International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials.

PURPOSE: Complications associated with intravitreal anti-VEGF therapies are reported inconsistently 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: Twenty-five 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 who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to 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 categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 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 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. CONCLUSIONS: 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. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Observation of topological phenomena in a programmable lattice of 1,800 qubits.

The work of Berezinskii, Kosterlitz and Thouless in the 1970s1,2 revealed exotic phases of matter governed by the topological properties of low-dimensional materials such as thin films of superfluids and superconductors. A hallmark of this phenomenon is the appearance and interaction of vortices and antivortices in an angular degree of freedom-typified by the classical XY model-owing to thermal fluctuations. In the two-dimensional Ising model this angular degree of freedom is absent in the classical case, but with the addition of a transverse field it can emerge from the interplay between frustration and quantum fluctuations. Consequently, a Kosterlitz-Thouless phase transition has been predicted in the quantum system-the two-dimensional transverse-field Ising model-by theory and simulation3-5. Here we demonstrate a large-scale quantum simulation of this phenomenon in a network of 1,800 in situ programmable superconducting niobium flux qubits whose pairwise couplings are arranged in a fully frustrated square-octagonal lattice. Essential to the critical behaviour, we observe the emergence of a complex order parameter with continuous rotational symmetry, and the onset of quasi-long-range order as the system approaches a critical temperature. We describe and use a simple approach to statistical estimation with an annealing-based quantum processor that performs Monte Carlo sampling in a chain of reverse quantum annealing protocols. Observations are consistent with classical simulations across a range of Hamiltonian parameters. We anticipate that our approach of using a quantum processor as a programmable magnetic lattice will find widespread use in the simulation and development of exotic materials.

Multiple Attempts of Peripheral Intravenous Catheter Insertion in a Preterm Infant Provoke Toxic Stress: A Case Report.

Premature infants admitted to the NICU often require intravenous (IV) therapy. Peripheral intravenous catheter (PIVC) insertion is a common painful/stressful/invasive procedure. Repeated exposure to stressors produces toxic stress: a prolonged, frequent activation of the body's stress response that occurs when buffering relationships, that is, mother/supportive adult, are absent. This article presents an exemplar case study of a PIVC insertion to describe toxic stress responses a premature infant experienced during the procedure. The infant was admitted for extreme prematurity and respiratory failure. Twenty-nine days later, the infant developed possible necrotizing enterocolitis that necessitated cessation of enteral feedings, gastric decompression, IV administration of fluids, parenteral nutrients, and antibiotics. The PIVC insertion procedure was monitored and observed. The infant showed physiologic dysregulation, including bradycardia, tachycardia, oxygen desaturation, and high skin conductance responses, resulting from the stress exposure and insufficient nonpharmacologic/pharmacologic stress interventions. Education and practice change are needed to promote pain/stress management.

Closure of Full-Thickness Macular Holes Associated with Macular Edema with Medical Therapy.

PURPOSE: The purpose of this study was to report the closure of macular hole without surgery in 7 cases using medical therapies. METHODS: The retrospective review of 7 cases of full-thickness macular holes, which closed after medical therapy without surgery. RESULTS: Seven eyes of 7 patients developed full-thickness macular holes, which initially closed on medical therapy without surgery. Six patients were kept on maintenance therapy; 1 recurred and 5 did not develop recurrence. One patient was taken off of maintenance therapy and later developed recurrent macular hole requiring macular hole surgery. CONCLUSIONS: Medical therapy to decrease macular edema may facilitate macular hole closure and should be considered, especially for small macular holes with significant edema. Reopening of macular holes may occur after stopping topical maintenance therapy for macular edema, which occurred at 10 weeks and 9 months after maintenance therapy was discontinued or markedly tapered.

The impact of clinical uncertainty in the graduate medical education (GME) learning environment: A mixed-methods study.

BACKGROUND: Uncertainty is ubiquitous in medicine. Studies link intolerance of uncertainty to burnout, ineffective communication, cognitive bias, and inappropriate resource use. Little is known about how uncertainty manifests in the clinical learning environment. We aimed to explore the perceptions and experiences of uncertainty among residents and attendings. METHODS: We conducted a mixed-methods study including a survey, semi-structured interviews, and ethnographic observations during rounds with residents and attendings at an academic medical center. The survey included three validated instruments: Physicians' Reaction to Uncertainty Scale; Maslach Burnout Inventory 2-item; and Educational Climate Inventory. RESULTS: 35/60 (58%) of eligible residents and 14/21 (67%) attendings completed the survey. Residents reported higher anxiety due to uncertainty than attendings, higher concern about bad outcomes, and greater reluctance to disclose uncertainty to patients. Residents reported increased symptoms of burnout (p < .05). Perceiving the learning environment as more competitive correlated with reluctance to disclose uncertainty (r = -0.44; p < .01). Qualitative themes included: recognizing and facing uncertainty, and consequences for the learning environment. Observations revealed senior clinicians have greater comfort acknowledging uncertainty. CONCLUSIONS: Medical curricula should be developed to promote recognition and acknowledgement of uncertainty. Greater acknowledgement of uncertainty, specifically by attendings and senior residents, may positively impact the clinical learning environment.

Temporally independent association of multiple evanescent white dot syndrome and optic neuritis.

PURPOSE: To describe three patients that developed temporally distinct episodes of optic neuritis and multiple evanescent white dot syndrome (MEWDS). METHODS: We retrospectively reviewed the medical records and imaging studies of three women evaluated at a tertiary referral center for both optic neuritis and MEWDS. RESULTS: Three otherwise healthy women, aged 17, 36, and 41, developed temporally separated episodes of optic neuritis and MEWDS. The time periods between the two events were 3, 48, and 60 months, and in two of the three cases, the optic neuritis event preceded the episode of MEWDS. No patient endorsed prodromal flu-like symptoms prior to developing vision loss. The mean presenting visual acuities were better with the optic neuritis episode (LogMAR 0.360, Snellen 20/46) than with retinal event (LogMAR 0.684, Snellen 20/97). All three patients had improvement in vision, with mean visual acuity of 20/29 (LogMAR 0.165) at last follow-up. One patient later developed idiopathic noninfectious posterior uveitis and another developed multiple sclerosis requiring treatment. CONCLUSION: While a rare association, patients can develop both optic neuritis and MEWDS within the same eye at different time points. It is unknown whether such patients are at even higher risk of developing systemic autoimmune disease than are patients with either MEWDS or optic neuritis alone.

A novel OCT signature in leukemic papillopathy masquerading as autoimmune or infectious uveitis.

PURPOSE: With therapeutic advances, central nervous system (CNS) involvement in leukemia has become more common. Leukemic optic disc infiltration, often a clinical diagnosis, can present as an isolated finding in primary or relapsed CNS disease and therefore requires early recognition. Not previously well appreciated, we report here signs of intraocular inflammation accompanying leukemic optic disc infiltration, suggesting infectious or non-infectious uveitis as an alternative diagnosis. We describe a novel optical coherence tomography (OCT) sign favoring leukemic infiltration. METHODS: Retrospective consecutive case series of all leukemic patients with disc edema (5 patients, 6 eyes) presenting to the University of Michigan's Ocular Oncology Clinic between October 2019 and March 2020. RESULTS: We report five leukemic patients (6 eyes) who were evaluated for disc edema and vitritis and eventually diagnosed with leukemic papillopathy. All five patients initially had a bland lumbar puncture (LP), and all four patients who underwent magnetic resonance imaging (MRI) had no retrobulbar nerve involvement. Clinical findings included preserved visual acuity (n = 5 eyes, 83%), anterior chamber (AC) cell (n = 3 eyes, 50%), vitreous cell (n = 6 eyes, 100%), and retinal whitening (n = 4 eyes, 66%). In five eyes (83%), a diagnosis of infectious or non-infectious uveitis was initially considered. The OCT finding of inner retinal thickening and loss of inner retinal lamination with largely preserved outer retinal architecture helped point towards a leukemic infiltrative process emanating from the disc and spreading retrograde through the nerve fiber layer. CONCLUSIONS: These cases highlight the difficulty of distinguishing intraocular inflammation associated with leukemic papillopathy from infectious or non-infectious uveitis, especially considering bland LP and negative retrobulbar MRI signal in all our patients. We propose juxtapapillary inner retinal infiltration with the loss of inner retinal lamination and relative preservation of outer retinal architecture on OCT imaging as a finding that supports the diagnosis of leukemic papillopathy.

Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits.

Loss-of-function (LOF) mutations in CC2D1A cause a spectrum of neurodevelopmental disorders, including intellectual disability, autism spectrum disorder, and seizures, identifying a critical role for this gene in cognitive and social development. CC2D1A regulates intracellular signaling processes that are critical for neuronal function, but previous attempts to model the human LOF phenotypes have been prevented by perinatal lethality in Cc2d1a-deficient mice. To overcome this challenge, we generated a floxed Cc2d1a allele for conditional removal of Cc2d1a in the brain using Cre recombinase. While removal of Cc2d1a in neuronal progenitors using Cre expressed from the Nestin promoter still causes death at birth, conditional postnatal removal of Cc2d1a in the forebrain via calcium/calmodulin-dependent protein kinase II-alpha (CamKIIa) promoter-driven Cre generates animals that are viable and fertile with grossly normal anatomy. Analysis of neuronal morphology identified abnormal cortical dendrite organization and a reduction in dendritic spine density. These animals display deficits in neuronal plasticity and in spatial learning and memory that are accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming. Cc2d1a conditional knockout mice therefore recapitulate features of both cognitive and social impairment caused by human CC2D1A mutation, and represent a model that could provide much needed insights into the developmental mechanisms underlying nonsyndromic neurodevelopmental disorders.

Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome.

The Ts65Dn mouse is the most studied animal model of Down syndrome. Past research has shown a significant reduction in CA1 hippocampal long-term potentiation (LTP) induced by theta-burst stimulation (TBS), but not in LTP induced by high-frequency stimulation (HFS), in slices from Ts65Dn mice compared with euploid mouse-derived slices. Additionally, therapeutically relevant doses of the drug memantine were shown to rescue learning and memory deficits in Ts65Dn mice. Here, we observed that 1 µM memantine had no detectable effect on HFS-induced LTP in either Ts65Dn- or control-derived slices, but it rescued TBS-induced LTP in Ts65Dn-derived slices to control euploid levels. Then, we assessed LTP induced by four HFS (4xHFS) and found that this form of LTP was significantly depressed in Ts65Dn slices when compared with LTP in euploid control slices. Memantine, however, did not rescue this phenotype. Because 4xHFS-induced LTP had not yet been characterized in Ts65Dn mice, we also investigated the effects of picrotoxin, amyloid beta oligomers, and soluble recombinant human prion protein (rPrP) on this form of LTP. Whereas ≥10 µM picrotoxin increased LTP to control levels, it also caused seizure-like oscillations. Neither amyloid beta oligomers nor rPrP had any effect on 4xHFS-induced LTP in Ts65Dn-derived slices.

Rates of Vitrectomy among Enrollees in a United States Managed Care Network, 2001-2012.

PURPOSE: To determine whether vitrectomy surgery rates have changed over the past decade and factors affecting the odds of undergoing this procedure. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: All enrollees 21 years of age or older between 2001 and 2012 in a United States managed care network. METHODS: Claims data from a managed care network were analyzed to identify all enrollees who underwent 1 vitrectomy or more each year from 2001 through 2012. Rates of vitrectomy per 1000 enrollees were computed each year from 2001 through 2012 for the entire group and separately for patients with and without diabetes mellitus. Multivariate logistic regression assessed factors affecting the odds of undergoing vitrectomy surgery. MAIN OUTCOME MEASURES: Annual rates of vitrectomy surgery from 2001 through 2012 and odds ratios (ORs) of undergoing a vitrectomy with 95% confidence intervals (CIs). RESULTS: Among the 11 161 907 eligible enrollees, 40 892 (0.4%) underwent vitrectomy over the 12-year period. The average age of those undergoing vitrectomy was 57±13 years. Overall vitrectomy rates increased 31% from 2001 to 2012 (from 1.47 to 1.92 per 1000 patients). During this same period, the vitrectomy rate among persons with diabetes mellitus decreased by 43% (from 5.84 to 3.31 per 1000 patients with diabetes). Women had 24% decreased odds of undergoing vitrectomy (adjusted odds ratio [OR], 0.76; 95% confidence interval [CI], 0.72-0.79). The odds of undergoing a vitrectomy were 17% greater for black persons (adjusted OR, 1.17; 95% CI, 1.07-1.27) and 7% higher for persons with diabetes (adjusted OR, 1.07; 95% CI, 1.01-1.14). CONCLUSIONS: Overall, we observed an increase in the vitrectomy rates per 1000 enrollees in this large managed care network over the course of the past decade. However, among persons with diabetes mellitus, vitrectomy rates declined substantially over this period. These changes may be explained, in part, by advances in surgical instrumentation and imaging methods to detect retinal diseases changing indications for surgery, improvements in diabetes care, and alternative treatment options for managing retinal conditions. These results may be useful for future planning of manpower needs and highlight the need for aggressive prevention of complications in black persons with diabetes.

Postoperative Hemorrhagic Occlusive Retinal Vasculitis: Expanding the Clinical Spectrum and Possible Association with Vancomycin.

PURPOSE: To describe a syndrome of hemorrhagic occlusive retinal vasculitis (HORV) that developed after seemingly uncomplicated cataract surgery. DESIGN: Retrospective case series. SUBJECTS: Eleven eyes of 6 patients from 6 different institutions. METHODS: Cases were identified after discussion among retina specialists. The findings on presentation, clinical course, and outcome of a series of 7 eyes of 4 patients were compared with a previous report of 4 eyes of 2 patients, and data from both series were combined for a comprehensive analysis. MAIN OUTCOME MEASURES: Historical data, examination findings, imaging results, systemic evaluation findings, treatment regimens, and visual outcomes. RESULTS: Eleven eyes of 6 patients underwent otherwise uncomplicated cataract surgery, receiving viscoelastic and prophylactic intracameral vancomycin during the procedure. Despite good initial vision on postoperative day 1, between 1 to 14 days after surgery, all eyes demonstrated painless vision loss resulting from HORV. Extensive ocular and systemic evaluations were unrevealing in all patients. All patients were treated with aggressive systemic and topical corticosteroids. Additional treatments included systemic antiviral medication in 4 patients, intravitreal antibiotics in 4 eyes, and pars plana vitrectomy in 4 eyes. Skin testing for vancomycin sensitivity showed negative results in 3 patients and was not performed in the others. Neovascular glaucoma developed in 7 eyes, and all eyes received intravitreal anti-vascular endothelial growth factor (VEGF) injection, panretinal photocoagulation, or both for retinal ischemia. Final visual acuity was less than 20/100 in 8 of 11 eyes. CONCLUSIONS: Postoperative HORV is an exceedingly rare and potentially devastating condition that can occur after otherwise uncomplicated cataract surgery. Although the precise cause remains unknown, this disease may represent a delayed immune reaction similar to vancomycin-induced leukocytoclastic vasculitis. Despite treatment with high-dose corticosteroids, antiviral medication, and early vitrectomy in many patients, visual outcomes typically were poor in this series. Early intervention with intravitreal anti-VEGF medication and panretinal photocoagulation may help to prevent additional vision loss resulting from neovascular glaucoma.

Vision Loss Caused by Retinal and Lateral Geniculate Nucleus Infarction in H1N1 Influenza.

A 13-year-old girl developed encephalopathy and severe bilateral vision loss to the level of light perception within 24 hours of having fever and myalgias heralding H1N1 influenza A. Ophthalmoscopy demonstrated findings of confluent ischemic retinopathy. Brain MRI disclosed lateral geniculate body signal abnormalities indicative of hemorrhagic infarction. Despite aggressive treatment with intravenous corticosteroids, intravenous immunoglobulin, and plasmapheresis, vision did not substantially improve. This case demonstrates that H1N1 can cause simultaneous retinal and lateral geniculate body infarctions, a combination of findings not previously described in any condition. We postulate an immunologic response to the virus marked by occlusive damage to arteriolar endothelium.

Compassionomics: The Science and Practice of Caring.

PURPOSE: To summarize the scientific evidence that compassion can measurably improve patient outcomes, health care quality and safety, and the well-being of health care providers, and to consider specific strategies for cultivating compassion and better communicating it to patients. DESIGN: Perspective. METHODS: We selectively reviewed the literature on compassion in health care, including obstacles to its expression and the demonstrated effects of provider compassion on patient outcomes, health care quality and cost, and provider well-being. We also review evidence regarding the trainability of compassion, discuss proven methods for cultivating individual compassion, and recommend strategies for incorporating it into routine medical practice. RESULTS: Compassion is the emotional response to another's pain or suffering, accompanied by a desire to alleviate it. Review of the literature shows that compassionate health care measurably improves physical and psychological patient outcomes, increases patient adherence, improves health care quality and safety, increases financial margins, and prevents physician burnout. Psychophysiological research shows that empathy and compassion can be actively cultivated through intentional practice. Validated models of compassion-based interactions can facilitate the consistent expression of compassion in daily medical practice. CONCLUSIONS: Given its many proven benefits to patients, health care organizations, and providers, compassion should be cultivated by health care providers and systems and considered an essential component of optimal medical care.

Drug Approval for the Treatment of Geographic Atrophy: How We Got Here and Where We Need to Go.

PURPOSE: To discuss the clinical trial results leading to the US Food and Drug Administration (FDA) approval of anti-complement therapies for geographic atrophy (GA), perspectives on functional data from the GA clinical trials, and how lessons from the FDA approval may guide future directions for basic and clinical research in AMD. DESIGN: Selected literature review with analysis and perspective METHODS: We performed a targeted review of publicly available data from the clinical trials of pegcetacoplan and avacincaptad for the treatment of GA, as well as scientific literature on the natural history of GA and the genetics and basic science of complement in AMD. RESULTS: The approval of pegcetacoplan and avacincaptad was based on an anatomic endpoint of a reduction in the rate of GA expansion over time. However, functional data from 2 phase 3 clinical trials for each drug demonstrated no visual benefit to patients in the treatment groups. Review of the genetics of AMD and the basic science of the role for complement in AMD provides only modest support for targeting complement as treatment for GA expansion, and alternative molecular targets for GA treatment are therefore discussed. Reasons for the disconnect between anatomic and functional outcomes in the clinical trials of anti-complement therapies are discussed, providing insight to guide the configuration of future clinical studies for GA. CONCLUSION: Although avacincaptad and pegcetacoplan are our first FDA-approved treatments for GA, results from the clinical trials failed to show any functional improvement after 1 and 2 years, respectively, calling into question whether the drugs represent a "clinically relevant outcome." To improve the chances of more impactful therapies in the future, we provide basic-science rationale for pursuing non-complement targets; emphasize the importance of ongoing clinical research that more closely pins anatomic features of GA to functional outcomes; and provide suggestions for clinical endpoints for future clinical trials on GA.