Gender representation in Canadian surgical leadership and medical faculties: a cross-sectional study.

BACKGROUND: Over the past two and half decades, Canadian medical school students have become majority female, and the medical workforce is therefore increasingly comprised of female physicians. Whether this change, however, has been reflected in the gender balance within medical school faculty positions and leadership has not been well studied in Canada. METHODS: This cross-sectional study examined the genders of full-time faculty members from the most recently available AFMC data, the current heads of departments of medicine and surgery from department websites and confirmed with respective universities. RESULTS: Overall, women held 40.5% of full-time faculty positions in Canadian faculties of medicine. Female representation decreased with increasing academic rank, from 57.8% of instructors to 50.8% of assistant, 39.2% of associate, and 28.1% of full professors, respectively, with the greatest rate of increase over the past decade among full professors (0.75% per year). The heads of departments of family medicine were majority female (67%), and heads internal medicine at parity (50% female), consistent with numbers of practicing physicians. However, the heads of surgical divisions were majority male (86% overall). Accounting for the gender balance of practicing surgeons, male compared to female surgeons were 2.9 times as likely to be division head (95% CI 1.78-4.85, p < 0.0001). CONCLUSIONS: Women remain underrepresented in Canadian faculties of medicine in leadership positions. Leadership in departments of surgery has particularly low female representation, even relative to the proportion of practicing female surgeons within the respective discipline.

From Hair Loss to Vision Loss: Minoxidil-Associated CRVO in a Young Female.

Introduction: Central retinal vein occlusion (CRVO) is a common retinal vascular disorder that is most often seen in older adults and individuals with vascular risk factors. Case Presentation: We report a case of CRVO with cystoid macular edema (CME) in a young, otherwise healthy patient taking minoxidil for hair loss. The patient had no known vascular risk factors, and a comprehensive coagulability workup was negative. The CRVO with CME resolved without intervention upon cessation of minoxidil. Conclusion: Possible mechanisms for minoxidil-associated retinal vascular disorders are explored. Thorough medication histories and the consideration of possible adverse drug events in patients without traditional risk factors are recommended.

Gender trends in Canadian medicine and surgery: the past 30 years.

BACKGROUND: While the number of women entering medicine has steadily increased since the 1970s in Canada, the gender composition along each stage of the medical training pathway has not been comprehensively reported. We therefore sought to systematically examine the gender composition of students, residents, and practicing physicians over the past 30 years in Canada. RESULTS: In this cross-sectional analysis of Canadian medical trainees including MD applicants (137,096 male, 169,099 female), MD students (126,422 male, 152, 967 female), MD graduates (29,413 male, 34,173 female), residents by the decade (24,425 male, 28,506 female) and practicing surgeons (total 7,457 male, 3,457 female), we find that increased female representation in medicine is not matched by representation in surgery, with the key being the specialty choice process. The likelihood of female applicants matriculating to medical school was less than male applicants in the 90s (OR 0.92, 95% CI 0.92-0.93), greater in the early 2000s (OR 1.03, 95% CI 1.03-1.04), and has since balanced out (OR 1.00, 95% CI 1.00-1.01), with medical school classes being nearly 60% female for the past two decades. Despite this, females have remained underrepresented in most surgical residency programs, with odds of female medical students entering surgical residency other than Ob/Gyn being about half that of male students (OR 0.56, 95% CI 0.44-0.71), resulting in a slow increase in practicing female surgeons of less than 0.5% per year in many surgical disciplines and projected parity decades or centuries in the future. CONCLUSIONS: While undergraduate medical education has been majority female in Canada for nearly three decades, females remain greatly underrepresented in the physician workforce within surgical specialties. To build a representative medical workforce equipped to care for diverse patient populations, factors influencing the specialty choices of early career physicians will need to be examined and addressed.

Ophthalmology referrals from optometry: a comparative study (the R.O.C.S study).

OBJECTIVE: To characterize emergency optometrist referrals triaged at a tertiary ophthalmology care centre by physical examination findings and provisional diagnosis accuracy. DESIGN: Prospective case review. PARTICIPANTS: Consecutive patients referred to a tertiary eye care clinic for an after-hours ocular consult. METHODS: Variables extracted from the patient charts included date of referral, age, sex, eye(s) under examination, referral visual acuity (VA), referral intraocular pressure (IOP), the referring optometrist's provisional diagnosis, VA at the time of the ophthalmologist consultation, IOP at the time of the ophthalmologist consultation, number of days between referral and ophthalmic consultation, and the ophthalmologist's diagnosis. Optometrist VA measures were correlated against ophthalmologist measures for left eye, right eye, diseased eye, and nondiseased eye. The independent t test was used to compare IOP measures between clinicians, and the absolute frequency of agreement between localization of eye pathology was reported. RESULTS: After categorizing disease by anatomic location, absolute agreement between optometrist provisional diagnosis and ophthalmologist diagnosis was 60.0%. Strong correlations were found between optometrist and ophthalmologist VA measurements. IOP measurements were reported less frequently by optometrists. In cases in which referral IOP was documented, no significant difference was observed between clinician measures. CONCLUSIONS: VA and IOP measurements by optometrists are reliable, although IOP measurements were included less frequently in optometrist referrals. Optometrist referrals correctly localized eye pathology in 60.0% of cases. Two cases of retinal tear and 2 cases of retinal detachment, for which a precise reason for referral is ideal, were referred for other reasons.

Patient satisfaction with wait times at an emergency ophthalmology on-call service.

OBJECTIVE: To assess patient satisfaction with emergency ophthalmology care and determine the effect provision of anticipated appointment wait time has on scores. DESIGN: Single-centre, randomized control trial. PARTICIPANTS: Fifty patients triaged at the Hamilton Regional Eye Institute (HREI) from November 2015 to July 2016. METHODS: Fifty patients triaged for next-day appointments at the HREI were randomly assigned to receive standard-of-care preappointment information or standard-of-care information in addition to an estimated appointment wait time. Patient satisfaction with care was assessed postvisit using the modified Judgements of Hospital Quality Questionnaire (JHQQ). In determining how informing patients of typical wait times influenced satisfaction, the Mann-Whitney U test was performed. As secondary study outcomes, we sought to determine patient satisfaction with the intervention material using the Fisher exact test and the effect that wait time, age, sex, education, mobility, and number of health care providers seen had on satisfaction scores using logistic regression analysis. RESULTS: The median JHQQ response was "very good" (4/5) and between "very good" and "excellent" (4.5/5) in the intervention and control arms, respectively. There was no difference in patient satisfaction between the cohorts (Mann-Whitney U = 297.00, p = 0.964). Logistic regression analysis demonstrated that wait times influenced patient satisfaction (OR = 0.919, 95% CI 0.864-0.978, p = 0.008). Of the intervention arm patients, 92.0% (N = 23) found the preappointment information useful, whereas only 12.5% (N = 3) of the control cohort patients noted the same (p < 0.001). CONCLUSION: Provision of anticipated wait time information to patients in an emergency on-call ophthalmology clinic did not influence satisfaction with care as captured by the JHQQ.

Trends in subspecialty training by Canadian ophthalmology graduates.

OBJECTIVE: To evaluate the trends in subspecialty fellowship training by Canadian ophthalmology graduates over the last 25 years. DESIGN: Cross-sectional study. PARTICIPANTS: Canadian-funded, Royal College-certified graduates from 1990 to 2014 who completed a full residency in an English-language Canadian ophthalmology postgraduate training program. METHODS: Data were obtained by contacting all 11 English-language ophthalmology residency programs across Canada for demographic and fellowship information regarding their graduates. Society web sites were then used to corroborate and complement the data set, including those of the Canadian Ophthalmology Society, American Academy of Ophthalmology, and Provincial Colleges of Physicians and Surgeons. Data were organized by demographic variables, and analysis was performed using SPSS v22.0. RESULTS: Of the 528 graduates from 1990 to 2014, 63.5% pursued fellowship training. Males and females were equally likely to undertake fellowship training. The proportion of graduates obtaining fellowship training did not change significantly during this 25-year period. The most popular subspecialty choices were vitreoretinal surgery (24.5%), glaucoma (16.7%), and anterior segment (16.7%). Significantly more males than females pursued vitreoretinal surgery and oculoplastics fellowships (p = 0.001, χ(2) test), whereas females were more likely to train in a paediatric ophthalmology and strabismus fellowship (p = 0.001, χ(2) test). CONCLUSIONS: The majority of ophthalmology graduates from English-language residency programs pursue subspecialty fellowship training. An understanding of trends in fellowship training may be helpful for both workforce planning and career decision making.

Sexually transmitted infections and viral hepatitides in patients presenting for non-occupational HIV post-exposure prophylaxis: results of a prospective cohort study.

Data evaluating the screening practices for viral hepatitides and sexually transmitted infections (STIs) in patients presenting for non-occupational HIV post-exposure prophylaxis (nPEP) care are limited. Screening practices and prevalences of viral hepatitides and STIs were evaluated in 126 patients presenting to a dedicated HIV prevention clinic for HIV nPEP. Three patients (2.4%) were diagnosed with chronic hepatitis C infection, 28 (22.2%) did not have surface antibodies in sufficient quantity to confer immunity to hepatitis B, and six (4.8%) were diagnosed with an STI. A multivariate regression model did not predict any demographic or clinical features predictive of HBV non-immunity. Beyond screening for HIV infection, evaluation for viral hepatitides and STIs is an important feature in the care of patients presenting for HIV nPEP.

Transitioning to HIV Pre-Exposure Prophylaxis (PrEP) from Non-Occupational Post-Exposure Prophylaxis (nPEP) in a Comprehensive HIV Prevention Clinic: A Prospective Cohort Study.

The uptake of pre-exposure prophylaxis (PrEP) for HIV prevention remains low. We hypothesized that a high proportion of patients presenting for HIV non-occupational post-exposure prophylaxis (nPEP) would be candidates for PrEP based on current CDC guidelines. Outcomes from a comprehensive HIV Prevention Clinic are described. We evaluated all patients who attended the HIV Prevention Clinic for nPEP between January 1, 2013 and September 30, 2014. Each patient was evaluated for PrEP candidacy based on current CDC-guidelines and subjectively based on physician opinion. Patients were then evaluated for initiation of PrEP if they met guideline suggestions. Demographic, social, and behavioral factors were then analyzed with logistic regression for associations with PrEP candidacy and initiation. 99 individuals who attended the nPEP clinic were evaluated for PrEP. The average age was 32 years (range, 18-62), 83 (84%) were male, of whom 46 (55%) men who had have sex with men (MSM). 31 (31%) met CDC guidelines for PrEP initiation, which had very good agreement with physician recommendation (kappa=0.88, 0.78-0.98). Factors associated with PrEP candidacy included sexual exposure to HIV, prior nPEP use, and lack of drug insurance (p<0.05 for all comparisons). Combining nPEP and PrEP services in a dedicated clinic can lead to identification of PrEP candidates and may facilitate PrEP uptake. Strategies to ensure equitable access of PrEP should be explored such that those without drug coverage may also benefit from this effective HIV prevention modality.

MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways.

Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR-146a and miR-146b are induced in endothelial cells upon exposure to pro-inflammatory cytokines. Despite the rapid transcriptional induction of the miR-146a/b loci, which is in part mediated by EGR-3, miR-146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression. We demonstrate that miR-146 negatively regulates inflammation. Over-expression of miR-146a blunts endothelial activation, while knock-down of miR-146a/b in vitro or deletion of miR-146a in mice has the opposite effect. MiR-146 represses the pro-inflammatory NF-κB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR-146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro-inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases.

Functions of the Epstein-Barr virus EBNA1 protein in viral reactivation and lytic infection.

EBNA1 is the only nuclear Epstein-Barr virus (EBV) protein expressed in both latent and lytic modes of infection. While EBNA1 is known to play several important roles in latent infection, the reason for its continued expression in lytic infection is unknown. Here we identified two roles for EBNA1 in the reactivation of latent EBV to the lytic cycle in epithelial cells. First, EBNA1 depletion in latently infected cells was shown to positively contribute to spontaneous EBV reactivation, showing that EBNA1 has a role in suppressing reactivation. Second, when the lytic cycle was induced, EBNA1 depletion decreased lytic gene expression and DNA amplification, showing that it positively contributed to lytic infection. Since we have previously shown that EBNA1 disrupts promyelocytic leukemia (PML) nuclear bodies, we investigated whether this function could account for the effects of EBNA1 on lytic infection by repeating the experiments with cells lacking PML proteins. In the absence of PML, EBNA1 did not promote lytic infection, indicating that the EBNA1-mediated PML disruption is responsible for promoting lytic infection. In keeping with this conclusion, PML silencing was found to be sufficient to induce the EBV lytic cycle. Finally, by generating cells with single PML isoforms, we showed that individual PML isoforms were sufficient to suppress EBV lytic reactivation, although PML isoform IV (PML IV) was ineffective because it was most efficiently degraded by EBNA1. Our results provide the first function for EBNA1 in lytic infection and show that EBNA1 interactions with PML IV lead to a loss of PML nuclear bodies (NBs) that promotes lytic infection.

Contributions of the Epstein-Barr virus EBNA1 protein to gastric carcinoma.

Approximately 10% of gastric carcinomas (GC) are comprised of cells latently infected with Epstein-Barr virus (EBV); however, the mechanism by which EBV contributes to the development of this malignancy is unclear. We have investigated the cellular effects of the only EBV nuclear protein expressed in GC, EBNA1, focusing on promyelocytic leukemia (PML) nuclear bodies (NBs), which play important roles in apoptosis, p53 activation, and tumor suppression. AGS GC cells infected with EBV were found to contain fewer PML NBs and less PML protein than the parental EBV-negative AGS cells, and these levels were restored by silencing EBNA1. Conversely, EBNA1 expression was sufficient to induce the loss of PML NBs and proteins in AGS cells. Consistent with PML functions, EBNA1 expression decreased p53 activation and apoptosis in response to DNA damage and resulted in increased cell survival. In addition, EBNA1 mutants unable to bind CK2 kinase or ubiquitin-specific protease 7 had decreased ability to induce PML loss and to interfere with p53 activation. PML levels in EBV-positive and EBV-negative GC biopsy specimens were then compared by immunohistochemistry. Consistent with the results in the AGS cells, EBV-positive tumors had significantly lower PML levels than EBV-negative tumors. The results indicate that EBV infection of GC cells leads to loss of PML NBs through the action of EBNA1, resulting in impaired responses to DNA damage and promotion of cell survival. Therefore, PML disruption by EBNA1 is one mechanism by which EBV may contribute to the development of gastric cancer.

Epstein-Barr virus nuclear antigen 1 replication and segregation functions in nasopharyngeal carcinoma cell lines.

Nasopharyngeal carcinomas (NPC) are usually Epstein-Barr virus (EBV) positive, but, with the exception of C666-1 cells, these cells lose the EBV genomes when grown in culture. Maintenance of EBV requires the viral EBV nuclear antigen 1 (EBNA1) protein, which ensures the replication and mitotic segregation of the genomes through interactions with OriP. Here we compare the abilities of C666-1 and NPC cells that have lost EBV genomes to replicate and segregate OriP plasmids. We found that either cell line can replicate and maintain OriP plasmids for extended periods under conditions where low levels of EBNA1 are expressed but that high EBNA1 levels selectively interfered with mitotic segregation.

Epstein-Barr virus nuclear antigen 1 Hijacks the host kinase CK2 to disrupt PML nuclear bodies.

Latent Epstein-Barr virus (EBV) infection is an important causative factor in the development of several cancers, including nasopharyngeal carcinoma (NPC). The one EBV protein expressed in the nucleus of NPC cells, EBNA1, has been shown to disrupt promyelocitic leukemia (PML) nuclear bodies (NBs) by inducing the degradation of PML proteins, leading to impaired DNA repair and increased cell survival. Although EBNA1-mediated PML disruption is likely to be an important factor in the development of NPC, little is known about its mechanism. We now show that an interaction between EBNA1 and the host CK2 kinase is crucial for EBNA1 to disrupt PML bodies and degrade PML proteins. EBNA1 increases the association of CK2 with PML proteins, thereby increasing the phosphorylation of PML proteins by CK2, a modification that is known to trigger the polyubiquitylation and degradation of PML. The interaction between EBNA1 and CK2 is direct and occurs through the ß regulatory subunit of CK2 and EBNA1 amino acids 387 to 394. The binding of EBNA1 to the host ubiquitin specific protease USP7 has also been shown to be important for EBNA1-mediated PML disruption. We show that EBNA1 also increases the occupancy of USP7 at PML NBs and that CK2 and USP7 bind independently and simultaneously to EBNA1 to form a ternary complex. The combined results indicate that EBNA1 usurps two independent cellular pathways to trigger the loss of PML NBs.

Epstein-Barr nuclear antigen 1 contributes to nasopharyngeal carcinoma through disruption of PML nuclear bodies.

Latent Epstein-Barr virus (EBV) infection is strongly associated with several cancers, including nasopharyngeal carcinoma (NPC), a tumor that is endemic in several parts of the world. We have investigated the molecular basis for how EBV latent infection promotes the development of NPC. We show that the viral EBNA1 protein, previously known to be required to maintain the EBV episomes, also causes the disruption of the cellular PML (promyelocytic leukemia) nuclear bodies (or ND10s). This disruption occurs both in the context of a native latent infection and when exogenously expressed in EBV-negative NPC cells and involves loss of the PML proteins. We also show that EBNA1 is partially localized to PML nuclear bodies in NPC cells and interacts with a specific PML isoform. PML disruption by EBNA1 requires binding to the cellular ubiquitin specific protease, USP7 or HAUSP, but is independent of p53. We further observed that p53 activation, DNA repair and apoptosis, all of which depend on PML nuclear bodies, were impaired by EBNA1 expression and that cells expressing EBNA1 were more likely to survive after induction of DNA damage. The results point to an important role for EBNA1 in the development of NPC, in which EBNA1-mediated disruption of PML nuclear bodies promotes the survival of cells with DNA damage.

Regulation of the EBNA1 Epstein-Barr virus protein by serine phosphorylation and arginine methylation.

The Epstein-Barr virus (EBV) EBNA1 protein is important for the replication and mitotic segregation of EBV genomes in latently infected cells and also activates the transcription of some of the viral latency genes. A Gly-Arg-rich region between amino acids 325 and 376 is required for both the segregation and transcriptional activation functions of EBNA1. Here we show that this region is modified by both arginine methylation and serine phosphorylation. Mutagenesis of the four potentially phosphorylated serines in this region indicated that phosphorylation of multiple serines contributes to the efficient segregation of EBV-based plasmids by EBNA1, at least in part by increasing EBNA1 binding to hEBP2. EBNA1 was also found to bind the arginine methyltransferases PRMT1 and PRMT5. Multiple arginines in the 325-376 region were methylated in vitro by PRMT1 and PRMT5, as was an N-terminal Gly-Arg-rich region between amino acids 41 and 50. EBNA1 was also shown to be methylated in vivo, predominantly in the 325-376 region. Treatment of cells with a methylation inhibitor or down-regulation of PRMT1 altered EBNA1 localization, resulting in the formation of EBNA1 rings around the nucleoli. The results indicate that EBNA1 function is influenced by both serine phosphorylation and arginine methylation.