Toward low-cost gene therapy: mRNA-based therapeutics for treatment of inherited retinal diseases.

Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. Gene therapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. Nevertheless, the associated costs impede widespread access, particularly in low-to-middle income countries. The primary challenge remains: how can we make these therapies globally affordable? Leveraging advancements in mRNA therapies might offer a more economically viable alternative. Furthermore, transitioning to nonviral delivery systems could provide a dual benefit of reduced costs and increased scalability. Relevant stakeholders must collaboratively devise and implement a research agenda to realize the potential of mRNA strategies in equitable access to treatments to prevent vision loss.

The genetic counselor workforce in inherited retinal disease clinics: a descriptive assessment.

BACKGROUND: Genetic counselors (GCs) have practiced in Inherited Retinal Disease (IRD) clinics for several decades. In this small subspecialty of genetic counseling, GCs are critical for patient understanding of genetic information, which can have prognostic, systemic, family planning and therapeutic implications. Recently, both access to genetic testing for IRDs and the number of genes associated with IRDs (>350) has increased dramatically. However, the practice models and roles of IRD GCs have not been previously described. MATERIALS AND METHODS: GCs working in academic IRD clinics were surveyed to assess their experience, clinical practices, and roles performed. The collected data was compared to the broader genetic counseling profession and to other specialties using publicly available data on GC professional practices. RESULTS: While roles of IRD GCs were overlapping with those of the overall genetic counseling profession, all survey respondents reported diverse roles that included both clinical and non-clinical duties, spending up to half their time on research and educational responsibilities. Most respondents (89%) felt that their clinic's MD to GC ratio was too high, while clinical load varied. IRD GCs report varying degrees of prior genetic counseling and ophthalmology-specific experience but unanimously desire additional subspecialty-specific training. CONCLUSIONS: This descriptive assessment of a small subspecialty suggests a need for growth in the number of GCs practicing in IRD clinics and could help to inform development of new GC positions in IRD centers. It also highlights the desire for additional GC-specific education and may be relevant to curriculum development within GC programs.

Low rates of optical coherence tomography utilization in the diagnosis and management of retinovascular diseases in a lower middle-income economy.

Background: Optical coherence tomography (OCT) is widely used as the standard of care in evaluating macular and retinovascular diseases. However, the degree of OCT utilization is yet to be researched in a resource-limited country where wide gaps exist in access to healthcare. Aim: To determine the rate of utilization of the OCT in diagnosis, pre-treatment, and post-treatment evaluation of macular and retinovascular diseases treated with intravitreal anti-vascular endothelial growth factor injection (IVI). Patients and Methods: Retrospective, consecutive, and non-comparative case series of eyes diagnosed and treated from Jan 2017 to Jan 2022 for seven macular and retinovascular diseases in five eye clinics in Nigeria. Data extracted include demographics, indication for IVI, eye treated, use or non-use of OCT at the diagnosis (pre-treatment) and after the last IVI (post-treatment), and central macular thickness (CMT) of pre-treatment OCT scans. Results: Seven hundred and forty two eyes were diagnosed with retinovascular and macular diseases (389 right eyes and 353 left eyes).The male to female ratio was 430: 312 eyes. The mean age was, 63.89 years (SD 12.58). Four hundred and fifty two eyes (60.9%) had a pre-treatment OCT, 235 eyes (31.7%) had a post-treatment OCT, and 190 eyes (25.6%) had both pre- and post-treatment OCTs. The rate of pre-treatment OCT varied with the diagnosis (P = 0.000); DME had the highest rate, 74.4%, and HRVO had the lowest, 40%. Post-treatment OCT rate varied with the diagnosis (P = 0.009); non-AMD CNVM had the highest rate, 49.1%, and PCV had the lowest, 24.6%. Pre-treatment OCT rate was influenced by clinic location (P = 0.000); higher in clinics having an OCT. Post-treatment OCT was not influenced by clinic location (P = 0.37). A CRVO eye had the highest maximum CMT (1031 microns) of all the pre treatment eyes and the lowest minimum CMT of all the pre treatment eyes was in a BRVO eye (138 microns). Mean CMT was highest in HRVO (475.33 microns) and lowest in CNVM (307.62 microns). Conclusion: Though OCT is the standard of care for managing retinovascular and macular diseases, this research quantifies the extent of its use in Nigeria and finds it to be low. A post-treatment OCT rate of 32% suggests that urgent steps are required to improve access to OCT for IVI patients.

Cost-effectiveness of voretigene neparvovec in the treatment of patients with inherited retinal disease with RPE65 mutation in Switzerland.

OBJECTIVE: We aimed to evaluate the cost-effectiveness of voretigene neparvovec (VN) compared with standard of care (SoC) for patients with inherited retinal disease (IRD) caused by a biallelic RPE65-mutation. VN is a live, non-replicating adeno-associated virus serotype 2 (AAV2). SoC is best supportive care provided to patients with visual impairment. Patients under SoC may experience progressive vision loss leading to complete blindness. METHODS: We adapted a previously published Markov cohort model for IRD. An annual cycle length, life-long time horizon, discount rate of 3% for cost and health outcomes, and Swiss health system perspective were used. Data from a randomised controlled phase III trial of VN versus SoC (ClinicalTrials.gov: NCT00999609) were used to estimate transitions between health states in the first year, after which VN patients were assumed to remain for 39 subsequent years in the health state they were in at the end of the first year. After the 40th year for VN patients and 1st year for SoC patients, visual decline was modelled based on observational data on the natural progression of the disease. Quality-adjusted life years (QALYs) were calculated based on an external study which elicited clinicians' EQ-5D-5L-based utility estimates for IRD patients with a RPE65-mutation. Costs (Swiss Francs (CHF), year 2018-2019) included drug acquisition/ administration, adverse events, testing for sufficient viable retinal cells, and healthcare-related costs of blindness. Societal costs of blindness were added in a complementary analysis. Robustness of the model results were tested in sensitivity and scenario analyses. RESULTS: For the base-case, VN resulted in incremental costs per patient of CHF 764'402 (VN: CHF 901'654, SoC: CHF 137'252), incremental blindness-free years of 7.67 (VN: 28.32, SoC: 20.65) and incremental QALYs of 6.73 (VN: 18.35, SoC: 11.62), leading to an incremental cost-effectiveness ratio of CHF 113'526 per QALY gained. In probabilistic sensitivity analysis, the cost-effectiveness of VN was better than CHF 100,000 per QALY gained in 41% of iterations. For the scenario analysis in which a societal perspective was adopted and for which a 50% work-related productivity loss from blindness was assumed, incremental costs of CHF 423,837 and an ICER of CHF 62'947 per QALY gained were produced. The scenario assuming VN treatment effect lasts for 20 years produced an ICER of CHF 156'171 per QALY gained, whereas assuming a life-long VN treatment effect resulted in an ICER of CHF 96'384 per QALY gained. CONCLUSION: The incremental cost-effectiveness ratio of VN compared to the SoC was estimated to be CHF 113'526 and CHF 62'947 per QALY gained, respectively, from a Swiss healthcare system, and societal perspective assuming a 50% productivity loss.

Challenges of Cost-Effectiveness Analyses of Novel Therapeutics for Inherited Retinal Diseases.

PURPOSE: To investigate the challenges and potential improvement strategies of cost-effectiveness analyses performed for therapeutics targeting inherited retinal diseases (IRDs). DESIGN: Perspective. METHODS: A literature review was conducted with discussion of current limitations and improvement recommendations. RESULTS: Cost-effectiveness analysis (CEA) performed for IRD therapeutics has multiple limitations. First, the available methods used to measure health-related quality of life and health utilities can be inaccurate when used in IRDs. Second, the financial burden to patients and society from vision impairment associated with IRDs has been inadequately studied and includes a variety of expenditures ranging from direct costs of IRD specialty health care to indirect expenses associated with daily living activities. Third, our collective understanding is limited in the areas of IRD natural history and health benefits gained from new IRD treatments (eg, gene therapies). In addition, the therapeutic effect from a patient perspective and its duration of action are not fully understood. Due to the scarcity of data, CEA for newly approved therapies has relied on assumptions and creations of predictive models for both costs and health benefits for these new therapeutics in order to calculate the incremental cost-effectiveness ratio. CONCLUSIONS: CEA studies performed for IRD therapeutics have been limited by the established health utilities in ophthalmology and the lack of disease-specific information. The assumptions and extrapolations in these studies create substantial uncertainty in incremental cost-effectiveness ratio results. An improved framework is required for CEA of IRD therapeutics in order to determine the cost-effectiveness of each therapy brought from clinical trials to clinical practice.

Photoaversion in inherited retinal diseases: clinical phenotypes, biological basis, and qualitative and quantitative assessment.

Severe light sensitivity is a feature common to a range of ophthalmological and neurological diseases. In inherited retinal diseases (IRDs) particularly, this may be accompanied by significant visual disruption. These symptoms are extremely debilitating for affected individuals and have significant implications in terms of day-to-day activities. Underlying mechanisms remain to be fully elucidated. Currently, there are many assessments of photoaversion (PA), however, all have limitations, with quantitative measurement in particular needing further evaluation. To understand the complexities associated with photoaversion from different pathologies, qualitative and quantitative assessments of the light aversion response must be standardized. There is no treatment to date, and strategies to alleviate symptoms focus on light avoidance. With respect to IRDs, however, gene therapy is currently being investigated in clinical trials and promising and further treatments may be on the horizon. The better characterization of these symptoms is an important end point measure in IRD gene therapy trials.

COVID-19 Launches Retinal Telemedicine into the Next Frontier.

INTRODUCTION: Telemedicine in ophthalmology, and specifically in retinal diseases, has made significant advancements in recent years. The COVID-19 pandemic has launched telehealth into a new era by creating demand from patients and physicians alike, while breaking down previous insurance, reimbursement, access and educational barriers. METHODS: This paper reviews mulitple studies demonstrating the use of telemedicine in managing various retinal conditions before and during the COVID-19 pandemic. CONCLUSION: Moving forward, promising new devices and models of care ensure that tele-retinal care will continue to expand and become a vital part of how we screen, diagnose and monitor retinal diseases.

Methodological Challenges in the Economic Evaluation of a Gene Therapy for RPE65-Mediated Inherited Retinal Disease: The Value of Vision.

The emergence of gene therapies challenge health economists to evaluate interventions that are often provided to a small patient population with a specific gene mutation in a single dose with high upfront costs and uncertain long-term benefits. The objective of this study was to illustrate the methodological challenges of evaluating gene therapies and their implications by discussing four economic evaluations of voretigene neparvovec (VN) for the treatment of RPE65-mediated inherited retinal disease. The checklist for economic evaluations of gene therapies of Drummond et al. was applied to the economic evaluations of VN performed by US Institute for Clinical and Economic Review, two country adaptations of the company model in the UK and the Netherlands, and another US publication. The main differences in methodological choices and their impact on cost-effectiveness results were assessed and further explored with sensitivity analyses using the Dutch model. To enable comparison between the economic evaluations, costs were converted to US dollars. Different methodological choices were made in the economic evaluations of VN resulting in large differences in the incremental cost-effectiveness ratio varying from US$79,618 to US$643,813 per QALY. The chosen duration of treatment effect, source of utility values, discount rate and model structure had the largest impact on the cost-effectiveness. This study underlines the findings from Drummond et al. that standard methods can be used to evaluate gene therapies. However, given uncertainty about (particularly long-term) outcomes of gene therapies, guidance is required on the acceptable extrapolation of treatment effect of gene therapies and on how to handle the uncertainty around this extrapolation in scenario and sensitivity analyses to aid health technology assessment research and align submissions of future gene therapies.

Ocular abnormalities in beta thalassemia patients: prevalence, impact, and management strategies.

BACKGROUND: Beta thalassemia (ß-thalassemia) is a hereditary disease caused by defective globin synthesis and can be classified into three categories of minor (ß-TMi), intermedia (ß-TI), and major (ß-TM) thalassemia. The aim of our study is to investigate the effects of ß-thalassemia and its treatment methods on different parts of the eye and how early-diagnostic methods of ocular complications in this disorder would prevent further ocular complications in these patients by immediate treatment and diet change. METHODS: We developed a search strategy using a combination of the words Beta thalassemia, Ocular abnormalities, Iron overload, chelation therapy to identify all articles from PubMed, Web of Science, Scopus, and Google Scholar up to December 2018. To find more articles and to ensure that databases were thoroughly searched, the reference lists of selected articles were also reviewed. RESULTS: Complications such as retinopathy, crystalline lens opacification, color vision deficiency, nyctalopia, depressed visual field, reduced visual acuity, reduced contrast sensitivity, amplitude reduction in a-wave and b-wave in Electroretinography (ERG), and decrease in the Arden ratio in Electrooculography (EOG) have all been reported in ß-thalassemia patients undergoing chelation therapy. CONCLUSION: Ocular problems due to ß-thalassemia may be a result of anemia, iron overload in the body tissue, side effects of iron chelators, and the complications of orbital bone marrow expansion.

The Foundation Fighting Blindness Plays an Essential and Expansive Role in Driving Genetic Research for Inherited Retinal Diseases.

The Foundation Fighting Blindness leads a collaborative effort among patients and families, scientists, and the commercial sector to drive the development of preventions, treatments, and cures for inherited retinal diseases (IRDs). When the nonprofit was established in 1971, it sought the knowledge and insights of leaders in the retinal research field to guide its research funding decisions. While the Foundation's early investments focused on gaining a better understanding of the genetic causes of IRDs, its portfolio of projects would come to include some of the most innovative approaches to saving and restoring vision, including gene replacement/augmentation therapies, gene editing, RNA modulation, optogenetics, and gene-based neuroprotection. In recent years, the Foundation invested in resources such as its patient registry, natural history studies, and genetic testing program to bolster clinical development and trials for emerging genetic therapies. Though the number of clinical trials for such therapies has surged over the last decade, the Foundation remains steadfast in its commitment to funding the initiatives that hold the most potential for eradicating the entire spectrum of IRDs.

Cost Utility of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease.

OBJECTIVE: The gene therapy voretigene neparvovec (VN) is the first Food and Drug Administration-approved treatment for vision loss owing to the ultra-rare RPE65-mediated inherited retinal disorders. We modeled the cost-utility of VN compared with standard of care (SoC). STUDY DESIGN: A 2-state Markov model, alive and dead, with a lifetime horizon. METHODS: Visual acuity (VA) and visual field (VF) were tracked to model quality-adjusted life-years (QALYs). VN led to an improvement in VA and VF that we assumed was maintained for 10 years followed by a 10-year waning period. The cost of VN was $850 000, and other direct medical costs for depression and trauma were included for a US healthcare system perspective. A modified societal perspective also included direct nonmedical costs and indirect costs. RESULTS: VN provided an additional 1.3 QALYs over the remaining lifetime of an individual. The average total lifetime direct medical cost for individuals treated with VN was $1 039 000 compared with $213 400 for SoC, leading to an incremental cost-effectiveness ratio (ICER) of $643 800/QALY from the US healthcare system perspective. Direct nonmedical costs totalled $1 070 900 for VN and $1 203 300 for SoC, and indirect costs totalled $405 400 for VN and $482 900 for SoC, leading to an ICER of $480 100/QALY from the modified societal perspective. CONCLUSIONS: At the current price, VN was unlikely to reach traditional cost-effectiveness standards compared with SoC. VN has important implications for both development and pricing of future gene therapies; therefore clinical and economic analyses must be carefully considered.

The Burden of Macular Diseases in Central and Eastern Europe-Implications for Healthcare Systems.

BACKGROUND: Despite the significant impact of retinal diseases such as wet age-related macular degeneration (wAMD) and diabetic macular edema (DME), there is a limited understanding of how these conditions are managed in Central and Eastern Europe (CEE). OBJECTIVES: To provide a comprehensive overview of the clinical and economic burden of wAMD and DME in CEE and the status quo associated with their management. METHODS: A narrative literature review was undertaken to identify existing data on wAMD and DME, including epidemiology, economic burden, clinical guidelines, and available and reimbursed treatments. Data were collected from relevant sources such as PubMed, ophthalmology associations, national statistical offices, and government agency websites; practical viewpoints were provided by local ophthalmologists and healthcare economics experts in CEE. RESULTS: Epidemiological data on wAMD and DME are limited in CEE, and intercountry comparison is difficult because of differences in data collection methodologies. There are effective treatment options for wAMD and DME, and international guidelines advocate the use of intravitreal anti-vascular endothelial growth factor injections as first-line therapy. Local expert organizations broadly support these recommendations; nevertheless, no clinical practice guidelines exist on the treatment of wAMD and DME in CEE. Access to and reimbursement of anti-vascular endothelial growth factor agents vary significantly in the region and, as a result, many patients remain untreated or inadequately treated. CONCLUSIONS: There is an urgent need for the creation of a wAMD/DME treatment program in CEE to ensure that patients have timely access to the most appropriate treatments.

The assessment of retina in pregnant women with myopia.

OBJECTIVES: Myopia is associated with increased frequency of retinal degenerative changes which are the risk factors of intra- and postpartal ophthalmological complications. Aim of this study was to analyze the degenerative lesions detected in opthalmological examination (including peripheral retinal lesions) as a potential risk factors for eyes' status in terms of delivery in myopic women. MATERIAL AND METHODS: 254 pregnant women affected with myopia underwent opthalmological examination as a screening method to examine retina. In case of any degenerative lesions, the qualification for laser photocoagulation treatment was performed. Furthermore, study group was divided into two subgroups due to presence or absence of the retinal lesions and opthalmological outcomes compared. Follow up examination was performed in every patient from the study group between 3 and 6 months after the delivery. RESULTS: Among 508 eyes, retinal lesions were revealed in 69 women (121 eyes) what constituted for 23.8%. In remaining 185 patients results of the opthalmological examination were normal. Average maternal age was higher in group affected with degenerative lesions (p<0.001). Myopia in women with retinal lesions ranged between -0.25 and -12 dioptries (D), while in 43 cases of degenerative lesions qualified for laser photocoagulation this value ranged between -0.5 and -12.0 D (p=ns). Postpartal follow-up examination did not reveal any abnormalities in this group, as well. CONCLUSION: Degenerative retinal lesions are present in one fourth of pregnant women. Both the severity and type of the lesions are not associated with severity of myopia. Among pregnant patients, retinal lesions occur in patients with more advanced maternal age. opthalmological examination remains an important prophylactic modality in retinal disorders, especially in primary retinal detachment due degenerative disorders.

A simulation tool for better management of retinal services.

BACKGROUND: Advances in the management of retinal diseases have been fast-paced as new treatments become available, resulting in increasing numbers of patients receiving treatment in hospital retinal services. These patients require frequent and long-term follow-up and repeated treatments, resulting in increased pressure on clinical workloads. Due to limited clinic capacity, many National Health Service (NHS) clinics are failing to maintain recommended follow-up intervals for patients receiving care. As such, clear and robust, long term retinal service models are required to assess and respond to the needs of local populations, both currently and in the future. METHODS: A discrete event simulation (DES) tool was developed to facilitate the improvement of retinal services by identifying efficiencies and cost savings within the pathway of care. For a mid-size hospital in England serving a population of over 500,000, we used 36 months of patient level data in conjunction with statistical forecasting and simulation to predict the impact of making changes within the service. RESULTS: A simulation of increased demand and a potential solution of the 'Treat and Extend' (T&E) regimen which is reported to result in better outcomes, in combination with virtual clinics which improve quality, effectiveness and productivity and thus increase capacity is presented. Without the virtual clinic, where T&E is implemented along with the current service, we notice a sharp increase in the number of follow-ups, number of Anti-VEGF injections, and utilisation of resources. In the case of combining T&E with virtual clinics, there is a negligible (almost 0%) impact on utilisation of resources. CONCLUSIONS: Expansion of services to accommodate increasing number of patients seen and treated in retinal services is feasible with service re-organisation. It is inevitable that some form of initial investment is required to implement service expansion through T&E and virtual clinics. However, modelling with DES indicates that such investment is outweighed by cost reductions in the long term as more patients receive optimal treatment and retain vision with better outcomes. The model also shows that the service will experience an average of 10% increase in surplus capacity.

Guidance of Medical Care for Familial Exudative Vitreoretinopathy：Research on Rare and Intractable Diseases, Health and Labour Sciences Research Grants.

Familial exudative vitreoretinopathy is a hereditary insufficiency of retinal vascularture, which manifests a variety of vitreoretinal abnormalities, including nonvascularlized retina, abnormality of retinal vessel growing, dragged retina, retinal folds and total retinal detachment. While causative genes have been identified, cases are often sporadic. Periodic examination is necessary to find recurrence of the disease and late complications, including rhegmatogenous retinal detachment, cataract and glaucoma.

What Is Next for Retinal Gene Therapy?

The field of gene therapy for retinal blinding disorders is experiencing incredible momentum, justified by hopeful results in early stage clinical trials for inherited retinal degenerations. The premise of the use of the gene as a drug has come a long way, and may have found its niche in the treatment of retinal disease. Indeed, with only limited treatment options available for retinal indications, gene therapy has been proven feasible, safe, and effective and may lead to durable effects following a single injection. Here, we aim at putting into context the promise and potential, the technical, clinical, and economic boundaries limiting its application and development, and speculate on a future in which gene therapy is an integral component of ophthalmic clinical care.

Tendencias y costos del uso de antiangiogénicos en Colombia / Trends and costs of the use the antiangiogenics in Colombia

Objetivo: determinar la tendencia de uso de medicamentos AntiVEGF en las patologías oftalmológicas en la Clínica de Oftalmología de Cali y comparar con otros escenarios nacionales. Metodología: se realizó un estudio descriptivo que determinó la tendencia de uso de AntiVEGF en la Clínica de Oftalmología de Cali. Se construyeron indicadores sobre el número de inyecciones ordenadas por cada 100 consultas de oftalmología y se determinó la tendencia de aplicación por cada tipo de AntiVEGF, en el periodo 2013-2014. Basados en los datos de ventas por Lucentis por ciudad, se construyeron indicadores proxy similares para las otras ciudades, teniendo en cuenta las poblaciones mayores de 35 años proyectadas para las ciudades por el DANE. Los datos se expresan en tasas por 100.000 habitantes. La comparación de tasas se realizó por el método indirecto. Adicionalmente se realizó una revisión documental sobre los costos de los medicamentos AntiVEGF y las disposiciones legales y normativas sobre su uso en Colombia. Estos se presentan de forma descriptiva. Resultados: se encontró que la tendencia de uso de AntiVEGF está en aumento, con una frecuencia de 8 indicaciones de AntiVEGF por cada 100 consultas por retinólogo. En 2013 fue de 7 por cada 100 consultas que aumentó a 9 por cada 100 consultas en el año 2014. Existe una tendencia creciente de aplicar 2 inyecciones más de AntiVEGF por cada mes transcurrido El Avastin mantiene una tendencia estable con escasas variaciones Existe una variación importante en la tasa de inyecciones por 100.000 habitantes entre las diferentes ciudades en Colombia. Conclusiones: hay una tendencia al aumento del uso de medicamentos AntiVEGF intravitreos, con el consecuente gasto en salud asociado. Esto necesariamente afecta los recursos del Sistema general de Seguridad Social en Salud de Colombia, por lo que es importante conocer adecuadamente las indicaciones y el costo-beneficio del tratamiento, no sólo en términos del individuo, sino en términos de la comunidad.

Objective: to determine trend of use of anti VEGF in eye diseases in an ophthalmology clinic in Cali and compare with other national settings. Methodology: a descriptive study that determined the use of anti-VEGF trend in Clínica de Oftalmología de Cali was conducted. Indicators on the number of injections per 100 ophthalmology visits and trend of application for each type of anti-VEGF was determined, in the period 2013-2014. Based in sales data by a pharmacological company, proxy indicators were built to compare with other cities, considering population above 35 years old acording to DANE projections. Data are expressed in rates per 100,000 inhabitants rates comparison was performed by the indirect method. Additionally a literature review on the costs of the anti-VEGF drugs and the laws and regulations on its use in Colombia was made. These are presented descriptively. Results: It was found that the anti-VEGF's trend is increasing, with a frequency of 8 indications of antiVEGF per 100 consultations by retina specialist. In 2013 it was 7 indications per 100 consultations and increased to 9 indications per 100 consultations in 2014. There is a growing tendency to apply two more injections of anti-VEGF for each month elapsed. Avastin maintained a stable trend with few variations There is considerable variation injection rate per 100,000 among different cities in Colombia. Conclusions: There is a trend towards increased use of intravitreal anti-VEGF drugs, with consequent associated health spending. This necessarily affects the resources of the General System of Social Security in Health of Colombia, so it is important to properly understand the indications and the cost-benefit of treatment, not only in terms of the individual, but in terms of the community.