivalence was high across all modes (Cohen κ > 0.5). There were insufficient data to make robust time and cost comparisons. Patients reported high levels of acceptability providing data via IVRs, web surveys, and CATIs. Conclusions and Relevance: Selecting an appropriate and cost-effective modality to elicit SES data is an important first step toward advancing equitable effective service coverage. This systematic review did not identify evidence that remote and automated data collection modes differed from human-led and in-person approaches in terms of reliability, cost, or acceptability.

Endoplasmic Reticulum-Mitochondria Contacts Modulate Reactive Oxygen Species-Mediated Signaling and Oxidative Stress in Brain Disorders: The Key Role of Sigma-1 Receptor.

Significance: Mitochondria-Associated Membranes (MAMs) are highly dynamic endoplasmic reticulum (ER)-mitochondria contact sites that, due to the transfer of lipids and Ca2+ between these organelles, modulate several physiologic processes, such as ER stress response, mitochondrial bioenergetics and fission/fusion events, autophagy, and inflammation. In addition, these contacts are implicated in the modulation of the cellular redox status since several MAMs-resident proteins are involved in the generation of reactive oxygen species (ROS), which can act as both signaling mediators and deleterious molecules, depending on their intracellular levels. Recent Advances: In the past few years, structural and functional alterations of MAMs have been associated with the pathophysiology of several neurodegenerative diseases that are closely associated with the impairment of several MAMs-associated events, including perturbation of the redox state on the accumulation of high ROS levels. Critical Issues: Inter-organelle contacts must be tightly regulated to preserve cellular functioning by maintaining Ca2+ and protein homeostasis, lipid metabolism, mitochondrial dynamics and energy production, as well as ROS signaling. Simultaneously, these contacts should avoid mitochondrial Ca2+ overload, which might lead to energetic deficits and deleterious ROS accumulation, culminating in oxidative stress-induced activation of apoptotic cell death pathways, which are common features of many neurodegenerative diseases. Future Directions: Given that Sig-1R is an ER resident chaperone that is highly enriched at the MAMs and that controls ER to mitochondria Ca2+ flux, as well as oxidative and ER stress responses, its potential as a therapeutic target for neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer, Parkinson, and Huntington diseases should be further explored. Antioxid. Redox Signal. 37, 758-780.

Performance and resource requirements of in-person versus voice call versus automated telephone-based socioeconomic data collection modalities for community-based health programmes: a systematic review protocol.

INTRODUCTION: Gathering data on socioeconomic status (SES) is a prerequisite for any health programme that aims to assess and improve the equitable distribution of its outcomes. Many different modalities can be used to collect SES data, ranging from (1) face-to-face elicitation, to (2) telephone-administered questionnaires, to (3) automated text message-based systems. The relative costs and perceived benefits to patients and providers of these different data collection approaches is unknown. This protocol is for a systematic review that aims to compare the resource requirements, performance characteristics, and acceptability to participants and service providers of these three approaches to collect SES data from those enrolled in health programmes. METHODS AND ANALYSIS: An information specialist will conduct searches on the Cochrane Library, MEDLINE, Embase, Global Health, ClinicalTrials.gov, the WHO ICTRP and OpenGrey. All databases will be searched from 1999 to present with no language limits used. We will also search Google Scholar and check the reference lists of relevant articles for further potentially eligible studies. Any empirical study design will be eligible if it compares two or more modalities to elicit SES data from the following three; in-person, voice call, or automated phone-based systems. Two reviewers will independently screen titles, abstracts and full-text articles; and complete data extraction. For each study, we will extract data on the modality characteristics, primary outcomes (response rate and equivalence) and secondary outcomes (time, costs and acceptability to patients and providers). We will synthesise findings thematically without meta-analysis. ETHICS AND DISSEMINATION: Ethical approval is not required, as our review will include published and publicly accessible data. This review is part of a project to improve equitable access to eye care services in low-ioncome and middle-income countries. However, the findings will be useful to policy-makers and programme managers in a range of health settings and non-health settings. We will publish our findings in a peer-reviewed journal and develop an accessible summary of results for website posting and stakeholder meetings. PROSPERO REGISTRATION NUMBER: CRD42021251959.

Trends, geographical variation and factors associated with the use of anti-VEGF intravitreal injections in Portugal (2013-2018): a retrospective analysis of administrative data.

AIMS: The arrival of anti-vascular endothelial growth factor (anti-VEGF) therapies represented a treatment shift for several ophthalmological disorders and led to an increasing number of patients undergoing intravitreal injections. The aims of this observational study were to assess the expansion of anti-VEGF intravitreal injections in the Portuguese National Health System (NHS) and to identify factors correlated with geographical variations in episode rates. METHODS: Administrative database on discharge from Portuguese NHS hospitals was analysed for annual values and rates of intravitreal anti-VEGF injections at a national and regional level, between 2013 and 2018. RESULTS: The number of episodes of anti-VEGF treatment and patients treated increased 16% and 9% per year, respectively, between 2013 and 2018. During the study period around 72% of patients were treated in the Metropolitan areas of Lisbon and Porto and in the Central region. Intravitreal anti-VEGF treatment rates in 2018 were 560 per 100 000 population and presented high variability between municipalities. Higher anti-VEGF treatment rates at the municipality level were associated with shorter distances between their residence and the hospital. At the hospital level, higher ratio of ophthalmologists and higher organisational level were associated with higher anti-VEGF treatment rates. CONCLUSION: The number of episodes and patients treated with anti-VEGF injections has been growing in recent years. Proximity to healthcare, more access to ophthalmologists and hospitals with higher organisational levels are associated with higher anti-VEGF treatment rates. Improving access is crucial to reduce regional discrepancies and ensure optimal treatment frequency, which may improve health outcomes.

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.

Cross-sectional study investigating the prevalence and causes of vision impairment in Northwest Portugal using capture-recapture.

OBJECTIVES: The aim of this study was to estimate the prevalence and causes of vision impairment (VI) in Portugal. SETTING: Information about people with VI was obtained from primary care centres, blind association (ACAPO) and from hospitals (the PCVIP study) in the Northwest of Portugal during a period spanning years 2014-2015. Causes of VI were obtained from hospitals. PARTICIPANTS: Administrative and medical records of people with visual acuity in the better seeing eye of 0.5 decimal (0.30logMAR) or worse and/or visual field less than 20° were investigated. Capture-recapture with log-linear models was applied to estimate the number of individuals missing from lists of cases obtained from available sources. PRIMARY AND SECONDARY OUTCOME MEASURES: Log-linear models were used to estimate the crude prevalence and the category specific prevalence of VI. RESULTS: Crude prevalence of VI was 1.97% (95% CI 1.56% to 2.54%), and standardised prevalence was 1% (95% CI 0.78% to 1.27%). The age-specific prevalence was 3.27% (95% CI 2.36% to 4.90%), older than 64 years, 0.64% (95% CI 0.49% to 0.88%), aged 25-64 years, and 0.07% (95% CI 0.045% to 0.13%), aged less than 25 years. The female-to-male ratio was 1.3, that is, higher prevalence among females. The five leading causes of VI were diabetic retinopathy, cataract, age-related macular degeneration, glaucoma and disorders of the globe. CONCLUSIONS: The prevalence of VI in Portugal was within the expected range and in line with other European countries. A significant number of cases of VI might be due to preventable cases and, therefore, a reduction of the prevalence of VI in Portugal seems possible. Women and old people were more likely to have VI and, therefore, these groups require extra attention. Future studies are necessary to characterise temporal changes in prevalence of VI in Portugal.

Selective laser trabeculoplasty versus 0·5% timolol eye drops for the treatment of glaucoma in Tanzania: a randomised controlled trial.

BACKGROUND: Glaucoma is a major cause of sight loss worldwide, with the highest regional prevalence and incidence reported in Africa. The most common low-cost treatment used to control glaucoma is long-term timolol eye drops. However, low adherence is a major challenge. We aimed to investigate whether selective laser trabeculoplasty (SLT) was superior to timolol eye drops for controlling intraocular pressure (IOP) in patients with open-angle glaucoma. METHODS: We did a two-arm, parallel-group, single-masked randomised controlled trial at the Eye Department of Kilimanjaro Christian Medical Centre, Moshi, Tanzania. Eligible participants (aged ≥18 years) had open-angle glaucoma and an IOP above 21 mm Hg, and did not have asthma or a history of glaucoma surgery or laser. Participants were randomly assigned (1:1) to receive 0·5% timolol eye drops to administer twice daily or to receive SLT. The primary outcome was the proportion of eyes from both groups with treatment success, defined as an IOP below or equal to target pressure according to glaucoma severity, at 12 months following randomisation. Re-explanation of eye drop application or a repeat SLT was permitted once. The primary analysis was by modified intention-to-treat, excluding participants lost to follow-up, using logistic regression; generalised estimating equations were used to adjust for the correlation between eyes. This trial was registered with the Pan African Clinical Trials Registry, number PACTR201508001235339. FINDINGS: 840 patients were screened for eligibility, of whom 201 (24%) participants (382 eligible eyes) were enrolled between Aug 31, 2015, and May 12, 2017. 100 (50%) participants (191 eyes) were randomly assigned to the timolol group and 101 (50%; 191 eyes) to the SLT group. After 1 year, 339 (89%) of 382 eyes were analysed. Treatment was successful in 55 (31%) of 176 eyes in the timolol group (16 [29%] of 55 eyes required repeat administration counselling) and in 99 (61%) of 163 eyes in the SLT group (33 [33%] of 99 eyes required repeat SLT; odds ratio 3·37 [95% CI 1·96-5·80]; p<0·0001). Adverse events (mostly unrelated to ocular events) occurred in ten (10%) participants in the timolol group and in eight (8%) participants in the SLT group (p=0·61). INTERPRETATION: SLT was superior to timolol eye drops for managing patients with open-angle high-pressure glaucoma for 1 year in Tanzania. SLT has the potential to transform the management of glaucoma in sub-Saharan Africa, even where the prevalence of advanced glaucoma is high. FUNDING: Christian Blind Mission, Seeing is Believing Innovation Fund, and the Wellcome Trust. TRANSLATIONS: For the Kiswahili, French and Portuguese translations of the abstract see Supplementary Materials section.

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.

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).

Comparative research aspects on hospitalizations for ambulatory care sensitive conditions: the case of Brazil and Portugal.

Hospitalizations for ambulatory care sensitive conditions have been used to measure access, quality and performance of the primary health care delivery system, as timely and adequate care could potentially avoid the need of hospitalization. Comparative research provides the opportunity for cross-country learning process. Brazil and Portugal have reformed their primary health care services in the last years, with similar organizational characteristics. We used hospitalization data of Brazil and Portugal for the year 2015 to compare hospitalizations for ambulatory care sensitive conditions between the two countries, and discussed conceptual and methodological aspects to be taken into consideration in the comparative approach. Brazil and Portugal presented similarities in causes and standardized rates of hospitalizations for ambulatory care sensitive conditions. There was great sensitivity on rates according to the methodology employed to define conditions. Hospitalizations for ambulatory care sensitive conditions are important sources of pressure for both Brazil and Portugal, and there are conceptual and methodological aspects that are critical to render the country-comparison approach useful.

Comparative research aspects on hospitalizations for ambulatory care sensitive conditions: the case of Brazil and Portugal / Aspectos de pesquisa comparativa em internações por condições sensíveis à atenção primária: o caso de Brasil e Portugal

Abstract Hospitalizations for ambulatory care sensitive conditions have been used to measure access, quality and performance of the primary health care delivery system, as timely and adequate care could potentially avoid the need of hospitalization. Comparative research provides the opportunity for cross-country learning process. Brazil and Portugal have reformed their primary health care services in the last years, with similar organizational characteristics. We used hospitalization data of Brazil and Portugal for the year 2015 to compare hospitalizations for ambulatory care sensitive conditions between the two countries, and discussed conceptual and methodological aspects to be taken into consideration in the comparative approach. Brazil and Portugal presented similarities in causes and standardized rates of hospitalizations for ambulatory care sensitive conditions. There was great sensitivity on rates according to the methodology employed to define conditions. Hospitalizations for ambulatory care sensitive conditions are important sources of pressure for both Brazil and Portugal, and there are conceptual and methodological aspects that are critical to render the country-comparison approach useful.

Resumo As internações por condições sensíveis à atenção primária têm sido usadas para medir o acesso, a qualidade e o desempenho da atenção primária à saúde, uma vez que o atendimento oportuno e adequado poderia evitar a necessidade de internação. A pesquisa comparativa oferece oportunidade para o processo de aprendizagem entre países. Brasil e Portugal reformaram seus serviços de atenção primária à saúde nos últimos anos, com características organizacionais semelhantes. Utilizamos dados de internação do Brasil e de Portugal para o ano de 2015 para comparar internações por condições sensíveis à atenção primária entre os dois países, e discutimos aspectos conceituais e metodológicos a serem considerados na abordagem comparativa. Brasil e Portugal apresentaram semelhanças nas causas e taxas padronizadas de internações por condições sensíveis à atenção primária. Houve grande sensibilidade nas taxas de acordo com a metodologia empregada para definir as condições. Internações por condições sensíveis à atenção primária são importantes fontes de pressão tanto para o Brasil quanto para Portugal, e há aspectos conceituais e metodológicos que são fundamentais para tornar a abordagem comparativa entre países útil.

Direct and lost productivity costs associated with avoidable hospital admissions.

BACKGROUND: Hospitalizations for ambulatory care sensitive conditions are commonly used to evaluate primary health care performance, as the hospital admission could be avoided if care was timely and adequate. Previous evidence indicates that avoidable hospitalizations carry a substantial direct financial burden in some countries. However, no attention has been given to the economic burden on society they represent. The aim of this study is to estimate the direct and lost productivity costs of avoidable hospital admissions in Portugal. METHODS: Hospitalizations occurring in Portugal in 2015 were analyzed. Avoidable hospitalizations were defined and their associated costs and years of potential life lost were calculated. Direct costs were obtained using official hospitalization prices. For lost productivity, there were estimated costs for absenteeism and premature death. Costs were analyzed by components, by conditions and by variations on estimation parameters. RESULTS: The total estimated cost associated with avoidable hospital admissions was €250 million (€2515 per hospitalization), corresponding to 6% of the total budget of public hospitals in Portugal. These hospitalizations led to 109,641 years of potential life lost. Bacterial pneumonia, congestive heart failure and urinary tract infection accounted for 77% of the overall costs. Nearly 82% of avoidable hospitalizations were in patients aged 65 years or older, therefore did not account for the lost productivity costs. Nearly 84% of the total cost comes from the direct cost of the hospitalization. Lost productivity costs are estimated to be around €40 million. CONCLUSION: The age distribution of avoidable hospitalizations had a significant effect on costs components. Not only did hospital admissions have a substantial direct economic impact, they also imposed a considerable economic burden on society. Substantial financial resources could potentially be saved if the country reduced avoidable hospitalizations.

Chitosan Nanoparticles: Shedding Light on Immunotoxicity and Hemocompatibility.

Nanoparticles (NPs) assumed an important role in the area of drug delivery. Despite the number of studies including NPs are growing over the last years, their side effects on the immune system are often ignored or omitted. One of the most studied polymers in the nano based drug delivery system field is chitosan (Chit). In the scientific literature, although the physicochemical properties [molecular weight (MW) or deacetylation degree (DDA)] of the chitosan, endotoxin contamination and appropriate testing controls are rarely reported, they can strongly influence immunotoxicity results. The present work aimed to study the immunotoxicity of NPs produced with different DDA and MW Chit polymers and to benchmark it against the polymer itself. Chit NPs were prepared based on the ionic gelation of Chit with sodium tripolyphosphate (TPP). This method allowed the production of two different NPs: Chit 80% NPs (80% DDA) and Chit 93% NPs (93% DDA). In general, we found greater reduction in cell viability induced by Chit NPs than the respective Chit polymers when tested in vitro using human peripheral blood monocytes (PBMCs) or RAW 264.7 cell line. In addition, Chit 80% NPs were more cytotoxic for PBMCs, increased reactive oxygen species (ROS) production (above 156 µg/mL) in the RAW 264.7 cell line and interfered with the intrinsic pathway of coagulation (at 1 mg/mL) when compared to Chit 93% NPs. On the other hand, only Chit 93% NPs induced platelet aggregation (at 2 mg/mL). Although Chit NPs and Chit polymers did not stimulate the nitric oxide (NO) production in RAW 264.7 cells, they induced a decrease in lipopolysaccharide (LPS)-induced NO production at all tested concentrations. None of Chit NPs and polymers caused hemolysis, nor induced PBMCs to secrete TNF-α and IL-6 cytokines. From the obtained results we concluded that the DDA of the Chit polymer and the size of Chit NPs influence the in vitro immunotoxicity results. As the NPs are more cytotoxic than the corresponding polymers, one should be careful in the extrapolation of trends from the polymer to the NPs, and in the comparisons among delivery systems prepared with different DDA chitosans.