Sustained injudicious and indiscriminate use of antimicrobials has exerted selection pressure for developing antimicrobial resistance (AMR), requiring behaviour change from healthcare professionals (HCPs) based on their knowledge, attitudes and practices (KAP) on antimicrobials, AMR and antimicrobial stewardship (AMS).A cross-sectional online questionnaire-based survey was conducted nationally amongst doctors, pharmacists and nurses from November 2017 to January 2018. The questionnaire comprised demographic information and KAP questions.Respondents comprised of 1120 doctors, 744 pharmacists and 659 nurses. Antimicrobial resistance was considered a severe problem globally and nationally by majority of HCPs. Self-assessment of knowledge revealed gaps in understanding of antimicrobials, AMR and AMS. Confidence scores in prescribing by doctors, pharmacists and nurses were 57.82%, 32.88% and 45.28%, respectively. Doctors, 441 (45.2%) indicated no confidence in using combination therapy. Prescribing correctly showed a confidence level of 33.99% from 436 doctors, 41.88% from nine pharmacists and 35.23% from 107 nurses. Healthcare professionals (1600 [91.22%]) stated educational campaigns would combat AMR. Only 842 (40.13%) HCPs attended training on these topics and 1712 (81.60%) requesting more education and training.This is the first comparative survey on KAP of practising doctors, pharmacists and nurses in South Africa. Doctors had the highest knowledge score followed by nurses and pharmacists. Practice scores did not corroborate knowledge and the higher attitude scores. Gaps in KAP were evident. Healthcare professionals indicated the need for more education and training, thus requiring a review of pre-service and in-service education and training in addition to continued professional development programmes for practising HCPs. Of these, strategic objective 1 is increased awareness of AMR through effective communication, education and training.2 Education for all HCPs on antimicrobial prescribing needs to begin at undergraduate levels, and should continue in post-graduation with specific training in using treatment guidelines.5 The range of antimicrobial prescribers has been changing, with legislation allowing nurses, pharmacists and emergency care personnel to prescribe antimicrobials under certain conditions in South Africa (SA).8 Healthcare professionals are responsible for managing antimicrobials, namely prescribing, dispensing and administering antimicrobials to patients. They must be knowledgeable and up-to-date on issues related to antimicrobials, AMR and antimicrobial stewardship (AMS). This study therefore ascertained the knowledge, attitudes and practices (KAP) of doctors, pharmacists and nurses in order to identify gaps for educational intervention.This would be achieved by each member state implementing interventions to: (1) increase national awareness of AMR via programmes that target the different audiences in human health, animal health and the environment, (2) incorporate AMR as a core component in professional education, training and certification, (3) incorporate antimicrobial use and resistance into the school syllabus to improve understanding and further awareness with all information being accurate and relevant, (4) prioritise AMR as an important health issue requiring urgent action from all governmental departments and (5) create a multisectoral committee to address AMR from a One Health perspective.A descriptive cross-sectional online survey was conducted nationally. Study sample included 15 111 (40.77%) pharmacists, including community-service pharmacists registered with the South African Pharmacy Council (SAPC). There were also 16 260 (43.87%) doctors and 5695 (15.36%) nurses, comprising of 5630 registered nurses and 65 enrolled nurses, who subscribed to Medpages, an SA database with contact information of HCPs in SA. The SAPC provided contact information of pharmacists and community-service pharmacists to the principal investigator, which was used to email the survey questionnaires. Medpages distributed the survey questionnaire to all doctors and nurses on their database. The study was undertaken from November 2017 to January 2018.The data were collected using a self-administered, web-based questionnaire with voluntary informed consent.12 Responses were anonymous. Questionnaire was divided into four sections and consisted of open-ended, closed-ended (yes or no) and Likert style questions .Questionnaire  was adapThe first section collected demographic, academic and professional data of the participants.Second section consisted of questions that assessed the participants’ knowledge on antimicrobials, AMR and stewardship, contributing factors to AMR, sources of information and confidence in prescribing antimicrobials. Third section evaluated the participants’ attitudes and beliefs on antimicrobials, AMR and their contribution to AMR. Final section was practice-related and involved antimicrobial sensitivity-testing, empiric-prescribing, use of standard treatment guidelines (STGs), advice imparted to patients and prescribing for diagnosed medical conditions.t-test or Wilcoxon test as appropriate. Categorical variables, such as groups, were described as proportions and compared using Chi-square test or Fisher’s exact test as appropriate. The analysis of variance (ANOVA) statistical test was used to compare the KAP scores between the three professions, and the Bonferroni post-hoc test further described the pairwise statistically significant difference between the professions. For each factual question, a mark was allocated when the answer was correct. Other questions were assessed and given a mark for the most appropriate correct response. Responses for ‘strongly agree’ and ‘agree’ were combined as well as for ‘disagree’ and ‘strongly disagree’. The study population had declined from Section 1–4 of the questionnaire, thus completed sections were analysed separately. Partially completed questionnaires were also considered, hence the different ‘n’ values per section. The South African STGs were used to assess doctors and nurses’ choices of antimicrobial treatment for given medical conditions and the primary care drug treatment (PCDT) list was used to assess pharmacists’ choice of antimicrobial treatment in Section 4 of the questionnaire.Dataset was analysed using IBM Statistical Package for the Social Sciences (IBM SPSS) version 25  using simple descriptive statistics to create frequencies and percentages. Continuous variables, such as ages, were described as mean ± standard deviation or median and compared using the Student’s Ethical approval was obtained from the Humanities and Social Sciences Research Ethics Committee of University of KwaZulu-Natal (HSS/0868/017M) prior to the study.Total number of respondents in this study was 2523 (6.81%) HCPs, consisting of 1120 doctors, 744 pharmacists and 659 nurses with response rates of 6.89%, 4.92% and 11.57%, respectively. There were 1520 (60.25%) females and 1003 (39.75%) males. The modal-age groups were 31–40 years (30.71%) for doctors, 21–30 years (30.24%) for pharmacists and 51–60 years (36.87%) for nurses. Amongst nurses, 392 (59.48%) possessed a diploma qualification. A greater proportion of HCPs, that is 1843 (73.05%), occupied jobs in urban areas whilst the number for those in rural areas was 306 (12.13%). Most HCPs, 1205 (47.76%), worked in private practice and 792 (31.39%) worked in public .p = 0.002) with nurses being least aware. Similar numbers of HCPs agreed it was a national problem. However, much lower number of HCPs (73.77%) agreed AMR was a serious problem in their hospital or practice and there was a statistically significant difference between them (p = 0.011).The majority of HCPs (93.37%) perceived AMR to be a serious problem globally . Using ap = 0.0001, 0.00001 and 0.009, respectively). A Bonferroni post-hoc test indicated that doctors were different from nurses and pharmacists were different from nurses, however doctors and pharmacists were not statistically different.The self-assessment of knowledge indicated that 791 (37.70%) HCPs were 75% confident of their knowledge on all three topics with 349 (16.6%) HCPs showing 100% confidence . Notablyp = 0.000), and a majority of HCPs correctly stated common colds are caused by viruses  were noted between the three groups of HCPs in seven of the nine contributing factors.Healthcare professionals identified the overuse of antimicrobials by prescriptions , patient pressure for antimicrobial prescriptions  and non-adherence of patients to prescribed treatment  as most contributory towards AMR, as depicted in p < 0.05) were noted between the three groups of HCPs in eight aspects of prescribing.Self-assessment on confidence in 10 aspects of prescribing antimicrobials showed 587 (60.21%) doctors were confident in 7 (70%) aspects. No confidence was reported by 433 (44.40%) doctors about using combination therapy when necessary, about when to stop or streamline therapy according to clinical evaluations and investigations and about making decision not to prescribe antimicrobials when there’s fever with no serious criteria . A totalThe most preferred sources of information on appropriate use of antimicrobials for doctors were STGs  followed by South African Medicines Formulary (SAMF) . The pharmacists preferred the SAMF  and STGs , whilst nurses used STGs  and indicated equal usage of the SAMF and WHO guidelines .A majority  of HCPs agreed that there were risks associated with the irrational use of antimicrobials, most noted risks being AMR , side effects  and adverse drug reactions . Only 842 (40.13%) HCPs had attended any workshops or training on antimicrobials and AMS.A total of 1712 (81.60%) HCPs requested more education and training on antimicrobial use, AMR and AMS.p < 0.05), with the knowledge scores being 65.74%, 60.07% and 60.14%, respectively.There was a statistically significant difference in total knowledge of antimicrobials, AMR and AMS between the three groups of HCPs. Using the Bonferroni post-hoc tests, it was observed that doctors scored significantly higher than both the pharmacists and nurses , pharmacists  and nurses  disagreed that antimicrobials were safe drugs that could be commonly prescribed. Majority  agreed that prescribing antimicrobials to patients who did not really need them, would ultimately have a negative impact on their health.p < 0.05) were observed for two strategies , use of therapeutic guidelines  and improved infection control . Vaccination campaigns  were surprisingly reported to be least important. Statistically significant differences (rategies .p = 0.000). A total of 545 (63.4%) doctors, 221 (42.9%) pharmacists and 126 (33.2%) nurses believed they personally contributed towards AMR in some form (p = 0.000).Varying numbers of HCPs – 600 (69.8%) doctors, 414 (80.4%) pharmacists and 323 (85.0%) nurses – believed skipping or missing a dose or two of antimicrobials contributed to the development of AMR and this difference was statistically significant (p = 0.013). Using the Bonferroni post-hoc analysis, doctors and pharmacists scored statistically higher than nurses (p = 0.014).With respect to attitude towards antimicrobials, AMR and AMS, using a one-way ANOVA, there was a statistically significant difference between doctors, pharmacists and nurses with attitude scores of 68.71%, 68.59% and 65.94%, respectively  prescribed antimicrobial drugs. In this study, 82 (16.50%) pharmacists and 33 (8.89%) nurses prescribed antimicrobials without a licence. Majority of antimicrobials were prescribed by doctors.Only 22 (4.43%) pharmacists possessed Section 22A (15) permit, which allowed them to prescribe for PCDT, of which only 16 (3.22%) pharmacists prescribed antimicrobial drugs. Almost a third of nurses  possessed the concession permit in terms of Section 22A (12) of the p = 0.000). Four hundred and forty-one (52.38%) doctors, seven (1.41%) pharmacists and 83 (22.37%) nurses sent samples for microbiology testing before initiating antimicrobials. Only 496 (58.90%) doctors, 349 (70.22%) pharmacists and 185 (49.87%) nurses possessed the latest South African STGs (p = 0.000). However, only 197 (23.40%) doctors, 42 (8.45%) pharmacists and 66 (17.79%) nurses always used the STGs (p = 0.000).Six hundred and seventy-eight (80.52%) doctors, 19 (3.82%) pharmacists and 61 (16.44%) nurses prescribed antimicrobials empirically (p < 0.00).Advice imparted to patients on antimicrobial use is reported in p < 0.05).Based on a range of practice scores, between 0 (poor) and 100 (best practice), average scores for doctors, pharmacists and nurses were 57.68% ± 16.42%, 43.14% ± 16.53% and 54% ± 14.34%, respectively. Using an ANOVA test, practice scores for the three groups of HCPs were statistically significantly different (There was a higher percentage of appropriate treatment (41.88%) provided by nine pharmacists compared to 33.99% from 436 doctors and 35.23% from 107 nurses. However, there were fewer pharmacists who were eligible to provide treatment for the given conditions. It must be noted only 1.87% of nurses provided the correct strength, interval and duration for treatment.To our knowledge, this is the largest national study ascertaining KAP on antimicrobials, AMR and AMS amongst prescribers, dispensers and administrators of antimicrobial medicines to patients. This is the first KAP study amongst doctors, pharmacists and nurses in SA using the same tool and it provides valuable insights and information on strengths and weaknesses of KAP amongst HCPs and indicates areas where interventions are required.13 Awareness of AMR is the first step in addressing and reducing this global problem.2 We found that majority of HCPs in SA have been sensitised to AMR as a national and global concern, with doctors having most awareness followed by pharmacists and then nurses who had the least conceptual awareness. However, as a group, HCPs’ awareness of AMR was comparable to a study by Burger et al. (2016), in which final year pharmacy students in SA reported 97.7% awareness to AMR as a global problem.14 Our HCPs’ national awareness of AMR was similar to the studies by Vaillant et al. (2019), where French HCPs reported 93% national awareness of AMR, and Farley et al. (2018), where 95.8% of primary care prescribers in SA stated AMR was a national problem.16Antimicrobial resistance is an increasingly serious public health threat.15 Our research findings with respect to AMR awareness amongst HCPs are similar to Wasserman et al. (2017), who reported that 87% of final year medical students in SA agreed AMR was a global problem and only 61% saw it as a problem in their practice.17 Similar results were reported in other studies by Pulcini et al. (2010), where there was 95% national awareness with 63% local awareness for AMR by junior doctors, and Garcia et al. (2011), who reported 97% global and national awareness with 73% local awareness by prescribing doctors.18 However, our local awareness results contrasted with the study by Salsgiver et al. (2018) where it was reported that majority (89%) of prescribers in the United States agreed AMR was a problem at their hospitals and prescribers actively supported AMS programmes at all hospitals.19The appreciation of the problem of AMR in context of their own work showed there was a much lower awareness of AMR in their hospitals or practices. This being stated, our findings showed higher awareness at practice level compared to the study by Vaillant et al. (2019), who reported 51.5% of French HCPs had awareness of AMR at practice level.20 Several aspects must be comprehensively considered when prescribing antimicrobials and complete confidence in each aspect is essential in achieving positive patient outcomes. In this study, diminished levels of confidence in the 10 aspects of prescribing antimicrobials were observed, with 587 (60.21%) doctors confident in only seven aspects. A third of pharmacists stated confidence in all aspects whilst almost a quarter of the nurses were not confident in prescribing. Wasserman et al. (2017) reported that only a third of the students were confident in prescribing.17 Our results are also similar to findings by Pulcini et al. (2010), where it was found junior doctors in France and Scotland shared similar overall confidence (57.61%) in prescribing antimicrobials to that of our doctors (57.82%).9Based on their self-assessment, only 16.6% of HCPs were 100% confident in their knowledge of antimicrobials, AMR and AMS. The percentage of HCPs that had 75% confidence in their knowledge of antimicrobials and AMR, respectively, was 43% and 37%. This is in contrast to the report by Dall (2019) whereby 80% of HCPs from 30 European countries stated they possessed sufficient knowledge on correct antimicrobial use and 96% stated having knowledge of AMR.14 This was confirmed by Farley et al. (2018) where numerous prescribers requested more education on appropriate antimicrobial use and in Wasserman et al. (2017) where medical students wanted more education to aid in antibiotic prescribing.17 On the safe use of antimicrobials, close to two-thirds of HCPs indicated an awareness that in general antimicrobials are safe, however continuous use without due regard can have undesired effects. Majority of HCPs indicated that there could be negative effects on patients if antimicrobials were unnecessarily prescribed. The latter finding was supported by Burger et al. (2016).14Forty per cent of HCPs had attended or received training on antimicrobials and AMS with majority (81.61%) indicating a need for more education and training. Our research findings are similar to those reported by Burger et al. (2016) whereby only 37.75% of pharmacy students had training on AMS and 90% needed more training.14 A similar observation was made by Wasserman et al. (2017), who reported inappropriate use of antimicrobials (> 95%) as the primary cause of AMR.17. Similar findings were also reported in other studies by Pulcini et al. (2010) in France and Scotland, where > 90% of the junior doctors selected over-prescription of antimicrobials as being causative; Abera et al. (2014) in Ethiopia, where the nurse prescribers and doctors stated poor patient adherence (86%) and overuse of antimicrobials (80.5%) were responsible for AMR; and Dyar et al. (2014) in Europe, where final year medical students reported over-prescription of antimicrobials (> 95%) resulted in AMR.21Numerous contributing factors result in AMR. In this study, the leading causes identified by majority of HCPs were: over-prescription of antimicrobials, patients’ non-adherence to treatment and patient pressure for antimicrobial treatment. Burger et al. (2016) similarly reported widespread and overuse of antimicrobials (94.2%) and poor patient adherence to medication (89.5%) as contributing to AMR.17 The important strategies chosen for combatting AMR by majority of HCPs were educational campaigns (91.22%) and usage of therapeutic guidelines (84.72%). This finding was similar to Burger et al. (2016) who reported that education on antimicrobial therapy (92.3%), antimicrobial usage policies (86.9%) and development of treatment guidelines (86.2%) would combat AMR.14 Interestingly only 60.2% of HCPs were in possession of the latest South African STGs and only 17.8% always used it.According to our research, the most appropriate resources for antimicrobial selections were STGs, SAMF and international guidelines, respectively. This is in contrast to Wasserman et al. (2017) who reported that medical textbooks (87%), registrars (85%) and consultants (83%) were most common learning resources.Attitude scores amongst all professions were slightly higher than knowledge scores and practice scores were the lowest. The doctors and pharmacists indicated higher attitude scores than nurses. Doctors obtained the highest knowledge scores. Practice scores did not corroborate the self-proclaimed knowledge and attitude scores.Gatekeeper permission to contact the HCPs proved problematic. The Protection of Personal Information Act (POPI) precluded access to the databases of the Health Professions Council of SA. The SA Nursing Council and Forum of University Nursing Deans of SA could not assist. The survey was conducted from November 2017 to January 2018, which is a festive period in SA, resulted in reduced participation from professionals.Participation was voluntary, and, combined with the above constraints; the response rate was relatively poor.n’ values for different sections.The results should thus be extrapolated to the wider HCP community with caution. Not all the questionnaires were fully completed resulting in different ‘This is the first comparative survey on KAP of practising doctors, pharmacists and nurses in SA. Doctors had the highest knowledge score followed by nurses and pharmacists, respectively. Practice scores did not corroborate knowledge and the higher attitude scores.22Self-assessment of knowledge showed that marginally more than half (< 55%) of HCPs were ≥ 75% confident in their knowledge on these topics. Confidence on prescribing antimicrobials showed that < 60% of doctors were confident in prescribing antimicrobials, with the confidence level even further reduced for pharmacists and nurses. Confidence in prescribing the correct treatment for given conditions ranged between 34% and 42% for the HCPs. Gaps in KAP were thus evident. Healthcare professionals indicated the need for more education and training, thus requiring a review of pre-service and in-service education and training in addition to CPD programmes for practising HCPs. It is recommended that both higher education institutions offering medical, pharmacy and nursing degrees as well as professional bodies regulating this education should map and update their existing curricula and scopes of practice, respectively, against the World Health Organization’s competency framework and associated curriculum for healthcare workers’ education and training on AMR.


The life and work of Heather K. AllenOctober 24, 1980 – March 7th, 2020Exposure, Risks, and Drivers of the Mobile Antimicrobial Resistance Genes in the Environment—a Global Perspective.”In 2010, Dr. Heather K. Allen published a foundational review paper on the emerging field of environmental antibiotic resistance. “Call of the wild: antibiotic resistance genes in natural environments”  bacteria and antibiotic resistance determinants (ARD) through the soil and water can lead to a seemingly endless web of interconnected public health consequences and the environment. While we, generally, are aware of the many sources of AMR, we still don't understand the environmental fate and ultimately the public health consequences of AMR bacteria. The goal of this Research Topic is to present current research on the source of AMR from both anthropogenic and animal sources, elaborate on the potential movement through the environment, and present new approaches to surveying for AMR and ARD.E. coli at swine farms  to whole genome sequencing of common foodborne pathogen indicator species, such as vancomycin resistant Enterococcus spp. . Poultry production in Brazil is covered by original research demonstrating extended spectrum beta lactamase producing E. coli in samples through production and the immediate food production environment . On farm anaerobic treatment of manure and effects of wastewater treatment plants on ARD and their surveillance were investigated by Agga et al.; Majeed et al., respectively. Surveillance of ARD and AMR bacteria utilizing metagenomics is a highly sought-after topic, particularly while trying to understand the context of baseline levels of these pollutants in the environment. Finally, we have near retail meat products destined for human consumption and potential for AMR exposure , and review of the current literature summarizing antibiotic resistance genes in animal manure and potential fate following land application.The human and animal sources of AMR have long been tied to spread to the environment. Long considered a major source for environmental pollution, these respective sources are key control points in the reduction of AMR in the environment. Animal feeding operations and municipal wastewater treatment plants are considered “ideal” milieu for promoting the proliferation of AMR and selection and exchange of ARD. In the current special section, we have gathered international contributions from teams working on the presence of AMR in the environment, with those focusing on farm and wastewater treatment plants. While foodborne bacterial pathogens are typically investigated, and rightly so, we have papers focused on commensal bacteria as well. We have gathered papers covering the diversity of gene cassettes in commensal Yang et al.). We have also gathered similar research in an urban watershed impacted by wastewater treatment plant recharge . These two studies focused on the targeting of ARD in the environment. A method to control surface runoff is irrigation return flows, however return flows are known to harbor high levels of contaminants and bacteria. A study by Dungan and Bjorneberg investigated E. coli and enterococcal AMR profiles in return flows.One primary interface between the public and AMR bacteria is in watersheds and surface freshwater. Manure and wastewater treatment by products are often disposed of in pasture and row crop fields which are buffered by surface water bodies. One process that drives AMR bacteria and ARGs from manure is via rain associated runoff. In the current special section, we have an article covering the effect of long-term pasture management on ARD in runoff  to find the existing and novel ARGs and MGEs for future AMR work . For instance, swine manure application to agricultural soil can introduce diverse set of tet resistances genes into low tet resistance agricultural soil. One of the major concerns after manure or wastewater application to agricultural soil is the dissemination of chemicals of emerging concern (CEC) through the food chain. This was observed when 11 fosfomycin-resistant Citrobacter freundii strains from 270 samples were identified from flowers and the retail environment . The authors noted that these isolates were multidrug-resistant, and most were simultaneously resistant to fosfomycin, cefotaxime, ciprofloxacin, and amikacin, therefore potentially posing a public health threat to workers. It is interesting to note that there is a high prevalence of widespread acquired resistance genes among bacteria such as Enterococcus strains exposed to anthropogenic antibiotic pressure in the environment . However, they noted that E. faecium strains in their dataset were found within the same host species or environmental origin, confirming the previous findings that E. faecalis from the same ST can be found in human as well as in other animal species, while E. faecium strains tend to be host specific . These authors suggested that successful reuse of wastewater in agriculture will depend on appropriate mitigation and management strategies to guarantee safe water supply. In an integrated study to understand factors influencing the occurrence, distribution, and fate of antibiotic resistance genes in vegetable production systems, Wind et al., suggested that pre-harvest and potentially post-harvest interventions may be warranted to minimize risk of propagating antibiotic resistance in the food chain. They demonstrated a holistic approach as the best options to identifying key control points for the propagation of ARGs in vegetable production systems, identifying potential ARG-MGE combinations that could inform future surveillance. They suggested that agroecosystems are a key reservoir of antibiotic resistance and appropriate mitigation strategies are needed to limit potential for ARGs to spread and negatively influence human and animal health.In the broad environment, livestock manure application to cropland for soil fertility presents a concern that ARG and bacteria may proliferate and be transported in the environment (All told, this special section covers a wide swath of research from AMR and ARD in wastes and products derived from both human and animal sources, and their potential movement through the environment, ultimately culminating in potential public health consequences.JB, LD, and AI were involved in the conception, execution, and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The calculated permeability coefficients of the neural retina were as follows: ganciclovir, 33.89 ± 12.64; brimonidine, 29.83 ± 11.58; bevacizumab, 0.0205 ± 0.0074 (×10−6 cm/s). Between brimonidine and ganciclovir, lipophilic brimonidine presented better RCS and CS permeability, whereas ganciclovir showed better calculated neural retinal permeability. The large molecular weight drug bevacizumab demonstrated a much lower permeability than brimonidine and ganciclovir. In conclusion, the ophthalmic drug permeability of RCS and CS is affected by the molecular weight and lipophilicity, and influences the intravitreal half-life.In this study, Retina-RPE-Choroid-Sclera (RCS) and RPE-Choroid-Sclera (CS) were prepared by scraping them off neural retina, and using the Ussing chamber we measured the average time–concentration values in the acceptor chamber across five isolated rabbit tissues for each drug molecule. We determined the outward direction permeability of the RCS and CS and calculated the neural retina permeability. The permeability coefficients of RCS and CS were as follows: ganciclovir, 13.78 ± 5.82 and 23.22 ± 9.74; brimonidine, 15.34 ± 7.64 and 31.56 ± 12.46; bevacizumab, 0.0136 ± 0.0059 and 0.0612 ± 0.0264 (×10 The advancement of ophthalmic drug delivery to the posterior segment requires extensive knowledge of intraocular pharmacokinetics (PK). Representative intraocular PK parameters, such as intravitreal half-life, mean residence time, observed maximum concentration, and clearance rate, were considered as the substantial indicators of drug efficacy ,2. Thus,Since retinal permeability is crucial for intraocular pharmacokinetics and dynamics, numerous experiments have been conducted previously, which found that RPE drug permeability was largely affected by molecular physicochemical properties such as molecular weight (MW) and lipophilicity ,13,14. TThus, the purpose of our study was to provide systematic data on the pre-clinically measured permeability coefficients in posterior segment tissues, and to help clinicians and researchers to assess the intraocular pharmacokinetics of three substantial drug compounds being investigated and engineered for the advancement of ocular drug delivery systems. Prior investigations concentrating on the retinal permeability and its effect on intraocular PK parameters have not been adequate, especially the measurement or calculation of the experimental values. Therefore, in this study, we experimented with three ophthalmic drugs, including ganciclovir, brimonidine, and bevacizumab, to evaluate retinal and RPE-choroid-sclera permeability from the vitreous to the systemic blood circulation (outward direction) in New Zealand white rabbit eyes. As mentioned above, both ganciclovir and brimonidine are small molecular weight drugs, and sustained-release intravitreal implants have been developed. Bevacizumab is a representative large molecular weight anti-VEGF drug that has been applied to various retinal diseases. Then, together with seven different small drug molecules studied in previous literature, we analyzed the association between intravitreal half-life and retinal permeability in various ophthalmic drugs.Approval was obtained from the Seoul National University Bundang Hospital Institutional Animal Care and Use Committee, and animal experiments were conducted in accordance with the guidelines of the Association for Research in Vision and Ophthalmology for animal use in research.A total of 30 eyes from 15 healthy New Zealand white rabbits weighing 1.5–2.0 kg and aged 8–10 weeks were used for the study; five eyes each for the three ophthalmic drugs  with two different ocular tissues (retina-RPE-choroid-sclera and RPE-choroid-sclera). The rabbits were anesthetized with 15 mg/kg tiletamine hydrochloride/zolazepam hydrochloride  and 5 mg/kg of xylazine hydrochloride , and the rabbit eyes were enucleated immediately after euthanization and stored in ice-cold Ringer buffer until use. We then removed the adherent muscles and fats on the outer sclera, divided the anterior and posterior segments by circumferential cutting behind the limbus, and gently separated the lens and vitreous from the neural retina to obtain retina-RPE-choroid-sclera tissues. Finally, we carefully detached the neural retina using forceps to obtain RPE-choroid-sclera tissues. Isolated tissues were stored in phosphate-buffered saline . To minimize the damage to tissue integrity, the extracted tissues were used immediately.2 which was enclosed with micropore membranes , and mounted in the Ussing chamber . Both sides of the chamber  were filled with 4 mL of PBS solution, with drug concentrations of ganciclovir and brimonidine  dissolved at 0.244 mg/mL, and bevacizumab  at 4.469 mg/mL on the donor side. Both compartments in the Ussing chamber were filled with oxygen or a mixture of 95% O2 and 5% CO2. Permeability was measured only in the outward direction, which resembles the elimination pathway from the vitreous to the choroid to the systemic blood circulation.Two different ocular tissues (retina-RPE-choroid-sclera and RPE-choroid-sclera) were placed in a tissue insert with ring-shaped silicone adapters and a circular diffusion area of 0.19625 cmv/v) was isocratic. The buffer consisted of 10 mM trimethylamine, adjusted to pH 3.2 with phosphoric acid. The UV detector was set to 248 nm, and the retention time was 6 min. Symmetry C18  was used for the separation of ganciclovir. The flow rate was 1.0 mL/min, and the mobile phase of methanol:buffer  was isocratic. The buffer was prepared by diluting 1 mL of trifluoroacetic acid in 1000 mL distilled water, and the pH was adjusted to 2.5.Samples (0.1 mL) were taken from the acceptor chambers at eight different time points  and replaced with fresh buffer of the same volume. For the small molecular weight drugs, ganciclovir and brimonidine, drug concentrations from acceptor chambers were quantified by high-performance liquid chromatography . Zorbax Eclipse Plus C18  was used for the separation of brimonidine. The flow rate was 1.0 mL/min, and elution of the mobile phase of acetonitrile:buffer  was performed to measure the drug concentrations. The specific immunoassay procedure was previously described in multiple articles published by our group ,22,23,24®, Allergan plc, Dublin, Ireland) is currently under human clinical trial and showed positive results in improving geographic atrophy in neovascular AMD eyes [®, Bausch & Lomb, Rochester, NY, USA). Lastly, we selected bevacizumab to determine the effects of a large molecular weight on permeation. Identifying the permeability of these three ophthalmic drugs is crucial for posterior segment drug delivery to treat various retinal diseases.In this study, three ophthalmic drugs, including ganciclovir, brimonidine, and bevacizumab, were selected for permeability measurements. Brimonidine is an α2-adrenergic agonist that is widely used in glaucoma treatment. Brimonidine is currently highlighted for its neuroprotective benefit by promoting retinal ganglion cell survival . MoreoveAMD eyes . Thus, wAMD eyes . GanciclPapp) of the three ophthalmic drug molecules  were calculated from the slope of the compound amount versus time profile on the acceptor side.The apparent permeability coefficients (2)The slope of the time–concentration curve was derived from the concentration differences between the final time point (4 h) and the initial time point at the presumed steady-state, in this case, 30 min for brimonidine and ganciclovir, and 1.5 h for bevacizumab.Since we conducted permeability studies with two different ocular tissues (retina-RPE-choroid-sclera (RCS) and RPE-choroid-sclera (CS) scraped off the neural retina), we calculated the neural retina permeability coefficients according to the equation below, which presents the overall contribution to the total permeability with multiple barriers and various permeation resistances.2) of over 0.9 was obtained. For the retina-RPE-choroid-sclera tissues, the linear fit model of ganciclovir was y = 0.3272x − 0.175 (R2 = 0.9613), brimonidine y = 0.3037x + 0.1143 (R2 = 0.9786), and bevacizumab y = 0.0087x − 0.0256 (R2 = 0.9237). For the RPE-choroid-sclera tissues, the linear fit model of ganciclovir was y = 0.8229x − 0.1262 (R2 = 0.9907), brimonidine y = 0.7948x + 0.8319 (R2 = 0.9965), and bevacizumab y = 0.0484x − 0.0703 (R2 = 0.9473). In this way, to derive every permeability coefficient for three ophthalmic drugs with two different ocular tissues, we calculated each The average time–concentration values (μg/mL) of retina-RPE-choroid-sclera (RCS) and RPE-choroid-sclera (CS) rabbit ocular tissues in the acceptor chamber are shown in Papp) (×10−6 cm/s) of ganciclovir in retina-RPE-choroid-sclera and RPE-choroid-sclera were 13.78 ± 5.82 and 23.22 ± 9.74, brimonidine 15.34 ± 7.64 and 31.56 ± 12.46, and bevacizumab 0.0136 ± 0.0059 and 0.0612 ± 0.0264, respectively. Between the two small molecular weight drugs, brimonidine, which is more lipophilic with a higher log P and lower water solubility than ganciclovir, showed better permeability in RCS and CS tissues. On the other hand, bevacizumab, a much larger molecular weight drug compared to both ganciclovir and brimonidine, presented much worse permeability in RCS and CS tissues. According to the experimental data, we could estimate the permeability coefficients of the neural retina: ganciclovir 33.89 ± 12.64, brimonidine 29.83 ± 11.58, and bevacizumab 0.0205 ± 0.0074 (×10−6 cm/s). Unlike the RCS and CS, neural retinal permeability is greater in ganciclovir than in brimonidine, suggesting that rather than lipophilicity, the molecular weight might be the main pharmacokinetic (PK) parameter that affects drug molecule transport in the neural retinal layer.The representative physicochemical properties, molecular weight, lipophilicity (log P and water solubility), and the measured permeability coefficients from the experimental and calculated data  are summIn addition, using the experimental data of three ophthalmic drugs from this study, we evaluated the association between intravitreal half-life and posterior segment ocular tissue permeability. The log scale graph is shown in In this study, we measured the retina-RPE-choroid-sclera and RPE-choroid-sclera permeability coefficients of three ophthalmic drugs, including ganciclovir, brimonidine, and bevacizumab, from rabbit ocular tissues, and calculated the neural retinal permeability coefficients. As a result, the large molecular weight biologic drug bevacizumab showed very restricted permeation across the posterior segment compared to small molecular weight drugs. Between ganciclovir and brimonidine, a more lipophilic drug, brimonidine, demonstrated better permeation through the RPE-choroid-sclera, even though its molecular weight is slightly larger than that of ganciclovir. However, ganciclovir was estimated to have better neural retinal permeability than brimonidine. Therefore, we propose that molecular weight might be the main factor affecting permeability in the neural retina, whereas both molecular weight and lipophilicity influence permeation through the retinal pigment epithelium (RPE) barrier. In addition, we could postulate that a longer intravitreal half-life might be negatively associated with posterior segment permeability, especially in the neural retina .The retinal pigment epithelium (RPE) layer separates the neural retina from the choroid and exhibits intercellular tight junctions, working as a part of the blood-retinal barrier and restricting molecular transport. Therefore, numerous studies have focused on the mechanism of drug delivery across the RPE layer. To determine the RPE function for transport and permeation, the Ussing chamber was introduced as two separate baths divided by the epithelium, and electric potentials and concentrations were recorded to investigate the transepithelial ion transport . Kimural−6 cm/s). The smaller molecular weight and lipophilic drug lidocaine  revealed the highest permeability, whereas the larger molecular weight and hydrophilic drug ciprofloxacin  exhibited the lowest permeability. Recently, Ramsay et al. measured the bovine RPE-choroid permeability of eight small molecular weight drugs and bevacizumab antibody, and found that the outward permeability for ganciclovir was 9.70 ± 7.90, and bevacizumab was 0.0035 ± 0.0020  [Together with the RPE function of molecular transport, considerable efforts have been made to determine the relationship between molecular physicochemical properties and diffusion/permeation in the posterior segment of ocular tissues. Ambati et al. investigated the in vitro scleral permeability of high molecular weight compounds in rabbit eyes with the Ussing chamber, and proposed that the scleral permeability was negatively correlated with molecular weight and radius . Pitkane−6 cm/s) .Other than experimental data, some researchers have developed a simulated model to focus on the retinal permeability and clearance mechanism. Hutton-Smith et al. established a three-compartment  semi-mechanistic model to interpret the intraocular distribution and elimination process, including the ILM and RPE permeability . In thisThis study had some limitations. First, we should be cautious in extrapolating these data because the estimated neural retina permeability data might not coincide with the real values; because we calculated the neural retina permeability indirectly by the equation with experimental values of retina-RPE-choroid-sclera (RCS) and RPE-choroid-sclera (CS). As the neural retinal layer is very difficult to separate accurately from the RPE-choroid, our method of scraping off the neural retina and measuring the permeability of RCS and CS was an inevitable option. Second, we performed experiments using only three ophthalmic drugs from one animal species. Previous studies have used larger numbers of drug molecules and different species, such as rabbit, porcine, and bovine ocular tissues. Accordingly, we could not derive a statistical correlation between the molecular physicochemical properties and permeability. Moreover, instead of using rabbit eyes, previous studies have analyzed the association between intravitreal half-life and permeability using bovine and porcine eyes to measure the permeability coefficients; thus, direct comparison might be difficult. Finally, since we experimented only in the outward (vitreous to choroid) direction of permeation, there might be a measurement error, even though we assessed the drug concentration after reaching the steady-state time points.Nonetheless, our study has some strengths that need to be addressed. To the best of our knowledge, this is the first study to analyze and document the neural retinal permeability of ophthalmic drugs. Almost all prior experiments performed permeability studies with RPE-choroid tissues; therefore, in this study, we determined the permeability differences of the neural retina and RPE-choroid tissues. Another strength of our study is that we demonstrated a negative association between intravitreal half-life and permeability in 10 different ophthalmic drug molecules, including the large molecular weight biologic drug bevacizumab, even though the experimental values were obtained for different animal species. To be comprehensive, we will extend the permeability studies with diverse molecules and ex vivo experiments examining both outward and inward directions in bovine, porcine, and rabbit eyes.In conclusion, we evaluated the RCS and CS permeability of three ophthalmic drugs and calculated the neural retinal permeability. As a result, both molecular weight and lipophilicity are important PK parameters in the posterior segment drug clearance; however, drug transport and permeation in the neural retinal layer are likely to be affected largely by molecular weight. In addition, the intravitreal half-lives of these molecules may be negatively associated with the permeability coefficients. Subsequent studies should be carried out to determine the exact correlation between molecular physicochemical properties, drug permeation, and intraocular pharmacokinetics, represented as intravitreal half-lives.


Antimicrobial resistance (AMR) is considered one of the biggest health challenges of the 21st century. It has both social and economic consequences; therefore, timely review of public health policies that have been designed to manage AMR is essential. Brazil too has developed and implemented various polices for the prevention and control of AMR. However, till date, no study provides insights regarding the various public health policies or other programs implemented by Brazilian institutes.The objective is to define a scoping review protocol of policies that were developed to address prevention and control of antimicrobial resistance in Brazil, from a human health perspective.10.17605/OSF.IO/EC9ZJ). Indexed literature in English, Spanish and Portuguese published till December 2020 in Lilacs, PubMed, Embase, and official websites of the Brazilian government will be reviewed. This review considers all studies identified through a comprehensive search of peer-reviewed and grey literature databases that have a reference for policies made for managing AMR in Brazil. The criteria for the scoping review will be set by two evaluators. A third evaluator will be consulted, if there is any disagreement between the two primary evaluators. A standardized form will be used for data extraction from the selected studies. The results will be presented in a tabular form with narrative abstracts related to the topics identified through the scoping review protocol. The PRISMA extension for Scoping Reviews tool will be used.This protocol has been registered in the Open Science Framework (DOI  Antimicrobial resistance (AMR) occurs when microorganisms  develop the capacity to adapt and grow in the presence of substances that were capable of eliminating them . This phAMR is now recognized as a global human health problem by the World Health Organization (WHO), Food and Agriculture Organization (FAO), the World Organization for Animal Health (OIE), World Bank, and other institutions of international relevance , 4. An eNation Plan on Prevention and Resistance Control to Antimicrobials on the Scope of One Health 2018–2022 (PAN-BR) [To overcome this threat, in 2015, the WHO published the Global Action Plan on Antimicrobial Resistance, at its 68th World Health Assembly. It impelled its member states to write their own national plans in accordance to the Global Action Plan [(PAN-BR) .The history and evolution of public policies to tackle AMR are well documented by the United Kingdom, France, Sweden, and Denmark –11. HoweIt is important to bridge this gap and collate evidence of action against AMR. Considering that mapping of available evidence can be ideally done through the scoping review method , 13, thiCochrane Database of Systematic Reviews, PubMed and Epistemonikos, produced no scoping reviews on prevention and control of AMR in Brazil. It is hoped that this study can contribute literature for future scientific studies.We emphasize that a search (in December 2020) of What are the various policies and strategies, from a human health perspective, that exist in Brazil for prevention, surveillance, and control of antimicrobial resistance? Mainly, what has been done about this issue in Brazil and what are the gaps in implementation and research?The aim of the paper is to define a review protocol of policies and strategies that were developed to address prevention and control of antimicrobial resistance in Brazil, from a human health perspective.10.17605/OSF.IO/EC9ZJ).This protocol employed a scoping review method . This reTo define the eligibility criteria for the review, factors such as population, concept, and context, were established in accordance with the Joanna Briggs Institute Reviewers Manual . These fThe concept of AMR policies is very broad . This scThe concept of AMR will be verified in accordance with the content of The context of the concepts classified in the previous section are as follows: item (i) includes policies developed by federal or state governments and item (ii) comprise strategies developed by one or more Brazilian health institutions, public or private.The scoping review will include all studies published before December 2020, in either English, Spanish or Portuguese, and will consider all study designs that have a reference for policies and strategies made for managing AMR in Brazil.Studies will be excluded if they are not conducted in Brazil or in partnership with brazilian institutions or if they are literature reviews describing the concept of AMR without interventions. Studies will also be excluded if they estimated the burden of AMR without describing interventions used to address it.For this study, an electronic search was carried out using keywords and synonyms pertaining to AMR. For example, “antibiotic resistance,” “antiviral resistance,” “antifungal resistance,” and “antimicrobial stewardship,” in tandem with restrictive operators like “Brazil.” The full electronic search strategy from each database is presented in https://www.gov.br/saude/pt-br) and the National Health Surveillance Agency–Anvisa (https://www.gov.br/anvisa/pt-br).Search for information was carried out electronically on the following databases -PubMed, Embase, and Lilacs. The search for gray literature was performed on Brazilian government websites, as the Ministry of Health Click here for additional data file.S2 Appendix(DOC)Click here for additional data file.S1 Checklist(DOCX)Click here for additional data file.


Antimicrobial resistance (AMR) is a global crisis that evolves from a complex system of factors. Understanding what factors interact is key to finding solutions. Our objective was to identify the factors influencing AMR in the European food system and places to intervene.We conducted two workshops involving participants with diverse perspectives to identify the factors influencing AMR and leverage points (places) to target interventions. Transcripts were open coded for factors and connections, then transcribed into Vensim 8.0.4 to develop a causal loop diagram (CLD) and compute the number of feedback loops. Thematic analysis followed to describe AMR dynamics in Europe’s food system and places for intervention. The CLD and themes were confirmed via participant feedback.Seventeen participants representing human, animal and agricultural sectors identified 91 CLD factors and 331 connections. Seven themes  describing AMR dynamics in Europe’s food system, five ‘overarching factors’ that impact the entire CLD system  and fourteen places for intervention  emerged from workshop discussions. Most leverage points fell on highly networked feedback loops suggesting that intervening at these places may create unpredictable consequences.Our study produced a CLD of factors influencing AMR in Europe’s food system that implicates sectors across the One Health spectrum. The high connectivity between the CLD factors described by participants and our finding that factors are connected with many feedback mechanisms underscores the complexity of the AMR problem and the challenge with finding long-term solutions. Identifying factors and feedbacks helped identify relevant leverage points in the system. Some actions, such as government’s setting AMU standards may be easier to implement. These actions in turn can support multi-pronged actions that can help redefine the vision, values and goals of the system to sustainably tackle AMR. Antimicrobial resistance (AMR) claims 700,000 lives globally and threatens health, social and economic well-being –3, with Because many types of actors are involved in AMR, tools that can integrate knowledge about how their actions directly or indirectly impact AMR or are impacted by AMR are needed. Causal loop diagrams (CLDs) are a tool used in system science to integrate the diverse perspectives of actors from different sectors and model the range of factors that may impact complex systems. CLDs are visual models that illustrate the relationship between explanatory factors and outcomes –15. In aWhile drivers of AMR have been identified, greater understanding about how micro and macro factors interconnect to generate AMR is needed. Thus, our objectives were to gain insights from diverse perspectives to understand the broad range of factors influencing the development and spread of AMR in the food system and identify leverage points for intervention with potential to effectively address AMR long-term. We successfully conducted our study with a focus on Europe.This study used qualitative methods. We followed the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist for reporting our qualitative research . This stThe study was designed and conducted by a core team (co-authors: SE Majowicz (SEM); EJ Parmley (EJP), IA Lambraki (IAL), M Cousins (MC), CA Carson (CAC)) who consulted with a larger interdisciplinary project team of academics with specialties in human medicine, aquaculture, clinical microbiology, and evolutionary biology, throughout the design, data collection and analysis steps. The core team has disciplinary backgrounds in public health, epidemiology, and veterinary medicine and bring experience with qualitative methods, systems thinking, food safety, and antimicrobial resistance.Using a participatory approach and systems thinking, we engaged stakeholders from across the One Health spectrum in two group model-building workshops to develop an interdisciplinary CLD relating to AMR in the European food system . We defiParticipants were identified through: Google, LinkedIn, and Twitter searches; professional organizations’ websites that may impact AMR in human, animal, agricultural, and environment sectors; and via the research team’s , A Léger (AL), P Henriksson (PH), M Troell (MT), S Harbarth (SH), D Wernli (DW), and P Søgaard Jørgensen (PSJ) professional networks who identified individuals to approach that represented expertise that is less traditionally engaged in AMR discussions. We purposively selected participants with diverse perspectives from Europe, with either traditionally recognized expertise in AMR , or expertise in areas that may directly or indirectly impact AMR . Efforts were made to recruit participants across human, agriculture , and environment sectors.We approached 64 participants via email with a maximum of two follow-up contacts in alignment with the University of Waterloo Ethics Committee approved protocols. Twenty-six participants did not respond. Twenty-one individuals declined due to work conflicts, AMR not being deemed a priority for the approached participant’s organization, or the individual did not see their role in AMR relevant to the food system. Seventeen participants agreed to participate. Almost half of the participants were female. Participants represented the following perspectives: epidemiology, food safety and microbiology, veterinary sciences, aquatic sciences and aquatic foods, agricultural crops and policy, animal welfare, human medicine, nursing, public health, public health advocacy, consumer advocacy, pharmaceutical marketing, pharmaceutical law, trade and economics, urban agricultural innovation, sustainable foods and innovation, dietetics, peace and conflict resolution, and leadership. These participants represented organizations at sub-national, national, or regional  levels, including governmental and non-governmental organizations, health care organizations, private consultants, and industry. Over half of the participants were from Sweden, and the remaining from France, Italy, Spain, United Kingdom, and Belgium. Participants did not have previous relationships with research team members.th and 20th, 2019 at the Stockholm Resilience Centre . Both workshop days had a mix of AMR experts and experts in other content areas relevant to the food system that may not usually be engaged in discussions about AMR. However, workshop day one brought together participants that could provide a broad understanding of AMR in the European food system context, and thus had a greater representation of AMR experts. Workshop day two brought together participants that could provide an understanding of sectors in the food system at a national and sub-national level which may influence AMR directly or indirectly, and thus had a greater representation of experts in content areas that may not usually be engaged in AMR discussions and varying levels of knowledge about AMR.We held two in-person 6.5-hour workshops over two days: September 19The purpose of the workshops was to have participants with diverse perspectives brainstorm the system of factors that may influence AMR and identify where in that system to intervene. Workshops were audio-recorded, guided by a semi-structured interview guide, and facilitated by our team . Co-authors  attended the workshops to listen and provide expert input if requested by participants. Each workshop started with a welcome, icebreaker activity, overview of the workshop objectives, and a brief presentation on AMR to provide a common understanding and terminology. A practice system thinking activity followed, in preparation for the modelling process.To initiate conversations, participants were introduced to an existing CLD of AMR in the Canadian food system , and tasThe workshops produced five data sources that were analysed: the facilitator-revised CLDs  Figs; eaThe research team classified the leverage points for intervention that participants identified as ‘shallow’  or ‘deep’  per Meadows . Then weThe CLD of AMR in the European food system contained 91 factors and 331 connections ; for easa major hot spot for the selection of resistant organisms…” (workshop Day 1), depending on standards. AMU in aquaculture was described as an under-examined source for AMR development and spread through water. Other modes of AMR spread identified were abattoirs (via employee contact with affected livestock), animal transport for trade, and the movement of people due to migration and health tourism.Participants identified antimicrobial misuse in food production  and in human health care as a major driver of AMR, which contributes to the number of antimicrobial-resistant organisms (AROs) in the environment. Antibiotics and antibiotic residues that get released into the environment  were identified as contributing to the development, frequency and spread of AROs in the environment . Human and animal excreta were also noted to spread AROs and residues, such as when faecal waste and wastewater are recycled as manure in agri- or aquaculture. All these practices were noted to spread AMR to animals , plants, and humans . Participants also identified wastewater treatment facilities as impacting AMR spread, noting them as “…big costs upfront…” to farmers who already operate with a “low margin…”(workshop day 1).Economics was a motivator for antibiotic use in animal farming. Participants identified the market-driven economy as driving industry to higher density farming practices to meet demands and generate profit, which increases animal stress, illness, and antibiotic use  as a cost-effective intervention. Good farming practices and non-antimicrobial infection prevention and control (IPC) measures  in terrestrial and aquaculture food production  were identified as necessary to improve animal welfare, reduce illness, and limit the need for antibiotics. Technologies that treat and repurpose existing waste  by extracting nutrients for use in fertilizer on crops and feed in animals were also described as having potential to contribute to good farming practices by improving nutrition and the health of animals. Implementing good farm management practices, however, was identified as requiring training  and incurring “…Demand for products and antibiotics by individuals was perceived to influence antibiotic use. Participants highlighted that consumer demand impacts the types of products retailers bring into the marketplace and increases food production involving AMU . Consumer demand for less expensive food was also said to influence the purchasing of imported meat that may be produced using unregulated AMU or that may contain unknown levels of ARO loads due to the absence of testing at borders . However, participants noted that consumer willingness to pay more for niche markets could shift food production practices and reduce AMU. Religious factors and an individual’s experience with disease or AMR were said to shape consumer demand and willingness to pay more for food products produced without antibiotics, such as kosher meat or organic food. Consumers’ level of understanding of where food comes from and how it is produced was noted to potentially shape consumer demand. In Sweden for instance, a high level of awareness about food and the importance of sustainable practices was described to increase consumer demand for foods raised with good farm practices and higher animal welfare standards.quick fix” (workshop day 2) and cultural norms were said to drive adults to demand antibiotics to avoid using sick days to meet work productivity standards. Previous experiences were also identified such as immigrant families demanding antibiotics at first sign of mild colds because “….that mild cold in their own country can kill that child” (day 2 workshop). Family members purchasing antibiotics while travelling “…because it’s easier [to access] than in the country they live in” (workshop day 1) and passing them on to family and friends was another factor influencing AMU or inappropriate AMU and potential development of AMR. High previous antibiotic exposure was noted to influence an individual’s resistance and in turn the potential effectiveness of treating infections with antibiotics. Unpacking the individual, social, economic, and policy factors that influence consumer choices was identified as necessary to developing effective behaviour change interventions.Beyond food, participants identified how patients and companion animal owners may demand and use antibiotics when not indicated, potentially reducing the efficacy of existing antimicrobials. Human’s search for a “wearable devices” (workshop day 2) and rising e-health solutions  will impact prescriptions or human behaviour. Resource issues, such as high costs of diagnostic kits that reduces their use and drives prescription of broad-spectrum antibiotics, insufficient physicians per population that reduce physician-patient consultation time and increase the potential for suboptimal diagnoses and antibiotic prescriptions, and a lack of adequate hospital IPC staff found in countries with significant AMR problems were also described as impacting stewardship. The movement of people  was also noted to increase resource demands and capacity issues by introducing diverse opinions, trainings and cultures that may impact stewardship in human and agricultural contexts.Participants described the presence or absence of antimicrobial stewardship  in human and animal health care settings, social care settings  and the communities they serve as impacting AMU and AMR spread , the burden of illness, and health and social care costs. Several factors were identified as impacting stewardship, such as pressures on physicians and veterinarians to prescribe antibiotics . Technological advancements that have led to increased digitization in health care were also described as increasing physicians’ reliance on lab results to diagnose rather than spending adequate physician-patient time to make a holistic assessment of symptoms, potentially impacting early accurate diagnosis and antibiotic prescriptions. Participants also noted that little is known about how technologies such as “Health and psychological well-being were highlighted as important to preventing illness in animals and humans and reducing AMU and healthcare costs. Vaccinations were viewed as important to illness prevention although participants recognized efforts to increase vaccination in humans and animals in Europe have not translated into widespread uptake. Reducing stress and improving overall health status in animals via good farming practices and high animal welfare standards and improved lifestyle behaviours and nutritional intake in humans were identified as useful to cure some minor illnesses. Changing the environments in which we live to be more health promoting was also deemed important to reducing stress. Using narrow spectrum antimicrobials was also identified as important to treating illnesses. All these practices were also said to reduce AMU and preserve host gut microflora, which may build immunity and resilience to illness and reduce AMU. Promoting producer mental health was also identified as important to good farming practices, as farmer stress levels may translate into less care for others, including their animals.patterns of resistance are linked to social inequalities–to areas…that have deprivation…” (workshop day 1), which may increase diseases and health and social care costs. Countries, populations and individuals experiencing poverty were said to be at greater risk of experiencing transient employment with no sick pay, food and water insecurity, compromised nutritional intake, and preventable chronic diseases, which contribute to stress and poorer psychological well-being, and health complications that may require antibiotic treatment compared to those with greater affluence.Social and economic conditions were identified as influencing AMR and health and psychological well-being. Participants noted that “when it comes to antibiotics, we need the entire portfolio, so we need to find ways to both safeguard the existing…ones because we will need them also in the future, but also find of course new business models to come up with new antimicrobials…” (day one workshop).” New sustainable funding models and incentives that are potentially funded by the government or through the support of public-private partnerships were viewed as needed to assist pharmaceutical companies in the costly development of new antimicrobials. Additional ways to protect the effectiveness of antimicrobials and tackle AMR were identified, such as exploring the gut microbiota and the microbiome to find alternatives to antibiotics and improve health and well-being; genomics research to advance personalized medicine; development of recommended antimicrobial lists for use in animals and humans plus rapid diagnostics that distinguish between different infections to inform treatment guidelines and responsible AMU; development of new foods ; and surveillance of AMR spread in the environment, including via aquaculture. The need to get ahead of the AMR crisis by overcoming existing debates between sectors about the need for a strong evidence-base before acting versus acting when warranted to accumulate the evidence  was discussed. Better political alignment between government departments was also identified as important to increase research budgets and release funds allocated to different issues  for joint action “…where…co-benefits exist” (workshop day 1) .Participants identified many actions and approaches to tackle AMR. Participants noted that “how effective is it if you’re not using it [regulations] in one area and your neighbouring country is…” (workshop day 1). For instance, participants said some European countries require a prescription for antibiotics while others allow antibiotics to be purchased over the counter. Moreover, participants noted (in)formal domestic and international agreements  “…drive the political agenda in a certain way and they might not always be moving in the same direction” (workshop day 1) potentially circumventing AMR mitigation efforts. Ensuring international agreements have restrictions on AMU in food animals including use of antimicrobial pesticides, and that code of practices or standards such as from Codex Alimentarius are implemented were noted by participants as important.‘Agreements, standards, and regulations’ were said to impact the entire CLD with beneficial and negative consequences. In Europe, agreements, standards, and regulations were noted to promote responsible AMU and limit AMR  yet participants said surveillance systems to track the ARO load in imported food products was lacking. Moreover, participants described negative consequences due to regulations for farmers. For example, in some Northern European countries, the domestic animal-food industry was said to potentially spend more to comply with domestic restrictions to reduce AMU and certain bacteria in their food products, and are often outcompeted by less expensive products imported from other countries which produce animals or food under different conditions. Concern was also raised that strict import regulations in some Northern European countries may eventually motivate some producers to export their products to countries with growing economic purchasing power and less stringent regulatory requirements. Participants also highlighted that different European countries have varying levels of AMR, do not necessarily operate with the same regulations, and if they do, have different interpretations, which raised questions about “trustable system” (workshop day 2) and citizens follow the rules because decision-makers have demonstrated their commitment to ensuring public well-being by achieving peace and affluence. Having “…no wars in Sweden for …at least two hundred years [has given us] time to worry about the future, and to put energy…and financial resources into what is coming” (workshop day 2). This context was said to have enabled Sweden to be forward-thinking , and to take actions to deter corruption . Participants also described the need for leadership to set agendas and make legislative decisions based on scientific evidence rather than “…the agenda [being] so directed by, or influenced by, some stakeholders…” (workshop day 1).‘Leadership’ was viewed as strongly shaping the factors governing AMR. Participants noted that leaders could be anyone and that individuals and non-governmental organizations could play an important role in raising awareness and taking action to address the AMR problem. Governments were identified as key leaders because they set the vision and policies that can influence changes in how a nation or society operates. Moreover, participants noted the importance of leaders cultivating trusting and respectful relationships with others to develop a shared mindset about the ideal future and inspire action. Participants illustrated how, in Sweden, the government is generally viewed as a “fake news” (workshop day 1) to the public, or framing messages to “scare us” (workshop day 2), with the power to shape public opinion that can help or hinder AMR mitigation efforts.‘Media’ and social media were said to drive information, either translating scientific evidence in appropriate or inappropriate ways, delivering “‘Collaboration’ within and between governments and industries was identified as an overarching factor because it impacts sharing of data about AMU and actions between sectors to tackle AMR, and this can be limited if there are fears from sectors  of repercussions from this transparency.interlinked in many ways” (workshop day one). One way that participants said climate change would impact the system was via rising temperatures. A sector where climate change was described to be “having a direct impact on AMR is in…salmon farming, where the season is now two degrees warmer, [and] the second you get even a degree warmer, you get more disease outbreaks because the animals are more stressed” (workshop day one). These changes in turn were said to potentially increase the need for AMU for treatment and the emergence and spread of AMR, threaten food security, increase the retail cost of food, and negatively impact people and countries experiencing inequities in the social determinants of health as they will bear a disproportionate climate burden. Selecting or genetically modifying food-animal and crop species that are less vulnerable to climatic changes was described as potentially useful to shift consumer demand and potentially reduce the need for AMU in food production. Climate change was also described to impact water via, for instance, flooding, which could overwhelm wastewater treatment systems causing the potential spread of antimicrobial residues and AMR. Increasing research funding directed to AMR in the environment and in aquaculture was viewed as likely due to climate change. Participants also noted that differing levels of commitment across nations regarding achieving the Sustainable Development Goals was challenging society’s ability to address the climate crisis.‘Climate change’ was identified as an overarching factor. Participants described climate change and other parts of the system as “Participants identified 14 factors  as leverage points with the potential to transform the system to combat AMR, and suggested associated actions, which we classified as shallow and deep leverage points per Meadows (1999) .The final CLD contained several feedback loops, which occur when an outcome of some causal process is also an input and provide a measure of the complexity of a system. Of the 91 factors in the CLD, the majority were involved in up to 30,000 feedback loops or more, with a given feedback loop involving up to 33 other CLD factors. The remaining CLD factors were either not part of any feedbacks: ; one feedback ; or two feedbacks (n = 1: ‘new and emerging foods’).Eight of the 14 CLD factors identified as leverage points involved up to 30,000 feedbacks or more, one CLD factor was part of one feedback, and two CLD factors and the three overarching factors identified as leverage points were not part of any feedback loops, the latter because participants indicated they impact the entire system .This study aimed to identify the complex system of factors influencing AMR relevant to the European food system and leverage points for intervention to address AMR. Two CLDs were developed by different sets of participants across our two workshop sessions. While workshop day one uniquely identified three CLD factors and several new connections between CLD factors and workshop day two uniquely identified ten CLD factors and many new connections, the models were combined into one participant validated CLD because the majority of factors overlapped. Despite the many similarities, the richness of the data differed between the two days. For instance, workshop day two participants, who were more likely to represent perspectives that are less traditionally engaged in AMR discussions, tended to provide greater sector-specific and contextual information about issues than workshop day one participants who were more likely to have expertise and experience in AMR. Workshop day two participants also identified and discussed in greater detail social factors such as trust in leadership and inequities, and issues relevant to CLD factors such as ‘non-antimicrobial infection prevention and control by the public ’ and ‘non-antimicrobial infection prevention and control in other social settings ’. Thus, by engaging different sectors, we were able to identify a broader range of factors and deeper understanding of how actions in particular sectors may influence AMR.Many of the factors identified across both workshop days align with factors previously described in the literature. AMU for human health care, for animal food production and AMR spread were identified as key drivers of AMR and re-emphasized a strong need to better understand the factors driving AMU, and AMR spread in the environment –23, to fOur study identified three shallow and eleven deep leverage points for AMR interventions per Meadows . ShallowUnderstanding whether the above leverage points are ideal targets for sustainable change requires assessing feedback loops. For example, the leverage point ‘national budgets, money and funding’ had zero feedbacks based on participant input, suggesting that changing national budgets will directly impact investments in things like health care and research, surveillance, development and innovation, which will themselves have impacts . The absence of a feedback mechanism suggests that this action has less potential to create unpredictable effects in the system. In contrast, eight of the 14 leverage points participants described were part of thousands of feedbacks, connecting to up to 33 other CLD factors, such as ‘consumer choice, demand and behaviour’ which has potential to change the system in ways that promote or constrain AMU depending on public demand but makes long-term impacts on other parts of the system difficult to anticipate or to control. This high degree of connectivity underscores participants’ perceptions of the complexity of the AMR problem and the challenge with finding long-term solutions, and additional research is needed to determine how effective these leverage points are in potentially disrupting or slowing down vicious feedback mechanisms or amplifying virtuous cycles within the context of these highly networked feedbacks. This underlines the need for the development of a learning system that can capture the most important feedbacks in a specific context .A strength of our study was the use of a participatory and systems thinking approach to integrate a breadth of perspectives from stakeholders representing different sectors and disciplines, including those less traditionally engaged in AMR discussions, but whose domains of expertise directly or indirectly impact AMR and who are thus essential to addressing the problem. Our approach enabled participants to share, ask questions about, and build on each other’s knowledge in ways that were respectful of different views and knowledge and led to the development of a complex CLD. Thus, our approach demonstrates that bringing together participants from different sectors, with different priorities, and varying levels of AMR expertise is a successful way to generate new, shared understandings about the complexities of AMR, and where and how to potentially intervene, reinforcing these methods as useful to build capacity for systems thinking and systems-informed decision-making . MoreoveA limitation is that while the CLD was developed with a European view, workshop discussions had a European Union and Sweden focus as participants came from these areas. While participants did discuss factors impacting Europe as a whole, it is possible that factors unique to other parts of Europe may not have been captured. We successfully engaged diverse perspectives from human, animal and crop systems and different organizational types at subnational, national and regional levels, however, inclusion of other sectors such as travel industry and the environment sector may have shed insights on additional factors not captured in this study.While we purposefully engaged a wide range of experts in different content areas with varying knowledge of the technicalities about AMR, we did not independently verify their statements and did not determine the relative importance of the identified factors which can be explored in future research.By engaging diverse perspectives, we created an interdisciplinary CLD of factors influencing AMR relevant to the European food system that spanned the One Health spectrum and numerous potential connections between these factors and potential feedback mechanisms. This demonstrates the complexity of the AMR problem and challenges with finding long-term solutions. The identification of factors and feedbacks was useful to find relevant leverage points or places in the system to target interventions. Leverage points that target regulations, such as government’s setting AMU limits, or investing national budgets in prevention or research may be easier to implement. These actions in turn can support broader comprehensive cross-sector multi-pronged actions to redefine the vision, values, and goals of the system and sustainably transform AMU and tackle AMR. This provides the foundation for building more resilient societies in the face of growing AMR.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S1 Fig(PDF)Click here for additional data file.S2 Fig(JPG)Click here for additional data file.S3 Fig(JPG)Click here for additional data file.S4 Fig(JPG)Click here for additional data file.


IntroductionThere are limited educational studies on effective ways to teach and learn medical eponyms. While there is no consensus on how to best address this issue, developing novel strategies to teach medical eponyms has become critical in many branches of medicine, including ophthalmology. Materials & MethodsAn ophthalmologic eponymic database was created using eight source texts  and included the year the eponym was introduced, related name, nationality, specialty, and the eponym’s description. PubMed database with a Medical Subject Headings (MeSH) keyword for “eponym” and “eye” and “ophthalmology” and a Google search for a combination of related keywords was also performed. A careful biographical search was conducted for each name in the second phase to obtain further biographical details. Inclusion criteria for eponyms in the dataset were: i) named after at least one person, ii) identified as a specific medical term in the literature, iii) related to any field of medicine. Names derived from art, history, mythology, patient, family, chemistry, botany (or other fields outside of medicine) were excluded. The three authors independently screened to eliminate duplicated names and ensure eligible names met inclusion and exclusion criteria.ResultsA total of 1,257 unique ophthalmologic eponyms representing 8.8% of 14,332 medical eponyms were identified. Three-hundred fifty-one of 743 (47.2%) eponyms were named after ophthalmologists representing 36 countries. The United States of America and Germany comprised the largest fraction of nationalities (40.2%), not necessarily representing their birthplace. Signs, syndromes, and diseases composed the largest category (45.8%) of eponymous ophthalmologic names.DiscussionThe current volume of eponymous names impedes the ability of a learner to retain this information. Classifying eponyms based on form, intention, or function, provides a more refined method for placing eponyms in their respective categories. Teaching eponyms by enumerating their historical content, demonstrating the correct performance of the eponym, assessing the technique, and providing feedback, affords the learner a more fruitful and meaningful learning experience. Understanding the context of the signs, syndrome, or techniques further allows the learner to gain insights into the clinical application of eponyms in diagnostic decision-making.ConclusionThe teaching model proposed incorporates key aspects that may facilitate retention and recall of the eponymous name. The model includes imparting historical knowledge about the person who described the sign, technique, or process; demonstrating the correct procedure as originally reported; and coaching to ensure that the appropriate skill is mastered. Before abandoning eponyms, it is first necessary to understand their efficacy, effectiveness, usefulness, and role in clinical medicine. Eponyms provide a rich cultural perspective to the literature and remind us about our historical medical heritage. Despite this, the routine use of eponyms remains controversial, with not all physicians embracing their widespread use -3. UnforData were obtained from research utilizing primarily eight sources representing medical or eponymic books, dictionaries, encyclopedias, indexes, medical periodicals, and one online source. The following criteria were considered in selecting eponyms: i) the eponym should be named after at least one person, ii) the eponym should be identified as a specific medical term in the literature, and iii) the eponyms should be related to any field of medicine. Names derived from art, history, mythology, patient or family names were excluded from the list identified. Moreover, eponymic names related to chemistry, biology, botany (or other fields outside of medicine) were also excluded.In the first phase, an eponymic database was created. The eight sources were scanned by one of the authors , identifying names, year introduced, related name, nationality and specialty, and the eponym description. The PubMed database was searched with a Medical Subject Headings (MeSH) keyword for “eponym” and “eye” and “ophthalmology” in humans published from inception to June 1, 2021. A Google search for a combination of related keywords was also performed to find any other names not appearing in text sources. A biographical search was conducted for each name in the second phase to obtain further biographical details. Obituaries were extremely helpful in this regard. For those names whose gender was not apparent, a photographic search was also conducted. The three authors independently screened to eliminate duplicated names and ensure eligible names met inclusion and exclusion criteria.This type of research has its limitations. Despite our efforts, it is inevitable to have several names missed in this list or the derivation undetermined, especially those known only with their surname or the initial letters of their names. Therefore we cannot claim this list is precisely complete in its current form.We identified and classified 1,257 (8.8%) unique ophthalmologic eponyms representing 14,332 total eponyms in the eponymous literature -13. We cSigns, syndromes, and diseases represented the largest category at 576 (45.8%), followed by those including devices, instruments, medical products and supplies at 260 (20.7%), clinical/pathological aspects of disease at 185 (14.7%), techniques at 127 (10.1%), and other subcategories  from 36 countries, the vast majority (97.9%) of these are names honored men, reflecting the preponderance of men in this specialty before the mid-twentieth century. Interestingly, the nationality of these individuals, not necessarily the country from which the eponym was written, were American (20.9%), German (19.3%), and Austrian (10.2%); followed by French (9.8%), Swiss (7.6%), and English (7.1%) among many others.Eponyms used in the context of clinical medicine are honorific terms bestowed to an individual(s) who identified or discovered a disease, sign, symptom, syndrome, test, or finding. They may also represent a designation of an anatomical structure, devices, procedures or techniques, views or phenomena, treatments, classifications or indexes, prediction rules, laws or principles, or algorithms. Eponymic signs and findings are rarely pathognomonic by themselves. When used in combination with other symptoms, signs, and physical findings, it assists in diagnosis. Their use should be strictly reserved to honor individuals whose contribution(s) embody the rich tradition of the art of medicine for centuries.There are drawbacks to the use of medical eponyms, which have led to reservations regarding their use. Limitations with eponyms include inaccessibility of the original publication or presentation because it was written in a different language or presented at a conference or in a monograph, historical misinformation, lack of attribution of all authors, naming , and transcription challenges from non-Latin scripts such as Arabic, Greek, and Russian or sometimes from umlaut letters  in the extended Latin alphabet. Other issues regarding eponyms are the routine use by authors of the possessive form of the name and inclusion within the literature of eponymic names derived from individuals who committed atrocities against humanity or bore racist or antisemitic remarks. The latter has improved as of more recent times as there has been increased awareness and confirmation of these claims. As a result, diseases were renamed and replaced with more descriptive terms . The possessive form of the eponymous name continues to be used in the literature even though its use should be restricted to cases whereby the person had the sign, disease, or syndrome for which they described. The most highly recognized example of where the possessive form is an acceptable designation is Trousseau's sign named for Armand Trousseau (1801-1867), who developed phlebitis occurring in association with a gastric tumor .It is unrealistic to think that hundreds of ophthalmologic eponymic names could be taught, processed, remembered, and recalled. This is compounded in that many eponymous names having more than one designation in the same category. Furthermore, it may not be recognized that an eponym may also be named for both a father and son, as in Sturge-Weber syndrome or von Hippel-Lindau disease. Several papers recommend standardizing terminology when naming new and existing morphological abnormalities and new diseases that can also be applied when classifying ophthalmologic eponyms -17. ThisDespite these limitations, which apropos constitute a small portion of the eponymous corpus, we believe that eponyms should be retained and further studied unless there is compelling evidence to the contrary. We concur with the words of Sir Gordon Gordon-Taylor 1878-1960), a pioneering British surgeon and past President of the Royal Society of Medicine, “This may sound antiquated, but it goes against me to sacrifice names which for centuries have proved to be good and useful. The honorable names of our science are thereby fixed in the memory of posterity, and through them, there is awakened in the student a certain historical interest which stimulates him to further investigation" [78-1960, The field of ophthalmology is replete with eponyms that have been assigned to nearly every conceivable structure within the eye or as part of a systemic process that secondarily involves the eye. Interest in eponyms is likely to grow in recent years, with many journals publishing articles on ophthalmologic eponyms such as Eales disease and Sjögren syndrome or eponyms named to honor female ophthalmologists -22.Clarifications regarding eponyms and their clinical applications can only come about through further studies that examine their validity, reliability, and reproducibility. Physicians make cognitive errors in clinical decision-making that involve biases and heuristic shortcuts. This may be further perpetuated based on anchoring and premature closure, which leads physicians astray from identifying the correct diagnosis. Other errors are linguistic, based on a physician's lack of knowledge regarding the meaning of a structure, process, disease, symptom, syndrome, or sign. These failures include physician's inability to distinguish Bell  palsy as idiopathic facial nerve paralysis from other known causes of peripheral facial nerve paralysis, or that William John Adie (1886-1935) described the findings of areflexia found predominantly in women with a known tonic pupil and thus constitutes a syndrome (Adie syndrome), a constellation of signs, symptoms, and findings, "All the evidence seems to me to support the notion that the tonic convergence reaction in pupils apparently inactive to light is a thing apart. The peculiar extra-ocular phenomena (symptomless areflexia) that are frequently associated with it also suggests that we are confronted by a unique condition" . TherefoDisease, syndromes, and signs will continue to become better defined as they are studied, leading to, in some cases, a more refined and specific disease classification. Eponymically named signs and syndromes by themselves lack sufficient specificity alone for diagnostic purposes. In most cases, they represent only the anatomic , physiologic (Donder law), or pathologic  expression of the disease or algorithm , classification , theory , or formula . These eponymic signs, syndromes, findings, devices, and techniques, when used in some cases in combination with other more sophisticated diagnostic tests, assist in better understanding, sorting out, and sorting through, the various disease processes.Classifying ophthalmologic eponyms based on a mechanistic approach assists the reader to understand better their representation  and purpose , as shown in Table Eponyms that are studied and deemed most relevant to a particular aspect of ophthalmology  should be identified by a panel of experts, emphasized, and taught.We propose a learning model that involves teaching historical aspects of the person(s) who described the sign, the signs as originally described, and its application, if available, in medical practice. Teaching history imparts purpose to the eponym and, in some cases, a more in-depth understanding of the process or steps involved in identifying the particular finding. Teaching the finding as described by the author avoids misattribution or communication errors. Lastly, the application of the finding in clinical practice should be covered, incorporating known and evolving techniques and technologies to understand the disease or disease process better.To the best of our knowledge, only one recent study evaluated a method for teaching eponyms. Viveen et al. assessed knowledge involving ten common eponymous questions before and after a two-day course among 20 orthopedic trauma surgeons in an Arbeitsgemeinschaft für Osteosynthesefragen (Swiss working group for bone fusion issues) advanced trauma course on complex elbow fractures . The epoWe believe that eponyms are interesting to learn, and information about them should be retained and taught using an evidence-based approach. When teaching eponyms, we recommend that the components include a brief historical perspective of the person who described the sign, its original description, and its application in clinical practice. The teacher should explain and, in some cases, demonstrate the proper performance of the eponym and its application in clinical practice. The eponym should be practiced with feedback provided, and in the case of eponyms involving signs, their utility in assisting in diagnosis be emphasized ,24.Teaching and learning eponyms in the context of a historical perspective and, as described by the author, tells a story using a case-based learning applied model approach. This way of learning provides a meaningful way best to understand the application of eponyms in clinical practice. There is a continued impetus to remove eponyms and to substitute them using more descriptive terms. Although we do not favor this approach, we emphasize that eponyms must first be studied before devoting time to this endeavor to determine their effectiveness in clinical medicine. Those eponyms deemed to have utility in clinical practice should be retained and classified using predetermined criteria.