Social inequity in healthcare persists even in countries with universal healthcare. The Social Health Bridge-Building Programme aims to reduce healthcare inequities. This paper provides a detailed description of the programme. The Template for Intervention Description and Replication (TIDieR) was used to structure the description. The programme theory was outlined using elements from the British Medical Research Council’s framework, including identifying barriers to healthcare, synthesising evidence, describing the theoretical framework, creating a logic model, and engaging stakeholders. In the Social Health Bridge-Building Programme, student volunteers accompany individuals to healthcare appointments and provide social support before, during, and after the visit. The programme is rooted in a recovery-oriented approach, emphasising personal resources and hope. The programme finds support in constructs within the health literacy framework. Student volunteers serve as health literacy mediators, supporting individuals in navigating the healthcare system while gaining knowledge and skills. This equips students for their forthcoming roles as healthcare professionals, and potentially empowers them to develop and implement egalitarian initiatives within the healthcare system, including initiatives that promote organisational health literacy responsiveness. The Social Health Bridge-Building Programme is a promising initiative that aims to improve equity in healthcare by addressing individual, social, and systemic barriers to healthcare. The programme’s description will guide forthcoming evaluations of its impact. The social gradient in health is a growing concern worldwide, with persistent and increasing social inequalities in some countries ,2. In EuThese determinants stem from social, economic, and political mechanisms, which subsequently give rise to a set of socioeconomic positions, whereby populations are stratified according to education, occupation, income, gender, ethnicity and other factors. In turn, these socioeconomic positions shape specific determinants of health status depending on individual’s place within social hierarchies. According to their respective social position, individuals experience differences in exposure and differences in vulnerability to health problems . The undThe healthcare system does, however, play an important role in mitigating the consequences of social inequalities. The healthcare system can both exacerbate existing inequalities, and actively contribute towards reducing social inequality through the way in which activities are organised . EnsurinEven in publicly funded healthcare systems like those in Canada, the UK, and Scandinavia, healthcare inequities persist ,9. DisadTo address these issues, the Social Health Bridge-Building Programme was established with the objective of reducing healthcare inequity while educating future healthcare professionals . The proHence, the aim of this paper is to provide a detailed description of the key elements of the Social Health Bridge-Building Programme, and to unfold the programme theory.The Template for Intervention Description and Replication (TIDieR) was used as a structural framework for the description of the key elements of the Social Health Bridge-building Programme . The proA problem analysis was conducted in order to gain a profound understanding of the public health issue targeted by the Social Health Bridge-Building Programme. Hence, barriers to healthcare among individuals in vulnerable situations were identified and examined. The identification of barriers drew upon a recent systematic review conducted by the Danish Health Authorities , and ethA comprehensive evidence synthesis was conducted to explore the existing evidence regarding the engagement of healthcare student volunteers in improving social equity in healthcare. The literature searches and study selection procedures followed the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement . SearcheTheory offers a structural foundation for comprehending the fundamental causal connections and mechanisms that contribute to a specific problem or challenge. Through the identification of pertinent theoretical models or concepts that are relevant to the context of the intervention, one can gain deeper insight into the efficacy of specific approaches and the factors involved . ConsequA logic model was formulated to systematically present and visualise the proposed pathways, starting from the resources and activities within the programme to the attainment of increased equity in healthcare . This moThe programme description was elaborated by the research team  in close collaboration with board members and the CEO of the Social Health Bridge-Building Programme . Initially, a draft version of the TIDieR checklist, including the programme theory, was conducted at a workshop with the representatives of the Social Health Bridge-Building Programme. Then, the description underwent multiple refined iterations through a collaborative effort between the research team and the stakeholders. The elaborations were based on inputs from the literature review and the qualitative research. Hence, empirical evidence and theory were employed to explicate and substantiate the assumptions regarding the causal pathways through which the desired effects of the programme are achieved. Lastly, the refined programme theory was visualised in a simplified logic model.The programme theory (element 1–4) is explained in the following sections. The programme theory predominantly corresponds to item 2 (why) and item 3 (what) of the TIDieR checklist. The remaining items in the TIDieR checklist are available in The systematic review applied to identify barriers to healthcare for individuals in vulnerable situations encompassed 14 quantitative and 10 qualitative peer-reviewed studies, published between 2010 and 2020 . These sAt the intrapersonal level, barriers to healthcare include unhealthy living conditions such as poor housing and environmental stress , low heaThe systematic review on interventions to reduce healthcare inequity through student volunteers yielded 482 references, after removing the duplicates. These references were screened for eligibility and 445 records were excluded. A total of 37 papers were read in full-text of which 30 were excluded. The reasons for exclusion were (1) study design  (n:10), (2) intervention  (n:9), (3) population  (n:3) or (4) providers  (n:4). In addition, studies that were included in the systematic review by Wilson et al. ,48,49,50The impact of clinical exposure in student-run or shelter-based health clinics was explored in two papers ,46. WilsScreening for health related social needs was covered in four studies ,48,49,50The proposed pathways, from accompanying individuals to healthcare appointments to increased social equity in healthcare, finds support in theoretical constructs within the health literacy framework. Health literacy is defined as “the combination of personal competencies and situational resources needed for people to access, understand, appraise and use information and services to make decisions about health” . EvidencIn recent years, the literature has drawn attention to the intersection between health literacy and social context acknowledging that an individual’s health literacy skills are supplemented by those of others  . The conOrganisational Health Literacy Responsiveness is another construct of relevance to the Social Health Bridge-Building Programme within the health literacy framework. Organizational Health Literacy Responsiveness pertains to “the way in which services, organizations and systems make health information and resources available and accessible to people according to health literacy strengths and limitations” . It encoMandatory teaching of bridge-builders based on a recovery-oriented approach is a fundamental element of the Social Health Bridge-building Programme ,56. The The logic model  visualisThe key ingredients in the Social Health Bridge-Building Programme are operation of the Advisory Hotline, accompaniment to healthcare appointments, recruitment, training and supervision of bridge-builders and lobbying for social equity in healthcare. The main aim of the programme’s Advisory Hotline is to connect an individual in need of accompaniment with a bridge-builder. The Advisory Hotline is staffed by employed coordinators, all of whom have backgrounds in social work, communication, relationship-building and/or healthcare education. The contact is established when the individual in need of accompaniment or more often someone close to the individual  reaches out to the Advisory Hotline. In addition, the Social Health Bridge-Building Programme also conducts outreach work in different community settings. The bridge-builder’s primary responsibility is to provide support and assistance to individuals before, during and after healthcare appointments. Before the appointment, the bridge-builder meet the individual at a designated location . Following an initial dialogue regarding the individual’s expectations and requirements related to the healthcare appointment, the bridge-builder accompanies the individual to the appointment, utilizing transportation methods such as taxis, buses, or other means of transport. During the appointment, the bridge-builder participates in the appointment or waits as requested by the individual. Afterward, the bridge-builder accompanies the individual to their place of residence, discussing the appointment if necessary. If authorised by the individual, pertinent information concerning the outcome of the healthcare appointment may be shared with their caregivers or relatives. To become a bridge-builder, healthcare students are required to complete a 20 h foundational training course on social determinants on health, communication, and boundary setting. The course teachers are individuals with educational background in social work and recovery, some with personal experiences of social vulnerability. The modules contain elements of theoretical, practical (case-based) and experience-based (role-play) knowledge. The bridge-builders are briefed by the employed coordinator before an assignment and debriefed afterwards. Additionally, ongoing supervision is provided by external supervisors to all bridge-builders to increase their ability to interact with individuals in vulnerable situations. During supervision, the bridge builders reflect on the experiential knowledge and expertise they bring from their experiences in healthcare accompaniment, and act as co-reflectors on each other’s experiences. In order to increase awareness and utility as well as funding for the Social Health Bridge-Building Programme, the employed coordinators extensively lobby with the community, healthcare system, and health educational institutions. In the logic model, the expected outcomes of the programme are delineated as intermediate, short-term (1–3 years), and long-term outcomes (4–6 years) across three distinct levels: (1) individuals in vulnerable situations, (2) bridge-builders, and (3) the healthcare system. The intermediate outcomes correspond to the underlying mechanisms of the intervention. Lastly, the model outlines the projected societal impact of the programme. The Social Health Bridge-Building Programme aims to enhance equity in healthcare by addressing various barriers at multiple levels. At the individual level, receiving accompaniment and support for healthcare appointments is expected to contribute to increased trust in the healthcare system, improved health literacy, or increased compensatory Distributed Health Literacy, and improved social support. These intermediary outcomes are expected to yield several short-term effects at the individual level, such as a more responsive utilisation of general practitioners, improved adherence to healthcare appointments, and reduced un-planned acute hospital visits. Furthermore, it is anticipated that the programme can enhance communication with healthcare professionals and self-efficacy. Consequently, these short-term outcomes are expected to result in improved health outcomes for the individuals.At the bridge-builder level, accompanying individuals provides bridge-builders with valuable insights into recognising and addressing social determinants of health, and enables them to perceive the individuals from a holistic standpoint beyond their diagnosis. Furthermore, bridge-builders gain experience in effectively communicating and establishing respectful relationships with individuals in vulnerable situations, thereby enhancing their professional competencies to improve and cater to the individuals’ health literacy. As a short-term outcome, the acquired competencies are expected to enhance the bridge-builder’s understanding of the lived reality of individuals in vulnerable situations. These competencies are also anticipated to have a positive impact on appointments and other social circumstances, as they improve the bridge-builder’s communication skills, empathy, and respect when interacting with individuals. Furthermore, the improved competencies and experience with the individuals’ lived lives may help to reduce stigmatisation and prejudicial experiences within appointments or similar settings for this target group. As a result of these short-term outcomes, bridge-builders potentially become better equipped to meet the complex needs of individuals living in vulnerable situations in their future healthcare careers. At the healthcare system level, the Social Health Bridge-Building Programme is anticipated to promote organisational health literacy responsiveness by enhancing the understanding of health literacy among future healthcare professionals. Additionally, it aims to raise awareness of barriers within the healthcare system through extensive advocacy endeavours directed at various stakeholders, such as policymakers, healthcare system leaders, citizens, and both current and future health professionals.Overall, the changes at the three levels have the potential to result in increased social equity in access to and benefits from the healthcare system.The Social Health Bridge-Building Programme aims to address healthcare inequities in universal healthcare systems while educating future healthcare professionals. This paper provides a comprehensive description of the programme and its theoretical foundation, laying the groundwork for evaluations and potential implementation in different settings. The programme targets the barriers to healthcare by providing social support and assistance in navigating the healthcare system. It offers students first-hand exposure to the social determinants of health. The theoretical framework is based on a recovery-oriented approach, emphasising personal resources and hope. The student volunteers serve as health literacy mediators, supporting individuals in navigating the healthcare system while gaining knowledge and skills. This equips students for their forthcoming roles as healthcare professionals, and potentially empowers them to develop and implement egalitarian initiatives within the healthcare system, including initiatives that promote organisational health literacy responsiveness. Ethnographic research supports the role of student volunteers as substitutes for absent family or social networks, and it highlights the insights gained from accompanying individuals to healthcare appointments. Healthcare systems worldwide are facing significant challenges as a result of the profound demographic shift characterised by a growing population of individuals over the age of 80, and a decline in the number of healthcare professionals and caregivers . Amidst Currently, the Social Health Bridge-Building Programme is being implemented in multiple cities in Denmark, with future aspirations for further national and international expansion. The successful and sustainable implementation of the programme relies on a well-structured organisation, including programme coordinators in the specific setting as well as a strong administration led by a CEO, who is backed by solid board. Additionally, support and endorsement from a diverse range of stakeholders are crucial for ensuring the programme’s sustainability. Firstly, sufficient funding is necessary to cover the expenses related to the Advisory Hotline, as well as the recruitment, education, and supervision of student volunteers. Secondly, close collaboration with universities and other healthcare educational institutions is essential to enhance the recruitment of student volunteers. Thirdly, outreach efforts to the community and the social and healthcare system are vital to raise awareness about the programme among the target population, healthcare professionals, and caregivers. Lastly, extensive lobbying and continuous dialogue with policymakers are required to prioritise equity-creating initiatives on the political agenda. The Social-Health Bridge-Building Programme may face challenges when considering broader implementation. Given its extracurricular status, the programme’s success hinges on effectively recruiting, training, and involving a significant number of student volunteers. In rural areas, this recruitment is particularly challenging due to the concentration of healthcare students in urban centres near their educational institutions. A potential remedy might be to incorporate the Social Health Bridge-Building Programme into the formal curriculum. However, this approach requires in-depth research, and a thorough understanding of educational paradigms. While such integration might alleviate some recruitment issues, it does not necessarily resolve the challenge of attracting student volunteers in rural settings.Despite the growing societal and political attention given to social inequality within the healthcare system, there remains a significant research gap regarding the underlying mechanisms that contribute to social inequality in patient-healthcare system interactions. Our socio-ecological model of barriers to healthcare access provides a detailed examination of these mechanisms. However, several knowledge gaps still exist, limiting the insights that can be derived from existing scientific literature. More studies, particularly in healthcare settings with universal coverage are needed, focusing on investigating the causes of social inequities in healthcare encounters. Furthermore, there is a substantial lack of knowledge regarding interventions aimed at reducing social inequity in healthcare. Therefore, future research should prioritise exploring the impact of such interventions. As the implementation of the Social Health Bridge-Building Programme progresses, it is crucial to gain further insights into its effectiveness, implementation process, mechanisms of impact, and potential for scaling up. Consequently, a comprehensive evaluation of the programme, utilising both qualitative and quantitative research methods, is underway. This paper has the potential to inform future enhancements, modifications, and expansions of the programme, thus further addressing healthcare inequities.This study offers valuable insights into a unique programme aimed at promoting equity in healthcare. The Social Health Bridge-Building Programme stands out from other existing programmes in several aspects. Firstly, while existing evidence primarily focuses on programmes developed and implemented in an American healthcare setting, this paper presents a programme developed and implemented in a setting with universal healthcare coverage. Secondly, the target population is not limited to disadvantaged individuals but includes a broader range of individuals. In a universal healthcare setting, access to healthcare is not directly influenced by income or occupation, as it might be in other countries with more private financing of healthcare, such as the United States. However, a significant group of individuals still encounter challenges in navigating the healthcare system. Therefore, the Social Health Bridge-Building Programme focuses on providing assistance in navigating the healthcare system and obtaining social support, rather than solely addressing the issue of legal access to healthcare or social resources. Additionally, unlike existing publications, student volunteers in this programme are not limited to medical students but include individuals from various educational backgrounds, ranging from nurses to public health students. Thirdly, the active engagement of student volunteers with individuals in vulnerable situations, accompanying them and being present at their bedside, enhances their ability to understand the patient’s perspective and exposes them to different ways of life. Some methodological strengths and limitations should be discussed. A major strength of this paper is the thorough use of evidence and the theory-driven elaboration within the context of the Social Health Bridge-Building Programme. The well-designed logic model, which addresses the programme’s impact at multiple levels , is a noteworthy strength. This, together with the systematic and transparent documentation of programme details using the TIDieR checklist, enhances reproducibility and make the implementation of the Social Health Bridge-Building Programme in various contexts more feasible. The close collaboration with stakeholders involved in the programme enhances the overall credibility of this study. A limitation of this paper is that the programme theory was elaborated after the implementation of the programme and not during the programme’s initial development. If the programme theory had been developed at an earlier stage, it would have allowed the evidence review and theory to guide the programme’s development. Instead, empirical evidence and theory were employed to explicate and substantiate the assumptions regarding the causal pathways through which the desired effects of the programme are achieved. Nonetheless, this paper still provides crucial knowledge for establishing the foundation for future evaluations and implementation in other settings.In conclusion, this study provides important insights into a unique programme aimed at promoting equity in healthcare while educating future healthcare professionals. Considering the contextual differences across healthcare settings, understanding the specific context in which a programme is implemented is crucial. As the implementation of the Social Health Bridge-Building Programme progresses, there is a need to gain further insights into its effectiveness, implementation and mechanism of impact, and potential for scaling up. Hence, a comprehensive evaluation of the programme covering qualitative and quantitative research methods is forthcoming. This paper can inform future improvements, modifications, and expansion of the programme to further address healthcare inequities.


The topical administration of medicines is the preferred route in ocular therapy, at least for the anterior segment of the eye. However, the eye’s inherent functional and biological barriers all work against the active pharmaceutical ingredient (API) to efficiently reach the targeted retinal structures. The main objective of this article is to offer a systematic review of the scientific literature in recent years, focusing on the latest developments of topical treatment intended for retinal degenerative diseases. Database search returned 102 clinical studies, focused on topical treatment for age macular degeneration, macular edemas  or glaucoma. After the exclusion of low-powered studies and those combining vitreo-retinal surgery, 35 articles remained for analysis. Currently, the topical treatment of retinal degenerative diseases is limited by the difficulty to deliver effective drug concentrations to the posterior eye structures. However, in the case of drug classes like NSAIDs, the presence of certain molecular and metabolic features for specific representatives makes the topical administration currently feasible in several clinical contexts. For other drug classes, either a fine-tuning of the API’s pharmacokinetic profile or the use of more advanced formulation strategies, such as rationally designed nanostructured drugs and vehicles, crystalline polymorphs or supramolecular complexes, could bring the much awaited breakthrough for a more predictable and controlled delivery towards the retinal structures and could eventually be employed in the future for the development of more effective ways of delivering drugs to the posterior eye, with the ultimate goal of improving their clinical efficacy. The complexity of the eye is probably unmatched in the human body, even by the brain itself. Different mechanisms operate together for the formation of images. Optical, structural, muscular and neural components work simultaneously to keep the object in focus and to generate electric patterns interpreted by the brain into images. It is a well-calibrated system, which uses large amounts of energy, and it is stimulated by large amounts of energy, in the form of light.The immune privilege of the eye has the purpose of keeping all these components intact and the optical axis transparent. The functional integrity of the eye is maintained by a series of barriers, both external and internal. There is also a particular immunological response of the eye.The topical application of treatment onto the eye surface is the preferred route in ocular drug administration, by clinicians and patients alike ,2. HowevWhen using eye drops, the first barrier is the blinking system. The drops  are placed into the conjunctival sac, beneath the lower eyelid. The volume of the eye drops varies from 25 to 70 microliters, but the tear film has a volume of 7 microliters, and the ocular surface can only retain a maximum of 30 microliters of liquid [The small amounts of drug still remaining on the eye’s surface will have the difficult task of penetrating the corneal epithelium. The cornea consists of five different layers. Among them, the epithelium  and the stroma are the most important corneal barriers. The epithelium consists of cells linked together into tight junctions, not easily penetrated by large molecules. Epithelium is hydrophobic, while the stroma is hydrophilic. Lipophilic agents, in principle, penetrate better through the cornea. Inside the eye, in the anterior chamber, there is an aqueous outflow, which will flush the xenobiotic towards the irido-corneal angle, into the aqueous drainage system, and outside the eye. The crystallin lens follows in the series of biological barriers in front of the vitreous body. In a pure axial manner of ocular biointernalization, the APIs will have to pass through cornea, aqueous humor, crystallin and vitreous body to reach the retina.Another trajectory for the ocular internalization of the topically administered bioactives formulated as eye drops is transconjunctival, followed by the transscleral route. Hydrophilic agents have a better penetration through this route. The conjunctiva is more permeable than the cornea . HoweverThe retina is a part of the central nervous system, benefiting from the same protection as the brain . The vascularization of the retina is provided through the central retinal artery and vein, which, however, provide nutrients only for the inner part of the retina. The inner surface of the retina is in contact with the vitreous body, an avascular structure. An internal limiting membrane will provide a barrier (however weak) between the retina and the vitreous body. The outer retinal surface, where the photoreceptors are located, is separated from the rich vascularized choroid by the retinal pigment epithelium . The vascular route of any drug will provide little bioavailability of the substance inside the retina. In the transconjunctival route, drugs will also have to pass through this external retinal barrier.The retina is placed in the focus of the lenses of the eye. The high levels of light, together with the very processes of vision, in high demand of energy and oxygen, place the retina under various stresses—oxidative stress, inflammation. The prevalence of retinal diseases related to oxidative damage is very high. Age-related macular degeneration (AMD), with its two forms, wet and dry, was found in 2019 in 18 million people, in the United States alone . Among tAll these retinal diseases are considered to benefit from antioxidant supplementation, which is currently included in the standard treatment. The route of administration is so far systemic. Lutein, Zeaxanthin (and metabolites: Mesozeaxanthin and Astaxanthin) and vitamins C and E are usually found together in capsules formulated from AREDS studies, for oral administration .In different stages of AMD and diabetic retinopathy, or in the case of any other retinal disease progressing with macular edema, Anti-VEGF treatment is also indicated although a more invasive route of administration, through intravitreal (IVT) injections, is commonly approached.Finally, anti-inflammatory drugs can be prescribed in certain pathologies of the macula . Moreover, cystoid macular edema (CME) is another important cause of vision loss after ocular surgical procedures. In fact, the results of a study showed that CME has been reported in 19% of patients subjected to modern, small-incision cataract surgery, using fluorescein angiography criteria .Anti-inflammatory drugs are administered topically , via intravitreal (Triamcinolon), parabular or subtenon injection (corticosteroids) and systemically . Low bioavailability is the main limitation, especially in topical administration, while systemic administration frequently causes systemic adverse reactions.Intravitreal injections seem to provide the best retinal access for all drug molecules, in general, although this procedure is invasive and associated with certain risks . Usually, very small amounts of the drug are necessary in the injection .The biological barriers upon topical treatment encountered by the APIs following either the corneal or the transconjunctival route are depicted in This review focuses on the topical treatment targeting different retinal diseases having in common oxidative stress and inflammation, from a clinical point of view, including only medicines that reached into clinical trials. Previous reviews documented various routes for drug delivery, with only tangential references to topical route ; others The main objective of this article is to provide a systematic review of the scientific literature in recent years, focusing on the recent developments of topical treatment intended for retinal degenerative diseases. Database search included PubMed/Medline  and Scopus , starting 2010 until 2023, with mesh terms “Topical and Retina”, in English language. The search returned 1891 results and 102 clinical studies .Inclusion criteria were established: focus only on degenerative retinal disease or oxidative stress-related damage, at least 10 patients enrolled in the study, no previous posterior vitrectomy surgery. Eyes with macular edema (CME) after cataract surgical procedures were also included, considering the presence of mechanisms common to degenerative pathologies . Posterior vitrectomy removes the vitreous body, changing the pharmacodynamics of any drug reaching the eye. After applying the aforementioned criteria, 35 studies were finally included. One case of Alzheimer’s disease was also included  as it inThe outcome of topical treatment was usually measured in a comparable fashion. Most studies reported change in best corrected visual acuity (BCVA) and ocular coherence tomography (OCT)—especially changes in central retinal thickness (CRT). Some studies focused on functional gains (microperimetry) or electrophysiological changes . In total, 2262 eyes were investigated.The clinical trials included in the review investigated 13 classes of medicines in topical administration: NSAIDs ; Corticosteroids ; Carbonic anhydrase inhibitors (Dorzolamide); Antioxidants (Coenzyme Q10); Integrine inhibitors (OTT166); Anti-VEGF drugs ; Immunomodulators (Interferon); Prostaglandin analogues (Unoprostone); Serotonin receptor agonists (Tandospirone); Neuroprotective drugs (Citicoline); Growth factors (Human nerve growth factor); Nicotine receptor antagonists (Mecamylamine); and Aminosterol antibiotics . The majority of clinical trials focused on topical use of NSAIDs (15 studies), carbonic anhydrase inhibitors (5 studies) and Anti-VEGF (4 studies). The timeline for these studies is illustrated in The topical treatment targeted diseases located in the macula , diseases inducing retinal photoreceptor changes , diseases changing the retinal vessels (diabetic retinopathy) and diseases of the optic nerve (glaucoma).The clinical effectiveness of an ophthalmic drug is influenced by three main factors: (i) the nature and number of physiological barriers of the eye to be overcome by the API; (ii) the particularities of the pharmacodynamic and pharmacokinetic profile of the API ; and (iii) the characteristics of the pharmaceutical dosage form in which the active molecule is incorporated.Considering the difficulty of obtaining effective concentrations at the posterior segment of the eye, intravitreal injections would seem the optimal choice to achieve the much-desired therapeutical goal at this level. This route of administration is not, however, void of risk, and in case of long-term treatments, it requires careful timing between consecutive injections or administration of prodrugs, reservoir-type or controlled-release pharmaceutical systems  able to ensure therapeutical levels of API for prolonged periods of time. The formulation of these complex systems involves the use of excipients that lack toxicity, which significantly limits the choice of these auxiliary ingredients; that in turn implies constraints in the development of these dosage forms.Clinical studies suggest that the IVT administration is advantageous in the case of molecules with high molecular weight demonstrating poor ocular bioavailability upon topical administration. Current trends, however, aim for the development of topical pharmaceutical forms able to ensure therapeutically effective concentration at retinal level, for a variety of classes of APIs.Despite all the limitations of the topical route of administration, studies included in the current review have demonstrated the absorption of some APIs up to the level of the retina, the routes involved being corneal or non-corneal . The corneal pathway ensures the absorption of small lipophilic molecules, which reach effective concentrations in the aqueous humor, while the exposure of drugs on the conjunctiva ensured lower concentrations in the aqueous humor but allowed the delivery of molecules to the posterior eye, this being observed even in the case of some larger molecules . StudiesAlthough the concentrations of APIs in the vitreous after topical administration are 10–100 times lower compared to the aqueous humor and the cornea, the use of sensitive analytical methods enable their accurate quantification .The concentration of some molecules in the posterior eye can also be explained by their particularity of preferentially targeting the choroid or the retina, the mechanism that best explains this behavior being the binding to melanin . As an eSurprisingly, even if ophthalmic drops are considered a dosage form that does not ensure clinical efficiency in the treatment of posterior eye conditions, experimental studies on animal models have demonstrated the presence of APIs in the vitreous or retina , while tTopical application is a convenient method to deliver medicines to the eye, as it ensures the highest patient compliance and also enables self-administration. However, the bioavailability of the medicine is very low, and the effectiveness in attaining therapeutic API levels is usually limited to the surface of the eye. Nevertheless, there are some exceptions. Reports indicate some NSAIDs to penetrate better inside the eye, especially Nepafenac. The corneal absorption of a drug depends on its lipid solubility and inversely on its polarity or degree of ionization . To effeOn the other hand, Diclofenac, Ketorolac and Bromfenac are relatively water-soluble phenylalkanoic (Ketorolac) and phenylacetic  acids and should have limited ability to penetrate corneal epithelium. These are weakly acidic molecules, which ionize at the tear’s pH and thus penetrate the cornea with difficulty. The formulation of topical ophthalmic dosage forms with NSAIDs is limited to the use of compounds with higher solubility in water  while adjusting the pH of the formulation to an acidic value that favors the fraction of the non-ionized form, eventually leading to the increase of their absorption rate. Nevertheless, the acidic nature of the NSAID molecules and the acidic pH of the formulation could be irritating to the eye, through chronic use .NSAIDs represent a heterogeneous group of compounds with different physicochemical characteristics, being approved by the FDA for use in various eye diseases to be administered by various routes. The clinical efficiency and absorption in the posterior segment are still controversial, with some studies demonstrating increased concentrations in the vitreous after topical application, results that can be supported by the possibility of absorption through the mucosal surfaces . In addiBromfenac, a molecule with a similar chemical structure to amfenac (exception of a bromine atom at the C4 position) showed increased penetrability, a fact that prolongs its cyclooxygenase-2 (COX2) inhibitory action ,65. BromIn vitro studies showed that Nepafenac pro-drug readily penetrates the rabbit cornea well and distributes in all ocular tissues, including aqueous humor, iris, ciliary body, retina and choroid . PredictIn specific clinical situations like cataract surgical trauma, local cyclooxygenases could be excessively activated, leading to high levels of prostaglandins within the eye’s structures. These pro-inflammatory molecules can cause pain and discomfort to the eye, their inhibition with non-steroidal anti-inflammatory drugs being common after ocular surgery. Moreover, anti-inflammatory drugs proved also a favorable effect on visual outcomes .Among the 14 NSAID included studies, 8 reported clinical success . This inKessel et al.  performeTopical administration of Corticosteroids is the preferred route targeting the anterior segment of the eye, the drug reaching the anterior chamber 15–30 min after administration . The maiCorticosteroids provide powerful anti-inflammatory and anti-edematous effects by targeting not only the synthesis of proinflammatory mediators involved in DME  but also a decrease in VEGF synthesis. The only clinical trial included in the review found no benefit in high dose Prednisolone for preventing CME after surgery. BCVA, retinal thickness on OCT-CRT remained similar to low dose corticosteroid regimen. This may point to low penetrability of Prednisolone alone through the cornea.Two clinical studies incorporating corticosteroids in microparticles were also included in the review. With their lipophilic central cavity and their hydrophilic outer surface, cyclodextrins and their derivatives can be successfully used for the preparation of aqueous eye drop containing corticosteroids . Their supramolecular complexes with cyclodextrins were proven to increase water solubility and stability, and the drug permeability through biological membranes and hence allowed for an efficient delivery of the drug to the retina and vitreous humor ,74,75,76It was proposed that drug-cyclodextrin complexes can aggregate in aqueous media to form nano- or microparticles, the latter being broken into nanoscale structures and even single drug-cyclodextrin complexes once they reach the surface of the eye ,78. FurtIn an animal model (rabbits), microparticles of dexamethasone-ɣ-cyclodextrin with increased residence time on the eye surface were evaluated for the delivery of the corticosteroid, and the results showed that Dexamethasone’s concentration in the posterior segment of the eye (vitreous and retina) was comparable with the concentrations achieved from the intravitreal injection of the corticosteroid . In a clRelated to corticosteroid topical use, but not included in this review, Niffenegger et al.  observedAnother study that did not meet the inclusion criteria investigated Nepafenac for the prevention of CME after pars plana vitrectomy. Mandelcorn et al.  comparedNaithani et al.  also invTopical Carbonic Anhydrase inhibitor (Dorzolamide) was investigated in 5 clinical studies . All reported success . Tilma et al.  found thDorzolamide in slightly acidic solution is usually used for glaucoma treatment . It is sAnimal studies suggested that Dorzolamide penetrates to the retina, with high concentrations of the drug 1 and 2 h after topical administration . Kadam eSeveral theories exist as to how Dorzolamide-timolol may be helping in nAMD. The effect on carbonic anhydrase together with β-blockade from Timolol is a potent decrease of aqueous humor flow, hence turnover of intraocular fluid may be slower, delaying drug clearance. Mouse models also suggested the role of the β-adrenergic pathway in VEGF upregulation .Anti-VEGF IVT injections are the main treatment regimen in nAMD. Repeated dosage is usually needed (1×/months). The shift to topical administration is a demand from both ophthalmic specialists and patients. Four studies were included in the present review, investigating Pazopanib, Regorafenib and Acrizanib in topical formulations. Danis et al.  found PaIntegrin inhibitor (OTT166) decreases angiogenesis, exudation, inflammation and fibrosis . Due to its physiochemical properties, including incorporation of fluorine atoms in specific positions on the molecule, OTT166 penetrates the conjunctiva and traverses the sclera and choroid, distributing to the retina upon topical application. OTT166 has demonstrated pharmacologic effects in animal models of neovascularization, vascular leakage and angiogenesis. Boyer  found a Citicoline, a neuroenhancer (stabilizes cell membranes by increasing phosphatidylcholine and sphingomyelin synthesis) is also currently available for topical treatment. It is documented that, in an animal experimental model, Citicoline reaches the vitreous  ; therefoAnother neuroprotector, Tandospirone, had good results on animal models. In albino and pigmented rats subjected to a severe acute photo-oxidative stress, Tandospirone protected photoreceptors and RPE cells in a dose dependent manner. In Jaffe’s clinical trial investigating GA-AMD , TandospBeykin, in 2022 , also foIsopropyl Unoprostone (Rescula), 2×/day, is a standard treatment for glaucoma patients. Tawada  used ResCoenzyme Q10 0.1%, 2×/day, for 6 months, proved effective in Alzheimer’s patients, targeting retinal ganglion cells, and increasing retinal nerve fiber layer on OCT. Coenzyme Q10 has activity on mitochondrial dysfunction, oxidative stress and chronic neuro-inflammation.Mecamylamine is a nonspecific nicotinic acetylcholine (nACh) receptor antagonist that was approved as an oral antihypertensive agent in the 1950s. It is known to pass through blood-brain barrier. Blocking nACh receptor could reduce abnormal vascular permeability in patients with DME. The effect was tested on animal settings, using topical concentrations varying 0.1 to 1%. Campochiaro’s study showed no local side effects on Mecamylamine topical administration  in patients with DME . The cliSqualamine lactate, an angiostatic aminosterol interferes with the calmodulin mediated signaling for VEGF, platelet-derived growth factor, basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF). Adding Squalamine to Ranibizumab (selective inhibitor of VEGF) may benefit from the inhibition of the other cytokines  as well. Wroblewski et al.  treated Interferons have antiproliferative, antiangiogenic and immunomodulatory properties. This makes Interferon a suitable candidate for the treatment of DME, and systemic use was proven effective in inflammation-related CME . RetrobuSome of the inconsistencies between the encouraging results obtained on animal models and the unsatisfactory outcome of certain subsequent clinical studies may reside on the lack of linear translation in between different mammals. Significant differences between species could influence both pharmacokinetic parameters and efficacy of topically applied drugs in ophthalmology and could affect the translation of promising data obtained in preclinical settings to clinical use. The eye size is variable between different species with a vitreous volume of 0.013–0.054 mL in rats, 1.5–1.8 mL in rabbits and 4 mL in humans, leading to differences in apparent volume of distribution and elimination of half-lives in the vitreous .The study of Sadeghi et al.  showed tThe studies presented here took place over a short period of time and included a relatively small number of subjects, which does not cover the medical need, considering the incidence of retinal diseases. Many of the published results refer to the clinical efficiency or to the drug concentration in vitreous, as a result of the comparative testing of different pharmaceutical dosage forms, as well as two different APIs, administered by different routes , a fact that does not confirm the effectiveness of these preparations or molecules.On the other hand, the concentration of the APIs identified in the vitreous, at relatively short time intervals of application, is not relevant for formulating conclusions regarding the use of the respective molecules in chronic treatment, especially since their kinetics in the eye are not known for the long term. In addition, considering the high sensitivity of the anatomical structures at the level of the eye, long-term testing of the toxicity of the preparations in the eye is also required. Also, comparing the results obtained in different studies, using APIs from different generations, or surgical techniques, instruments, equipment and even different patients’ samples, is not relevant and may mislead in formulating some conclusions.Despite the considerable scientific reasons, the existing evidence is insufficient, as convincing clinical results are needed to recommend a certain type of preparations and active principles for chronic clinical use in retinal diseases. Nevertheless, the prospects of bringing more and more sensitive imaging and spectroscopic tools able to locally monitor the API’s ocular biointernalization, its kinetics and even record changes upon the applied topical treatment in the pathophysiological profile at metabolites level could bring an extra boost in the in vivo assessment of the (pre)clinical efficacy of this route of administration on retinal diseases. Magnetic resonance imaging and spectroscopic techniques (MRI/MRS) are widely used in humans both for clinical diagnostic applications and in basic research areas . Such anThe numerous biological and functional barriers of the eye rose too many challenges for topical translation of the drug molecules originally developed for systemic or parenteral administration, rendering the topical route of administration less appealing for ocular drug development. However, the relatively small number of successful pre-clinical  and clinical studies demonstrated that these barriers can in fact be efficiently circumvented, at least in case of selected representatives of drug classes. The development of a product intended for topical application at the level of the eye to target the retina represents a major challenge, considering the advantages of this non-invasive and economical way of administration. On the other hand, it is imperative to achieve an optimal combination between the system in which the API is incorporated or processed , the dosage form and the physicochemical and pharmacokinetic characteristics of the API ,95,96. IThis development could lead eventually to a gradual replacement in the current clinical practice of the more invasive modes of administration of APIs  with the more convenient and patient-friendly topical route, except maybe those requiring immediate interventions.Topical administration of drugs to the eye surface is easy to perform and does not induce significant discomfort, having very good acceptance rates from patients, compared to other more invasive routes of ocular drug administration.Currently, the topical treatment of retinal degenerative diseases is limited by the difficulty to deliver effective drug concentrations to the posterior eye structures. However, in case of drug classes like NSAIDs, the presence of certain molecular and metabolic features for specific representatives makes the topical administration possible and feasible in several clinical contexts.For other drug classes, several formulation strategies like the use of nanostructured drugs and vehicles, crystalline polymorphs or supramolecular complexes could enhance drug diffusion towards retinal structures and could be employed in the development of more effective ways of delivering drugs to the posterior eye, with the ultimate goal of improving their clinical efficacy.


Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening, rapidly progressive, and heterogeneous disease caused by the accumulation of variant (ATTRv) or wild-type (ATTRwt) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs . While AShije et al. conducted a study to investigate the prevalence of the V122I mutation in African Americans with bilateral carpal tunnel syndrome (CTS) and to determine whether various demographic and clinical factors are associated with an increased likelihood of having the mutation. Despite the small sample size, the study found that 12.5% of the patients were V122I carriers, indicating that the frequency of the V122I mutation in this cohort may be higher than expected (3–4%). The presence of a family history of neuropathy, diagnosis of carpal tunnel syndrome after the 5th or 6th decade of life, and cardiomyopathy were factors associated with an increased likelihood of carrying the mutation. Periodic follow-up of these patients to rule out CTS, cardiomyopathy, or sensory disturbances in the extremities allows for earlier diagnosis and management of the disease, which improves outcomes in affected individuals.Up to this point, over 140 TTR variants have been identified , with a In recent years, significant advances have been made in the diagnosis and treatment of ATTRv amyloidosis, allowing for the slowing of disease progression and preservation of quality of life (QOL) for those affected . DespiteUneus et al. explored the utility of a new imaging technique, [18F]flutemetamol PET/CT, for diagnosis and monitoring of CNS involvement in ATTR V30M amyloidosis patients. The major finding of the study was that amyloid deposition is mostly confined to the cerebellum. The study also found that amyloid deposition is related to age of disease onset but not to disease duration, in contrast with previously reported findings (Although Magnetic Resonance Imaging (MRI) has been suggested to be the most reliable tool for identification of cerebral amyloid angiopathy (CAA) and meningeal amyloid deposits, its use is limited due to the high percentage of patients who have pacemakers. Cerebral amyloid angiopathy (CAA) is typically linked to specific MRI biomarkers indicating small-vessel brain damage, such as strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities , 8. PET findings .Periodic assessment of patients treated for polyneuropathy of ATTRv amyloidosis is mandatory in order to adjust therapy, delay clinical deterioration, and preserve their quality of life (QOL), as well as their social, economic, and psychological wellbeing .Di Stefano et al. showed that nerve conduction studies (NCSs) and handgrip strength (HGS) measurement could be useful tools for monitoring disease progression in patients with ATTRv amyloidosis, particularly those with major upper limb involvement such as carpal tunnel syndrome ; and were more likely to have cardiomyopathy. Remarkably, the study also found that 8% of presymptomatic carriers reported neuropathic pain. This suggests that neuropathic pain may be an early symptom of ATTRv amyloidosis and may be worth monitoring in terms of disease progression and the identification of early manifestations of the disease.Symptom management is of major importance in ATTR amyloidosis due to its impact on patients' daily activities and QOL. One of the major symptoms is neuropathic pain caused by axonal peripheral neuropathy , 13. To In summary, all the articles and studies included in this Research Topic provide novel insights into diagnosis and disease monitoring, presenting ideas with the potential to improve management of ATTRv amyloidosis.The author confirms being the sole contributor of this work and has approved it for publication.


In the context of the digital economy, achieving rural industrial revitalization in China hinges on digitization. This study delves into the synergistic mechanisms of diverse factors that contribute to Rural Industrial Revitalization across three dimensions: technology, organization, and environment. To investigate these mechanisms, a combination of the necessary condition analysis method and the fuzzy set qualitative comparative analysis method is employed. The research findings indicate that no necessary conditions exist for achieving high-level rural industrial revitalization. However, digital infrastructure and the digital financial environment have a universally significant impact. The study identifies four distinct pathways driving high-level rural industrial revitalization: digitaldriven, digital-government-talentdriven, digital-enterprisedriven, and digital-enterprise-talentdriven. Furthermore, significant variations exist in the driving pathways for rural industrial revitalization among the eastern, central, and western regions of China. By unveiling the multifaceted mechanisms underpinning the revitalization of rural industries, this research provides valuable practical insights for the future development of rural industries in China. Presently, China grapples with a widening urban-rural development disparity, marked by substantial challenges and decline in rural areas. To address these concerns regarding agriculture, rural regions, and farmers ("San Nong" in Chinese), China has implemented the rural revitalization strategy. Recognizing digital infrastructure and digital finance as pivotal and dynamic elements that align with the progress of traditional industries, China actively merges the digital economy with the real economy. This convergence has emerged as a pivotal propeller for China’s pursuit of high-quality economic development . The ChiIn the realm of complex organizational governance, the "configurational perspective" has gained wide recognition as a means to comprehend the intricate causal complexity within organizations . This peThis paper adopts the Technology-Organization-Environment (TOE) framework and employs Fuzzy Set Qualitative Comparative Analysis (fsQCA) to elucidate the complex interplay of multiple conditions behind rural industrial revitalization in the context of the digital economy, addressing the limitations of previous research in explaining these issues. The contributions of this paper are as follows:By adopting a "configurational perspective," the study shifts the focus of RIR research from singular perspectives, such as policy support and technological means, to a holistic view of the interplay between technology, organization, and environment.The introduction of the fsQCA method enriches the methodological toolbox in the field of rural industrial development research. It provides a comprehensive perspective on the complex interactions and causal asymmetry among various conditions involved in its governance, offering a more integrated view.In addition to conducting configurational analysis at the national level, the study also considers geographical and economic differences to analyze the diverse pathways of rural industrial development in China’s eastern, central, and western regions. This exploration is of significant importance for different regional governments in formulating more effective policies in the context of the digital economy.As the digital economy progresses, a plethora of scholars have delved into comprehensive investigations concerning the association between digital infrastructure and rural industries. In relation to the investigation of the correlation between e-commerce and the development of diverse rural industries, rural e-commerce assumes a prominent position as a crucial element within the realm of rural industries. It serves as a catalyst for the rejuvenation of the rural economy and the augmentation of farmers’ income , 8. HoweDigital inclusive finance, which possesses features such as high efficiency, inclusiveness, and low cost, is becoming a new trend in rural financial development. The utilization of digital finance technology can enhance the business processes and risk management capabilities of rural financial institutions, decrease operational costs, elevate service efficiency, and effectively stimulate the prosperity of rural industries . ConsequIn conclusion, the RIR is a multifaceted undertaking. Prior investigations have scrutinized the interplay between digital infrastructure, digital financial environment, and rural industries, underscoring the paramount significance of digital infrastructure and digital finance in the prevailing age of digitization. Nevertheless, the majority of studies have primarily focused on analyzing individual industries or specific factors, neglecting comprehensive research on the holistic impact of rural industries and lacking an in-depth exploration of attribution configurations and diverse driving mechanisms. Furthermore, existing empirical research has predominantly examined causal relationships characterized by symmetry, disregarding the synergistic effects among multiple conditions and asymmetrical causal analysis. Consequently, the phenomenon of differentiation in RIR has not been fully considered. Lastly, owing to the intricate and dynamic nature of RIR, it becomes apparent that alterations in a single factor often yield far-reaching consequences and interact with other factors, giving rise to interconnected outcomes.The Technology-Organization-Environment (TOE) framework, originally proposed by Tornatizky and Fleischer in 1990, serves as a comprehensive analytical tool for technology governance . This frThe TOE theory is a versatile framework capable of encompassing multiple factors and adapting flexibly to various research questions and contexts. Due to its wide applicability, the TOE theory is not limited to use in e-government and e-open systems; it is also being adopted to explore the diffusion of innovative technologies within public organizations. For instance, Tan et al. utilized the TOE theory to analyze organizational behavior and identify the factors influencing the performance of local government websites, taking into consideration technological, organizational, and environmental conditions. Subsequently, they conducted fsQCA configurational analysis using a sample of 31 provincial-level government portal websites in China . TherefoThe initial determinant of RIR is the technological condition, encompassing digital infrastructure. The advancement of digital infrastructure, comprising communication infrastructure, computer infrastructure, data center infrastructure, cloud computing infrastructure, and other associated facilities, assumes a pivotal role in furnishing indispensable technological support for rural revitalization within the digital economy . ThroughThe second factor is the organizational condition, which comprises two sub-variables: digital enterprises and government support . Both diThe third factor is the environmental condition, consisting of two sub-variables: digital financial environment and human resources . The digIn conclusion, the influencing factors of "RIR" are multifaceted and varied. By analyzing the three key elements: technology, organization, and environment, we have identified a strong logical connection among them. Firstly, digital infrastructure plays a vital role in providing organizations with essential services such as information, data, and communication, facilitating efficient sharing of information and resources within the organization. Simultaneously, enterprises can leverage technology to achieve digital transformation, while enhanced infrastructure enables the government to provide more targeted policy support. Secondly, technological advancements require supportive environmental conditions. The digital financial environment offers financial backing for technological development, while the human resources environment contributes high-quality talent for technological progress. It is evident that the advancement of technology relies on critical factors at the environmental level. Lastly, the development of digital enterprises necessitates a stable digital financial environment and an ample supply of human resources. Thus, improving environmental conditions ensures necessary prerequisites for the development of organizational conditions. In summary, the factors influencing RIR are not isolated or simplistic; instead, they form a systemic and intricate framework. The interplay among technology, organization, and environment generates interconnected relationships, propelling RIR in a configurational fashion.The Fuzzy Set Qualitative Comparative Analysis (fsQCA) method is a multivariate statistical technique used to examine causal relationships . It was Sample selection for this study involved selecting 30 provinces of China  as research cases, which meets the requirements for a small sample size in QCA research methods. The selection was made according to the principles of sufficient homogeneity and maximum heterogeneity within the population. The 30 selected provinces have significant differences in rural industry development, which ensures sufficient homogeneity of the case population and maximum heterogeneity within it.The data sources and descriptive analysis are shown in Agricultural development is a fundamental pillar and cornerstone of rural economic progress, and the core of RIR is agricultural development. Rural industries mainly encompass sectors such as plantation, forestry, animal husbandry, and fisheries. Therefore, this study defines RIR in the context of increasing agricultural production, enhancing agricultural value, and boosting agricultural income . BuildinDigital Infrastructure (DI) encompasses the fundamental components that support the digital economy and social development, encompassing computer networks, communication networks, data centers, and related infrastructure. The measurement of digital infrastructure can be approached through multiple indicators. Therefore, in this study, the entropy method is employed to assess and rank the level of digital infrastructure in 30 provinces of China. The evaluation indicators Number of Domains, Number of Web Pages, Internet broadband access ports, Internet broadband access users, Length of long-distance fiber optic cable lines, Mobile Phone Penetration Rate. For a comprehensive description of these indicators, please consult Digital Enterprise (DE) are businesses that leverage digital and information technologies to enhance various aspects of their operations, including management, production, and sales. In this study, the level of digital enterprise development in each province is measured using the proportion of enterprises engaged in e-commerce transactions out of the total number of operating enterprises in that province. Therefore, this indicator serves as an objective measure of the extent of digital enterprise development within a province.Government Support (GS) After reviewing the existing literature, it is apparent that previous studies have mainly focused on measuring for agriculture based on fiscal spending. Therefore, this study employs the ratio of fiscal spending on agriculture, forestry, and water conservancy to the rural population aged six and above, obtained from the 2020 statistical yearbook of each region, as a proxy for government support.Digital Financial Environment (DFE) The degree of development in the digital financial environment can be gauged by the Digital Inclusive Finance Index. This index employs data from the "Peking University Digital Inclusive Finance Index" which is issued by the Peking University Digital Finance Research Center. It serves as a metric to assess the level of development in the digital financial environment across different regions.In terms of Human Resources (HR) level, this study adopts the average years of education as a measurement, based on Fan et al. approach to measuring residents’ digital literacy level . This inIn the fuzzy set qualitative comparative analysis (fsQCA) method, each of the five conditional variables and the result variable of RIR can be considered as a distinct set, with each case having corresponding degree of membership scores. The calibration process involves assigning membership scores to each case set. In this study, we utilized the direct calibration method ,which inThe necessary condition analysis (NCA) method is useful in determining if a set of conditions is necessary in a particular situation and identifying the minimum level of necessary conditions required for a specific outcome based on their effect sizes . Table 5To gain a deeper understanding of the essential factors influencing the outcomes, this study integrates the NCA method with the fsQCA method to conduct a comprehensive analysis of the necessary conditions and determine whether individual conditions are crucial for RIR. A condition is deemed necessary for the outcome if its consistency exceeds 0.9. Based on the findings presented in The analysis of sufficiency focuses on the perspective of influencing factors. If a specific configuration of multiple conditions always leads to a particular result, then that configuration is a sufficient condition for the result, and the set represented by the configuration is a subset of the result. Typically, a consistency threshold of 0.8 is used to select a standard for sufficiency analysis, although this threshold should not be set lower than 0.7 . In thisBased on the Y1 configuration, attaining high-level RIR necessitates improvements in digital infrastructure and the digital financial environment. Strengthening digital infrastructure can expand and deepen information accessibility, allowing rural enterprises to efficiently and intelligently access information from both upstream and downstream sources and reach bottom-level consumers. Concurrently, a robust digital financial environment offers rural enterprises greater opportunities for financing and investment, thus further stimulating rural industrial development and fostering innovation. The enhancement of these two conditions will unlock additional development opportunities and potential for rural industries. The Y1 configuration can explain cases in Anhui, Fujian, Jiangxi, Shandong, and Henan. For example, Henan Province has made significant efforts to advance the development of digital infrastructure, including constructing 12.47 million 5G base stations, resulting in complete 5G network coverage in rural hotspots. In addition, the government in Henan is actively promoting digital inclusive financial services, and the digital economy has grown to reach 1.6 trillion yuan. The ongoing enhancement of digital infrastructure and the digital financial environment has facilitated the integration of rural IoT, which has created new opportunities for digital rural industries.Building upon the Y1 configuration, two additional edge conditions, namely government support and human resources, play vital roles in contributing to RIR. Together with improved digital infrastructure and a favorable digital financial environment, these conditions form a driving pathway for promoting RIR. Government support assumes a crucial role in various aspects, encompassing policy formulation, financial funding, and tax incentives, providing robust guarantees for rural industrial development. Moreover, the government establishes platforms for rural industrial growth, fostering industry integration and coordinated progress. Additionally, the government’s supervision and services ensure the legitimate rights and stable development of rural industries. Regarding human resources, the support of highly skilled talents proves indispensable for RIR. The government can enhance the quality of farmers through training and educational programs, elevating their skills and knowledge to provide robust talent support for industrial development. Furthermore, implementing relevant policies to attract external talents to venture into rural areas not only enriches the talent pool but also facilitates the exchange and inheritance of experience and technology. In Zhejiang Province, for example, rural industry development is heavily reliant on significant financial investment from the government. In 2020, the Zhejiang provincial government invested 37.86 billion yuan in rural informatization funds. With government guidance, the Digital Economy Talent Training and Evaluation (Ningbo) Base was established to meet the talent requirements of the digital age.In the Y3 configuration, the presence of robust digital infrastructure and a sound digital financial environment emerges as crucial factors for RIR. Meanwhile, digital enterprises assume a supportive role, and government support is not deemed a necessary condition for RIR. This suggests that with strong digital infrastructure and a well-established digital financial environment, the development of digital enterprises can still drive RIR even in the absence of financial support from local governments. Sufficient digital infrastructure and a sound digital financial environment provide essential support for rural enterprises, facilitating information acquisition, financing, and investment, thus propelling rural industrial development and innovation. It is worth emphasizing that digital enterprises, as the primary organizational form, act as a significant driving force behind RIR, thanks to their robust financial capabilities and technological expertise. Moreover, the organizational coordination ability of digital enterprises fosters the establishment of industrial and value chains, creating a complete rural industrial ecosystem. Furthermore, through the application of advanced digital technologies and management practices, digital enterprises expedite the digitization and intelligence of rural industries, enhancing production efficiency and product quality. In Shandong Province, the growth of digital-related enterprises has been remarkable, providing robust support for the digital transformation of rural industries in the region. Shandong boasts more than 126,000 digital-related enterprises, the second-highest number in the country. These enterprises have digitized and made intelligent various links in agricultural production, processing, and sal es, thus enhancing production efficiency and quality. The development of digital enterprises has also spurred agricultural technological innovation and rural talent training, augmenting the overall competitiveness and innovation capacity of rural industries in Shandong Province.Building on the Y3 configuration, the incorporation of human resources becomes essential. Rural areas encounter challenges in attracting talent, as highly skilled individuals often prefer to remain in urban centers, resulting in a shortage of talents in rural regions. However, the development of digital enterprises typically necessitates a considerable number of technical professionals, presenting an opportunity for rural areas to entice talent back. The growth of digital enterprises not only offers employment opportunities and developmental platforms for human resources but also relies on exceptional talent as a critical support for their own progress. These highly skilled individuals play pivotal roles within digital enterprises, being responsible for tasks such as technological research and development, innovative design, market expansion, and other crucial areas. By tapping into the potential of human resources and luring talent to return to rural areas, the advancement of digital enterprises contributes not only to RIR but also to the overall development of rural communities. For instance, Guangdong, as an economically developed province, possesses a relatively complete digital infrastructure and digital financial environment, and has the highest number of digital enterprises in the country. This lays a solid foundation and provides support for the digital transformation and development of rural industries, as well as digital solutions and technical support. Moreover, Guangdong has been consistently strengthening the development of rural talent and has implemented policies such as the "Work Plan for Rural Revitalization Assistance by Stationed Personnel in Guangdong Province." This involves sending technology experts to assist in rural revitalization and selecting agricultural science and technology personnel to be stationed in rural areas to provide targeted assistance.There are various methods for conducting robustness tests in fsQCA research. When the results of the robustness test have a subset relationship with the original results, it indicates that the results are robust. In this study, robustness tests were conducted by changing the consistency threshold to 0.85 and 0.75, respectively. The consistency threshold was also increased from 0.8 to 0.85. The results of both analyses were consistent with the original results, confirming the reliability of the research findings.The vast expanse of China’s territory and the diverse distribution of economic development and resources lead to significant regional disparities in the development of the digital economy, technological infrastructure, and organizational applications. In addition, the institutional environment in various regions can significantly influence the development of rural industries. To tackle this problem, this research divides the sample data into three major economic zones in accordance with China’s "Seventh Five-Year Plan" (1986–1990): eastern, central, and western China. Through a comparison and analysis of the effects of technology, organization, and environmental conditions on RIR in each region, this study aims to examine the differences in the impact of RIR across different regions, providing valuable insights for policy formulation. The findings of this study are presented in In the eastern region, path E1 is characterized by the digital financial environment as its core condition, whereas the absence of digital enterprises serves as its core absence condition. Paths E2 to E4, on the other hand, share the core condition of DE and the core absence condition of human resources. The developed economy and high level of digitalization in the eastern regions of China allow for the promotion of RIR, even in the absence of digital enterprises. This is made possible through a combination of government support and improvements to the digital financial environment; Digital enterprises play a critical role in the RIR, facilitating their development even in the absence of government support and human resources. Digital enterprises play a pivotal role in facilitating the growth of rural industries by providing access to state-of-the-art digital technology and robust network platforms that connect them with markets. Additionally, with support from digital finance, these enterprises offer specialized technology and industry chains, enabling rural industries to upgrade their operations and increase their competitiveness. Hence, policymakers in the eastern region ought to augment policy support and promote the guidance and encouragement of more enterprises to invest in the advancement of digital rural industries.In the central region, path M1 reveals that the region lags behind the eastern region in terms of economic development, digitalization, and talent attraction. Despite this, achieving high-level RIR is still feasible through other crucial factors, even without government support and human resources. In the central region, digital enterprises and the digital financial environment are not essential conditions for RIR, implying significant room for growth and development in these aspects. digital infrastructure is a core existing condition in the central region, indicating that the region has a solid foundation in DI, which provides crucial support for the growth and development of digital enterprises and digital finance. In conclusion, the central region should augment investment and policy support in digital enterprises and the digital financial environment, and capitalize on the benefits of digital infrastructure to boost digitalization and talent acquisition. This approach can foster economic development and industrial upgrading.In the western region, there are two high-level  configuration paths for RIR, both of which require DI, DE, and DFEs. Due to harsh natural conditions, sparse population, poor transportation, and backward agricultural technology, rural economic development in the western region faces many challenges. Therefore, improving DI is essential for promoting RIR. The western region is characterized by economic underdevelopment and a relative lack of digital technology. Additionally, due to its vast size and sparse population, the region experiences significant talent loss, which further impedes the development of rural industries. The Chinese government has been addressing these challenges by gradually increasing investments in DI, aimed at promoting the development of the digital economy and creating a new pattern of western development. When promoting the RIR, it is crucial to take into account the conditions in the economically under developed western region. Therefore, increasing investment in DI and digital enterprise development, as well as providing stronger supervision and support for the DFE, is essential to address these challenges. Encouraging all parties to actively participate in the development of the digital economy is also crucial. These measures can effectively promote the RIR in the western region and facilitate sustainable development of the rural economy.It can be observed that the core conditions from Configuration 1 to Configuration 4 all involve digital infrastructure and the digital financial environment, both of which play a universal role in achieving high-level RIR. The digital financial environment is closely related to the level of digital infrastructure, and the two mutually influence each other. The development of digital infrastructure provides the conditions for the modernization transformation of rural industries and lays the foundation for the development of the digital financial environment . With imHuman resources, as a core prerequisite for innovation, play a crucial role, as well-educated talents actively participate in innovative activities . High-leIn rural development, the government plays a pivotal role; however, research indicates that government-led rural construction has certain drawbacks that can negatively impact rural development . As suchThis study has made several significant contributions to the field of RIR in China. Firstly, unlike many previous studies that focused on exploring the net effects of various potential factors on rural industrial development, this research goes beyond the net effect approach . It recoBy employing a combination of fsQCA and NCA methods, we have effectively identified and distinguished the sufficiency and necessity causal relationships in the context of RIR. Unlike traditional regression analysis, which primarily identifies sufficient conditions for outcomes, this research incorporates necessary analysis to identify the essential factors determining the outcomes. The integration of both approaches was advocated by Fainshmidt, the editor-in-chief of the International Business Journal, as a means to explore complex causal relationships. Therefore, this paper contributes to the advancement of research on the necessary and sufficient relationships among the influencing factors of RIR in the context of the digital economy.In addition to conducting a configurational analysis at the national level, this study also takes into account geographical and economic differences to analyze the diverse pathways of rural industrial development in the eastern, central, and western regions of China. This provides valuable practical implications for policymakers in regions at different stages of development. The universality demonstrated by digital infrastructure and the digital financial environment at the national level highlights the critical significance of developing digital rural areas for industrial growth in the current digital economy context. However, the relatively superior economic development in the eastern region compared to the western region, along with its more advanced digital infrastructure and digital financial environment, necessitates a greater focus on other factors to achieve RIR . This isCommencing with path configurations, the "digitaldriven" trajectory necessitates a focus on enhancing digital rural infrastructure and digital finance to propel rural digitalization. Concurrently, harnessing digital financial platforms can facilitate the attainment of RIR. By fostering the digital advancement of rural industries within the context of digitalization, significant opportunities and revitalization prospects will undoubtedly ensue for rural industrial development. In the "digital-government-talentdriven" configuration path, the government should augment investments in rural education, thereby enhancing the learning environment and educational resources available to rural youth. Moreover, implementing pertinent policies to incentivize high-quality talents to participate in entrepreneurial activities and seek employment opportunities in rural areas is essential. Furthermore, the integration of top-notch research teams and skilled professionals into rural regions can foster the convergence of technological innovation and industrial development. In the "digital-enterprisedriven" configuration path, the emphasis should be on the pivotal role of digital enterprises, harnessing their digital technologies and innovative management practices to propel the digital transformation of rural industries. In the "digital-enterprise-talentdriven" configuration path, the leadership role of digital enterprises should be fully harnessed, relying on the support of high-quality talents to propel the development of rural industries. Emphasizing talent recruitment and development is essential, as high-quality talent plays a pivotal role in the growth of digital enterprises. Thus, enterprises must bolster their efforts in talent cultivation and recruitment to attract exceptional individuals and contribute to the RIR.From the perspectives of different regions, the analysis of China’s eastern, central, and western regions reveals significant disparities in their paths toward RIR. Consequently, local governments should consider their respective economic development levels and resource endowments when determining strategies for RIR. In the eastern region, leveraging its existing advantages, there should be encouragement for more enterprises to invest in the development of rural digital industries. For the central region, the focus should be on enhancing the construction of digital financial environments to provide rural enterprises with increased opportunities for financing and investment. Additionally, utilizing the existing digital infrastructure can facilitate rural enterprises in accessing market information more intelligently and conveniently, thereby promoting their digital transformation and upgrading. As for the western region, which is at a relatively backward stage, increased investment in digital infrastructure and the development of digital enterprises is essential to bridge the digital development gap. Strengthening supervision and support for digital finance is crucial to ensure the stable development of the digital financial environment. Simultaneously, encouraging active participation from social organizations, governments, and enterprises in rural digital development can effectively implement China’s Western Development Strategy.This article applies the TOE framework and employs the fsQCA method to analyze the path of grouping in 30 Chinese provinces . The study explores the "joint effect" of different groupings formed by five factors on the RIR and analyzes the key paths affecting the RIR through multiple combinations. The main research conclusions are as follows: first,from an individual variable standpoint, none of the five influencing factors can be deemed a necessary condition for achieving high-level RIR. Second, based on distinct combinations of core conditions, the paths to attaining high-level RIR can be categorized into four types: digital-driven, digital-government-talent-driven, digital-enterprise-driven, and digital-enterprise-talent-driven. These four configuration paths signify that high-level RIR emerges from the collaborative efforts of multiple factors, all aiming towards the common objective of revitalization. Among these paths, digital infrastructure and digital financial environment serve as core conditions found in all four, highlighting their universal role in facilitating high-level RIR. Third, significant disparities exist in the driving paths of RIR across the eastern, central, and western regions of China. Within the eastern region, the path led by organization primarily hinges on digital enterprises serving as the core condition. In the central region, the path led by technology primarily relies on digital infrastructure as the core condition. As for the western region, the path led by technology-organization-environment primarily depends on digital infrastructure, digital enterprises, and digital financial environment as the core conditions. These discernible variations in paths across different regions further elucidate the diverse conditions contributing to the varying levels of high-level RIR.This study has several limitations that warrant consideration. Firstly, the dataset used in this research is limited to data from a single year, and it lacks cross-year case data. Consequently, the temporal dimension of the research findings may be constrained in terms of explanatory power. Future studies could enhance the robustness of the research by incorporating multi-year data for dynamic quantitative analysis.Secondly, the structural comparison method of fsQCA serves as a methodological bridge between qualitative and quantitative approaches, providing a systematic framework to examine the complex causality within cases and explore the interrelationships among cause-related variables. However, it is imperative to acknowledge that the method is still evolving, and it has faced critique regarding data calibration and the potential reduction of nuanced insights and richness inherent in qualitative data. Therefore, future scholars should diligently address and optimize these controversies to advance the application and effectiveness of the fsQCA method in research endeavors.