Perspectives of Resident and Attending Ophthalmologists on Common Ethical Dilemmas in Research.

Purpose To assess how resident and attending ophthalmologists perceive and evaluate ethically controversial scenarios regarding mentorship, authorship, and ethics compliance that may occur during research involving residents. Methods An online survey was developed and contained 14 controversial vignettes based on common research scenarios that can occur when conducting research with trainees. The scenarios were designed to capture issues regarding three themes: mentorship, authorship, and compliance with ethical guidelines. Resident and attending ophthalmologists at eight military and civilian academic residency programs in the United States were invited to participate. Respondents used a Likert scale to assess the ethicality of the situations in addition to self-reported demographic characteristics. Results The response rate was 35.6% (77/216), consisting of 37.7% ( n = 29) residents and 62.3% ( n = 48) attendings. More attending ophthalmologists responded than residents ( p = 0.004). Many respondents identified controversies around compliance (67.3%) and authorship (57.1%) as unethical, whereas situations regarding mentorship were largely viewed as neutral to ethical (68.0%). Responses to two scenarios, one regarding mentorship and one regarding authorship, significantly differed between residents and attendings ( p = 0.001 and p = 0.022, respectively). Conclusion Academic ophthalmologists' perceptions of the ethicality of common research scenarios varied. There is a need for more prescriptive guidelines for authorship and mentorship ethics at all training levels to ensure consistency, fairness, and integrity of research.

Navigating the Ophthalmology & Urology Match with a Significant Other.

OBJECTIVE: Medical students with a significant other in medical school face challenges when applying for residency as they attempt to match in proximity to their partner. The National Resident Matching Program (NRMP) offers a Couples Match to aid such applicants. This system is not available for ophthalmology and urology because these specialties utilize match systems outside the NRMP and have an early match timeline. The purpose of this study is to analyze usage of the Couples Match and assess ophthalmology and urology applicant viewpoints on the Couples Match system. DESIGN & SETTING: First, NRMP data on the Couples Match from 1987 to 2021 was reviewed. Second, an online survey was sent to 559 ophthalmology and 321 urology applicants to The Johns Hopkins University School of Medicine in the 2021 match cycle. PARTICIPANTS: 342 ophthalmology and urology applicants (39% response rate). RESULTS: There is increased usage of the Couples Match over time. In response to the survey, 89% of participants agreed that a Couples Match should be implemented in their specialty. 107 (31%) had a significant other in medicine. 78% of 68 respondents whose significant other also applied in 2021 reported that they would have used the Couples Match had it been available. 21% of those with a significant other considered not applying to ophthalmology or urology because there was no Couples Match. There are mixed responses regarding whether the early match timeline is beneficial to couples. Female applicants were more likely to report hesitancy about mentioning a significant other during the application process. CONCLUSIONS: The Couples Match is highly desired by applicants to ophthalmology and urology, and the lack of such a system is a deterrent to pursuing these fields. Future studies will help elucidate how the match system can be leveraged to aid individuals applying with a significant other.

Racial and Ethnic Diversity Within U.S. Residencies: Trends from 2011 to 2019.

OBJECTIVE: Examine trends in the proportion of underrepresented minority (URM) residents from 2011 to 2019 across all specialties and investigate differences between surgical and non-surgical specialties. DESIGN: Cross-sectional study. SETTING: N/A. PARTICIPANTS: The authors extracted data on the proportion of URM residents in all specialties from the Accreditation Council for Graduate Medical Education yearly reports. RESULTS: There was a statistically significant decline in the proportion of URM residents in surgical specialties (p < 0.01) from 2011 (9.9%) to 2019 (9.1%) and a significant increase in the proportion of URM residents in non-surgical specialties (p < 0.01) from 2011 (9.6%) to 2019 (10.2%). CONCLUSIONS: This study emphasizes the need to increase recruitment of URMs in medicine, especially in surgical specialties. Findings from this study can inform much-needed initiatives to address barriers to entry for diverse applicants within specialties that lack diversity and have shown minimal improvement over time.

Analysis of Sex Diversity Trends Among Ophthalmology Match Applicants, Residents, and Clinical Faculty.

IMPORTANCE: The proportion of women in the field of ophthalmology in the US trails the proportion of women in the general population. Sex diversity trends have been studied in other specialties, but there is a dearth of such literature in ophthalmology. OBJECTIVE: To investigate trends in the proportion of female ophthalmology match applicants, residents, and clinical faculty. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study examined data from the San Francisco Match, the Association of University Professors of Ophthalmology, Accreditation Council for Graduate Medical Education, Association of American Medical Colleges, and American Academy of Ophthalmology (AAO) from January 1, 2011, to December 31, 2019. Data from ophthalmology match applicants, residents, clinical faculty at US medical schools, and AAO members were collected. MAIN OUTCOMES AND MEASURES: The proportion of female applicants, residents, and medical school clinical faculty in ophthalmology. RESULTS: Data were obtained from a total of 2807 ophthalmology applicants (35.3% female), 1 004 563 residents (43.8% female), 463 079 clinical faculty members (42.5% female), and 78 968 AAO members (26.1% female). Male ophthalmology residency applicants outnumbered female applicants by a ratio of 1.6:1 from 2016 to 2019. The percentage of female matched applicants in 2016 (41% [168/406]) and 2019 (42% [184/436]) differed by 1% (percent change, 0.99; 95% CI, -1.12 to 3.1; P = .36). There was a 2.3% increase (percent change, 0.34; 95% CI, 0.24-0.43; P < .001) in the percentage of female residents across all surgical specialties from 2011 (39.7% [8710/21 985]) to 2019 (42% [10 951/26 082]) but a 2.5% decrease (percent change, -0.45; 95% CI, -0.84 to -0.06; P = .02) in the percentage of female residents in ophthalmology from 2011 (41.5% [589/1419]) to 2019 (39% [575/1473]). The percentage of female ophthalmology clinical faculty differed by 2% (percent change, 1.02; 95% CI, -0.21 to 2.24; P = .10) from 2017 (38% [1179/3102]) to 2019 (40% [1225/3060]). From 2016 to 2019, male practicing ophthalmologists in the AAO outnumbered female practicing ophthalmologists by a ratio of 3:1. CONCLUSIONS AND RELEVANCE: This study found that the percentage of women in the field of ophthalmology remains lower than percentages in other specialties, and the percentage of female ophthalmology residents has decreased in recent years. More efforts are needed to improve female representation in ophthalmology.

Supervision and autonomy of ophthalmology residents in the outpatient clinic in the United States II: a survey of senior residents.

BACKGROUND: A balance between autonomy and supervision can be difficult to obtain in medical education. In this study, we sought to determine whether the presence and level of supervision of ophthalmology resident outpatient clinic correlates with metrics of resident success, professionalism and stress. METHODS: A survey was emailed to all US ophthalmology program directors requesting it be forwarded to PGY4 residents. Questions included whether their program provided a resident-hosted outpatient clinic, and if so, whether residents were mandated to discuss every patient with faculty. Residents were assigned to three categories based on this question (0: no clinic, 1: mandated faculty input, 2: discretionary faculty input). Success metrics included numbers of manuscripts submitted, OKAP scores and success in obtaining fellowships. Professionalism metrics included rating comfort obtaining informed consent, breaking bad news, managing time in clinic, and confidence in providing care in various settings. Residents affirming participation in a continuity clinic also provided perceptions of the level of supervision and how the clinic affected stress. RESULTS: Category 1 residents perceived somewhat too much supervision, while category 2 residents felt that they had somewhat insufficient supervision. The majority of residents in either category did not feel that the continuity clinic affected their overall stress, although those who reported a change in stress usually indicated that the presence of the clinic increased stress. There were no other statistically significant differences between the responses from any category. CONCLUSIONS: The presence of a resident-hosted continuity clinic neither adds nor detracts from the success or sense of professionalism of ophthalmology residents. However, when such a clinic is present, the degree of supervision appears to correlate inversely with resident perception of autonomy. These results suggest that the decision of a training program to offer a clinic hosted by residents offering comprehensive continuity care can be informed primarily by faculty and trainee philosophy and personal preferences without comprising education quality, clinical efficiency, residents' perception of stress or their success in fellowship matching.

Probability of Success in the Ophthalmology Residency Match: Three-Year Outcomes Analysis of San Francisco Matching Program Data.

OBJECTIVE: To develop a probability model of matching into a US ophthalmology residency program using San Francisco Matching Program (SF Match) data. DESIGN: Retrospective data analysis of de-identified application and matching data. PARTICIPANTS: Registrants for the 2013, 2014, and 2015 ophthalmology residency matches conducted by the SF Match. METHODS: Descriptive statistics of candidates, comparison of continuous and categorical variables between matched and nonmatched candidates, and linear regression modeling were performed. A recursive partitioning method was used to create a probability of matching algorithm. MAIN OUTCOME MEASURES: Probability of successfully matching based on quantifiable candidate characteristics. RESULTS: Over the 3-year period, 1,959 individuals submitted an average of 64 applications and received a mean of nine interview invitations. The overall match rate was 71%, with 78% matching at one of their top five choices. Successful matches were more likely to occur in US medical school graduates (78% vs 20%, p < 0.001) and applicants on their first attempt (76% vs 29%, p < 0.001). The association between matching and number of programs applied became negative with > 48 applications. Probability of matching was "high" (> 80%) among US graduates with a step 1 United States Medical Licensing Examination (USMLE)score>243(regardless of number of programs applied to), a step 1 USMLE score of 231 to 243 who applied to at least 30 programs, and first-time applicants with a step 1 score >232. No international medical graduates or repeat applicants had a "high" probability of matching. CONCLUSIONS: Although advice must be individualized for each candidate, applicants for ophthalmology residency who fall into a "high" probability of matching group are likely to be successful with applications to 45 or fewer programs. Applying to 80 or more programs should be considered for international medical graduates and/or applicants who are previously unmatched. Modification of the match application data form may allow more detailed analysis of variables such as Alpha Omega Alpha or Gold Humanism Honor Society membership, research activity, and composite evaluation on a standardized letter of recommendation.

Enhanced disease reduction using clozapine, an atypical antipsychotic agent, and glatiramer acetate combination therapy in experimental autoimmune encephalomyelitis.

BACKGROUND: Atypical antipsychotic agents (AAP) alleviate the symptoms of severe mental health disorders, such as schizophrenia, by antagonizing dopamine and serotonin receptors. Recently, AAP have also been shown to exhibit immunomodulatory properties in the central nervous system (CNS). OBJECTIVE: Building on research which demonstrated the ability of the AAP risperidone and clozapine to modify the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we aimed to more fully investigate the potential of clozapine as a possible treatment for MS. RESULTS: We report that orally administered clozapine significantly reduced the disease severity of EAE in a dose-dependent manner and was effective when administered prophylactically and therapeutically. In comparison to risperidone, quetiapine, and olanzapine, clozapine was the best at reducing disease severity. While clozapine-treated mice had only modest changes to peripheral leukocytes and cytokine responses, these animals had significantly fewer CNS-infiltrating CD4 T cells and myeloid cells. Furthermore, the CNS myeloid cells displayed a less activated phenotype in mice treated with clozapine. Finally, we found that co-administration of clozapine with glatiramer acetate enhanced disease protection compared to either treatment alone. CONCLUSION: These studies indicate that clozapine is an effective immunomodulatory agent with the potential to treat immune-mediated diseases such as MS.

Pseudomonas aeruginosa MdaB and WrbA are water-soluble two-electron quinone oxidoreductases with the potential to defend against oxidative stress.

Water-soluble quinone oxidoreductases capable of reducing quinone substrates via a concerted two-electron mechanism have been implicated in bacterial antioxidant defence. Twoelectron transfer avoids formation of dangerously reactive semi-quinone intermediates, moreover previous work in Pseudomonas putida indicated a direct protective effect for the quinols generated by an over-expressed oxidoreductase. Here, the Pseudomonas aeruginosa orthologs of five quinone oxidoreductases--MdaB, ChrR, WrbA, NfsB, and NQO1--were tested for their possible role in defending P. aeruginosa against H2O2 challenge. In in vitro assays, each enzyme was shown to reduce quinone substrates with only minimal semiquinone formation. However, when each was individually over-expressed in P. aeruginosa no overt H2O2-protective phenotype was observed. It was shown that this was due to a masking effect of the P. aeruginosa catalase, KatA; in a katA mutant, H2O2 challenged strains over-expressing the WrbA and MdaB orthologs grew significantly better than the empty plasmid control. A growth advantage was also observed for H2O2 challenged P. putida strains over-expressing P. aeruginosa wrbA, mdaB or katA. Despite not conferring a growth advantage to wild type P. aeruginosa, it is possible that these quinone oxidoreductases defend against H2O2 toxicity at lower concentrations.

The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy.

Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the "gold standard" nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT.

Pseudomonas aeruginosa NfsB and nitro-CBI-DEI--a promising enzyme/prodrug combination for gene directed enzyme prodrug therapy.

BACKGROUND: The nitro-chloromethylbenzindoline prodrug nitro-CBI-DEI appears a promising candidate for the anti-cancer strategy gene-directed enzyme prodrug therapy, based on its ability to be converted to a highly cytotoxic cell-permeable derivative by the nitroreductase NfsB from Escherichia coli. However, relative to some other nitroaromatic prodrugs, nitro-CBI-DEI is a poor substrate for E. coli NfsB. To address this limitation we evaluated other nitroreductase candidates from E. coli and Pseudomonas aeruginosa. FINDINGS: Initial screens of candidate genes in the E. coli reporter strain SOS-R2 identified two additional nitroreductases, E. coli NfsA and P. aeruginosa NfsB, as being more effective activators of nitro-CBI-DEI than E. coli NfsB. In monolayer cytotoxicity assays, human colon carcinoma (HCT-116) cells transfected with P. aeruginosa NfsB were >4.5-fold more sensitive to nitro-CBI-DEI than cells expressing either E. coli enzyme, and 23.5-fold more sensitive than untransfected HCT-116. In three dimensional mixed cell cultures, not only were the P. aeruginosa NfsB expressing cells 540-fold more sensitive to nitro-CBI-DEI than pure cultures of untransfected HCT-116, the activated drug that they generated also displayed an unprecedented local bystander effect. CONCLUSION: We posit that the discrepancy in the fold-sensitivity to nitro-CBI-DEI between the two and three dimensional cytotoxicity assays stems from loss of activated drug into the media in the monolayer cultures. This emphasises the importance of evaluating high-bystander GDEPT prodrugs in three dimensional models. The high cytotoxicity and bystander effect exhibited by the NfsB_Pa/nitro-CBI-DEI combination suggest that further preclinical development of this GDEPT pairing is warranted.

Inefficient presentation of tumor-derived antigen by tumor-infiltrating dendritic cells.

BACKGROUND: Transplantable B16 melanoma is widely used as a tumor model to investigate tumor immunity. We wished to characterize the leukocyte populations infiltrating B16 melanoma tumors, and the functional properties of tumor-infiltrating dendritic cells (TIDC). MATERIALS AND METHODS: We used the B16 melanoma cell line expressing ovalbumin protein (OVA) to investigate the phenotype and T cell stimulatory capacity of TIDC. RESULTS: The majority of leukocytes in B16 melanoma were macrophages, which colocalized with TIDCs, B and T cells to the peripheral area of the tumor. Both myeloid and plasmacytoid DC populations were present within tumors. Most of these DCs appeared immature, but about a third expressed a mature phenotype. TIDCs did not present tumor-derived antigen, as they were unable to induce the proliferation of tumor-specific CD4+ and CD8+ T cells in vitro unless in the presence of specific peptides. Some presentation of tumor-derived antigen could be demonstrated in the tumor-draining lymph node using in vivo proliferation assays. However, while proliferation of CD8+ T cells was reproducibly demonstrated, no proliferation of CD4+ T cells was observed. CONCLUSION: In summary, our data suggest that DCs in tumors have limited antigen-presenting function. Inefficient antigen presentation extends to the tumor-draining lymph node, and may affect the generation of antitumor immune responses.

Tumor immunotherapy by epicutaneous immunization requires langerhans cells.

A role for Langerhans cells (LC) in the induction of immune responses in the skin has yet to be conclusively demonstrated. We used skin immunization with OVA protein to induce immune responses against OVA-expressing melanoma cells. Mice injected with OVA-specific CD8(+) T cells and immunized with OVA onto barrier-disrupted skin had increased numbers of CD8(+) T cells in the blood that produced IFN-gamma and killed target cells. These mice generated accelerated cytotoxic responses after secondary immunization with OVA. Prophylactic or therapeutic immunization with OVA onto barrier-disrupted skin inhibited the growth of B16.OVA tumors. LC played a critical role in the immunization process because depletion of LC at the time of skin immunization dramatically reduced the tumor-protective effect. The topically applied Ag was presented by skin-derived LC in draining lymph nodes to CD8(+) T cells. Thus, targeting of tumor Ags to LC in vivo is an effective strategy for tumor immunotherapy.

Post-LASIK epithelial dendritic defect associated with Alternaria.

PURPOSE: To report a case of a dendritic epithelial defect with interface inflammation associated with Alternaria sp. after laser in situ keratomileusis (LASIK) surgery. METHODS: A case report of a 46-year-old woman who presented with a dendritic epithelial defect and interface inflammation after LASIK surgery. RESULTS: After an apparent post-LASIK herpes simplex keratitis with related interface inflammation failed to respond to medical therapy, cornea culture results were positive for Alternaria fungal sp. 2 weeks and 6 days after presentation. Viral cultures and polymerase chain reaction were negative for herpes simplex virus. Six months after penetrating keratoplasty (and 1 year after LASIK), the patient underwent a cataract extraction OD. Best-corrected visual acuity 18 months after the original LASIK procedure was 20/25 OD. CONCLUSIONS: Alternaria keratitis may present with a dendritic epithelial defect with interface inflammation mimicking herpes simplex virus.

Procollagen with skipping of alpha 1(I) exon 41 has lower binding affinity for alpha 1(I) C-telopeptide, impaired in vitro fibrillogenesis, and altered fibril morphology.

Previous in vitro data on type I collagen self-assembly into fibrils suggested that the amino acid 776-796 region of the alpha1(I) chain is crucial for fibril formation because it serves as the recognition site for the telopeptide of a docking collagen monomer. We used a natural collagen mutation with a deletion of amino acids 766-801 to confirm the importance of this region for collagen fibril formation. The proband has type III osteogenesis imperfecta and is heterozygous for a COL1A1 IVS 41 A(+4) --> C substitution. The intronic mutation causes splicing of exon 41, confirmed by sequencing of normal and shorter reverse transcriptase-PCR products. Reverse transcriptase-PCR using RNA from proband dermal fibroblasts and clonal cell lines showed the mutant cDNA was about 15% of total alpha1(I) cDNA. The mutant transcript is translated; structurally abnormal alpha chains are demonstrated in the cell layer of proband fibroblasts by SDS-urea-PAGE. The proportion of mutant chains in the secreted procollagen was determined to be 10% by resistance to digestion with MMP-1, since chains lacking exon 41 are missing the vertebral collagenase cleavage site. Secreted proband collagen was used for analysis of kinetics of binding of alpha1(I) C-telopeptide using an optical biosensor. Telopeptide had slower association and faster dissociation from proband than from normal collagen. Purified proband pC-collagen was used to study fibril formation. The presence of the mutant molecules decreases the rate of fibril formation. The fibrils formed in the presence of 10-15% mutant molecules have strikingly increased length compared with normal collagen, but are well organized, as demonstrated by D-periodicity. These results suggest that some collagen molecules containing the mutant chain are incorporated into fibrils and that the absence of the telopeptide binding region from even a small portion of the monomers interferes with fibril growth. Both abnormal fibrils and slower remodeling may contribute to the severe phenotype.in