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OBJECTIVE: Irritable bowel syndrome (IBS) is a chronic disorder associated with an abnormal gastrointestinal microbiome. Microbiome-host interactions are known to influence organ function including in the central nervous system; thus, we sought to identify whether IBS may be a risk factor for the development of glaucoma.DESIGN: Two prospective cohort studies.SUBJECTS: The 1958 United Kingdom Birth Cohort (UKBC; 9091 individuals) and the Danish National Registry of Patients (DNRP; 62,541 individuals with IBS and 625,410 matched general population cohort members).METHODS: In the UKBC, participants were surveyed throughout life (including at ages 42 and 50). The DNRP contains records of hospital-based contacts and prescription data from the national prescription database.MAIN OUTCOME MEASURE: The main outcome measure was incidence of glaucoma. In the UKBC, incident glaucoma at age 50 (n = 48) was determined through comparison of survey responses at ages 42 and 50 years. In the DNRP, glaucoma was assessed by hospital diagnosis (n = 1510), glaucoma surgery (n = 582) and initiation of glaucoma medications (n = 1674).RESULTS: In the UKBC, the odds ratio (OR) of developing glaucoma between ages 42 and 50 in persons with a chronic IBS diagnosis was increased [OR: 5.84, 95% confidence interval (CI): 2.26-15.13]. People with an IBS diagnosis in the DNRP had a hazard ratio (HR) of 1.35 for developing physician-diagnosed glaucoma (95% CI: 1.16-1.56), an HR of 1.35 for undergoing glaucoma surgery (95% CI: 1.06-1.70) and an HR of 1.19 for initiating glaucoma medication (95% CI: 1.03-1.38).CONCLUSIONS: In two large European cohort studies, IBS is a risk factor for glaucoma.

The etiology of exfoliation glaucoma (XFG) is poorly understood. We aimed to identify a prediagnostic plasma metabolomic signature associated with XFG.We conducted a 1:1 matched case-control study nested within the Nurses' Health Study and Health Professionals Follow-up Study. We collected blood samples in 1989-1990 (Nurses' Health Study) and 1993-1995 (Health Professionals Follow-up Study). We identified 205 incident XFG cases through 2016 (average time to diagnosis from blood draw = 11.8 years) who self-reported glaucoma and were confirmed as XFG cases with medical records. We profiled plasma metabolites using liquid chromatography-mass spectrometry. We evaluated 379 known metabolites (transformed for normality using probit scores) using multiple conditional logistic models. Metabolite set enrichment analysis was used to identify metabolite classes associated with XFG. To adjust for multiple comparisons, we used number of effective tests (NEF) and the false discovery rate (FDR).Mean age of cases (n = 205) at diagnosis was 71 years; 85% were women and more than 99% were Caucasian; controls (n = 205) reported eye examinations as of the matched cases' index date. Thirty-three metabolites were nominally significantly associated with XFG (P0.05), and 4 metabolite classes were FDR-significantly associated. We observed positive associations for lysophosphatidylcholines (FDR = 0.02) and phosphatidylethanolamine plasmalogens (FDR = 0.004) and inverse associations for triacylglycerols (FDR0.0001) and steroids (FDR = 0.03). In particular, the multivariable-adjusted odds ratio with each 1 standard deviation higher plasma cortisone levels was 0.49 (95% confidence interval, 0.32-0.74; NEF = 0.05).In plasma from a decade before diagnosis, lysophosphatidylcholines and phosphatidylethanolamine plasmalogens were positively associated and triacylglycerols and steroids (e.g., cortisone) were inversely associated with XFG risk.

Precis We conducted a literature review of younger patients with exfoliation syndrome (XFS) in an attempt to identify case similarities and better understand disease etiology. Purpose XFS that predisposes to secondary glaucoma is a strongly age-related condition. We performed a literature review of XFS and exfoliation glaucoma (XFG) in patients aged younger than 40 years to examine potential common characteristics and gain clues to its etiology. Methods We conducted a broad literature search with appropriate keywords and manually extracted key demographic and ocular features on younger XFS and XFG cases. Articles that did not provide past ocular history on early-onset XFS/XFG were excluded. Results We identified 12 cases of XFS and XFG in patients from 13 to 40 years old (8 females; 11 White; 5 from Iran). All had past ocular history remarkable for intraocular surgery for other glaucoma conditions (7 cases), other ocular diseases (3 cases), or ocular trauma (2 cases). Conclusions All reported early-onset XFS and XFG cases arise in the setting of events that produced a significant disruption of the blood-aqueous barrier. Understanding the metabolic alterations of aqueous humor from such cases could provide clues regarding how exfoliation material forms.

The purpose of this study was to identify the pattern of injuries that relates to abuse and neglect in children with burn injuries.The Nationwide Readmissions Database for 2010-2014 was queried for all patients aged less than 18 y admitted with burn injuries. The primary outcome was child maltreatment identified at the index admission. The secondary outcome was readmission for maltreatment. A subgroup analysis was performed on patients without a diagnosis of maltreatment during the index admission. Multivariable logistic regression was performed for each outcome.There were 57,939 admissions identified and 1960 (3.4%) involved maltreatment at the index admission. Maltreatment was associated with total body surface area burned20% (odds ratio (OR) 2.79, P 0.001) and burn of the lower limbs (OR 1.37, P 0.001). Readmission for maltreatment was found in 120 (0.2%), and the strongest risk factor was maltreatment identified at the index admission (OR 5.11, P 0.001). After excluding the patients with maltreatment identified at the index admission, 96 (0.17%) children were found to have a readmission for maltreatment that may have been present on the index admission and subsequently missed. The strongest risk factor was burn of the eye or ocular adnexa (OR 3.79, P = 0.001).This study demonstrates that a portion of admissions for burn injuries in children could involve maltreatment that was undiagnosed. Identifying these at-risk individuals is critical to prevention efforts.

Investigate associations of race/ethnicity and preferred language with baseline glaucoma severity, VF test frequency and disease progression.Retrospective cohort study.Patients receiving VF testing at a tertiary eyecare center between 1998 and 2020 with self-identified race, ethnicity and preferred language were included. Outcome measures were VF MD and age at first visit, VF test frequency, VF MD progression.Among 29,891 patients with VF measurements between 1998 and 2020, 55.1% were female, 71.0% self-identified as White/Caucasian, 14.0% as Black/African American, 7.4% as Asian and 6.4% as Hispanic, and 11.2% preferred a language other than English. Mean VF MD at presentation was worse among Black (-9.3±9.7 dB), Asian (-6.2±7.6 dB) and Hispanic (-8.3±9.3 dB) patients (vs. Whites [-5.5±7.3 dB, p0.001] or non-Hispanics [-6.2±7.8 dB, p0.001]). After controlling for age, gender and English proficiency, disparities in glaucoma severity at presentation were reduced, especially among Asian and Hispanic patients. Despite greater severity at presentation, Black patients had lower VF test frequency/person-years (1.07±0.53) compared to Whites (1.12±0.52, p=0.006) and worse VF MD progression (-0.43 dB/year, 95% CI -0.67 to -0.28, p0.001). In contrast, Hispanics had a higher VF frequency vs. non-Hispanics (1.18±0.64 vs. 1.11±0.52, p0.001), and no difference in VF progression (p=0.77).Black, Asian and Hispanic patients had greater baseline severity vs. Whites. Unlike other groups, Black patients had a lower VF frequency vs. Whites and greater VF progression. Disparities in baseline severity were partially explained by English proficiency, especially for Asian and Hispanic patients.

This study describes the natural history of dengue virus (DENV) infection in rhesus monkeys exposed to the bites of DENV-infected Aedes aegypti mosquitoes. Dengue virus–infected mosquitoes were generated by either intrathoracic inoculation or by oral feeding on viremic blood meals. Each of the six rhesus monkeys that were fed upon by intrathoracically infected mosquitoes developed non-structural protein 1 (NS1) antigenemia and an IgM response; viremia was detected in 4/6 individuals. No virological or immunological evidence of DENV infection was detected in the three monkeys exposed to mosquitoes that had been orally infected with DENV. These results demonstrate the utility of mosquito-borne challenge of rhesus monkeys with DENV.

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0–93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community.

Introduction This study evaluates a large cohort of college students after the 2009–2010 pandemic H1N1 influenza season. The objective was to assess influenza vaccination status, influenzalike illnesses (ILIs), and other characteristics associated with attaining immunizations. Methods This study was conducted during the summer 2010 the Reserve Officer Training Corps Leadership Development and Assessment Course involving 6272 college students. A voluntary, anonymous questionnaire was administered to assess study objectives. Results Vaccination rates were 39.9% for pandemic H1N1, 40.6% for seasonal influenza, and 32.6% for receiving both vaccinations. Age less than 25 and having a Reserve Officer Training Corps scholarship were associated with lower odds of receiving vaccinations, whereas entering the nursing field and simultaneous membership in the Army reserve forces were associated with higher odds of vaccination. There are 11.2% of respondents reported having an ILI, including 4.3% with severe ILI. There were 4184 reasons indicated for not attaining influenza vaccinations, which are listed in categorical groupings. Conclusions A historical anchor for vaccination rates and ILI is provided in a large cohort of college students following the 2009 H1N1 influenza pandemic. Influenza immunization locations were determined, as was self-reported obstacles to receiving vaccinations. These are important results for public health leaders seeking to increase vaccination rates during future influenza seasons.

Purpose To investigate if accounting for a cup-to-disc ratio (CDR) genetic risk score (GRS) modified the association between large CDR and cognitive function among women. Design This was a retrospective study using data from the Women’s Health Initiative. Methods Patients with glaucoma or ocular hypertension were excluded. Large CDR was defined as ≥ 0.6 in either eye. Cognitive function was measured by the Modified Mini-Mental State Examination (3MSE). We used the combined effects from 13 single nucleotide polymorphisms (SNPs) to formulate the GRS for CDR. We used logistic regression to investigate associations between weighted GRS and large CDR, then a linear regression to assess the association between weighted GRS and 3MSE scores, and between weighted GRS, CDR, and 3MSE scores, adjusted for demographic and clinical characteristics. Results Final analyses included 1,196 White women with mean age of 69.60 ± 3.62 years and 7.27% with large CDR. Mean GRS in women with and without large CDR was 1.51 ± 0.31 vs. 1.41 ± 0.36, respectively (p = 0.004). The odds of large CDR for a one unit increase in GRS was 2.30 (95% CI: (1.22, 4.36), p = 0.011). Adding the CDR GRS in the model with CDR and 3MSE, women with large CDR still had statistically significantly lower 3MSE scores than those without large CDR, yielding a predicted mean difference in 3MSE scores of 0.84 (p = 0.007). Conclusions Independent of the CDR GRS, women with large CDR had a lower cognitive function.

PURPOSE To quantitatively analyze the angle anatomy in eyes with a Boston type 1 keratoprosthesis (KPro) using anterior segment optical coherence tomography (AS-OCT) and to assess the diagnostic ability of AS-OCT in KPro-associated glaucoma. METHODS AS-OCT (RTVue) images from KPro eyes with and without glaucoma were reviewed. The angle opening distance at 500 μm from the scleral spur (AOD500), trabecular-iris angle at 500 μm from the scleral spur (TIA500), and trabecular-iris surface area at 500 μm from the scleral spur (TISA500) were measured by 2 observers masked to the diagnosis. The measurements for each visible quadrant were compared between KPro eyes with and without glaucoma. RESULTS Twenty-two eyes with glaucoma and 17 eyes without glaucoma from 39 patients with KPro were included. Of the 4 quadrants imaged, the temporal angle was the most visible (79.5%) and angle measurements of the temporal quadrant were the only ones that differentiated the 2 groups: the mean AOD500, TIA500, and TISA500 were significantly lower in KPro eyes with glaucoma than without glaucoma (388.2 ± 234.4 μm vs. 624.5 ± 310.5 μm, P = 0.02; 26.1 ± 14.0 degrees vs. 39.1 ± 17.1 degrees, P = 0.03; and 0.15 ± 0.09 mm vs. 0.23 ± 0.12 mm, P = 0.03; respectively). The highest area under the receiver operating characteristic curve for detecting glaucoma was 0.75 for temporal TIA500 (95% confidence interval 0.57-0.94, P = 0.02) with 50% specificity at 80% of sensitivity and a cutoff value of 37 degrees. CONCLUSIONS The temporal angle was the most visible on AS-OCT in eyes with a KPro. Significant narrowing of the temporal angle detected on AS-OCT was associated with glaucoma in these eyes.

Glaucoma, the world’s leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include: ABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including MMP9, HGF, HSP70, MFRP, and eNOS. In exfoliation glaucoma (XFG), genes implicated include LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.

We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; β = 0.14; P = 6.2 × 10−12). rs6410 (a synonymous variant in the first exon of CYP11B1 in high LD with rs6471570), was prioritized for functional follow-up being second most significant and the one closest to the first intron-exon boundary. In 208 adrenal RNA-seq samples from GTEx, C-allele of rs6410 was associated with intron 3 retention (P = 8.11 × 10−40), exon 4 inclusion (P = 4.29 × 10−34), and decreased exon 3 and 5 splicing (P = 7.85 × 10−43), replicated using RT-PCR in 15 adrenal samples. As CYP11B1 encodes 11-β-hydroxylase, involved in adrenal glucocorticoid and mineralocorticoid biosynthesis, our findings highlight the role of adrenal steroidogenesis in SA in healthy children, suggesting alternative splicing as a likely underlying mechanism., Olja Grgic, Matthew Gazzara, and Alessandra Chesi et al. perform a genome-wide association study meta-analysis for skeletal age in two pediatric cohorts. They observe that variation in the adrenal gene, CYP11B1, impacts its alternative splicing, suggesting that adrenal steroidogenesis may contribute toward variation in skeletal age in otherwise healthy children.

PURPOSE Metabolomic and preclinical studies suggest that branched-chain amino acids (BCAA) may be inversely associated with neurodegenerative diseases including glaucoma. We therefore assessed the long-term association between dietary intake of BCAA and incident primary open-angle glaucoma (POAG) and POAG subtypes. METHODS We followed biennially participants of the Nurses' Health Study (NHS; 65 531 women: 1984-2016), Health Professionals Follow-up Study (42 254 men: 1986-2016) and NHSII (66 904 women; 1991-2017). Eligible participants were 40+ years old and reported eye examinations. Repeated validated food frequency questionnaires were used to assess dietary intake of BCAA. Incident cases of POAG and POAG subtypes defined by visual field (VF) loss and untreated intraocular pressure (IOP) were confirmed by medical record review. Multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS We identified 1946 incident POAG cases. The pooled MVRRs of POAG for the highest quintile (Q5 = 17.1 g/day) versus lowest quintile (Q1 = 11.2 g/day) of total BCAA intake was 0.93 (95% CI, 0.73-1.19; ptrend = 0.45; pheterogeneity by sex = 0.24). For subtypes of POAG defined by IOP level or POAG with only peripheral VF loss, no associations were observed for men or women (ptrend ≥ 0.20); however, for the POAG subtype with early paracentral VF loss, there was a suggestion of an inverse association in women (MVRRQ5versusQ1 = 0.80 [95% CI, 0.57-1.12; ptrend = 0.12]) but not in men (MVRRQ5versusQ1 = 1.38 [95% CI, 0.81-2.34; ptrend = 0.28; pheterogeneity by sex = 0.06]). CONCLUSION Higher dietary intake of BCAA was not associated with POAG risk.

This systematic review summarizes evidence for associations between female reproductive factors (age at menarche, parity, oral contraceptive [OC] use, age at menopause, and postmenopausal hormone [PMH] use) and intraocular pressure (IOP) or open-angle glaucoma (OAG).Understanding the associations between female reproductive factors and glaucoma may shed light on the disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable, which may lead to new therapies.Two reviewers independently extracted articles in MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects aged18 years; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional, or randomized controlled trial design; a reported measure of association, such as the hazard ratio, relative risk, odds ratio, or mean difference, with an associated confidence interval; and a measured exposure of at least 1 of the following variables: age at menarche, parity, OC use, age at menopause, or PMH use.We included a total of 27 studies. Substantial differences in study designs, exposure and treatment levels, treatment durations, and variable reporting precluded a meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and a lower IOP were identified. Estrogen-only PMH use may be associated with lower OAG risk, which may be modified by race. No significant associations were found with combined estrogen-and-progesterone PMH use. No strong associations between parity or age at menarche and glaucoma were found, but a younger age at menopause was associated with an increased glaucoma risk, and adverse associations were identified with a longer duration of OC use, though no overall association with OC use was found.The association between PMH use and lower IOP or OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. Future research should examine associations with IOP specifically and how the relationship between genetic factors and OAG risks may be influenced by female reproductive factors.

Purpose To assess outcomes and glaucoma management in eyes with aniridia following Boston type 1 Keratoprosthesis (KPro) implantation. Design Retrospective, interventional comparative case series. Methods The population included patients with aniridia and patients with other preoperative diagnoses (excluding Stevens-Johnson syndrome, mucous membrane pemphigoid, and congenital disorders) who underwent KPro implantation at Massachusetts Eye and Ear with at least 2 years of follow-up. One eye per patient was selected based on the longer follow-up time. The main outcome was intermediate and long-term outcomes related to glaucoma. Results The aniridia (n = 22) and comparison (n = 61) groups had similar preoperative visual acuity (VA, mean ± standard deviation, 1.86 ± 0.52 logMAR, P = .33) and follow-up time (65.6 ± 26.3 months, P = .25). Before KPro implantation, eyes with aniridia had more glaucoma (76.2%) and glaucoma surgery (57.1%) than comparison eyes (51.8%, P = .053; 23.2%, P = .005, respectively). More Ahmed valves were co-implanted with KPro in aniridia (47.6%) vs comparison eyes (17.9%, P = .008). At final follow-up, more aniridia eyes had glaucoma (90.5%) than comparison eyes (64.3%, P = .02), but the 2 groups had similar percentages of eyes with cup-to-disc ratio (CDR) >0.8 (23.8% vs. 30.4%, P = .57) or CDR progression of ≥0.2 (42.9% vs 44.6%, P = .89, respectively). None of the eyes with prophylactic tube implantation developed glaucoma. Eyes with and without aniridia did not differ in post-KPro VA improvement (72.7%, 72.1%, P = .96), and final VA (1.28 ± 0.79 logMAR, 1.23 ± 0.98 logMAR, P = .51). Conclusion Despite a higher glaucoma prevalence, eyes with aniridia achieved similar VA as comparison eyes with more than 5 years of mean follow-up time. Boston KPro offers satisfactory visual rehabilitation in aniridia when glaucoma is managed aggressively.

To determine the association of aqueous humor cytokine concentrations with long-term treatment response to anti-vascular endothelial growth factor (VEGF) agents in diabetic macular edema (DME).Retrospective case series.Pooled data of aqueous humor cytokine concentrations collected at baseline and 2-month follow-up (2 injections) for treatment-naïve eyes with center-involving DME previously enrolled in a prospective study were reviewed. Subjects receiving intravitreal anti-VEGF injections outside of study protocol as per standard of care were classified into Responders versus Nonresponders based on qualitative assessment of optical coherence tomography for persistence of DME at longitudinal follow-up visits.Of the 41 eyes, 85% were classified as Responders with a significant decline in baseline central subfield thickness and macular volume (P values.001), and 15% were identified as Nonresponders to anti-VEGF therapy over 51.4 ± 18.7 months of follow-up. No significant difference in baseline aqueous humor VEGF concentration was noted, while at the 2-month follow-up the Nonresponder group had a significantly higher VEGF concentration compared with the Responder group (451.5 ± 690.9 pg/mL vs 113.7 ± 211.4 pg/mL; P = .02). The Responder group also demonstrated a significant decline from baseline to 2-month follow-up in concentration of intercellular adhesion molecule-1 (P.001), interleukin-10 (P = .041), monocyte chemotactic protein-1 (P = .046), placental growth factor (P = .027), and transforming growth factor-β2 (P = .017).Aqueous humor cytokine concentrations serve as an early biomarker for long-term response to anti-VEGF therapy and may enable more effective treatment regimens that improve anatomical outcomes in eyes with DME.

Background: Teleophthalmology is an evidence-based method for diabetic eye screening. It is unclear whether the type of eye care provider performing teleophthalmology interpretation produces significant variability. Introduction: We assessed grading variability between an optometrist, general ophthalmologist, and retinal specialist using images from an urban, diabetic retinopathy teleophthalmology program. Methods: Three readers evaluated digital retinal images in 100 cases (178 eyes from 90 patients with type 2 diabetes). Fisher's exact test, percent agreement, and the observed proportion of positive (Ppos) or negative agreement (Pneg) were used to assess variability. Results: Among cases deemed gradable by all three readers (n = 65), there was substantial agreement on absence of any retinopathy (88% ± 4.6%, Pneg = 0.91–0.95), presence of moderate nonproliferative or worse retinopathy (87% ± 3.9%, Ppos = 0.67–1.00), and presence of macular edema (99% ± 0.9%, Ppos = 0.67–1.00). There was limited agreement regarding presence of referable nondiabetic eye pathology (61% ± 11%, Ppos = 0.21–0.59) and early, nonroutine referral for a follow-up clinical eye exam (66% ± 8.1%, Ppos = 0.19–0.54). Among all cases (n = 100), there was acceptable agreement regarding which had gradable images (77% ± 5.0%, Ppos = 0.50–0.90). Discussion: Inclusion of multiple types of eye care providers as teleophthalmology readers is unlikely to produce significant variability in the assessment of diabetic retinopathy among high-quality images. Greater variability was found regarding image gradability, nondiabetic eye pathology, and recommended clinical referral times. Conclusions: Our results suggest that more extensive training and uniform referral standards are needed to improve consensus on image gradability, referable nondiabetic eye pathology, and recommended clinical referral times.

Precis Intraocular pressure (IOP) measurements, when used during telemedicine eye screening alongside nonmydriatic fundus photography, were shown to improve the likelihood of accurate glaucoma and glaucoma-related diagnoses at the follow-up eye examination. Purpose To determine if IOP measurements, used as an adjunct to nonmydriatic fundus photography, are useful in glaucoma telemedicine screening. Materials and methods A total of 902 high-risk individuals were screened for glaucoma at 7 primary care practices and 4 Federally Qualified Health Centers using telemedicine. Screening at visit 1 included fundus photography, assessing family history of glaucoma, and IOP measurements using a hand-held rebound tonometer. Participants with suspicious nerve findings for glaucoma, IOP>21 mm Hg or other ocular pathologies were invited for a follow-up appointment with an ophthalmologist (visit 2). Results Of the 902 individuals screened at visit 1, 19.6% (n=177/902) had elevated IOP (>21 mm Hg). Fifteen participants were found to have an IOP>30 mm Hg at visit 1, including 2 with an IOP of >40 mm Hg. Among all who attended visit 2 (n=347), 10.9% had glaucoma and 7.2% had ocular hypertension. For participants having both suspicious nerve findings and IOP>21 mm Hg compared with those with neither, the odds ratio (OR) of being diagnosed with glaucoma was 4.48 (95% CI, 1.50-13.93; P=0.007), whereas for participants with suspicious discs and IOP≤21 mm Hg the OR was 2.04 (95% CI, 0.83-5.53; P=0.15). Conclusions In this telemedicine vision screening setting, having a higher IOP at the screening visit increased the likelihood of receiving a final diagnosis of glaucoma. Therefore, this study supports incorporating IOP measurements, using a portable tonometer, into vision screening programs in high-risk populations.

Background A growing amount of data suggests that n-3 (ω-3) polyunsaturated fatty acid (PUFA) intake may modify the genetic association with weight change. Objectives We aimed to prospectively test interactions of habitual consumption of n-3 PUFAs or fish, the major food source, with overall genetic susceptibility on long-term weight change. Design Gene-diet interactions were examined in 11,330 women from the Nurses' Health Study (NHS), 6773 men from the Health Professionals Follow-Up Study (HPFS), and 6254 women from the Women's Health Initiative (WHI). Results In the NHS and HPFS cohorts, food-sourced long-chain n-3 PUFA intake showed directionally consistent interactions with genetic risk score on long-term changes in BMI (P-interaction = 0.01 in the HPFS, 0.15 in the NHS, and 0.01 in both cohorts combined). Such interactions were successfully replicated in the WHI, an independent cohort (P-interaction = 0.02 in the WHI and 0.01 in the combined 3 cohorts). The genetic associations with changes in BMI (in kg/m2) consistently decreased (0.15, 0.10, 0.07, and -0.14 per 10 BMI-increasing alleles) across the quartiles of long-chain n-3 PUFAs in the combined cohorts. In addition, high fish intake also attenuated the genetic associations with long-term changes in BMI in the HPFS (P-interaction = 0.01), NHS (P-interaction = 0.03), WHI (P-interaction = 0.10), and the combined cohorts (P-interaction = 0.01); and the differences in BMI changes per 10 BMI-increasing alleles were 0.16, 0.06, -0.08, and -0.18, respectively, across the categories (≤1, 1∼4, 4∼6, and ≥7 servings/wk) of total fish intake. Similar interactions on body weight were observed for fish intake (P-interaction = 0.003) and long-chain n-3 PUFA intake (P-interaction = 0.12). Conclusion Our study provides replicable evidence to show that high intakes of fish and long-chain n-3 PUFAs are associated with an attenuation of the genetic association with long-term weight gain based on results from 3 prospective cohorts of Caucasians.

The nitric oxide – guanylyl cyclase-1 – cyclic guanylate monophosphate (NO-GC-1–cGMP) pathway has emerged as a potential pathogenic mechanism for glaucoma, a common intraocular pressure (IOP)-related optic neuropathy characterized by the degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve. NO activates GC-1 to increase cGMP levels, which are lowered by cGMP-specific phosphodiesterase (PDE) activity. This pathway appears to play a role in both the regulation of IOP, where reduced cGMP levels in mice leads to elevated IOP and subsequent RGC degeneration. Here, we investigated whether potentiation of cGMP signaling could protect RGCs from glaucomatous degeneration. We administered the PDE5 inhibitor tadalafil orally (10 mg/kg/day) in murine models of two forms of glaucoma – primary open angle glaucoma (POAG; GC-1−/− mice) and primary angle-closure glaucoma (PACG; Microbead Occlusion Model) - and measured RGC viability at both the soma and axon level. To determine the direct effect of increased cGMP on RGCs in vitro, we treated axotomized whole retina and primary RGC cultures with the cGMP analogue 8-Br-cGMP. Tadalafil treatment increased plasma cGMP levels in both models, but did not alter IOP or mean arterial pressure. Nonetheless, tadalafil treatment prevented degeneration of RGC soma and axons in both disease models. Treatment of whole, axotomized retina and primary RGC cultures with 8-Br-cGMP markedly attenuated both necrotic and apoptotic cell death pathways in RGCs. Our findings suggest that enhancement of the NO-GC-1-cGMP pathway protects the RGC body and axon in murine models of POAG and PACG, and that enhanced signaling through this pathway may serve as a novel glaucoma treatment, acting independently of IOP.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function., Author summary The thickness of the inner retinal layers is one of the biomarkers for glaucoma, the leading cause of irreversible blindness globally. Here we utilised the large-scale of the UK Biobank and the images of the retina it contains to look for genetic variants that effect the thickness of the inner retina. We find many variants associated with this variable, but surprisingly only one that also affects glaucoma. Further analysis shows that glaucoma and genetically determined inner retinal thickness are not on the same genetic pathway and it is rather the change of thickness over time that is indicative of the disease. This is important as it invites the potential for the discovered variants to be used as a representation of baseline thickness in the clinic in the future. We also show that foveal hypoplasia, the lack of the normal valley-like shape of the central retina, is present at a population level in a mild form and is affected by three variants that also affect visual acuity. This is an interesting discovery as foveal hypoplasia was previously thought of as an outcome of rare Mendelian disease.

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Introduction In peacetime, it is challenging for Army Forward Resuscitative Surgical Teams (FRST) to maintain combat readiness as trauma represents Methods Over a 3-year period, all FRSTs were surveyed at one civilian center. Results Six hundred and thirteen FRST soldiers were provided surveys and 609 responded (99.3%), including 499 (81.9%) non-physicians and 110 (18.1%) physicians/physician assistants. The non-physician group included 69% male with an average age of 34 ± 11 years and consisted of 224 AR (45%) and 275 AD (55%). Rank ranged from Private to Colonel with officers accounting for 41%. For AD vs. AR, combat experience was similar: 50% vs. 52% had ≥1 combat deployment, 52% vs. 60% peri-deployment patient load was trauma-related, and 31% vs. 32% had ≥40 patient contacts during most recent deployment (all P > .15). However, medical experience differed for AD and AR: 18% vs. 29% had >15 years of experience in practice and 4% vs. 17% spent >50% of their time treating critically injured patients (all P Conclusions This is the first study of clinical practice patterns in AD vs. AR, non-physician members of Army FRSTs. In concordance with previous studies of military surgeons, FRST non-physicians seem to be lacking clinical experience as well. To maintain readiness and to provide optimal care for our injured warriors, the entire FRST, not just individuals, should embed within civilian centers.

PURPOSE: To determine the clinical relevance of prelaminar wedge defects (PLWDs) detected by swept-source optical coherence tomography (SS-OCT) in primary open angle glaucoma (POAG). MATERIALS AND METHODS: In this retrospective case-control study, PLWDs were defined as triangular-shaped defects at the surface of the optic nerve prelaminar tissue, not adjacent to blood vessels, present on cross-sectional SS-OCT scans. Two observers masked to diagnosis independently reviewed scans to detect PLWDs and lamina cribrosa defects. History of disc hemorrhage, occurring within 2 years prior to imaging, was obtained from chart review. One eye per subject was randomly selected. Two-sided t-tests, analysis of variance with Bonferroni correction, and multivariable logistic regression analysis were performed to explore demographic and clinical features associated with PLWDs. RESULTS: 40 POAG and 23 control eyes were included. PLWDS were found in 27.5% of POAG (n=11) and 4.3% of controls (n=1, p=0.04). Eyes with repeat SS-OCT imaging (7 POAG and 0 controls) had persistent PLWDs. More POAG eyes with PLWDs had a history of disc hemorrhage (45.5%) than POAG eyes without PLWDs (3.4%, p=0.004). On multivariable analysis, compared to POAG without PLWDs, POAG with PLWDs had increased odds of observed disc hemorrhage (OR=21.6, 95% CI, 2.2–589.0, p=0.02) after adjusting for age, gender, visual field mean deviation and maximum intraocular pressure (IOP). POAG with PLWDs had more lamina cribrosa defects (45.5%) than POAG without PLWDs (3.4%, p=0.01) but did not differ significantly from controls (8.7%, p=0.07). Compared to all patients without PLWDs, patients with PLWDs had increased odds of having lamina cribrosa defects (OR=44.8; 95% CI, 6.3–703.6, p

The role of renal biopsy prior to surgical intervention for a renal mass remains controversial despite the fact that for all other urological organs except the testicle, biopsy inevitably precedes treatment as is true for all other specialties dealing with solid masses (e.g. thyroid, breast, colon, liver, etc.). Accordingly, we sought to determine the impact of a routine biopsy regimen on the course of patients with cT1a lesions in comparison with a contemporary series of cT1a individuals who went directly to treatment without a preoperative biopsy.We analyzed a multi-institutional, prospectively maintained database of patients who underwent an office-based, ultrasound-guided, renal mass biopsy (RMB) for a cT1a renal mass (i.e. ≤4cm in largest dimension). Controls were selected from all patients in the database who had a cT1a renal lesion but did not undergo RMB. Both groups were analyzed for differences in treatment modality and surgical pathology results.A total of 72 RMB and 73 control patients were analyzed. The groups were similar in regards to their baseline characteristics. Overall RMB diagnostic rate was 75%. Surgical pathology revealed that excision of benign tumors was eight-fold less in the RMB cohort compared to the control group (3% vs. 23%; P0.001). Additionally, the rate of active surveillance in the RMB cohort was nearly three times higher at 35% vs. 14% for the controls (P0.001). Biopsy was concordant with surgical pathology in 97% of cases for primary histology (i.e. benign vs. malignant), 97% for histologic subtype, and 46% for low (I or II) vs. high (III or IV) grade. On multivariate analysis patients who underwent surgical intervention without preoperative RMB were 6.7 times more likely to have benign histopathology compared to patients who underwent preoperative RMB (OR 6.7, 95% CI = 0.714 - 63.626, P = 0.096). There were no procedural or post-procedural RMB complications.For patients with cT1a lesions, the implementation of routine office-based RMB led to a significant decrease in the rate of surgical intervention for benign tumors. This practice also resulted in a higher rate of active surveillance for the management of renal cortical neoplasms with benign histopathology compared to a control group.

BACKGROUND: Severe asthma (SA) may require frequent courses or chronic use of oral corticosteroids (OCS), inducing many known side effects and complications. Therefore, it is important to identify risk factors of chronic use of OCS in SA, considering the heterogeneity of clinical and inflammatory asthma phenotypes. Another aim of the present analysis is to characterize a subpopulation of severe asthmatics, in whom blood eosinophil counts (BEC) remain elevated despite chronic OCS treatment. METHODS: In a cross-sectional analysis of 982 SA patients enrolled in the Belgian Severe Asthma Registry (BSAR) between March 2009 and February 2019, we investigated the characteristics of the OCS treated patients with special attention to their inflammatory profile. RESULTS: At enrollment, 211 (21%) SA patients were taking maintenance OCS (median dose: 8 [IQR: 5-10]) mg prednisone equivalent). BEC was high (> 400/mm3) in 44% of the OCS treated population. Multivariable logistic regression analysis showed that risk factors for chronic use of OCS in SA were late-onset asthma (i.e. age of onset > 40 yr), frequent exacerbations (i.e. ≥2 exacerbations in the previous year) and non-atopic asthma. Late-onset asthma was also a predictor for persistently high BEC in OCS treated SA patients. CONCLUSION: These data showed a significant association between a persistently high BEC and late-onset asthma in OCS treated SA patients. Whether it is poor compliance to treatment or corticosteroid insensitivity the reasons for this association warrants further investigation., SCOPUS: ar.j, info:eu-repo/semantics/published

Importance Although rhegmatogenous retinal detachment (RRD) repair techniques have high anatomical reattachment rates, there may be differences in various aspects of postoperative vision-related quality of life (VRQoL). Objective To explore the differences in various aspects of VRQoL between pneumatic retinopexy (PnR) and pars plana vitrectomy (PPV) following RRD repair. Design, Setting, and Participants Post hoc exploratory analysis of the the Pneumatic Retinopexy vs Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes randomized clinical trial conducted between August 2012 and May 2017 at St Michael’s Hospital, Toronto, Ontario, Canada. Patients with RRD with a single break or multiple breaks within 1 clock hour of detached retina in the superior 8 clock hours of the retina with any number, location, and size of retinal breaks or lattice degeneration in attached retina. Main Outcomes and Measures Differences in the 25-Item National Eye Institute Visual Function Questionnaire 12 subscale scores between the PnR and PPV groups at 6 months following RRD repair. Results A total of 160 patients were included in this analysis, with 81 patients (92%) and 79 patients (90%) in the PnR and PPV groups, respectively. The PnR group consisted of 32% women with a mean (SD) age of 60.9 (9.3) years, while the PPV group consisted of 38% women with a mean (SD) age of 60.3 (7.6) years. For the 152 patients with 6-month follow-up (75 patients in PnR [85%] and 77 patients in PPV [88%]), there was evidence for an association of PnR with superior vision-related functioning compared with PPV for several subscales. There were no differences between groups at 1 year. After adjusting for age, sex, baseline macular status, visual acuity in the nonstudy eye, and lens status, patients who underwent PnR had higher scores for distance activities (mean [SD] PnR, 88.7 [13.4]; PPV, 82.8 [17.1]; adjusted difference, 6.5; 95% CI, 1.6-11.4;P = .01), mental health (mean [SD] PnR, 84.3 [17.4]; PPV, 78.7 [21.1]; adjusted difference, 6.7; 95% CI, 0.4-13;P = .04), dependency (mean [SD] PnR, 96.1 [10.1]; PPV, 91.1 [18.6]; adjusted difference, 5.7; 95% CI, 0.6-10.8;P = .03), and peripheral vision (mean [SD] PnR, 91.6 [16.2]; PPV, 81.2 [24.4]; adjusted difference, 10.8; 95% CI, 4.3-17.4;P = .001) at 6 months. Conclusions and Relevance These findings demonstrate that patients undergoing PnR for RRD report higher mental health scores and superior vision-related functioning scores in several subscales of the 25-Item National Eye Institute Visual Function Questionnaire during the first 6 months postoperatively compared with PPV. Trial Registration ClinicalTrials.gov Identifier:NCT01639209.

Background Atherosclerotic vertebrobasilar disease is a significant etiology of posterior circulation stroke. The prospective observational VER i TAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) study demonstrated that distal hemodynamic status is a robust predictor of subsequent vertebrobasilar stroke risk. We sought to compare predictive models using thresholds for posterior circulation vessel flows standardized to age and vascular anatomy to optimize risk prediction. Methods and Results VER i TAS enrolled patients with recent vertebrobasilar transient ischemic attack or stroke and ≥50% atherosclerotic stenosis/occlusion in vertebral and/or basilar arteries. Quantitative magnetic resonance angiography measured large‐vessel vertebrobasilar territory flow, and patients were designated as low or normal flow based on a prespecified empiric algorithm considering distal territory regional flow and collateral capacity. For the present study, post hoc analysis was performed to generate additional predictive models using age‐specific normalized flow measurements. Sensitivity, specificity, and time‐to‐event analyses were compared between the algorithms. The original prespecified algorithm had 50% sensitivity and 79% specificity for future stroke risk prediction; using a predictive model based on age‐normalized flows in the basilar and posterior cerebral arteries, standardized to vascular anatomy, optimized flow status thresholds were identified. The optimized algorithm maintained sensitivity and increased specificity to 84%, while demonstrating a larger and more significant hazard ratio for stroke on time‐to‐event analysis. Conclusions These results indicate that flow remains a strong predictor of stroke across different predictive models, and suggest that prediction of future stroke risk can be optimized by use of vascular anatomy and age‐specific normalized flows.

PRECIS In a cohort study of 120,307 participants with 25+ years of follow-up, a history of nonmelanoma skin cancer (NMSC) was associated with a 40% higher exfoliation glaucoma (XFG) risk. PURPOSE The purpose of this study was to evaluate the relationship between NMSC (a marker of ultraviolet radiation exposure) and XFG. METHODS We performed a cohort study of US women (n=79,102; 1980-2014) and men (n=41,205; 1986-2014), aged 40+ years and at risk for glaucoma who reported eye examinations. From 1984 (women)/1988 (men), we asked about basal cell carcinoma or squamous cell carcinoma history separately; in prior years, we asked about any NMSC history in a single question. Squamous cell carcinoma was confirmed with histopathology reports while basal cell carcinoma and any early (