International Classification System for Ocular Complications of Anti-Vascular Endothelial Growth Factor Agents in Clinical Trials.

OBJECTIVE: Complications associated with intravitreal anti-vascular endothelial growth factor (VEGF) therapies are inconsistently reported in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN: Systematic review and Delphi consensus process. PARTICIPANTS: 25 international retinal specialists participated in the Delphi consensus survey. METHODS: A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists that voted on inclusion, exclusion, rephrasing, and addition of complications. As well, surveys determined specifiers for the selected complications. This iterative process helped refine the final classification system. MAIN OUTCOME MEASURES: The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS: After screening 18,229 articles, 130 complications were initially categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 (70%) complications after three rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 (52%) complications in the final list. A total of 14 (11%) complications met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds were also excluded from the final classification system after the Delphi process terminated. In addition, 47 out of 75 (63%) proposed complication specifiers were included based on participant agreement. CONCLUSION: Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses.

Paediatric vision screening in the primary care setting in Ontario.

OBJECTIVES: Early intervention is critical to prevent treatable causes of vision loss in children. The objectives of the current study are: (1) to assess how well primary care physicians in Ontario follow the vision screening guidelines for children as recommended by the Canadian Paediatric Society and the Rourke Baby Record and (2) to identify barriers to vision screening in the primary care setting. DESIGN: Cross-sectional survey. METHODS: A 19-question survey was mailed out to 1000 randomly selected family physicians (family MDs), 1000 general practitioners (GPs) and 1000 paediatricians in Ontario as listed in the 2013 Canadian Medical Directory. RESULTS: A total of 719 completed surveys were included in the analysis (449 from family MDs/GPs and 270 from paediatricians). Vision screening was reported to be performed by 65% of family MDs/GPs and 52% of general paediatricians at every well child visit. While red reflex was reported to be checked by 94% of all physicians in children under 3, it was only performed by 25% of respondents for children over 3. Thirty seven percent of all physicians reported never performing a visual acuity test in any age group. When asked about the obstacles preventing them from performing vision screening, lack of training (family MDs/GPs: 50%, paediatricians: 42%), time constraints (family MDs/GPs: 42%; paediatricians: 40%) and inadequate reimbursement (family MDs/GPs: 17%; paediatricians: 15%) were the most commonly cited reasons. CONCLUSIONS: Strategies to improve vision screening are necessary given that early intervention is crucial to prevent treatable causes of vision loss in children.

Effect of Geography on the Analysis of Coccidioidomycosis-Associated Deaths, United States.

Because coccidioidomycosis death rates vary by region, we reanalyzed coccidioidomycosis-associated mortality in the United States by race/ethnicity, then limited analysis to Arizona and California. Coccidioidomycosis-associated deaths were shown to increase among African-Americans but decrease among Native Americans and Hispanics. Separately, in a Native American cohort, diabetes co-varied with coccidioidomycosis-associated death.

Diabetic Disease of the Eye in Canada: Consensus Statements from a Retina Specialist Working Group.

Despite advances in systemic care, diabetic disease of the eye (DDE) remains the leading cause of blindness worldwide. There is a critical gap of up-to-date, evidence-based guidance for ophthalmologists in Canada that includes evidence from recent randomized controlled trials. Previous guidance has not always given special consideration to applying treatments and managing DDE in the context of the healthcare system. This consensus statement aims to assist practitioners in the field by providing a spectrum of acceptable opinions on DDE treatment and management from recognized experts in the field. In compiling evidence and generating consensus, a working group of retinal specialists in Canada addressed clinical questions surrounding the four themes of disease, patient, management, and collaboration. The working group reviewed literature representing the highest level of evidence on DDE and shared their opinions on topics surrounding the epidemiology and pathophysiology of diabetic retinopathy and diabetic macular edema; diagnosis and monitoring; considerations around diabetes medication use; strategic considerations for management given systemic comorbidities, ocular comorbidities, and pregnancy; treatment goals and modalities for diabetic macular edema, non-proliferative and proliferative diabetic retinopathy, and retinal detachment; and interdisciplinary collaboration. Ultimately, this work highlighted that the retinal examination in DDE not only informs the treating ophthalmologist but can serve as a global index for disease progression across many tissues of the body. It highlighted further that DDE can be treated regardless of diabetic control, that a systemic approach to patient care will result in the best health outcomes, and prevention of visual complications requires a multidisciplinary management approach. Ophthalmologists must tailor their clinical approach to the needs and circumstances of individual patients and work within the realities of their healthcare setting.

STB5 is a negative regulator of azole resistance in Candida glabrata.

The opportunistic yeast pathogen Candida glabrata is recognized for its ability to acquire resistance during prolonged treatment with azole antifungals (J. E. Bennett, K. Izumikawa, and K. A. Marr. Antimicrob. Agents Chemother. 48:1773-1777, 2004). Resistance to azoles is largely mediated by the transcription factor PDR1, resulting in the upregulation of ATP-binding cassette (ABC) transporter proteins and drug efflux. Studies in the related yeast Saccharomyces cerevisiae have shown that Pdr1p forms a heterodimer with another transcription factor, Stb5p. In C. glabrata, the open reading frame (ORF) designated CAGL0I02552g has 38.8% amino acid identity with STB5 (YHR178w) and shares an N-terminal Zn(2)Cys(6) binuclear cluster domain and a fungus-specific transcriptional factor domain, prompting us to test for homologous function and a possible role in azole resistance. Complementation of a Δyhr178w (Δstb5) mutant with CAGL0I02552g resolved the increased sensitivity to cold, hydrogen peroxide, and caffeine of the mutant, for which reason we designated CAGl0I02552g CgSTB5. Overexpression of CgSTB5 in C. glabrata repressed azole resistance, whereas deletion of CgSTB5 caused a modest increase in resistance. Expression analysis found that CgSTB5 shares many transcriptional targets with CgPDR1 but, unlike the latter, is a negative regulator of pleiotropic drug resistance, including the ABC transporter genes CDR1, PDH1, and YOR1.

Anesthetic management of a pediatric patient undergoing a pancreatoduodenectomy with portal vein reconstruction.

A pancreatoduodenectomy involves the removal of a tumor from the head of the pancreas. It is a technically difficult procedure requiring experienced anesthesia and surgical teams. The addition of a portal vein reconstruction increases the complexity of the case. A pancreatoduodenectomy is rarely performed on pediatric patients. Although reports of pediatric pancreatoduodenectomies exist in the surgical literature, there are no reports in the anesthesia literature. Anesthesia providers must be prepared to manage these complicated cases because substantial fluid shifts, blood loss, and electrolyte disturbances may occur intraoperatively. We report the perioperative management of a pediatric patient undergoing this procedure.

Early Canadian Real-World Experience with Brolucizumab in Anti-Vascular Endothelial Growth Factor-Experienced Patients with Neovascular Age-Related Macular Degeneration: A Retrospective Chart Review.

Purpose: To assess early real-world outcomes with brolucizumab in Canadian patients with neovascular age-related macular degeneration (nAMD) for which they previously received ≥1 anti-vascular endothelial growth factor (anti-VEGF) agent(s). Patients and Methods: This multisite, real-world, retrospective chart review included data from a consecutive sample of 73 patients who received brolucizumab for nAMD after treatment with ≥1 other anti-VEGF agents. The principal reasons for switching to brolucizumab were to extend the treatment interval (51.6% of patients) and to treat persistent macular fluid (34.2%). The primary outcomes were best-corrected visual acuity (BCVA) and the incidence rates of intraocular inflammation (IOI), retinal vasculitis (RV), and retinal vascular occlusion (RVO). Secondary outcomes included central retinal thickness (CRT), injection interval, and presence of intraretinal and subretinal fluid (IRF and SRF). All parameters were measured at baseline until the last treatment visit between April 27, 2020, and August 31, 2021. Results: Over a mean follow-up of 28 weeks, a nonsignificant mean improvement in BCVA was identified (4.3 [standard deviation (SD) 8.3] letters; P=0.057), with 47.9% experiencing a gain of ≥5 letters. IOI was detected in 3 patients (4.1%), one of whom also developed RV and RVO (1.4%), which is consistent with existing brolucizumab data. Significant reductions were observed in mean CRT (-36.6 µm [SD 56.1 µm]; P=0.0002) and presence of any macular fluid (56.1% [SD 5.6%]; P<0.001), IRF (66.6% [SD 6.3%]; P<0.001), and SRF (62.7% [SD 6.3%]; P<0.001). The mean injection interval increased significantly by 2.1 weeks (SD 2.7; P<0.001). Conclusion: In the first real-world Canadian analysis, brolucizumab was associated with improvements in functional outcomes in treatment-experienced patients, consistent with other real-world studies. The incidence of IOI, RV, and RVO were in line with the post hoc safety analysis of HAWK and HARRIER data.

Germinoma of the Corpus Callosum.

A case is described of a young man presenting with diabetes insipidus and a junctional scotoma. A diffuse infiltrating mass centred in the corpus callosum and suprasellar area is found, which on pathological examination proved to be a primary intracranial germinoma. The case illustrates that rarely the corpus callosum can be involved by this tumour and that diagnosis may be delayed in atypical presentations.

Wet dressings used with topical corticosteroids for pruritic dermatoses: A retrospective study.

BACKGROUND: Wet dressings are a mainstay for initial management of pruritic adult dermatoses at Mayo Clinic, yet few recent reports describe their effectiveness for pruritic conditions other than atopic dermatitis in children. OBJECTIVE: To examine the effectiveness of wet dressings for pruritic dermatoses. METHODS: This is a retrospective study of adult patients admitted to our inpatient dermatology service between January 1, 2004, and August 31, 2007, treated with wet dressings and topical corticosteroids. Improvement was evaluated 1 day after admission and at dismissal. RESULTS: Three hundred thirty-one patients with pruritus (54 unique diagnoses) had 391 admissions. Improvement was reported for 146 (94%) of 156 admissions at 1 day after admission and for 351 (98%) of 357 admissions at dismissal. LIMITATIONS: Retrospective nature of study. CONCLUSIONS: Wet dressings effectively alleviate recalcitrant pruritic dermatoses in adults. The lack of published reports on this treatment method suggests that wet dressings are underused.

The feminisation of Canadian medicine and its impact upon doctor productivity.

OBJECTIVE: We examined the differences in work patterns between female and male doctors in Canada to gain insight into the effect of an increased number of female doctors on overall doctor productivity. METHODS: Data on the practice profiles of female and male doctors across Canada were extracted from the 2007 National Physician Survey. A doctor productivity measure, 'work hours per week per population' (WHPWPP), was created, based on the number of weekly doctor hours spent providing direct patient care per 100,000 citizens. The predicted WHPWPP was calculated for a hypothetical time-point when the female and male doctor populations reach equilibrium. The differences in current and predicted WHPWPP were then analysed. RESULTS: Female medical students currently (2007) outnumber male medical students (at 57.8% of the medical student population). The percentage of practising doctors who are women is highest in the fields of paediatrics, obstetrics and gynaecology, psychiatry and family practice. Female doctors work an average of 47.5 hours per week (giving 30.0 hours of direct patient care), compared with 53.8 hours worked by male doctors (35.0 hours of direct patient care) (P < 0.01, chi(2) test). Female doctors tend to work less on call hours per week and see fewer patients while on-call. Female doctors are also more likely to take parental leave or a leave of absence (P < 0.01, chi(2) test). The difference in current and predicted WHPWPP was found to be 2.6%, equivalent to 1853 fewer full-time female doctors or 1588 fewer full-time male doctors. CONCLUSIONS: Gender appears to have a significant influence on the practice patterns of doctors in Canada. If the gender-specific work patterns described in the present study persist, an overall decrease in doctor productivity is to be anticipated.

Evaluating the cost-effectiveness of anterior uveitis investigation by Canadian ophthalmologists.

BACKGROUND: To evaluate the cost-effectiveness of anterior uveitis investigation by Canadian ophthalmologists and to assess the role of implementing national clinical guidelines for such investigation. METHODS: Based on data extracted from the Canadian National Uveitis Survey (CNUS, 2007 version), the cost of investigating a patient with anterior uveitis, according to current practice patterns of Canadian ophthalmologists, was determined and grouped across 4 clinical scenarios: (i) nongranulomatous anterior uveitis in an adult, (ii) granulomatous anterior uveitis in an adult, (iii) granulomatous anterior uveitis with suspected sarcoidosis in an adult or a child, and (iv) nongranulomatous anterior uveitis in a child. Similarly, the cost of investigating a patient with anterior uveitis as per published evidence-based guidelines was determined and compared with the current practice pattern using a cost-minimization model, sensitivity analyses, and Monte Carlo simulations. RESULTS: Ophthalmologists were found to consistently order more tests than recommended by evidence-based guidelines, across each of the scenarios studied (p < 0.05). Overall, complete blood count, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, and rheumatoid factor were the most commonly ordered extraneous tests that were not included in the evidence-based guidelines for the routine investigation of anterior uveitis. Also, there were significant differences in the cost of investigating a patient with anterior uveitis when compared with those predicted by adhering to evidence-based clinical practice guidelines. Cost minimization and sensitivity analyses revealed that published guidelines imparted cost savings when compared with current practice patterns across the 4 clinical scenarios studied (p < 0.01). The maximum additional cost was associated with investigating nongranulomatous anterior uveitis in an adult, where a minimal additional cost of $75 per patient was spent. For granulomatous anterior uveitis in an adult, the additional cost was approximately $40, whereas the additional cost for investigating an adult or a child with suspected sarcoidosis was $36. Only $11 of additional cost was spent in the workup of a child with nongranulomatous anterior uveitis. When applied to the Canadian population, adherence to the Clinical Practice Guidelines recommended by the CNUS may result in cost savings of $600,000 per year to the Canadian health care system. INTERPRETATION: Adherence to the evidence-based Clinical Practice Guidelines recommended by the CNUS may result in significant cost savings, with virtually no loss of sensitivity in the routine investigation of anterior uveitis in Canada.

Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress.

Pathogenic fungi, including Candida glabrata, develop strategies to grow and survive both in vitro and in vivo under azole stress. However, the mechanisms by which yeast cells counteract the inhibitory effects of azoles are not completely understood. In the current study, it was demonstrated that the expression of the ergosterol biosynthetic genes ERG2, ERG3, ERG4, ERG10, and ERG11 was significantly upregulated in C. glabrata following fluconazole treatment. Inhibiting ergosterol biosynthesis using fluconazole also increased the expression of the sterol influx transporter AUS1 and the sterol metabolism regulators SUT1 and UPC2 in fungal cells. The microarray study quantified 35 genes with elevated mRNA levels, including AUS1, TIR3, UPC2, and 8 ERG genes, in a C. glabrata mutant strain lacking ERG1, indicating that sterol importing activity is increased to compensate for defective sterol biosynthesis in cells. Bioinformatic analyses further revealed that those differentially expressed genes were involved in multiple cellular processes and biological functions, such as sterol biosynthesis, lipid localization, and sterol transport. Finally, to assess whether sterol uptake affects yeast susceptibility to azoles, we generated a C. glabrata aus1∆ mutant strain. It was shown that loss of Aus1p in C. glabrata sensitized the pathogen to azoles and enhanced the efficacy of drug exposure under low oxygen tension. In contrast, the presence of exogenous cholesterol or ergosterol in medium rendered the C. glabrata AUS1 wild­type strain highly resistant to fluconazole and voriconazole, suggesting that the sterol importing mechanism is augmented when ergosterol biosynthesis is suppressed in the cell, thus allowing C. glabrata to survive under azole pressure. On the basis of these results, it was concluded that sterol uptake and sterol biosynthesis may act coordinately and collaboratively to sustain growth and to mediate antifungal resistance in C. glabrata through dynamic gene expression in response to azole stress and environmental challenges.

Impact of physician income source on productivity.

Based on data from the 2004 National Physician Survey, physicians whose primary payment method was fee-for-service saw more patients per week than physicians remunerated by other methods, including salary or blended payments. This result did not change when examined according to specialty or specialty grouping (Table 1), physician age (Table 2) Family physicians versus specialists, type of practice (office-based versus hospital-based; data not shown), or practice setting (urban versus rural; data not shown). Overall, fee-for-service (FFS) physicians saw approximately twice the number of patients per week as salaried physicians. These data provide convincing evidence that FFS physicians see substantially more patients.

Homeostatic plasticity improves signal propagation in continuous-time recurrent neural networks.

Continuous-time recurrent neural networks (CTRNNs) are potentially an excellent substrate for the generation of adaptive behaviour in artificial autonomous agents. However, node saturation effects in these networks can leave them insensitive to input and stop signals from propagating. Node saturation is related to the problems of hyper-excitation and quiescence in biological nervous systems, which are thought to be avoided through the existence of homeostatic plastic mechanisms. Analogous mechanisms are here implemented in a variety of CTRNN architectures and are shown to increase node sensitivity and improve signal propagation, with implications for robotics. These results lend support to the view that homeostatic plasticity may prevent quiescence and hyper-excitation in biological nervous systems.

Outcome of trabeculectomy with intraoperative mitomycin C for uveitic glaucoma.

BACKGROUND: The purpose of this study was to compare the outcomes of mitomycin C (MMC)-augmented trabeculectomy in glaucoma patients with uveitis to those without uveitis but with other high-risk characteristics. METHODS: A retrospective comparative cohort analysis consisting of 51 eyes of 51 patients (21 uveitic patients and 30 nonuveitic patients) was performed. Two outcome classifications were analyzed: absolute success (intraocular pressure [IOP]