Interaction of AI-Enabled Quantitative Coronary Plaque Volumes on Coronary CT Angiography, FFRCT, and Clinical Outcomes: A Retrospective Analysis of the ADVANCE Registry.

BACKGROUND: Luminal stenosis, computed tomography-derived fractional-flow reserve (FFRCT), and high-risk plaque features on coronary computed tomography angiography are all known to be associated with adverse clinical outcomes. The interactions between these variables, patient outcomes, and quantitative plaque volumes have not been previously described. METHODS: Patients with coronary computed tomography angiography (n=4430) and one-year outcome data from the international ADVANCE (Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care) registry underwent artificial intelligence-enabled quantitative coronary plaque analysis. Optimal cutoffs for coronary total plaque volume and each plaque subtype were derived using receiver-operator characteristic curve analysis. The resulting plaque volumes were adjusted for age, sex, hypertension, smoking status, type 2 diabetes, hyperlipidemia, luminal stenosis, distal FFRCT, and translesional delta-FFRCT. Median plaque volumes and optimal cutoffs for these adjusted variables were compared with major adverse cardiac events, late revascularization, a composite of the two, and cardiovascular death and myocardial infarction. RESULTS: At one year, 55 patients (1.2%) had experienced major adverse cardiac events, and 123 (2.8%) had undergone late revascularization (>90 days). Following adjustment for age, sex, risk factors, stenosis, and FFRCT, total plaque volume above the receiver-operator characteristic curve-derived optimal cutoff (total plaque volume >564 mm3) was associated with the major adverse cardiac event/late revascularization composite (adjusted hazard ratio, 1.515 [95% CI, 1.093-2.099]; P=0.0126), and both components. Total percent atheroma volume greater than the optimal cutoff was associated with both major adverse cardiac event/late revascularization (total percent atheroma volume >24.4%; hazard ratio, 2.046 [95% CI, 1.474-2.839]; P<0.0001) and cardiovascular death/myocardial infarction (total percent atheroma volume >37.17%, hazard ratio, 4.53 [95% CI, 1.943-10.576]; P=0.0005). Calcified, noncalcified, and low-attenuation percentage atheroma volumes above the optimal cutoff were associated with all adverse outcomes, although this relationship was not maintained for cardiovascular death/myocardial infarction in analyses stratified by median plaque volumes. CONCLUSIONS: Analysis of the ADVANCE registry using artificial intelligence-enabled quantitative plaque analysis shows that total plaque volume is associated with one-year adverse clinical events, with incremental predictive value over luminal stenosis or abnormal physiology by FFRCT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02499679.

Independent Plastic Surgery Match Regional Trends Comparing In-person and Virtual Interview Cycles.

Background: There is a trend toward matching in a different region than previous training for the independent plastic surgery match cycles from 2019 to 2021, which differs from the trend to match within the same region for integrated plastic surgery programs. Notably, residency interviews transitioned from in-person to virtual in 2020 due to the coronavirus pandemic. Therefore, we compared in-person versus virtual interview match trends from 2019 to 2023. Methods: Zip codes and regions of each successfully matched plastic surgery applicant's medical school, residency, and plastic surgery program were gathered from publicly available data for the 2019 and 2020 in-person interview cycles and 2021, 2022, and 2023 virtual interview cycles. Results: Although regions did not differ significantly in the proportions of positions each year (P = 0.85), there was a trend toward fewer positions in each region from 2019 to 2022. Overall, applicants were more likely to match in a different region as their medical school or residency during virtual compared with in-person interviews (P = 0.002 and P = 0.04). Applicants matched to programs further from their medical school zip code in virtual interview years (P = 0.02). There was no significant difference in distance between surgical residencies and plastic surgery residencies between the two time periods (P = 0.51). Conclusions: Trends toward matching into a different region than prior training after the switch to virtual interviews could be attributed to applicant accessibility to interview broadly. However, this could also be due to the decreased number of independent residency positions over the years, requiring applicants to move regions and travel further from where they began their training.

Association of plasma NRP2 and VEGF-C levels with prostate cancer disease severity.

BACKGROUND: Neuropilin 2 (NRP2) expression in tissue is an independent prognostic factor for aggressive prostate cancer. Since the NRP2 pathway activation is thought to occur in part through secondary resistance, quantification of NRP2 in initial tissue biopsy specimens collected at diagnosis may have limited utility in identifying patients at highest risk for morbidity and mortality. Given that metastatic tissue is only occasionally obtained for analysis, there is a need for development of a plasma biomarker indicative of NRP2 pathway activation to potentially inform prostate cancer prognosis. Therefore, we investigated if plasma levels of NRP2 or vascular endothelial growth factor C (VEGF-C), a known soluble ligand of NRP2, are prognostic for prostate cancer. We hypothesized that plasma NRP2 and VEGF-C would be associated with more advanced disease or relapsed disease. METHODS: NRP2 and VEGF-C levels were quantified by enzyme-linked immunoassay in plasma samples obtained from 145 prostate cancer patients in an opportunistic biobank. These patients were either (1) newly diagnosed (N = 28), (2) in remission (N = 56), or (3) relapsed disease (N = 61). Plasma samples from 15 adult males without known malignancy served as a comparator cohort. Statistical analysis was performed to investigate the association of plasma NRP2/VEGF-C with patient outcomes, adjusting for age, race, prostate-specific antigen (PSA), Gleason score, and tumor stage at diagnosis. RESULTS: Neither NRP2 nor VEGF-C levels were significantly different in cancer patients compared to noncancer controls. We observed no clear association between plasma NRP2 and disease severity. Increased plasma VEGF-C was significantly associated with disease remission and correlated with Stage I/II and intermediate-risk Gleason score. Neither NRP2 nor VEGF-C correlated with PSA level. CONCLUSIONS: Although tissue NRP2 expression correlates with severe disease, this was not observed for plasma NRP2. Plasma NRP2 levels did not correlate with disease severity or relapse. VEGF-C was highest in patients in remission and with less severe disease. Future investigation is needed to identify noninvasive methods to assess tumor NRP2 status.

Atypical Pattern of Leukocytoclastic Vasculitis in Granulomatosis With Polyangiitis.

Granulomatosis with polyangiitis (GPA), formerly Wegener's granulomatosis, is a small- and medium-vessel vasculitis with characteristic cutaneous morphologic presentation and systemic involvement. Most patients have palpable purpura at some point in their disease course, but this is not always the presenting manifestation. This autoimmune disorder can affect a range of organs, with the upper and lower respiratory tract, kidneys, and nervous system being commonly implicated, while gastrointestinal and cardiac involvement is less frequent. This is a 44-year-old female presenting to the emergency department (ED) with polyarthralgia and palpable purpura. Palpable purpura was distributed on the oral palate, elbow, and lower back, and a punch biopsy revealed leukocytoclastic vasculitis (LCV). While this was an atypical distribution for leukocytoclastic vasculitis, the skin biopsy provided the necessary evidence to diagnose GPA. This case characterizes non-specific and atypical signs and symptoms of GPA that all providers should be aware of in order to diagnose the condition early in its disease course.

DRAK2 contributes to type 1 diabetes by negatively regulating IL-2 sensitivity to alter regulatory T cell development.

Drak2-deficient (Drak2-/-) mice are resistant to multiple models of autoimmunity yet effectively eliminate pathogens and tumors. Thus, DRAK2 represents a potential target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Here, we demonstrate that resistance to T1D in non-obese diabetic (NOD) mice is due to the absence of Drak2 in T cells and requires the presence of regulatory T cells (Tregs). Contrary to previous hypotheses, we show that DRAK2 does not limit TCR signaling. Rather, DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation. We further demonstrate that enhanced sensitivity to IL-2 in the absence of Drak2 augments thymic Treg development. Overall, our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic Treg development and by impacting the sensitivity of conventional T cells to Treg-mediated suppression.

Microtubule Severing Enzymes Oligomerization and Allostery: A Tale of Two Domains.

Severing proteins are nanomachines from the AAA+ (ATPases associated with various cellular activities) superfamily whose function is to remodel the largest cellular filaments, microtubules. The standard AAA+ machines adopt hexameric ring structures for functional reasons, while being primarily monomeric in the absence of the nucleotide. Both major severing proteins, katanin and spastin, are believed to follow this trend. However, studies proposed that they populate lower-order oligomers in the presence of cofactors, which are functionally relevant. Our simulations show that the preferred oligomeric assembly is dependent on the binding partners and on the type of severing protein. Essential dynamics analysis predicts that the stability of an oligomer is dependent on the strength of the interface between the helical bundle domain (HBD) of a monomer and the convex face of the nucleotide binding domain (NBD) of a neighboring monomer. Hot spots analysis found that the region consisting of the HBD tip and the C-terminal (CT) helix is the only common element between the allosteric networks responding to nucleotide, substrate, and intermonomer binding. Clustering analysis indicates the existence of multiple pathways for the transition between the secondary structure of the HBD tip in monomers and the structure(s) it adopts in oligomers.

Src-Dependent DBL Family Members Drive Resistance to Vemurafenib in Human Melanoma.

The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a BRAFV600E mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease. We employed a genetic screening approach to identify gain-of-function mechanisms of BRAFi resistance in two independent melanoma cell lines. Our screens identified both known and unappreciated drivers of BRAFi resistance, including multiple members of the DBL family. Mechanistic studies identified a DBL/RAC1/PAK signaling axis capable of driving resistance to both current and next-generation BRAFis. However, we show that the SRC inhibitor, saracatinib, can block the DBL-driven resistance. Our work highlights the utility of our straightforward genetic screening method in identifying new drug combinations to combat acquired BRAFi resistance. SIGNIFICANCE: A simple, rapid, and flexible genetic screening approach identifies genes that drive resistance to MAPK inhibitors when overexpressed in human melanoma cells.

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.

Ophthalmic referrals from emergency wards-a study of cases referred for urgent eye care (The R.E.S.C.U.E Study).

OBJECTIVE: To characterize emergency department (ED) referrals in order to identify the most common pathologies, compare accuracy of diagnosis, and measure correlation of visual acuity (VA) and intraocular pressure (IOP) measurements between the ED and ophthalmology setting. DESIGN, SETTING, AND PARTICIPANTS: Retrospective chart review of consecutive patients referred for an ocular emergency after hours to a tertiary care emergency eye clinic in Hamilton, Ontario, between February 17, 2015, and May 3, 2015 (n = 288). METHODS: Variables extracted from the patients' charts included date of referral, age, sex, eye(s) under examination, VA at the time of referral, IOP at the time of the referral, site of referral, the referring physician'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. RESULTS: Agreement between ED provisional diagnosis and ophthalmology was good at 79.4% when classified according to anatomic location of pathology. A strong correlation was found between VA measurements in the ED and ophthalmology setting (p < 0.001). IOP measurement was infrequently checked in ED and a significant difference existed between ER physician and ophthalmologist measurements (p = 0.010) where ophthalmology reported lower IOP. CONCLUSIONS: The 5 highest volume diagnoses in descending order were posterior vitreous detachment/vitreous syneresis, corneal abrasion, keratitis, anterior uveitis, and retinal tear/detachment. Visual acuity measurements in ED are reliable. IOP is infrequently checked in the ED and more unreliable when measured over 20 mm Hg.

Role of journal club in Canadian ophthalmology residency training: a national survey of program directors.

OBJECTIVE: To conduct a national survey of journal club curricula in Canadian ophthalmology residency programs. DESIGN: Cross-sectional web-based survey. PARTICIPANTS: Fifteen Royal College of Physicians and Surgeons of Canada (RCPSC) ophthalmology residency program directors. METHODS: The 15 RCPSC ophthalmology residency program directors were invited to participate in a 31-item online survey. The survey inquired about the purpose, educational goals, and structure of journal club. Basic statistics were performed to compare responses across institutions. RESULTS: Thirteen of the 15 program directors replied, representing an 87% response rate. Twelve (92%) institutions maintained a journal club. All of the program directors surveyed felt that journal club had educational value. Resident attendance was typically mandatory (75%) and correspondingly high across programs. There was 100% agreement that randomized controlled trials were most often selected for review. The primary journal club objectives were for residents to develop critical appraisal skills and to conduct a literature search (67%). Formal teaching and evaluation of these skills were not prioritized by any program. Seventeen percent felt the most important objective was to impact clinical practice. CONCLUSIONS: Canadian ophthalmology program directors expressed high levels of satisfaction that journal club was effective in meeting its stated objectives. This indicates that the teaching model promoted resident critical appraisal skills; however, objective evaluation methods to assess resident competence in evidence-based medicine were not described by any respondents. As RCSPC ophthalmology programs transition to competency-based medical education, program directors may consider modifying journal club curriculum, broadening its utility toward a means of outcome assessment.

A facile and versatile methodology for cysteine specific labeling of proteins with octahedral polypyridyl d6 metal complexes.

We have synthesized and characterized four octahedral polypyridyl d(6) metal complexes bearing the 5,6-epoxy-5,6-dihydro-[1,10]phenanthroline ligand (L1) as cysteine specific labeling reagents. The proposed synthetic pathways allow the preparation of the metal complexes containing Re(I), Ru(II), Os(II) and Ir(III) while preserving the epoxide functionality. The complexes were characterized by (1)H and (13)C NMR, mass spectrometry, UV-visible and luminescence spectroscopies as well as cyclic voltammetry. As proof of concept, a set of non-native single cysteine P450 BM3 heme domain mutants previously developed in our laboratory was used to study the labeling reaction. We demonstrate that the proposed labels can selectively react, often in high yield, with cysteine residues of the protein via the nucleophilic thiol ring opening of the epoxide moiety. In addition, under basic conditions, subsequent loss of a water molecule led to the aromatization of the phenanthroline ring on the protein-bound label compounds, as observed by mass spectrometry and luminescence measurements.