A Retrospective Longitudinal Study of 460 Patients with ABCA4-Associated Retinal Disease.

PURPOSE: To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution. DESIGN: Retrospective, single-institution cohort review. PARTICIPANTS: Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4. METHODS: DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects. MAIN OUTCOME MEASURES: Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field. RESULTS: A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4-76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual. CONCLUSIONS: ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium-based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients' clinical findings in most cases will be more useful for predicting their clinical course than their genotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

MENISCUS MICROPYON: An Ophthalmoscopic Sign Possibly Associated With Epiretinal Proliferation After Retinal Surgery With Gas Tamponade.

PURPOSE: To describe an ophthalmoscopic sign, termed a meniscus micropyon, and its possible association with proliferative vitreoretinopathy/epiretinal membrane (ERM) formation after retinal surgery with gas tamponade. METHODS: Patients with intravitreal gas were examined postoperatively by one of six vitreoretinal surgeons from four institutions. A micropyon was defined as a white-yellow, solid-appearing consolidation along the meniscus (i.e., the fluid-gas interface). RESULTS: A micropyon was visualized and photographed in 49 patients who received intravitreal gas. Preoperatively, retinal breaks were present in all 49 eyes and rhegmatogenous retinal detachment in 45 (92%). Postoperatively, 39 eyes (80%) developed epiretinal proliferation: 16 eyes (33%) developed recurrent rhegmatogenous retinal detachment from proliferative vitreoretinopathy, 6 eyes (12%) re-detached without frank proliferative vitreoretinopathy, 9 eyes (18%) developed postoperative ERM/worsening, and 8 eyes (16%) had postoperative ERM but no preoperative optical coherence tomography to determine if the postoperative ERM was new or worsening. The single-operation anatomical success in eyes with a micropyon was 51%, which was lower than that of a contemporaneous rhegmatogenous retinal detachment control group (91%) in which no micropyon was detected. In two patients, micropyons were biopsied during pars plana vitrectomy and examined histopathologically; they consist predominantly of white blood cells. CONCLUSION: The meniscus micropyon is an ophthalmoscopic sign that can occur after retinal surgery with gas tamponade. Features that distinguish a micropyon from postvitrectomy fibrin/fibrinoid syndrome include delayed appearance, hyperautofluorescence, absence of translucent strands or sheets in the anterior chamber or vitreous cavity, and the histopathologic identification of white blood cells. A clinically detectable micropyon may be a biomarker of proliferative vitreoretinopathy/ERM formation.

SURGICAL OUTCOMES IN CONCURRENT SICKLE CELL AND DIABETIC RETINOPATHY.

PURPOSE: To report the clinical features and outcomes in eyes that underwent vitreoretinal surgery for complications of concurrent sickle cell retinopathy and diabetic retinopathy. METHODS: Retrospective, consecutive case series of all eyes that underwent vitreoretinal surgery for complications secondary to concurrent sickle cell retinopathy and diabetic retinopathy between January 01, 2014, and December 31, 2021. RESULTS: The study included 20 eyes of 14 patients. Indications for surgery included tractional retinal detachment in 12 eyes (60%), combined tractional retinal detachment/rhegmatogenous retinal detachment in 6 eyes (30%), and vitreous hemorrhage in 2 eyes (10%). Pars plana vitrectomy was performed in all eyes. One eye received a scleral buckle at the same time as pars plana vitrectomy. There was no change in mean best-corrected visual acuity at the last follow-up examination (1.5 [20/678]) when compared with mean preoperative best-corrected visual acuity (1.6 [20/762], P = 0.83). Preoperative best-corrected visual acuity correlated with postoperative best-corrected visual acuity at the last follow-up examination in eyes with retinal detachment (r = 0.49, P = 0.04). Single operation anatomic success was achieved in 11 of 17 eyes (65%) with retinal detachment. CONCLUSION: Functional and anatomic outcomes after surgery in eyes with concurrent sickle cell retinopathy and diabetic retinopathy are relatively poor.

A Network Science Approach to Sex-Polydrug Use Among Black Sexually Minoritized Men and Transgender Women: The N2 Cohort Study.

Black sexually minoritized men (SMM) and transgender women (TW) are subgroups with lower rates of substance use and comparable rates of condom use relative to White SMM and TW yet experience heightened vulnerability to HIV. This study sought to explore associations of substance use, including sex-drug use (i.e., drug or alcohol use during sex to enhance sex), and condomless sex among Black SMM and TW. Data were collected from Black SMM and TW living in Chicago, Illinois, enrolled in the Neighborhoods and Networks (N2) cohort study, from November 2018 to April 2019. We used bivariate analyses followed by a multilevel egocentric network analysis to identify factors associated with condomless sex. We conducted Spearman correlation coefficients to examine correlations between pairs of sex-drugs to enhance sex. We used a bipartite network analysis to identify correlates of sex-drug use and condomless sex. A total of 352 Black SMM and TW (egos) provided information about 933 sexual partners (alters). Of respondents, 45% reported condomless sex and 61% reported sex-drug use. In unadjusted analyses, marijuana (34%) and cocaine/crack (5%) sex-drug use were associated with condomless sex (p < 0.05). Condomless sex was positively associated with sex-polydrug use, or the use of 2+ drugs or 1 drug and alcohol (OR = 1.48; 95% CI: 1.02-2.14; p = 0.039), and negatively associated with sharing an HIV-negative serostatus with a sexual partner (OR = 0.57; 95% CI: 0.33-0.98; p = 0.041), having a different HIV serostatus with a sexual partner (OR = 0.37; 95% CI: 0.21-0.64; p < 0.001) or not knowing the HIV serostatus of a sexual partner (OR = 0.47; 95% CI: 0.26-0.84; p = 0.011). The following pairs of sex-polydrug use had Spearman correlation coefficients higher than 0.3: marijuana and alcohol, ecstasy and alcohol, cocaine/crack and ecstasy, and methamphetamine and poppers (p < 0.05). HIV prevention interventions for Black SMM and TW designed to reduce HIV transmission through egocentric sexual networks could address sex-drug use through sex-positive and pleasure-centered harm reduction strategies and provide and promote biomedical prevention and care options at supraoptimal levels.

Latent Profile Patterns of Network-Level Norms and Associations with Individual-Level Sexual Behaviors: The N2 Cohort Study in Chicago.

Individual-level behavior can be influenced by injunctive and descriptive social network norms surrounding that behavior. There is a need to understand how the influence of social norms within an individual's social networks may influence individual-level sexual behavior. We aimed to typologize the network-level norms of sexual behaviors within the social networks of Black sexual and gender minoritized groups (SGM) assigned male at birth. Survey data were collected in Chicago, Illinois, USA, between 2018 and 2019 from Black SGM. A total of 371 participants provided individual-level information about sociodemographic characteristics and HIV vulnerability from sex (i.e., condomless sex, group sex, use of alcohol/drugs to enhance sex) and completed an egocentric network inventory assessing perceptions of their social network members' (alters') injunctive and descriptive norms surrounding sexual behaviors with increased HIV vulnerability. We used Latent Profile Analysis (LPA) to identify network-level norms based on the proportion of alters' approval of the participant engaging in condomless sex, group sex, and use of drugs to enhance sex (i.e., injunctive norms) and alters' engagement in these behaviors (i.e., descriptive norms). We then used binomial regression analyses to examine associations between network-level norm profiles and individual-level HIV vulnerability from sex. The results of our LPA indicated that our sample experienced five distinct latent profiles of network-level norms: (1) low HIV vulnerability network norm, (2) moderately high HIV vulnerability network norm, (3) high HIV vulnerability network norm, (4) condomless sex dominant network norm, and (5) approval of drug use during sex dominant network norm. Condomless anal sex, group sex, and using drugs to enhance sex were positively and significantly associated with higher HIV vulnerability social network norm profiles, relative to low HIV vulnerability norm profiles. To mitigate Black SGM's HIV vulnerability, future HIV risk reduction strategies can consider using network-level intervention approaches such as opinion leaders, segmentation, induction, or alteration, through an intersectionality framework.

EVALUATION OF RETINAL DISPLACEMENT FOLLOWING PRIMARY SCLERAL BUCKLING FOR MACULA-INVOLVING RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To evaluate the incidence and degree of retinal displacement following scleral buckling surgery for macula-involving rhegmatogenous retinal detachment. METHODS: Retrospective interventional case series comprised of patients treated with primary scleral buckling procedure without gas tamponade for macula-involving rhegmatogenous retinal detachment and imaged postoperatively with fundus autofluorescence imaging between June 1, 2016 and July 25, 2021. Clinical notes, operative reports, fundus autofluorescence photographs, and optical coherence tomography images were reviewed. The presence and degree of retinal displacement were recorded. RESULTS: Twelve eyes of 11 patients were included. One (8%) eye with an epiretinal membrane demonstrated 0.1 mm of retinal displacement along the superior arcade and in the superotemporal periphery. The remainder of eyes (92%) did not show any identifiable signs of retinal displacement. CONCLUSION: Retinal displacement does not seem to be a frequent complication of primary scleral buckling surgery for macula-involving rhegmatogenous retinal detachment.

LONGITUDINAL ANALYSIS OF DIABETIC CHOROIDOPATHY IN PROLIFERATIVE DIABETIC RETINOPATHY TREATED WITH PANRETINAL PHOTOCOAGULATION USING WIDEFIELD SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Widefield swept-source optical coherence tomography (OCT) imaging was used to characterize choroidal thickness and vascularity at baseline in proliferative diabetic retinopathy (PDR) and longitudinally after panretinal photocoagulation (PRP). METHODS: Patients with treatment-naive PDR were imaged at baseline and at 1 week, 1 month, and 3 months after PRP. Previously validated algorithms were used to calculate the mean choroidal thickness (MCT) and choroidal vascularity index (CVI) in 5 regions of 12 mm × 12 mm scans. RESULTS: Fourteen PDR eyes were included. Baseline MCT in PDR eyes did not differ significantly from normal eyes, but CVI measurements in PDR eyes were lower in all regions (P < 0.001-0.008). After PRP, MCT measurements in PDR eyes were significantly lower at 1 month and 3 months in all regions (P < 0.001-0.005) except the fovea (P = 0.074). However, CVI measurements did not change over time in any region after PRP. CONCLUSION: The choroid in PDR eyes has a smaller CVI than that in normal eyes. After PRP, the choroidal thickness decreases outside the fovea, but the CVI remains constant, which suggests that a relative decrease in choroidal vascularity persists. These widefield swept-source OCT results are consistent with choroidal alterations found in histopathological reports of diabetic choroidopathy.

Noise in a phosphorelay drives stochastic entry into sporulation in Bacillus subtilis.

Entry into sporulation in Bacillus subtilis is governed by a phosphorelay in which phosphoryl groups from a histidine kinase are successively transferred via relay proteins to the response regulator Spo0A. Spo0A~P, in turn, sets in motion events that lead to asymmetric division and activation of the cell-specific transcription factor σF, a hallmark for entry into sporulation. Here, we have used a microfluidics-based platform to investigate the activation of Spo0A and σF in individual cells held under constant, sporulation-inducing conditions. The principal conclusions were that: (i) activation of σF occurs with an approximately constant probability after adaptation to conditions of nutrient limitation; (ii) activation of σF is tightly correlated with, and preceded by, Spo0A~P reaching a high threshold level; (iii) activation of Spo0A takes place abruptly just prior to asymmetric division; and (iv) the primary source of noise in the activation of Spo0A is the phosphorelay. We propose that cells exhibit a constant probability of attaining a high threshold level of Spo0A~P due to fluctuations in the flux of phosphoryl groups through the phosphorelay.

Episodic neurologic disorders: syndromes, genes, and mechanisms.

Many neurologic diseases cause discrete episodic impairment in contrast with progressive deterioration. The symptoms of these episodic disorders exhibit striking variety. Herein we review what is known of the phenotypes, genetics, and pathophysiology of episodic neurologic disorders. Of these, most are genetically complex, with unknown or polygenic inheritance. In contrast, a fascinating panoply of episodic disorders exhibit Mendelian inheritance. We classify episodic Mendelian disorders according to the primary neuroanatomical location affected: skeletal muscle, cardiac muscle, neuromuscular junction, peripheral nerve, or central nervous system (CNS). Most known Mendelian mutations alter genes that encode membrane-bound ion channels. These mutations cause ion channel dysfunction, which ultimately leads to altered membrane excitability as manifested by episodic disease. Other Mendelian disease genes encode proteins essential for ion channel trafficking or stability. These observations have cemented the channelopathy paradigm, in which episodic disorders are conceptualized as disorders of ion channels. However, we expand on this paradigm to propose that dysfunction at the synaptic and neuronal circuit levels may underlie some episodic neurologic entities.

Toward a New Staging System for Diabetic Retinopathy Using Wide Field Swept-Source Optical Coherence Tomography Angiography.

PURPOSE OF REVIEW: For over 50 years, diabetic retinopathy (DR) has been classified by pathologic features seen on clinical examination and conventional retinal photographs. However, newer technology such as optical coherence tomography angiography (OCTA) now enables rapid acquisition of retinal structural and vascular information in a reliable, non-invasive, high-resolution fashion. Here, we highlight recent studies that have explored wide field swept-source OCTA (WF SS-OCTA) for the diagnosis and management of DR. RECENT FINDINGS: Multiple studies have demonstrated the utility of WF SS-OCTA for detection of all clinically relevant features of DR. An updated DR staging system is proposed that leverages the advantages of WF SS-OCTA, including the ability to correlate detailed vascular and structural pathology over time with longitudinal imaging. WF SS-OCTA has tremendous potential for evaluating patients with DR. A new WF SS-OCTA-based staging system may be useful in routine clinical practice and for clinical trials.

Vector genetics, insecticide resistance and gene drives: An agent-based modeling approach to evaluate malaria transmission and elimination.

Vector control has been a key component in the fight against malaria for decades, and chemical insecticides are critical to the success of vector control programs worldwide. However, increasing resistance to insecticides threatens to undermine these efforts. Understanding the evolution and propagation of resistance is thus imperative to mitigating loss of intervention effectiveness. Additionally, accelerated research and development of new tools that can be deployed alongside existing vector control strategies is key to eradicating malaria in the near future. Methods such as gene drives that aim to genetically modify large mosquito populations in the wild to either render them refractory to malaria or impair their reproduction may prove invaluable tools. Mathematical models of gene flow in populations, which is the transfer of genetic information from one population to another through migration, can offer invaluable insight into the behavior and potential impact of gene drives as well as the spread of insecticide resistance in the wild. Here, we present the first multi-locus, agent-based model of vector genetics that accounts for mutations and a many-to-many mapping cardinality of genotypes to phenotypes to investigate gene flow, and the propagation of gene drives in Anopheline populations. This model is embedded within a large scale individual-based model of malaria transmission representative of a high burden, high transmission setting characteristic of the Sahel. Results are presented for the selection of insecticide-resistant vectors and the spread of resistance through repeated deployment of insecticide treated nets (ITNs), in addition to scenarios where gene drives act in concert with existing vector control tools such as ITNs. The roles of seasonality, spatial distribution of vector habitat and feed sites, and existing vector control in propagating alleles that confer phenotypic traits via gene drives that result in reduced transmission are explored. The ability to model a spectrum of vector species with different genotypes and phenotypes in the context of malaria transmission allows us to test deployment strategies for existing interventions that reduce the deleterious effects of resistance and allows exploration of the impact of new tools being proposed or developed.

Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment.

BACKGROUND: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models. METHODS: Mechanistic within-host models of parasite dynamics were identified through a review of published literature. For a subset of these, model code was reproduced and descriptive statistics compared between the models using fitted data. Through simulation and model analysis, key features of the models were compared, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability. RESULTS: The assessed within-host malaria models generally replicate infection dynamics in malaria-naïve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitaemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models. CONCLUSIONS: This study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, it is proposed that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterization and large stochasticity which inaccurately represent unknown disease mechanisms.

CLINICOPATHOLOGIC CORRELATION OF PRERETINAL TISSUES IN MYOPIC TRACTION MACULOPATHY.

PURPOSE: To evaluate histopathologic features of preretinal tissues removed from eyes with myopic traction maculopathy (MTM). METHODS: We retrospectively studied preretinal tissue specimens from eyes with MTM removed during pars plana vitrectomy. A control group of six idiopathic epiretinal membranes was studied for comparison. RESULTS: Six MTM specimens were studied histopathologically. Outer retinal schisis-like thickening was present in 100% of preoperative optical coherence tomography images; four of the six eyes had subfoveal neurosensory retinal detachment. Postoperative optical coherence tomography images demonstrated complete resolution of the schisis-like appearance in all eyes; a full-thickness macular hole occurred in two of the six eyes. Histopathologic examination disclosed fibrocellular tissue that was strongly positive for glial fibrillary acidic protein, weak to moderately positive for cytokeratin, and weakly positive for smooth muscle actin and CD68. There were no apparent histopathologic or immunohistochemical differences between preretinal tissues from eyes with MTM and idiopathic epiretinal membranes from control eyes. CONCLUSION: The outer retinal schisis-like thickening, commonly associated with subretinal fluid, that characterizes MTM is associated with preretinal tissues that are histopathologically indistinguishable from idiopathic epiretinal membranes. These findings suggest that anteroposterior traction caused by axial elongation rather than a uniquely abnormal cellular process is the etiologic mechanism of MTM.

WIDE-FIELD SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF DIABETIC TRACTIONAL RETINAL DETACHMENTS BEFORE AND AFTER SURGICAL REPAIR.

PURPOSE: Wide-field (WF) swept-source (SS) optical coherence tomography angiography (SS-OCTA) was used to image diabetic tractional retinal detachments (TRDs) before and after pars plana vitrectomy. The clinical utility of SS-OCTA was assessed. METHODS: Patients with diabetic TRDs were imaged prospectively with SS-OCTA. Ultrawide-field imaging was obtained when possible. Postoperative WF SS-OCTA imaging was performed. RESULTS: From January 2018 through December 2019, 31 eyes of 21 patients with diabetic TRDs were imaged. Wide-field SS-OCTA en-face images captured all areas of TRD and fibrovascular proliferation within the posterior pole that were visualized on ultrawide-field imaging. Optical coherence tomography angiography B-scans revealed the vascularity of preretinal membranes and identified areas of vitreoretinal traction and posterior vitreous detachment. Ten eyes underwent pars plana vitrectomy. Postoperative SS-OCTA imaging demonstrated removal of fibrovascular membranes, relief of traction, and resolution of TRDs. Retinal ischemia before and after surgical repair appeared similar. CONCLUSION: All clinically relevant features of diabetic TRDs were identified at baseline and assessed longitudinally after pars plana vitrectomy using WF SS-OCTA, which showed resolution of vitreoretinal traction and no apparent change in the status of retinal perfusion after surgery. If the media are clear and fixation is adequate, WF SS-OCTA is likely the only imaging modality needed for the diagnosis and longitudinal evaluation of diabetic TRDs.

Birth Prevalence of Congenital Cytomegalovirus Infection in HIV-Exposed Uninfected Children in the Era of Combination Antiretroviral Therapy.

OBJECTIVES: To estimate birth prevalence of congenital cytomegalovirus (cCMV) in HIV-exposed uninfected children born in the current era of combination antiretroviral therapy and describe cCMV-related neurodevelopmental and hearing outcomes. STUDY DESIGN: The Surveillance Monitoring for ART Toxicities cohort study follows HIV-exposed uninfected children at 22 sites in the US and Puerto Rico. Birth cCMV prevalence was estimated in a subset of participants who had blood pellets collected within three weeks of birth and underwent ≥1 of 6 assessments evaluating cognitive and language development including an audiologic examination between 1 and 5 years of age. Detection of CMV DNA by polymerase chain reaction testing of peripheral blood mononuclear cells was used to diagnose cCMV. Proportions of suboptimal assessment scores were compared by cCMV status using Fisher exact test. RESULTS: Mothers of 895 eligible HIV-exposed uninfected children delivered between 2007 and 2015. Most (90%) were on combination antiretroviral therapy, 88% had an HIV viral load of ≤400 copies/mL, and 93% had CD4 cell counts of ≥200 cells/µL. Eight infants were diagnosed with cCMV, yielding an estimated prevalence of 0.89% (95% CI, 0.39%-1.75%). After adjusting for a sensitivity of 70%-75% for the testing method, projected prevalence was 1.2%-1.3%. No differences were observed in cognitive, language and hearing assessments by cCMV status. CONCLUSIONS: Although birth cCMV prevalence in HIV-exposed uninfected children born to women with well-controlled HIV is trending down compared with earlier combination antiretroviral therapy-era estimates, it is above the 0.4% reported for the general US population. HIV-exposed uninfected children remain at increased risk for cCMV.

Use of a microfluidic platform to uncover basic features of energy and environmental stress responses in individual cells of Bacillus subtilis.

Bacteria use a variety of stress-sensing systems to sense and respond to diverse stressors and to ensure their survival under adverse conditions. The gram-positive bacterium Bacillus subtilis responds to energy stress (ATP depletion) and to environmental stressors using two distinct stress-sensing pathways that converge on the alternative sigma factor σB to provoke a general stress response. Past efforts to study the σB stress response in bulk culture and on agarose pads were unable to visualize the responses of individual cells under tightly controlled conditions for extended periods of time. Here we use a microfluidics-based strategy to discern the basic features of σB activation in single cells in response to energy and environmental stress, both immediately upon stressor exposure and for tens of generations thereafter. Upon energy stress at various levels of stressor, cells exhibited fast, transient, and amplitude-modulated responses but not frequency modulation as previously reported. Upon environmental stress, which is mediated by the stressosome complex, wild-type cells primarily exhibited a transient and amplitude-modulated response. However, mutant cells producing only one of the four paralogous RsbR stressosome proteins showed striking and previously unseen differences. Whereas RsbRA-only cells mimicked the wild type, RsbRC-only cells displayed a slower but sustained overall response composed of repeated activation events in single cells.

Masqueraders of multiple evanescent white dot syndrome (MEWDS).

PURPOSE: To describe disorders that can masquerade as multiple evanescent white dot syndrome (MEWDS). DESIGN: Retrospective, multicenter case series. PARTICIPANTS: Patients who presented with clinical findings compatible with a diagnosis of MEWDS but were ultimately diagnosed with an alternative inflammatory, infectious, or neoplastic disorder. METHODS: Clinical records and multimodal imaging findings including fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and OCT angiography (OCTA) were analyzed. MAIN OUTCOME MEASURES: Inclusion criteria to be defined as a masquerade syndrome for MEWDS included the presence of disseminated grayish-white outer retinal spots that were hyperautofluorescent on FAF and associated with ellipsoid zone (EZ) disruption on OCT. RESULTS: Twenty-two eyes of 13 patients were identified. All patients presented with the classic findings of MEWDS listed above. A MEWDS-like presentation was bilateral in nine of 13 patients (69%). Final diagnosis was determined on the basis of additional investigations including serologies and biopsy. These diagnoses included syphilis (three patients), lymphoma (three patients), idiopathic multifocal choroiditis (two patients), idiopathic retinal phlebitis (one patient), idiopathic acute zonal occult outer retinopathy (one patient), sarcoidosis (one patient), tuberculosis (one patient), and cancer-associated retinopathy (one patient). The outer retinal lesions and imaging findings resolved with treatment for the associated systemic disorders. CONCLUSIONS: Widespread grayish-white outer retinal spots associated with hyperautofluorescence on FAF and disruption of the EZ on OCT are not pathognomonic for MEWDS. A high index of suspicion must be maintained for masqueraders of MEWDS, which can include serious inflammatory, infectious, and neoplastic disorders.

Biomarkers of oral inflammation in perinatally HIV-infected and perinatally HIV-exposed, uninfected youth.

AIM: To examine oral biomarkers that have been associated with periodontal disease progression in HIV-infected adults in perinatally HIV-infected and HIV-exposed but uninfected youth. MATERIAL AND METHODS: This was a cross-sectional, multicentre substudy of youth participating in the Oral Health Pediatric HIV/AIDS Cohort study. Gingival crevicular fluid repository samples from participants with and without periodontal disease (using Gingival Index [GI] and Bleeding on Probing [BOP] parameters on dental examination) were tested for concentration levels of inflammatory biomarkers. Associations were assessed using Wilcoxon test and Spearman correlation. RESULTS: For perinatal HIV youth (n = 129), the markers consistently elevated (p < .05) in sites with GI ≥2 and in sites with BOP were interleukin-1ß, 6 and 13, macrophage inflammatory protein-1α and metalloproteinase-9. Serum tumour necrosis factor-α and soluble CD14 were positively correlated with a summary count of elevated cytokines. No associations were seen among HIV-uninfected subjects (n = 71). CONCLUSIONS: The association of oral biomarkers of inflammation with clinical indicators of periodontal inflammation and systemic immune activation suggests that perinatal HIV-infected youth may be at higher risk for developing significant periodontal disease, associated with tooth loss and HIV progression. More frequent dental care of this group is needed to prevent potential periodontal progression.

Prevalence of periodontal diseases in a multicenter cohort of perinatally HIV-infected and HIV-exposed and uninfected youth.

AIMS: To compare the prevalence and severity of periodontal diseases between 180 perinatally HIV-infected (PHIV) and 118 perinatally HIV-exposed and uninfected (PHEU) youth in a cross-sectional study conducted at 11 clinical sites in the United States and Puerto Rico from the Adolescent Master Protocol study of the Pediatric HIV/AIDS cohort study (PHACS) network. METHODS: Several analyses were conducted, employing the current CDC/AAP classification for periodontitis and incorporating a definition of gingivitis based on a bleeding on probing (BOP) threshold, and analyses based on more detailed whole-mouth, intra-oral regionally, site-based and tooth-based criteria of BOP, plaque levels, pockets depths and clinical attachment levels. RESULTS: After adjusting for plaque control habits and behavioural and sociodemographic factors, there were no significant differences in periodontal diseases between the PHIV and PHEU youth using any of these criteria. For PHIV youth, there was no significant association between parameters of periodontal disease and current HIV status. CONCLUSIONS: Although no significant differences in periodontal parameters were noted between the PHIV and PHEU youth, the influence of antiretroviral therapy merits further exploration in this cohort in a longitudinal study.