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Although there have been numerous innovations in the management of retinal detachment (RD) over the past decades, there is still limited understanding of the pathophysiological processes that take place before and after repair. Summarizing key concepts using animal studies may allow for a better assessment of common pre- and postoperative microstructural abnormalities in RD. We performed a systematic literature review on Ovid MEDLINE, EMBASE, and Cochrane Controlled Register of Trials from January 1968 to January 2022, searching animal or human studies reporting retinal histologic changes following primary or induced RD. Thirty-two studies were included. Main cellular events were summarized: photoceptor apoptosis occurs as early as 12 hours after RD and, although most cells survive, there is extensive remodeling. Outer segments progressively degenerate, while inner segments are reorganized. Rod and cone opsins are redistributed, and rod axons retract while cones undergo changes in shape. Second- and third-order neurons rearrange their dendritic processes, and Müller cells become hypertrophic, growing into the subretinal space. Finally, retinal pigment epithelium cells undergo a change in their morphology. Acknowledging critical morphologic changes following RD is crucial in understanding why anatomical and functional outcomes can vary. Insights from histological studies, together with high-resolution imaging, may be key in identifying novel biomarkers in RD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to compare the outcomes of ProKera versus amniotic membrane transplantation (AMT) in managing ocular surface disease., Methods: This study is a retrospective case series of patients who received either ProKera or sutured AMT for ocular surface disease. Patient demographics, treatment indications, retention time, percentage healed area, changes in visual acuity, and costs to the health care system were analyzed., Results: Fourteen patients were identified and analyzed for each group. The main indications for using ProKera and AMT were similar, including corneal ulcer or epithelial defect due to chemical burns, neurotropic state, or herpes zoster keratitis. The average time to dissolution or removal was 24.8 days in the ProKera group, compared with 50.1 days in the AMT group. The average percentage of healed corneal area was 59% for ProKera and 73% for AMT. There was no significant difference between the initial and the final visual acuity within groups and when comparing both groups. In our expense analysis, ProKera had a total cost of 699.00 Canadian dollars (CAD), whereas the cost of suture AMT was 1561.52 CAD. ProKera priced at 11.85 CAD for each percentage healed surface area and at 21.39 CAD for AMT., Conclusions: ProKera allowed for a faster corneal healing than sutured AMT, although its total healed area was less than the latter. Moreover, ProKera is more cost-effective than AMT, thus reducing financial burden to our health care system., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The 2019 Annual General Meeting and Young Investigators' Forum of the Canadian Society for Clinical Investigation / Société Canadienne de Recherche Clinique (CSCI/SCRC) and Clinician Investigator Trainee Association of Canada / Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Banff, Alberta on November 8-10th, 2019. The theme was "Positioning Early Career Investigators for Success: Strategy and Resilience". Lectures and workshops provided knowledge and tools to facilitate the attendees' development as clinician investigators. Dr. Jason Berman (President of CSCI/SCRC), Elina Cook (President of CITAC/ACCFC) and Drs. Doreen Rabi and Zelma Kiss (University of Calgary Organizing Co-Chairs) gave opening presentations. The keynote speakers were Dr. William Foulkes (McGill University) (Distinguished Scientist Award winner) and Dr. Andrés Finzi (Université de Montréal) (Joe Doupe Young Investigator Award winner). Dr. Robert Bortolussi (Dalhousie University) received the Distinguished Service Award for his work as the Editor-in-Chief of Clinical and Investigative Medicine and for being instrumental in the development of the Canadian Child Health Clinician Scientist Program. This meeting was the first to host a panel discussion with Drs. Stephen Robbins and Marcello Tonelli from the Canadian Institutes of Health Research. Workshops on communication, career planning and work-life balance were hosted by André Picard and Drs. Todd Anderson, Karen Tang, William Ghali, May Lynn Quan, Alicia Polachek and Shannon Ruzycki. The AGM showcased 90 presentations from clinician investigator trainees from across Canada. Most of the abstracts are summarized in this review. Eight outstanding abstracts were selected for oral presentation at the President's Forum.

Retinopathy of prematurity (ROP) is the leading cause of blindness in neonates. Inflammation, in particular interleukin-1β (IL-1β), is increased in early stages of the disorder, and contributes to inner and outer retinal vasoobliteration in the oxygen-induced retinopathy (OIR) model of ROP. A small peptide antagonist of IL-1 receptor, composed of the amino acid sequence, rytvela, has been shown to exert beneficial anti-inflammatory effects without compromising immunovigilance-related NF-κB in reproductive tissues. We conducted a longitudinal study to determine the efficacy of "rytvela" in preserving the integrity of the retina in OIR model, using optical coherence tomography (OCT) which provides high-resolution cross-sectional imaging of ocular structures in vivo . Sprague-Dawley rats subjected to OIR and treated or not with "rytvela" were compared to IL-1 receptor antagonist (Kineret). OCT imaging and custom automated segmentation algorithm used to measure retinal thickness (RT) were obtained at P14 and P30; gold-standard immunohistochemistry (IHC) was used to confirm retinal anatomical changes. OCT revealed significant retinal thinning in untreated animals by P30, confirmed by IHC; these changes were coherently associated with increased apoptosis. Both rytvela and Kineret subsided apoptosis and preserved RT. As anticipated, Kineret diminished both SAPK/JNK and NF-κB axes, whereas rytvela selectively abated the former which resulted in preserved monocyte phagocytic function. Altogether, OCT imaging with automated segmentation is a reliable non-invasive approach to study longitudinally retinal pathology in small animal models of retinopathy., (Copyright © 2020 Sayah, Zhou, Omri, Mazzaferri, Quiniou, Wirth, Côté, Dabouz, Desjarlais, Costantino and Chemtob.)

Retinopathy of prematurity (ROP) is characterized by an initial retinal avascularization, followed by pathologic neovascularization. Recently, choroidal thinning has also been detected in children formerly diagnosed with ROP; a similar sustained choroidal thinning is observed in ROP models. But the mechanism underlying the lack of choroidal revascularization remains unclear and was investigated in an oxygen-induced retinopathy (OIR) model. In OIR, evidence of senescence was detected, preceded by oxidative stress in the choroid and the retinal pigment epithelium. This was associated with a global reduction of proangiogenic factors, including insulin-like growth factor 1 receptor (Igf1R). Coincidentally, tumor suppressor p53 was highly expressed in the OIR retinae. Curtailing p53 activity resulted in reversal of senescence, normalization of Igf1r expression, and preservation of choroidal integrity. OIR-induced down-regulation of Igf1r was mediated at least partly by miR-let-7b as i) let-7b expression was augmented throughout and beyond the period of oxygen exposure, ii) let-7b directly targeted Igf1r mRNA, and iii) p53 knock-down blunted let-7b expression, restored Igf1r expression, and elicited choroidal revascularization. Finally, restoration of Igf1r expression rescued choroid thickness. Altogether, this study uncovers a significant mechanism for defective choroidal revascularization in OIR, revealing a new role for p53/let-7b/IGF-1R axis in the retina. Future investigations on this (and connected) pathway could further our understanding of other degenerative choroidopathies, such as geographic atrophy., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To observe the effect of acupuncture and moxibustion therapy of Tiaochongren Gushenyuan on ovulation and embryo implantation in luteal phase defect patients with spleen-kidney yang deficiency., Methods: A total of 80 patients were randomly divided into an observation group and a control group, 40 cases in each one.In the observation group,acupuncture was applied at Shenting (GV 24), Shenque (CV 8), Guanyuan (CV 4), Qixue (KI 13), Lieque (LU 7), Gongsun (SP 4), Taixi (KI 3), Zusanli (ST 36) and Taichong (LR 3). And moxibustion was given at Taixi (KI 3) using moxibustion box during follicular phase, the stimulation of Taichong (LR 3) was strengthened during ovulatory phase, moxibustion was adopted at Shenque (CV 8) to Guanyuan (CV 4), Zusanli (ST 36) and Taixi (KI 3) during luteal phase. In the control group, acupuncture was applied at Guanyuan (CV 4), Dahe (KI 12), Sanyinjiao (SP 6), Ciliao (BL 32), Zhibian (BL 54) and Shenque (CV 8). Moxibustion was given at Sanyinjiao (SP 6) using moxibustion box during follicular phase, and moxibustion was adopted at Shenque (CV 8) to Guanyuan (CV 4) during luteal phase. The treatment were given every Monday, Wednesday and Friday, and the treatment were stoped during menstrual period in the two groups. Totally 3 menstrual cycle treatment were required, and 3 menstrual cycles were followed up. The pregnancy rate was observed after treatment, the ovulation rate, maximum folliclular diameter and difference of maximum folliclular diameters in ovulatory phase, serum progesterone (P) and basal body temperature (BBT) were compared before and after treatment in the two groups., Results: In the observation group, 6 cases of successful pregnancy during treatment,10 cases in follow-up, the clinical pregnancy rate was 40.0% (16/40). In the control group, 1 case of successful pregnancy during treatment, 5 cases in follow-up, the clinical pregnancy rate was 15.0% (6/40). The clinical pregnancy rate in the observation group was higher than the control group ( P <0.05). The ovulation rate after treatment in the observation group was 90.0% (36/40), and the control group was 70.0% (28/40), compared before treatment, the ovulation rates were increased after treatment in the two groups ( P <0.05). The observation group was higher than the control group, but there was no significant difference between the two groups ( P >0.05). Compared before treatment, the maximum folliclular diameter and difference of maximum folliclular diameters in ovulatory phase, serum P after treatment were improved in the two groups ( P <0.05), and the improvements of the observation group were significant compared with the control group ( P <0.05). The BBT after treatment were superior to before treatment in the two groups ( P <0.05). After treatment, the normal BBT in the observation group was 33 cases, while the control group was 22 cases ( P <0.05)., Conclusion: Acupuncture and moxibustion therapy of Tiaochongren Gushenyuan can promote folliclar development, improve dominant follicle morphology, increase the level of serum P. The therapeutic effect is superior to routine acupuncture in increasing ovulation rate and improving pregnancy outcome.

A decade of CITAC Annual General Meetings: 2007-2017 In 2007, the Clinician Investigator Trainee Association of Canada (CITAC) launched its inaugural Annual General Meeting (AGM). The AGM has since become a major annual event, jointly organized by CITAC and leaders from the Canadian Society for Clinical Investigation (CSCI), and continues to provide a forum for clinician investigator (CI) trainees to exchange ideas, advance career prospects and engage with the broader community. Indeed, since its inception, all Canadian institutions with medical doctor and clinician investigator (MD+CI) training programs have participated in the AGM, while more than 1,000 trainees have registered as CITAC members. The 10th CITAC-CSCI AGM was recently held in Toronto (November 20-22, 2017). There were nearly 200 attendees, including CI trainees, faculty member and physician leaders from across Canada (Figure 1A, 1B). Trainees spanning diverse career stages had opportunities to participate in interactive poster sessions, workshops and lectures by leading physician-scientists. These exercises were designed to encourage and enhance networking, career development and mentorship for prospective physician-scientists.

The 2016 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national conference held in Toronto November 21-23, 2016, in conjunction with The University of Toronto Clinician Investigator Program Research Day. The theme for this year's meeting was "Mapping Your Career as a Clinician-Scientist"; emphasizing essential skills for developing a fruitful career as clinician-scientist. The meeting featured an opening presentation by Dr. Alan Underhill, Dr. Nicola Jones and Alexandra Kuzyk. The keynote speakers were Dr. Nada Jabado (McGill University), who discussed the association between cancer and histones, Dr. Norman Rosenblum (University of Toronto), who addressed the career path and the "calling" of the Clinician Scientist, Dr. Martin Schmeing (McGill University), who was the 2016 Joe Doupe Award recipient, and Dr. Linda Rabeneck (Cancer Care Ontario and University of Toronto), who received the Friends of CIHR lectureship. The workshops, focusing on career development for clinician scientists, were hosted by Drs. Alan Underhill, Nicola Jones, Lynn Raymond, Michael Schlossmacher and Norman Rosenblum, as well as University of Toronto communication specialists, Caitlin Johannesson and Suzanne Gold. In addition, the Young Investigators' Forum included presentations from clinician investigator trainees from across the country. The research topics were diverse and comprehensive: from basic sciences to clinical practice; from epidemiology to medical engineering. All scientific abstracts are summarized in this review. Over 70 abstracts were showcased at this year's meeting during two poster sessions, with six outstanding abstracts selected for oral presentations during the President's Forum.

Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity.

Clinician-scientists are physicians with training in both clinical medicine and research that enables them to occupy a unique niche as specialists in basic and translational biomedical research. While there is widespread acknowledgement of the importance of clinician-scientists in today's landscape of evidence-based medical practice, training of clinician-scientists in Canada has been on the decline, with fewer opportunities to obtain funding. With the increasing length of training and lower financial compensation, fewer medical graduates are choosing to pursue such a career. MD-PhD programs, in which trainees receive both medical and research training, have the potential to be an important tool in training the next generation of clinician-scientists; however, MD-PhD trainees in Canada face barriers that include an increase in medical school tuition and a decrease in the amount of financial support. We examined the available data on MD-PhD training in Canada and identified a lack of oversight, a lack of funding and poor mentorship as barriers experienced by MD-PhD trainees. Specific recommendations are provided to begin the process of addressing these challenges, starting with the establishment of an overseeing national body that would track long-term outcome data for MD-PhD trainees. This national body could then function to implement best practices from individual programs across the country and to provide further mentorship and support for early-career physician-scientists. MD-PhD programs have the potential to address Canada's growing shortage of clinician-scientists, and strengthening MD-PhD programs will help to effect positive change.

Background: The present study was conducted to compare 2 purification methods for isolation of human adipose-derived stromal vascular fraction or stem cells (ADSCs) based on red blood cell (RBC) lysis with 155 mM ammonium chloride (NH4Cl) and hypotonic sodium chloride (NaCl) solution, and try to develop a safe, convenient, and cost-effective purification method for clinical applications., Methods: Adipose-derived stem cells and RBC were harvested from the fatty and fluid portions of liposuction aspirates, respectively. The suitable concentration of hypotonic NaCl solution on RBC lysis for purification of ADSCs was developed by RBC osmotic fragility test and flow cytometry analysis. The effects of 155 mM NH4Cl or 0.3% NaCl solution on ADSCs proliferation and RBC lysis efficiency were examined by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide assay and lysis efficiency test, respectively. In addition, the adipogenic and osteogenic capabilities, phenotype and genetic stability of ADSCs were evaluated by oil red staining, alkaline phosphatase activity measurement, flow cytometry, and karyotype analysis, respectively., Results: Sodium chloride solution in 0.3% concentration effectively removed RBCs and did not influence the survival of ADSCs in the 10-minute incubation time. The lysis efficiency did not differ significantly between 0.3% NaCl and 155 mM NH4Cl. Moreover, the adipogenic and osteogenic capabilities, surface marker expression and karyotype of the ADSCs were not affected by lysis solutions or by lysis per se. However, the proliferation capacity in the 0.3% NaCl group was superior to that in 155 mM NH4Cl group., Conclusions: Our data suggest that 0.3% NaCl solution is useful for isolating ADSCs from liposuction aspirate for clinical applications with safety, convenience, and cost-effect.

Purpose: Spectral-domain optical coherence tomography (SD-OCT) is widely used in clinical ophthalmology and recently gained popularity in laboratory research involving small rodents. Its noninvasive nature allows repeated measurements, thereby decreasing the number of animals required. However, when used at a conventional dosage, xylazine (an α2-adrenoceptor) can cause irreversible corneal calcification, especially among young rodents. In the present study, we test whether corneal calcification associated with xylazine is mediated by the α2-adrenoceptor., Methods: Our study tested Sprague-Dawley rats, Long-Evans rats, and CD-1 mice (postnatal day [P]14). Retinal images were captured by SD-OCT. Quantitative PCR (qPCR) was used to study gene expression, whereas receptor localization was examined by immunofluorescent staining followed by confocal microscopy. Calcium deposits were detected via von Kossa staining., Results: When used at dosages appropriate for adult animals, ketamine-xylazine anesthetics led to a high rate of respiratory failure, increased apoptotic activity in the corneal epithelium, and irreversible corneal calcification in P14 rat pups. Meanwhile, OCT image quality decreased drastically as a result of corneal calcification among animals recovering from anesthesia. α2-Adrenoceptor subtypes were highly expressed on P14, in line with rodents' age-specific sensitivity to xylazine. Clonidine, a potent α2-adrenoceptor agonist, dose-dependently induced corneal calcification, which could be prevented by an α2-adrenoceptor antagonist., Conclusions: These data suggest that α2-adrenoceptors contribute to corneal calcification in young rodents. Therefore, we developed a suitable OCT imaging protocol for this cohort, including a carefully tailored ketamine-xylazine dosage (60 mg/kg and 2.5 kg/mg, respectively).

Retinopathy of prematurity (ROP), the most common cause of blindness in premature infants, has long been associated with inner retinal alterations. However, recent studies reveal outer retinal dysfunctions in patients formerly afflicted with ROP. We have recently demonstrated that choroidal involution occurs early in retinopathy. Herein, we investigated the mechanisms underlying the choroidal involution and its long-term impact on retinal function. An oxygen-induced retinopathy (OIR) model was used. In vitro and ex vivo assays were applied to evaluate cytotoxic effects of IL-1β on choroidal endothelium. Electroretinogram was used to evaluate visual function. We found that proinflammatory IL-1β was markedly increased in retinal pigment epithelium (RPE)/choroid and positively correlated with choroidal degeneration in the early stages of retinopathy. IL-1β was found to be cytotoxic to choroid in vitro, ex vivo, and in vivo. Long-term effects on choroidal involution included a hypoxic outer neuroretina, associated with a progressive loss of RPE and photoreceptors, and visual deterioration. Early inhibition of IL-1β receptor preserved choroid, decreased subretinal hypoxia, and prevented RPE/photoreceptor death, resulting in life-long improved visual function in IL-1 receptor antagonist-treated OIR animals. Together, these findings suggest a critical role for IL-1β-induced choroidal degeneration in outer retinal dysfunction. Neonatal therapy using IL-1 receptor antagonist preserves choroid and prevents protracted outer neuroretinal anomalies in OIR, suggesting IL-1β as a potential therapeutic target in ROP., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Retinopathy of prematurity (ROP) is a multifactorial disease and the main cause of visual impairment and blindness in premature neonates. The inner retina has been considered the primary region affected in ROP, but choroidal vascular degeneration and progressive outer retinal dysfunctions have also been observed. This review focuses on observations regarding neurovascular dysfunctions in both the inner and outer immature retina, the mechanisms and the neuronal-derived factors implicated in the development of ROP, as well potential therapeutic avenues for this disorder., Conclusion: Alterations in the neurovascular integrity of the inner and outer retina contribute to the development of ROP., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Platelet-activating factor (PAF) is a pleiotropic phospholipid with proinflammatory, procoagulant and angiogenic actions on the vasculature. We and others have reported the presence of PAF receptor (Ptafr) at intracellular sites such as the nucleus. However, mechanisms of localization and physiologic functions of intracellular Ptafr remain poorly understood. We hereby identify the importance of C-terminal motif of the receptor and uncover novel roles of Rab11a GTPase and importin-5 in nuclear translocation of Ptafr in primary human retinal microvascular endothelial cells. Nuclear localization of Ptafr is independent of exogenous PAF stimulation as well as intracellular PAF biosynthesis. Moreover, nuclear Ptafr is responsible for the upregulation of unique set of growth factors, including vascular endothelial growth factor, in vitro and ex vivo. We further corroborate the intracrine PAF signaling, resulting in angiogenesis in vivo, using Ptafr antagonists with distinct plasma membrane permeability. Collectively, our findings show that nuclear Ptafr translocates in an agonist-independent manner, and distinctive functions of Ptafr based on its cellular localization point to another dimension needed for pharmacologic selectivity of drugs.