Faculty Bibliography

Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite's own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation. When damaged proteins enter the proteasome, their attached PIs inhibit protease function, potentiating the parasiticidal action of ART and overcoming ART resistance. Binding of the PI moiety to the proteasome active site is enhanced by distal interactions of the extended attached peptides, providing a mechanism to overcome PI resistance. ATZs have an extra mode of action beyond that of each component, thereby overcoming resistance to both components, while avoiding transient monotherapy seen when individual agents have disparate pharmacokinetic profiles.

PURPOSE/OBJECTIVE:To study the effect of the pandemic-related lockdown (physical distance measures and movement restrictions) on the characteristics and management of retinopathy of prematurity (ROP). METHODS:In this controlled, multicenter cohort study, the medical records of patients born prematurely and screened for ROP in the neonatal intensive care unit during four time periods were reviewed retrospectively: (1) November 1, 2018, to March 15, 2019; (2) March 16, 2019, to August 2, 2019 (lockdown control period); (3) November 1, 2019, to March 15, 2020; and (4) March 16, 2020-August 2, 2020. RESULTS:A total of 1,645 patients met inclusion criteria. Among the 1,633 patients with complete data, mean gestational age (GA) at birth was 28.2, 28.4, 28.0, and 28.3 weeks across time periods 1 to 4, respectively (P = 0.16). The mean birth weight of all patients was 1079.1 ± 378.60 g, with no significant variation across time periods (P = 0.08). There were fewer patients screened during the lockdown period (n = 411) compared with the period immediately before (n = 491) and the same period in the prior year (n = 533). Significantly more patients were screened using indirect ophthalmoscopy, compared to digital imaging (telemedicine), during the lockdown (P < 0.01). There were 11.7%, 7.7%, 9.0%, and 8.8% of patients requiring treatment in each time period, respectively (P = 0.42), with a median postmenstrual age at initial treatment of 37.2, 36.45, 37.1, and 36.3 weeks, respectively (P = 0.32). CONCLUSIONS:We recorded a decrease in the number of infants meeting criteria for ROP screening during the lockdown. The GA at birth and birth weight did not differ. Significantly more infants were screened with indirect ophthalmoscopy, compared to digital imaging, during the lockdown.

Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies.

PURPOSE/OBJECTIVE:Retinal racemose hemangioma (RRH) is a rare congenital abnormality of the retinal vasculature with a variety of secondary manifestations that can cause vision loss, including macular edema. This report aims to demonstrate the utility of swept-source optical coherence tomography angiography (SS-OCTA) in further characterizing this abnormality. METHODS:Case report with multimodal imaging including SS-OCTA. RESULTS:A 56-year-old woman with blurred vision was diagnosed macular edema secondary to RRH. Localization of the arterial-venous connection was identified with SS-OCTA at the deep capillary plexus (DCP). Conservative management of the associated foveal exudation ultimately led to a favorable outcome. DISCUSSION/CONCLUSIONS:Observation or topical therapy may be useful and warranted in select cases of RRH. The anomalous vascular connection in RRH appears to originate at the level of the DCP in this case, however larger studies are necessary for corroboration. Evolving angiographic modalities like SS-OCTA may continue to provide insights for this rare disease.

PURPOSE OF REVIEW/OBJECTIVE:There is a rising interest in the impact of diet on the pathogenesis of common ophthalmic conditions. The purpose of this review is to summarize the potential preventive and therapeutic power of dietary interventions described in recent basic science and epidemiological literature. RECENT FINDINGS/RESULTS:Basic science investigations have elucidated a variety of mechanisms by which diet may impact ophthalmic disease, particularly through its action on chronic oxidative stress, inflammation and macular pigmentation. Epidemiologic investigations have shown the real-world influence of diet on the incidence and progression of a number of ophthalmic diseases, particularly cataract, age-related macular degeneration (AMD) and diabetic retinopathy. A large observational cohort study found a 20% reduction in the incidence of cataract among vegetarians compared with nonvegetarians. Two recent systematic reviews found that higher adherence to Mediterranean dietary patterns was associated with a decreased risk of progression of AMD to later stages. Finally, large meta-analyses found that patients following plant-based and Mediterranean diets had significant reductions of mean haemoglobin A1c scores and incidence of diabetic retinopathy as compared with controls. SUMMARY/CONCLUSIONS:There is a significant and growing body of evidence that Mediterranean diet and plant-based diets - those that maximize fruits, vegetables, legumes, whole grains and nuts; and that minimize animal products and processed foods - help prevent vision loss from cataract, AMD and diabetic retinopathy. These diets may hold benefits for other ophthalmic conditions, as well. Nevertheless, there is a need for further randomized, controlled and longitudinal studies in this area.

PURPOSE/OBJECTIVE:To highlight a case of chorioretinitis sclopetaria, with concomitant macular hole formation and orbital emphysema, caused by a commercial-grade pressure washer. PATIENT/METHODS:A 19-year-old male presented to the emergency department with a left eye injury, incurred after being sprayed with a commercial-grade pressure washer. He endorsed ipsilateral blurred vision, pain, and linear floaters. Left eye visual acuity was 20/40. Dilated fundus exam showed inferior vitreous hemorrhage, retinal whitening, and pre-, intra-, and sub-retinal hemorrhages, consistent with chorioretinitis sclopetaria. Optical coherence tomography revealed a full-thickness macular hole. Computed tomography scan of the orbits showed subcutaneous and post-septal orbital emphysema. Two months following injury, vitreous and retinal hemorrhages and macular hole resolved. Five months following injury, visual acuity improved to 20/20. DISCUSSION/CONCLUSIONS:Chorioretinitis sclopetaria is defined as a full-thickness chorioretinal disruption resulting from a high-velocity projectile passing adjacent to or into the orbit without penetrating the globe. Chorioretinal deformation and ocular comorbidities are influenced by the velocity of the missile and its spatial relationship to the orbit. While this pattern of injury is typically associated with indirect trauma to the globe by a BB or a bullet, this is the first report of chorioretinitis sclopetaria precipitated by a high-velocity liquid missile.

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer's disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

BACKGROUND:In private equity (PE) buyouts of medical practices, it is common for the PE firm to raise significant levels of debt in order to finance the purchase. This debt is subsequently shouldered by the acquired practice(s). There remains a scarcity of literature quantifying the effect of PE acquisition on the subsequent financial performance of eye care practices. We aim to identify and characterize debt valuations of ophthalmology and optometry private equity-backed group (OPEG) practices, which serve as an indicator of practice financial performance. METHODS:A cross-sectional study from March 2017 to March 2022 was conducted using business development company (BDC) quarterly/annual filings to the Securities and Exchange Commission (SEC). The 2021 BDC Report was used to identify all BDCs actively filing annual reports (Form 10-Ks) and quarterly reports (Form 10-Qs) in the United States in 2021. The public filings of BDCs lending to OPEGs were searched from the inception of the OPEG's debt instrument in a BDC's portfolio and the amortized cost and fair value of each debt instrument were tabulated. A panel linear regression was used to evaluate temporal changes in OPEG valuations. RESULTS: A total of 2,997 practice locations affiliated with 14 unique OPEGs and 17 BDCs were identified over the study period. Debt valuations of OPEGs decreased by 0.46% per quarter over the study period (95% CI: -0.88 to -0.03, P = 0.036). In the COVID-19 pre-vaccine period (March 2020 to December 2020), there was an excess (additional) 4.93% decrease in debt valuations (95% CI: -8.63 to -1.24, P = 0.010) when compared to pre-pandemic debt valuations (March 2017 to December 2019). Effects of COVID-19 on valuations stabilized during the pandemic post-vaccine period (February 2021 to March 2022), with no change in excess debt valuation compared to pre-pandemic baseline (0.60, 95% CI: -4.59 to 5.78, P = 0.822). There was an increase in practices that reported average discounted debt valuations from 20 practices (1.6%) associated with one OPEG to 1,213 practices (40.5%) associated with nine OPEGs (including 100% of newly acquired practices), despite the stabilization of COVID-19-related excess (additional) debt. CONCLUSIONS:Debt valuations of eye care practices have declined significantly post-PE investment from March 2017 to March 2022, suggesting that the financial health of these groups is volatile and vulnerable to economic contractions such as the COVID-19 pandemic. Eye care practice owners must consider long-term financial risks and impacts of subsequent patient care when selling their practice to a private equity group. Future research should assess the impact of secondary transactions of OPEGs on the financial health of practices, practitioner lifestyle, and patient outcomes.