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.

Preterm birth (PTB) is commonly accompanied by in utero fetal inflammation, and existing tocolytic drugs do not target fetal inflammatory injury. Of the candidate proinflammatory mediators, IL-1 appears central and is sufficient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the competitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efficacy in blocking IL-1 actions. Antenatal exposure to IL-1β induced ,, ,, and expression in placenta and fetal membranes, and it elevated amniotic fluid IL-1β, IL-6, IL-8, and PGF, resulting in PTB and marked neonatal mortality. Surviving neonates had increased ,, ,, ,, and expression in WBCs, elevated plasma levels of IL-1β, IL-6, and IL-8, increased IL-1β, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no benefit for gestation length, neonatal mortality, or placental inflammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inflammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic.

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.

Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes. Although the major pro-inflammatory cytokine IL-1β participates in retinopathy induced by hyperoxia (a predisposing factor to retinopathy of prematurity), the specific role of antenatal IL-1β associated with preterm birth (PTB) in retinal vasculopathy (independent of hyperoxia) is unknown. Using a murine model of PTB induced with IL-1β injection in utero, we studied consequent retinal and choroidal vascular development; in this process we evaluated the efficacy of IL-1R antagonists. Eyes of foetuses exposed only to IL-1β displayed high levels of pro-inflammatory genes, and a persistent postnatal infiltration of inflammatory cells. This prolonged inflammatory response was associated with: (1) a marked delay in retinal vessel growth; (2) long-lasting thinning of the choroid; and (3) long-term morphological and functional alterations of the retina. Antenatal administration of IL-1R antagonists – 101.10 (a modulator of IL-1R) more so than Kineret (competitive IL-1R antagonist) – prevented all deleterious effects of inflammation. This study unveils a key role for IL-1β, a major mediator of chorioamnionitis, in causing sustained ocular inflammation and perinatal vascular eye injury, and highlights the efficacy of antenatal 101.10 to suppress deleterious inflammation.

Purpose: Integrated MD/PhD programs are relatively new in Canada and represent a platform to train the next generation of clinician-scientists. However, MD/PhD programs vary substantially by structure, funding and mentorship opportunities, and there exists a paucity of data on the overall students’ successes and challenges. The purpose of this study is to assess objective and subjective metrics of the MD/PhD Program at the University of Ottawa. Methods: Students in all years of the program were invited to complete a 58- question survey, and the resulting data were analyzed by descriptive statistics. Results: Our survey had an 88.5% (23/26) participation rate. The program has been gaining interest and the number of applications increased by 178% between 2013 and 2018. Tuition support was considered an essential element in accepting the admission offer, as 47.8% of students would have declined admission without full tuition coverage. The MD/PhD students were heavily engaged in scholarly activities, with an average of 8.3 presentations/ publications per respondent. Respondents indicated low satisfaction with formal career planning advice (28.6% satisfied/very satisfied) and program transition guidance (22.2%). When delivered informally by peers, both career planning advice and program transition guidance were experienced as more satisfying (65.2% and 63.6%, respectively). Only 34.8% of survey respondents identified as female, highlighting the challenge of achieving diversity in clinician-scientist training programs. Conclusion: Our report contributes to the body of knowledge on concrete obstacles experienced by students within MD/PhD programs and key areas that can be improved upon—locally, provincially and nationally—to further advance student success.

Uterine labor requires the conversion of a quiescent (propregnancy) uterus into an activated (prolabor) uterus, with increased sensitivity to endogenous uterotonic molecules. This activation is induced by stressors, particularly inflammation in term and preterm labor. Neuromedin U (NmU) is a neuropeptide known for its uterocontractile effects in rodents. The objective of the study was to assess the expression and function of neuromedin U receptor 2 (NmU-R2) and its ligands NmU and the more potent neuromedin S (NmS) in gestational tissues, and the possible implication of inflammatory stressors in triggering this system. Our data show that NmU and NmS are uterotonic ex vivo in murine tissue, and they dose-dependently trigger labor by acting specifically via NmU-R2. Expression of NmU-R2, NmU, and NmS is detected in murine and human gestational tissues by immunoblot, and the expression of NmS in placenta and of NmU-R2 in uterus increases considerably with gestation age and labor, which is associated with amplified NmU-induced uterocontractile response in mice. NmU- and NmS-induced contraction is associated with increased NmU-R2-coupled Ca++ transients, and Akt and Erk activation in murine primary myometrial smooth muscle cells (mSMCs), which are potentiated with gestational age. NmU-R2 is upregulated in vitro in mSMCs and in vivo in uterus in response to proinflammatory interleukin 1beta (IL1beta), which is associated with increased NmU-induced uterocontractile response and Ca++ transients in murine and human mSMCs; additionally, placental NmS is markedly upregulated in vivo in response to IL1beta. In human placenta at term, immunohistological analysis revealed NmS expression primarily in cytotrophoblasts; furthermore, stimulation with lipopolysaccharide (LPS; Gram-negative endotoxin) markedly upregulates NmS expression in primary human cytotrophoblasts isolated from term placentas. Correspondingly, decidua of women with clinical signs of infection who delivered preterm display significantly higher expression of NmS compared with those without infection. Importantly, in vivo knockdown of NmU-R2 prevents LPS-triggered preterm birth in mice and the associated neonatal mortality. Altogether, our data suggest a critical role for NmU-R2 and its ligands NmU and NmS in preterm labor triggered by infection. We hereby identify NmU-R2 as a relevant target for preterm birth.

From the Section Editor: The JNO “Disease of the Year: Multiple Sclerosis” series concludes with a focus on cutting edge techniques used to qualitatively and quantitatively evaluate ocular motility abnormalities. In their article, “Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis,” Sheehy and colleagues expand on the earlier works published by Lee et al, and Nerrant et al, which provide an elegant overview of extra-ocular movement findings associated with brainstem disorders, and multiple sclerosis, respectively. The tools highlighted by Sheehy and colleagues add to our understanding of structure-function relationships in multiple sclerosis, and further expand the role of visual system models in multiple sclerosis research and clinical trials. In the series finale, “The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis,” Balcer and colleagues chronicle the inception, development, and achievements of IMSVISUAL, a consortium created by clinicians and researchers committed to advancing the role of visual outcomes in the care of multiple sclerosis patients. The ingenuity and accomplishments of IMSVISUAL will serve to inspire other international collaborations, and further advance scientific discovery in the field of neuro-ophthalmology. Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system causing the immune-mediated demyelination of the brain, optic nerve, and spinal cord and resulting in ultimate axonal loss and permanent neurological disability. Ocular motor dysfunction is commonly observed in MS but can be frequently overlooked or underappreciated by nonspecialists. Therefore, detailed and quantitative assessment of eye movement function has significant potential for optimization of patient care, especially for clinicians interested in treating visual symptoms or tracking disease progression. Methods: A brief history of eye tracking technology followed by a contextualized review of the methods that can be used to assess ocular motor dysfunction in MS—including a discussion of each method's strengths and limitations. We discuss the rationale for interest in this area and describe new tools capable of tracking eye movements as a possible means of monitoring disease. Results/Conclusions: This overview should inform clinicians working with patients with MS of how ocular motor deficits can best be assessed and monitored in this population. It also provides a rationale for interest in this field with insights regarding which techniques should be used for studying which classes of eye movements and related dysfunction in the disease.

BackgroundChronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored.MethodsPlasma neurofilament light chain (NfL) levels were measured from ReBUILD trial’s participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period.ResultsNfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=−0.035 [−0.068 to −0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [−0.0004 to 0.007], p=0.081). Based on a Cohen’s d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power.ConclusionsIn pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination.Trial registration numberNCT02040298.