The association of female reproductive factors with glaucoma and related traits: A systematic review

TOPIC: This systematic review summarizes the existing evidence for the association 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). CLINICAL RELEVANCE: Understanding the association between female reproductive factors and glaucoma may shed light on disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable which may lead to new therapies. METHODS: 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 over 18 years of age; a measured exposure of at least one of the following: age at menarche, parity, OC use, age at menopause, PMH use; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional or randomized-controlled trial design; and a reported measure of association including hazard, risk or odds ratio or mean difference with associated confidence intervals. RESULTS: We included a total of 27 studies. Substantial differences in study design, exposure and treatment levels, treatment duration and variable reporting precluded meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and lower IOP were identified. With respect to OAG, estrogen-only PMH use may be associated with lower OAG risk and this association may be modified by race. No significant associations were found with combined estrogen + 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 increased glaucoma risk, and adverse associations were identified with longer duration of OC use, though no overall association with OC use was found. CONCLUSION: The association between PMH use and lower IOP/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. There is a need for future research examining associations with IOP specifically, and how the relationship between genetic factors and OAG risk may be influenced by female reproductive factors

Relationships between retinal layer thickness and brain volumes in the UK Biobank cohort

Background and purpose: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image-derived phenotypes (IDPs) in a large cohort of healthy older people. Methods: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell-inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. Results: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs. Conclusions: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults

Alcohol, intraocular pressure and open-angle glaucoma: A systematic review and meta-analysis

TOPIC: This systematic review and meta-analysis summarizes the existing evidence for the association of alcohol use with intraocular pressure (IOP) and open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding and quantifying these associations may aid clinical guidelines or treatment strategies and shed light on disease pathogenesis. The role of alcohol, a modifiable factor, in determining IOP and OAG risk may also be of interest from an individual or public health perspective. METHODS: The study protocol was pre-registered in the Open Science Framework Registries (https://osf.io/z7yeg). Eligible articles (as of 14 May 2021) from three databases (PubMed, Embase, Scopus) were independently screened and quality assessed by two reviewers. All case-control, cross-sectional and cohort studies reporting a quantitative effect estimate and 95% confidence interval (CI) for the association between alcohol use and either IOP or OAG were included. The evidence for the associations with both IOP and OAG were qualitatively summarized. Effect estimates for the association with OAG were pooled using random effects meta-analysis. Studies not meeting formal inclusion criteria for systematic review, but with pertinent results, were also appraised and discussed. Certainty of evidence was assessed using the GRADE framework. RESULTS: Thirty four studies were included in the systematic review. Evidence from 10 studies reporting an association with IOP suggest that habitual alcohol use is associated with higher IOP and prevalence of ocular hypertension (IOP >21mmHg), although absolute effect sizes were small. Eleven of 26 studies, comprising 173 058 participants, that tested for an association with OAG met inclusion criteria for meta-analysis. Pooled effect estimates indicated a positive association between any use of alcohol and OAG (1.18; 95% CI, 1.02-1.36; p=0.03; I2=40.5%), with similar estimates for both prevalent and incident OAG. The overall GRADE certainty of evidence was very low. CONCLUSION: While this meta-analysis suggests a harmful association between alcohol use and OAG, our results should be interpreted cautiously given the weakness and heterogeneity of the underlying evidence base, the small absolute effect size and the borderline statistical significance. Nonetheless, these findings may be clinically relevant and future research should focus on improving the quality of evidence

Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants

IMPORTANCE: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. OBJECTIVE: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. DESIGN, SETTING, AND PARTICIPANTS: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. EXPOSURE: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. MAIN OUTCOMES AND MEASURES: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. RESULTS: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 μm [95% CI, -0.54 to -0.15 μm]; P = .001) and mRNFL (-0.16 μm [95% CI, -0.30 to -0.02 μm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). CONCLUSIONS AND RELEVANCE: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care

The association between serum lipids and intraocular pressure in two large UK cohorts

PURPOSE: Serum lipids are modifiable, routinely collected blood tests associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL-C) and triglycerides (TG)) with intraocular pressure (IOP). DESIGN: Cross-sectional study in the UK Biobank and EPIC-Norfolk cohorts. PARTICIPANTS: We included 94 323 participants of UK Biobank (mean age 57 years) and 6 230 participants of EPIC-Norfolk (mean age 68 years) with data on TC, HDL-C, LDL-C, TG collected between 2006-2009. METHODS: Multivariable linear regression adjusting for demographic, lifestyle, anthropometric, medical and ophthalmic covariables was used to examine the associations of serum lipids with IOPcc. MAIN OUTCOME MEASURES: IOPcc. RESULTS: Higher levels of TC, HDL-C and LDL-C were independently associated with higher IOPcc in both cohorts after adjustment for key demographic, medical and lifestyle factors. For each standard deviation increase in TC, HDL-C, and LDL-C, IOPcc (mmHg) was higher by 0.09 (95% CI: 0.06-0.11; P<0.001), 0.11 (95% CI 0.08-0.13; P<0.001), 0.07 (95% CI: 0.05-0.09, P<0.001), respectively in the UK Biobank cohort. In the EPIC-Norfolk cohort, each additional standard deviation in TC, HDL-C, and LDL-C was associated with a higher IOPcc (mmHg) by 0.19 (95% CI 0.07-0.31, P=0.001), 0.14 (95% CI 0.03-0.25, P=0.016), and 0.17 (95% CI 0.06-0.29, P=0.003). An inverse association between TGs and IOP in the UK Biobank (-0.05, 95% CI -0.08 to -0.03, P<0.001) was not replicated in the EPIC cohort (P=0.30). CONCLUSION: Our findings suggest that serum TC, HDL-C and LDL-C are positively associated with IOP in two UK cohorts and TGs may be negatively associated. Future research is required to assess whether these associations are causal in nature

The Association of Physical Activity with Glaucoma and Related Traits in the UK Biobank

PURPOSE: To examine the association of physical activity (PA) with glaucoma and related traits, to assess whether genetic predisposition to glaucoma modified these associations, and to probe causal relationships using Mendelian randomization (MR). DESIGN: Cross-sectional observational and gene-environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia. PARTICIPANTS: UK Biobank participants with data on self-reported or accelerometer-derived PA and intraocular pressure (IOP; n = 94 206 and n = 27 777, respectively), macular inner retinal OCT measurements (n = 36 274 and n = 9991, respectively), and glaucoma status (n = 86 803 and n = 23 556, respectively). METHODS: We evaluated multivariable-adjusted associations of self-reported (International Physical Activity Questionnaire) and accelerometer-derived PA with IOP and macular inner retinal OCT parameters using linear regression and with glaucoma status using logistic regression. For all outcomes, we examined gene-PA interactions using a polygenic risk score (PRS) that combined the effects of 2673 genetic variants associated with glaucoma. MAIN OUTCOME MEASURES: Intraocular pressure, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and glaucoma status. RESULTS: In multivariable-adjusted regression models, we found no association of PA level or time spent in PA with glaucoma status. Higher overall levels and greater time spent in higher levels of both self-reported and accelerometer-derived PA were associated positively with thicker mGCIPL (P < 0.001 for trend for each). Compared with the lowest quartile of PA, participants in the highest quartiles of accelerometer-derived moderate- and vigorous-intensity PA showed a thicker mGCIPL by +0.57 μm (P < 0.001) and +0.42 μm (P = 0.005). No association was found with mRNFL thickness. High overall level of self-reported PA was associated with a modestly higher IOP of +0.08 mmHg (P = 0.01), but this was not replicated in the accelerometry data. No associations were modified by a glaucoma PRS, and MR analyses did not support a causal relationship between PA and any glaucoma-related outcome. CONCLUSIONS: Higher overall PA level and greater time spent in moderate and vigorous PA were not associated with glaucoma status but were associated with thicker mGCIPL. Associations with IOP were modest and inconsistent. Despite the well-documented acute reduction in IOP after PA, we found no evidence that high levels of habitual PA are associated with glaucoma status or IOP in the general population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references

Associations with photoreceptor thickness measures in the UK Biobank.

Funder: DH | NIHR | Health Services Research Programme (NIHR Health Services Research Programme); doi: https://doi.org/10.13039/501100001923Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

The Early Clinical Features of Dengue in Adults: Challenges for Early Clinical Diagnosis

Dengue infection in adults has become increasingly common throughout the world. As most of the clinical features of dengue have been described in children, we undertook a prospective study to determine the early symptoms and signs of dengue in adults. We show here that, overall, dengue cases presented with high rates of symptoms listed in the WHO 1997 or 2009 classification schemes for probable dengue fever thus resulting in high sensitivities of these schemes when applied for early diagnosis. However, symptoms such as myalgia, arthralgia, retro-orbital pain and mucosal bleeding were less frequently reported in older adults. This trend resulted in reduced sensitivity of the WHO classification schemes in older adults even though they showed increased risks of hospitalization and severe dengue. Instead, we suggest that older adults who present with fever and leukopenia should be tested for dengue, even in the absence of other symptoms. This could be useful for early clinical diagnosis in older adults so that they can be monitored and treated for severe dengue, which is especially important when an antiviral drug becomes available

The Relationship Between Ambient Atmospheric Fine Particulate Matter (PM2.5) and Glaucoma in a Large Community Cohort.

Purpose: Glaucoma is more common in urban populations than in others. Ninety percent of the world's population are exposed to air pollution above World Health Organization (WHO) recommended limits. Few studies have examined the association between air pollution and glaucoma. Methods: Questionnaire data, ophthalmic measures, and ambient residential area air quality data for 111,370 UK Biobank participants were analyzed. Particulate matter with an aerodynamic diameter < 2.5 μm (PM2.5) was selected as the air quality exposure of interest. Eye measures included self-reported glaucoma, intraocular pressure (IOP), and average thickness of macular ganglion cell-inner plexiform layer (GCIPL) across nine Early Treatment Diabetic Retinopathy Study (ETDRS) retinal subfields as obtained from spectral-domain optical coherence tomography. We examined the associations of PM2.5 concentration with self-reported glaucoma, IOP, and GCIPL. Results: Participants resident in areas with higher PM2.5 concentration were more likely to report a diagnosis of glaucoma (odds ratio = 1.06, 95% confidence interval [CI] = 1.01-1.12, per interquartile range [IQR] increase P = 0.02). Higher PM2.5 concentration was also associated with thinner GCIPL (β = -0.56 μm, 95% CI = -0.63 to -0.49, per IQR increase, P = 1.2 × 10-53). A dose-response relationship was observed between higher levels of PM2.5 and thinner GCIPL (P < 0.001). There was no clinically relevant relationship between PM2.5 concentration and IOP. Conclusions: Greater exposure to PM2.5 is associated with both self-reported glaucoma and adverse structural characteristics of the disease. The absence of an association between PM2.5 and IOP suggests the relationship may occur through a non-pressure-dependent mechanism, possibly neurotoxic and/or vascular effects