Herpes zoster ophthalmicus: frequency and risk factors for developing uncommon ocular manifestations.

OBJECTIVE: To determine the frequency of herpes zoster ophthalmicus (HZO) and assess risk factors for developing uncommon ocular manifestations of laboratory-verified HZO. DESIGN: Retrospective cohort study. METHODS: The frequency of HZO out of all herpes zoster cases was calculated using International Classification of Diseases codes for patients seen at the University of Pittsburgh Medical Center from January 1, 2004 to October 31, 2021. We also collected demographic and clinical data of patients with HZO identified by polymerase chain reaction (PCR) detection of varicella zoster virus from January 1, 2011 to December 31, 2020. RESULTS: The frequency of HZO from 2004 to 2021 in all ages was 4.2% and ranged from 2.7% to 6.7% annually, with a consistent increase of 2.9% from 2012 to 2021. After the live zoster vaccine became available in 2008, the frequency of HZO decreased by 5.1% from 2008 to 2012 in patients aged 60 and older. Among 50 cases of PCR-verified HZO, 62% represented clinically-common ocular manifestations, mostly comprised of 13 cases of keratitis and 10 cases of anterior uveitis. Fifteen cases of acute retinal necrosis (ARN) represented the majority of uncommon HZO manifestations (38%), which were significantly more likely to occur in immunosuppressed patients (unadjusted odds ratio 4.55, 95% confidence interval 1.29-13.83). CONCLUSIONS: The overall frequency of HZO from 2004 to 2021 was 4.2% and has increased annually since 2012. Uncommon ocular manifestations of PCR-verified HZO, mostly comprised of ARN, were more likely to occur in immunosuppressed patients.

A Novel Approach to Teaching Fundoscopy Using a Virtual Format.

Introduction: Ophthalmology education has been underemphasized in medical school curricula despite the fact that patient eye-related complaints are commonplace across primary care specialties. Although previous curricula used direct ophthalmoscopy to teach medical students the fundamentals of ophthalmic examination, there has been a growing call to teach these fundamentals through reading fundus photos due to the increasing prevalence and decreased costs of fundus cameras in primary care settings. We developed a virtual workshop to teach ophthalmoscopy to medical students using fundus photography. Methods: First-year medical students were enrolled in a 2-hour, synchronous, virtual ophthalmoscopy workshop as part of an advanced physical exam curriculum at the University of Pittsburgh School of Medicine. Students participated in a pretest, introductory lecture, interactive small-group session, and posttest. Breakout groups were led by senior medical students or residents. We compared pre- and posttest results for improved understanding of concepts covered in the workshop. Results: Of 147 students, the average scores on the pretest and posttest were 39% and 75%, respectively (p < .01). Students were significantly more confident in their ability to identify various pathologies on fundus photography. After the workshop, the student preceptors indicated increased comfort in a teaching role and greater interest in medical education. The preceptors were also more confident in their own ability to interpret fundus photography and in their understanding of various ocular pathologies. Discussion: Our virtual, interactive workshop is effective in teaching medical students a systematic approach to the interpretation of fundus photographs.

Bilateral, chronic, bacterial conjunctivitis in giant fornix syndrome.

Giant fornix syndrome (GFS) results in chronic, relapsing conjunctivitis in elderly patients with enophthalmos and enlarged fornices, in which infectious material collects and perpetuates inflammation. A 98-year-old woman presented with persistent, bilateral, purulent conjunctivitis; corneal epithelial defects and progressive blepharospasm that did not respond to artificial tears, topical antibiotics and steroids and amniotic membrane grafts. Additional findings of deep-set orbits with enlarged upper fornices were diagnostic of GFS. Over the next 2 months, she responded to a combination of topical and systemic antibiotics, autologous serum eye drops, povidone-iodine forniceal rinses, and hypochlorous acid treatment of the eyelashes. GFS is an important diagnostic consideration in elderly patients with chronic conjunctivitis and deep-set orbits.

The Intersection of the Staphylococcus aureus Rex and SrrAB Regulons: an Example of Metabolic Evolution That Maximizes Resistance to Immune Radicals.

Staphylococcus aureus is the most pathogenic member of the Staphylococcaceae. While it acquired an arsenal of canonical virulence determinants that mediate pathogenicity, it has also metabolically adapted to thrive at sites of inflammation. Notably, it has evolved to grow in the presence of nitric oxide (NO·). To this end, we note that the Rex regulon, composed of genes encoding dehydrogenases, metabolite transporters, and regulators, is much larger in S. aureus than other Staphylococcus species. Here, we demonstrate that this expanded Rex regulon is necessary and sufficient for NO· resistance. Preventing its expression results in NO· sensitivity, and the closely related species, Staphylococcus simiae, also possesses an expanded Rex regulon and exhibits NO· resistance. We hypothesize that the expanded Rex regulon initially evolved to provide efficient anaerobic metabolism but that S. aureus has co-opted this feature to thrive at sites of inflammation where respiration is limited. One distinguishing feature of the Rex regulon in S. aureus is that it contains the srrAB two-component system. Here, we show that Rex blocks the ability of SrrA to auto-induce the operon, thereby preventing maximal SrrAB expression. This results in NO·-responsive srrAB expression in S. aureus but not in other staphylococci. Consequently, higher expression of cytochromes and NO· detoxification are also observed in S. aureus alone, allowing for continued respiration at NO· concentrations beyond that of S. simiae. We therefore contend that the intersection of the Rex and SrrAB regulons represents an evolutionary event that allowed S. aureus to metabolically adapt to host inflammatory radicals during infection. IMPORTANCE Pathogens must evolve virulence potential to improve transmission to new hosts as well as evolve metabolically to thrive within their current host. Staphylococcus aureus has achieved both of these, and here, we show that one such metabolic adaptation was the expansion of the Rex regulon. First, it affords S. aureus with efficient respiration-independent growth critical to surviving the inflammatory environment replete with respiration-inhibiting immune radicals. Second, it includes the srrAB operon encoding a two-component system critical to maximizing respiratory capacity in the face of host nitric oxide (NO·), a potent respiratory inhibitor. This second facet is only apparent in S. aureus and not in other closely related species. Thus, evolutionarily, it must have occurred relatively recently. The intertwining of the Rex and SrrAB regulons represents an important evolutionary event that affords S. aureus the metabolic flexibility required to thrive within inflamed tissue and cause disease.

Structural and ligand binding analyses of the periplasmic sensor domain of RsbU in Chlamydia trachomatis support a role in TCA cycle regulation.

Chlamydia trachomatis is an obligate intracellular bacteria that undergo dynamic morphologic and physiologic conversions upon gaining an access to a eukaryotic cell. These conversions likely require the detection of key environmental conditions and regulation of metabolic activity. Chlamydia encodes homologs to proteins in the Rsb phosphoregulatory partner-switching pathway, best described in Bacillus subtilis. ORF CT588 has a strong sequence similarity to RsbU cytoplasmic phosphatase domain but also contains a unique periplasmic sensor domain that is expected to control the phosphatase activity. A 1.7 Å crystal structure of the periplasmic domain of the RsbU protein from C. trachomatis (PDB 6MAB) displays close structural similarity to DctB from Vibrio and Sinorhizobium. DctB has been shown, both structurally and functionally, to specifically bind to the tricarboxylic acid (TCA) cycle intermediate succinate. Surface plasmon resonance and differential scanning fluorimetry of TCA intermediates and potential metabolites from a virtual screen of RsbU revealed that alpha-ketoglutarate, malate and oxaloacetate bound to the RsbU periplasmic domain. Substitutions in the putative binding site resulted in reduced binding capabilities. An RsbU null mutant showed severe growth defects which could be restored through genetic complementation. Chemical inhibition of ATP synthesis by oxidative phosphorylation phenocopied the growth defect observed in the RsbU null strain. Altogether, these data support a model with the Rsb system responding differentially to TCA cycle intermediates to regulate metabolism and key differentiation processes.