GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa.

Electrical responses from human retinal cone pathways associate with a common genetic polymorphism implicated in myopia.

Myopia is the commonest visual impairment. Several genetic loci confer risk, but mechanisms by which they do this are unknown. Retinal signals drive eye growth, and myopia usually results from an excessively long eye. The common variant most strongly associated with myopia is near the GJD2 gene, encoding connexin-36, which forms retinal gap junctions. Light-evoked responses of retinal neurons can be recorded noninvasively as the electroretinogram (ERG). We analyzed these responses from 186 adult twin volunteers who had been genotyped at this locus. Participants underwent detailed ERG recordings incorporating international standard stimuli as well as experimental protocols aiming to separate dark-adapted rod- and cone-driven responses. A mixed linear model was used to explore association between allelic dosage at the locus and international standard ERG parameters after adjustment for age, sex, and family structure. Significant associations were found for parameters of light-adapted, but not dark-adapted, responses. Further investigation of isolated rod- and cone-driven ERGs confirmed associations with cone-driven, but not rod-driven, a-wave amplitudes. Comparison with responses to similar experimental stimuli from a patient with a prior central retinal artery occlusion, and from two patients with selective loss of ON-bipolar cell signals, was consistent with the associated parameters being derived from signals from cone-driven OFF-bipolar cells. Analysis of single-cell transcriptome data revealed strongest GJD2 expression in cone photoreceptors; bipolar cell expression appeared strongest in OFF-bipolar cells and weakest in rod-driven ON-bipolar cells. Our findings support a potential role for altered signaling in cone-driven OFF pathways in myopia development.

Cone-driven strong flash electroretinograms in healthy adults: Prevalence of negative waveforms.

PURPOSE: Both rod and cone-driven signals contribute to the electroretinogram (ERG) elicited by a standard strong flash in the dark. Negative ERGs usually reflect inner retinal dysfunction. However, in diseases where rod photoreceptor function is selectively lost, a negative waveform might represent the response of the dark-adapted cone system. To investigate the dark-adapted cone-driven waveform in healthy individuals, we delivered flashes on a dim blue background, designed to saturate the rods, but minimally adapt the cones. METHODS: ERGs were recorded, using conductive fibre electrodes, in adults from the TwinsUK cohort. Responses to 13 cd m-2 s white xenon flashes (similar to the standard DA 10 flash), delivered on a blue background, were analysed. Photopic and scotopic strengths of the background were 1.3 and 30 cd m-2, respectively; through a dilated pupil, this is expected to largely saturate the rods, but adapt the cones much less than the standard ISCEV background. RESULTS: Mean (SD) participant age was 62.5 (11.3) years (93% female). ERGs from 203 right and 204 left eyes were included, with mean (SD) b/a ratios of 1.22 (0.28) and 1.18 (0.28), respectively (medians, 1.19 and 1.17). Proportions with negative waveforms were 23 and 26%, respectively. Right and left eye b/a ratios were strongly correlated (correlation coefficient 0.74, p < 0.0001). We found no significant correlation of b/a ratio with age. CONCLUSIONS: Over 20% of eyes showed b/a ratios less than 1, consistent with the notion that dark-adapted cone-driven responses to standard bright flashes can have negative waveforms. The majority had ratios greater than 1. Thus, whilst selective loss of rod function can yield a negative waveform (with reduced a-wave) in some, our findings also suggest that loss of rod function can occur without necessarily yielding a negative ERG. One potential limitation is possible mild cone system adaptation by the background.

The impact of Vitreo-Macular interface abnormalities on the response to Anti-VEGF therapy for centre involving diabetic macular oedema.

BACKGROUND: The influence of Vitreomacular Interface Abnormalities (VMIA) such as Epiretinal Membrane (ERM) and/or vitreomacular traction (VMT) on the response of patients with Centre Involving Diabetic Macular Edema (CIDME) to standard of care Anti-VEGF medications is under-researched. The aims of this study were: 1) To determine the incidence of VMIA at baseline and 12 months amongst treatment naive patients commencing anti-VEGF treatment 2) To compare the response to Anti-VEGF medications at 3 monthly intervals for 12 months in a large cohort of patients with and without VMIA on their baseline OCT scan. Response was determined in terms of: number of injections, central macular thickness and visual acuity. METHODS: A retrospective case notes review of treatment naïve patients with newly diagnosed CIDME. Included patients had been commenced on intravitreal Anti-VEGF injections (ranibizumab or aflibercept) at a single centre. Inclusion criteria were: treatment naïve DME patients with a CMT of 400µ or more receiving anti-VEGF treatment with at least 12 months follow up and in whom macular OCT scans and visual acuity (VA) measurements were available within two weeks of baseline, 3, 6, 9 and 12 months. Exclusion criteria included: previous intravitreal therapy, previous vitrectomy, cataract surgery during the follow-up period, concurrent eye conditions affecting vision or CMT. RESULTS: 119 eyes met the inclusion criteria and underwent analysis. Groups were comparable in their baseline demographics. Baseline CMT measurements were comparable at baseline (417µ and 430µ in the No-VMIA and VMIA groups respectively) and improved to approximately 300µ in both groups. From 6 months CMT continued to improve in the no-VMIA while progressively deteriorating in the VMIA group. Change in CMT was statistically different at 12 months between the 2 groups (108µ and 79µ, p= 0.04). There was a mean of 7 injections after 12 months. CONCLUSION: Our study has shown a 46% incidence of VMIA amongst patients newly diagnosed with centre involving DME undergoing treatment with anti-VEGF injections. We have also demonstrated a significant difference in CMT and VA response to anti-VEGF treatment in patients with and without VMIA. Initial response was similar between the 2 groups up until 6 months. From 6 to 12 months significant differences in treatment response emerged. Differences in clinical response between patients with and without VMIA may help guide further prospective controlled studies and optimise treatment strategies.

Evaluation of an emergency department opt-out provider-driven HIV and syphilis screening and linkage-to-care program.

OBJECTIVE: While the effectiveness of emergency departments (ED) in screening for HIV and syphilis is understood, less is known about dual screening programs. We aim to evaluate the impact of an opt-out provider-initiated HIV and syphilis program on screening, diagnosis, and linkage to care outcomes. METHODS: We performed a retrospective review of patients screened pre (2014-2017) and post (2017-2021) program implementation. Primary outcomes include HIV and syphilis screening, incidence of positive tests, and proportion of patients linked to care. Secondary outcomes included pre-exposure prophylaxis (PrEP) referral and successful linkage rates for HIV-negative syphilis-positive patients. RESULTS: Pre-implementation, 882 HIV tests were performed, of which 22 (2.49%) were new cases and 18 (81.82%) were linked to care; 754 syphilis tests were performed, of which 33 (4.38%) were active infections and 30 (90.91%) were treated. No eligible patients received PrEP referral. Post-implementation, 12,999 HIV tests were performed, of which 73 (0.56%) were new cases and 55 (75.34%) were linked to care; 10,885 syphilis tests were performed, of which 216 (1.98%) were active infections and 188 (87.04%) were treated. 25 (9.09%) eligible patients were referred for PrEP, and four (16.0%) attended their appointment. CONCLUSIONS: Post-implementation, there was a 1373.81% and 1343.63% increase in screening, and a 231.82% and 554.55% increase in positive cases of HIV and syphilis, respectively. Dual screening programs can be successfully implemented within the existing ED framework to increase screening and early detection for HIV and syphilis.

Patterns of Polysubstance Use in Young Black and Latinx Sexual Minority Men and Transgender Women and Its Association with Sexual Partnership Factors: The PUSH Study.

Background: Adult studies have demonstrated that polysubstance use increases HIV acquisition risk through increased sexual behaviors, however, few studies have examined polysubstance in young Black and Latinx sexual minority men (SMM) and transgender women (TW). Methods: We used cross-sectional data from 466 young Black and Latinx SMM and TW living in four high HIV-burden US cities enrolled in the PUSH Study, a status-neutral randomized control trial to increase HIV prevention and treatment adherence. We examined data for patterns of polysubstance use comparing age differences of use and explored associations between substance use and sexual partnership factors - inconsistent condom use, pressure to have condomless anal sex, and older partner, using bivariate and multivariate analyses. Results: Most participants described prior substance use with alcohol and cannabis being most common (76% each) and 23% described other illicit drug use, including stimulants, cocaine, hallucinogens, sedatives, opioids, and inhalants. Polysubstance use was common with nearly half (47%) of participants reporting alcohol and cannabis use, 20% reporting alcohol, cannabis, and one other illicit drug use, and 19% reporting alcohol or cannabis use plus one other illicit drug use. Polysubstance use was associated with greater adjusted odds of pressure to have condomless anal sex, older partner (>5 years older), and inconsistent condom use. Conclusions: Associations of polysubstance use with sexual practices and sexual partnerships that are known predictors of HIV acquisition or transmission among Black and Latinx SMM and TW underscore the need for combination interventions that include substance use treatment alongside antiretroviral-based and partner-based HIV prevention and treatment interventions.Trial Registration: ClinicalTrials.gov Identifier: NCT03194477.

Cannabis Use Associations with Adverse Psychosocial Functioning among North American College Students.

Introduction: Adolescent-onset cannabis use (CU) (before age 18) is associated with multiple adverse psychosocial outcomes, but rates of CU peak between the ages of 18 and 22, coinciding with college matriculation. Whether CU among college-enrolled young adults is associated with similar psychosocial outcomes is poorly understood. In the present study, we examined relationships between CU and multiple psychosocial outcomes in North American college students. Methods: Data for this report come from N = 40,250 North American college students ages 18-to-25 years (mean age = 20.7 years, 69% female, 66% Caucasian) who participated in the Healthy Minds Study (HMS) 2016-17. HMS is a web-based annual survey querying multiple mental health, substance use, and psychosocial variables in representative student populations from 53 universities across North America. Student respondents were stratified in two groups based upon their self-report of past 30-day CU and compared on psychosocial variables. Results: Approximately 20% (n = 8,327) of student respondents reported past 30-day CU. After adjusting for socio-demographics, knowledge of campus services, and use of other drugs, the odds of depression (aOR = 1.3), suicidal thoughts and behaviors (aORs ∼1.4-1.7), anxiety (aOR = 1.2), eating disorders (aOR = 1.2), and violence victimization (aOR = 1.4) were all higher for CU students. Additionally, CU students had higher rates of other drug use and lower rates of perceived supportive relationships. Conclusion: Our results indicated that CU is common among North American college students and associated with adverse psychosocial consequences across multiple domains. Based upon these findings, colleges should consider expanding educational, prevention, and early-intervention programs for students who use cannabis.

Genome-wide association study of corneal biomechanical properties identifies over 200 loci providing insight into the genetic etiology of ocular diseases.

Corneal hysteresis and corneal resistance factor are parameters that reflect the dynamic biomechanical properties of the cornea and have been shown to be biomarkers of corneal disease. In this genome-wide association study of over 100 000 participants, we identified over 200 genetic loci, all but eight novel, significantly associated with either one or both of these traits. In addition to providing key insights into the genetic architecture underlying normal corneal function, these results identify many candidate loci in the study of corneal diseases that lead to severe visual impairment. Additionally, using Mendelian randomization, we were able to identify causal relationships between corneal biomechanics and intraocular pressure measurements, which help elucidate the relationship between corneal properties and glaucoma.

Genome-Wide Association Study Identifies Two Common Loci Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Implicates Myopia in its Development.

PURPOSE: To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. DESIGN: A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. PARTICIPANTS: A total of 574 cases with PG or PDS and 52 627 controls of European descent. METHODS: Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-sample Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. MAIN OUTCOME MEASURES: The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. RESULTS: Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10-10) and glutamate metabotropic receptor 5 (GRM5)/TYR (lead SNP: rs661177, P = 3.9×10-9) as important factors in disease risk. Mendelian randomization showed significant evidence that negative refractive error (myopia) exerts a direct causal effect over PDS (P = 8.86×10-7). CONCLUSIONS: Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.

Low-concentration atropine eyedrops for myopia control in a multi-racial cohort of Australian children: A randomised clinical trial.

BACKGROUND: To test the hypothesis that 0.01% atropine eyedrops are a safe and effective myopia-control approach in Australian children. METHODS: Children (6-16 years; 49% Europeans, 18% East Asian, 22% South Asian, and 12% other/mixed ancestry) with documented myopia progression were enrolled into this single-centre randomised, parallel, double-masked, placebo-controlled trial and randomised to receive 0.01% atropine (n = 104) or placebo (n = 49) eyedrops (2:1 ratio) instilled nightly over 24 months (mean index age = 12.2 ± 2.5 and 11.2 ± 2.8 years, respectively). Outcome measures were the changes in spherical equivalent (SE) and axial length (AL) from baseline. RESULTS: At 12 months, the mean SE and AL change from baseline were -0.31D (95% confidence interval [CI] = -0.39 to -0.22) and 0.16 mm (95%CI = 0.13-0.20) in the atropine group and -0.53D (95%CI = -0.66 to -0.40) and 0.25 mm (95%CI = 0.20-0.30) in the placebo group (group difference p ≤ 0.01). At 24 months, the mean SE and AL change from baseline was -0.64D (95%CI = -0.73 to -0.56) and 0.34 mm (95%CI = 0.30-0.37) in the atropine group, and -0.78D (95%CI = -0.91 to -0.65) and 0.38 mm (95%CI = 0.33-0.43) in the placebo group. Group difference at 24 months was not statistically significant (p = 0.10). At 24 months, the atropine group had reduced accommodative amplitude and pupillary light response compared to the placebo group. CONCLUSIONS: In Australian children, 0.01% atropine eyedrops were safe, well-tolerated, and had a modest myopia-control effect, although there was an apparent decrease in efficacy between 18 and 24 months, which is likely driven by a higher dropout rate in the placebo group.

State of the Art in Substance Use Prevention and Early Intervention: Applications to Pediatric Primary Care Settings.

With changes to drug-related policies and increased availability of many drugs, we currently face a public health crisis related to substance use and associated health consequences. Substance use and substance use disorders (SU/SUDs) are complex developmental disorders with etiologies that emerge through the intergenerational transmission of biological, familial, and environmental factors. The family ecosystem both influences and is influenced by SU/SUDs, particularly in children and adolescents. Family dynamics and parent functioning and behaviors can represent either risk or protective factors for the development of SU/SUDs in children. Primary care providers who provide care for children, adolescents, and families are in an ideal position to deliver prevention messages and to intervene early in the development of substance misuse and SUD among their patients. Despite recommendations from the American Academy of Pediatrics, few pediatric primary care providers provide anticipatory guidance to prevent or screen for substance misuse. Many barriers to those practices can be overcome through the integration and application of findings from the field of prevention science and the many lessons learned from the implementation of evidence-based interventions. Consideration of the implications of prevention science findings would help clarify the relevant roles and responsibilities of the primary care clinician, and the benefit of referral to and consultation from addiction specialists. Additionally, the past decade has seen the development and validation of a continuum of evidence-based prevention and early SU/SUD intervention activities that can be adapted for use in primary care settings making wide-spread implementation of prevention feasible. We propose a paradigm shift away from a model based on diagnosis and pathology to one upstream, that of family-focused prevention and early intervention. Adapting and scaling out empirically based prevention and early SU/SUD interventions to primary care settings and removing barriers to collaborative care across primary care, addiction medicine, and mental health providers offer the potential to meaningfully impact intergenerational transmission of SU/SUD - addressing a leading health problem facing our nation.

Understanding caregiver acceptance of screening for family substance use in pediatric clinics serving economically disadvantaged children.

Background: Children of parents with substance use disorders are at greater risk for mental and physical health co-morbidities. Despite guidelines, pediatricians rarely screen for substance use in the family/household, citing fear of offending parents. The objectives of this study were to examine (1) caregiver acceptance of pediatricians screening for family/household substance use during well-child visits, (2) prevalence of family/household substance use, and (3) the association between family/household substance use and trust in their child's pediatrician. Methods: This cross-sectional study surveyed adult caregivers presenting a child for medical care at two urban pediatric outpatient clinics using a brief anonymous computer-based survey. The primary outcome measured the acceptability of pediatrician screening for family/household substance use. Substance use and concerns about use in the family/household were also assessed. Results: Adult caregivers (n = 271) surveyed were mean age 35 years, 73% mothers, 90% African American, and 85% on Medicaid. Over half (51%) of caregivers reported substance use by someone in the family/household, most commonly cigarettes (38%), followed by alcohol (19%) and marijuana (10%). Sixty-one percent of caregivers who reported family substance use expressed concern about the use of this substance. The majority (87%) agreed it is appropriate for pediatricians to ask caregivers about family/household substance use. No differences were found between caregivers who did and did not report substance use in their family/household. Caregivers with concerning substance use in their family/household were less likely to trust their pediatrician [OR = 0.21, 95%CI: 0.05, 0.85] Conclusions: Caregivers endorsed acceptance of universal screening for substance use, including illicit substances, and substance use disorders in the family/household during well-child visits. Pediatricians are trusted professionals with expertise in communicating with parents to maximize the health of their patients; assessing family history of substance use and substance use disorders is a natural extension of their role.

Altered effective connectivity of the reward network during an incentive-processing task in adults with alcohol use disorder.

BACKGROUND: Abnormalities of reward sensitivity and impulsivity are known to be correlated with each other and alcohol use disorder (AUD) risk, but the underlying aberrant neural circuitry involved is not clearly defined. We sought to extend the current knowledge of AUD pathophysiology by studying incentive processing in persons with AUD using functional neuroimaging data. METHODS: We utilized functional MRI data from the Human Connectome Project Database obtained during performance of a number-guessing incentive-processing task with win, loss, and neutral feedback conditions in 78 participants with either DSM-IV alcohol abuse or dependence (combined as the AUD group) and 78 age- and sex-matched control (CON) participants. Within a network consisting of anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), insula, ventral striatum, and dorsal striatum (DS) in the right hemisphere, we performed dynamic causal modeling analysis to test group-level differences (AUD vs. CON) in effective directional connectivity (EC) as modulated by "win" and "loss" conditions. We used linear regression analyses to characterize the relations between each EC outcome and measures of cumulative alcohol exposure and impulsivity. RESULTS: During wins, AUD participants had lower ECs from ACC to the other four nodes, greater ECs from insula to the other four nodes, greater ECs from DLPFC to the other four nodes, and greater DS to DS self-connection EC than CON participants. In the total sample, EC from the insula to the DLPFC (insula â†’ DLPFC) during wins was positively correlated with both impulsivity (as measured by the delay-discounting task) and cumulative alcohol exposure. The DS to DS self-connection EC during wins was positively correlated with impulsivity. Many of the altered ECs from the ACC and insula to other nodes were correlated with cumulative alcohol exposure. CONCLUSIONS: Individuals with AUD have disrupted EC in both instrumentally driven and automatized corticostriatal reward circuits during non-alcohol reward feedback. These results point to disrupted corticostriatal EC in both "top-down" and "bottom-up" pathways among individuals with AUD.

Change in the prevalence of myopia in Australian middle-aged adults across 20 years.

BACKGROUND: The prevalence of myopia is increasing globally including in Europe and parts of Asia but Australian data are lacking. This study aim described the change in myopia prevalence in middle-aged Australian adults over approximately a 20-year period. METHODS: Two contemporary Western Australian studies (conducted in mid-late 2010s): the coastal-regional Busselton Healthy Ageing Study (BHAS) and the urban Gen1 of the Raine Study (G1RS) were compared to two earlier studies (early-mid 1990s) in Australia: the urban Blue Mountains Eye Study (BMES) and urban/regional Melbourne Visual Impairment Project (MVIP). Refractive error was measured by autorefraction, vertometry, or subjective refraction. Participants (49-70 years) of European descent without self-reported/diagnosed cataract, corneal disease, or refractive or corneal surgery were included. RESULTS: After exclusions, data were available from 2217, 1760, 700, 2987 and 756 participants from BMES, urban MVIP, regional MVIP, BHAS, and G1RS, respectively. The mean age ranged from 57.1 ± 4.6 years in the G1RS to 60.1 ± 6.0 years in the BMES; 44-48% of participants were male. When stratified by location, the contemporary urban G1RS cohort had a higher age-standardised myopia prevalence than the urban MVIP and BMES cohorts (29.2%, 16.4%, and 23.9%, p < 0.001). The contemporary coastal-regional BHAS had a higher age-standardised myopia prevalence than the regional MVIP cohort (19.4% vs. 13.8%, p = 0.001). CONCLUSIONS: We report an increase in myopia prevalence in older adults in Australia born after World War ll compared to cohorts born before, accounting for urban/regional location. The prevalence of myopia remains relatively low in middle-aged Australian adults.

Do the Transmissible Liability Index (TLI) and Adolescent Cannabis Use Predict Paranoid and Schizotypal Symptoms at Young Adulthood?

Background: Adolescent cannabis use is an established risk factor for the development of psychosis, but the premorbid vulnerability factors and specificity versus generality of the psychotic symptom domains affected in cannabis-psychosis relationships remain incompletely understood. To improve our understanding of these relationships, we used longitudinal data to examine the individual and interactive effects of preadolescent transmissible liability to substance use disorders (SUD), measured via the transmissible liability index (TLI), and adolescent cannabis use on the development of two distinct psychotic symptom domains, paranoid and schizotypal personality traits in young adulthood. Methods: We performed secondary analysis of data from the Center for Education and Drug Abuse (CEDAR) study, which longitudinally assessed offspring of men with (N = 211) and without (N = 237) lifetime history of SUD at ages 10-12, and across adolescence as they transitioned to young adulthood. TLI scores were calculated at age 10-12, self-reported cannabis use was assessed at age 16, and paranoid and schizotypal symptoms were assessed at age 19. Results: Cannabis use at age 16 and family history of SUD were significantly associated with paranoid and schizotypal symptoms at age 19, but TLI scores were not. The interactive effect of TLI x cannabis use was also not significant. Paranoid and schizotypal symptoms showed different dose-dependent sensitivities to cannabis exposure at age 16. Conclusions: These findings indicate that adolescent cannabis use and family history of SUD differentially contribute to the development of paranoid and schizotypal personality traits through mechanisms that do not include behavioral disinhibition.

Advances, limitations and future perspectives in the diagnosis and management of dry eye in Sjögren's syndrome.

Primary Sjögren's syndrome is a complex systemic autoimmune disorder that primarily affects exocrine glands such as the lacrimal glands. Dry eye disease is one of the most prevalent complications of Sjögren's syndrome, affecting most patients. It significantly impairs quality of life and management is often difficult and unsatisfactory, in part due to weak correlation between symptoms and signs and poor recognition of the three main subtypes aqueous-deficient, evaporative and neuropathic dry eye. This review provides an overview of key aspects of dry eye disease, such as its multifactorial aetiology and recent insights into pathophysiology. The uses and pitfalls of commonly-used diagnostic tests for dry eye are reviewed, as well as the increasing number of new imaging technologies and biomarkers to refine diagnosis. There are many current and emerging treatment options for dry eye in Sjögren's syndrome, but high-level evidence of efficacy is mostly lacking, as are evidence-based treatment algorithms. All these aspects make the management of dry eye in Sjögren's syndrome challenging.

Self-Reported Symptoms of COVID-19, Including Symptoms Most Predictive of SARS-CoV-2 Infection, Are Heritable.

Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n = 3261) completing the C-19 COVID-19 symptom tracker app allowed classical twin studies of COVID-19 symptoms, including predicted COVID-19, a symptom-based algorithm to predict true infection, derived from app users tested for SARS-CoV-2. We found heritability of 49% (32-64%) for delirium; 34% (20-47%) for diarrhea; 31% (8-52%) for fatigue; 19% (0-38%) for anosmia; 46% (31-60%) for skipped meals and 31% (11-48%) for predicted COVID-19. Heritability estimates were not affected by cohabiting or by social deprivation. The results suggest the importance of host genetics in the risk of clinical manifestations of COVID-19 and provide grounds for planning genome-wide association studies to establish specific genes involved in viral infectivity and the host immune response.

Cannabis use among U.S. adolescents in the era of marijuana legalization: a review of changing use patterns, comorbidity, and health correlates.

Decriminalization, medicalization, and legalization of cannabis use by a majority of U.S. states over the past 25 years have dramatically shifted societal perceptions and use patterns among Americans. How marijuana policy changes have affected population-wide health of U.S. youth and what the downstream public health implications of marijuana legalization are topics of significant debate. Cannabis remains the most commonly used federally illicit psychoactive drug by U.S. adolescents and is the main drug for which U.S. youth present for substance use treatment. Converging evidence indicates that adolescent-onset cannabis exposure is associated with short- and possibly long-term impairments in cognition, worse academic/vocational outcomes, and increased prevalence of psychotic, mood, and addictive disorders. Odds of negative developmental outcomes are increased in youth with early-onset, persistent, high frequency, and high-potency Δ-9-THC cannabis use, suggesting dose-dependent relationships. Cannabis use disorders are treatable conditions with clear childhood antecedents that respond to targeted prevention and early intervention strategies. This review indicates that marijuana policy changes have had mixed effects on U.S. adolescent health including potential benefits from decriminalization and negative health outcomes evidenced by increases in cannabis-related motor vehicle accidents, emergency department visits, and hospitalizations. Federal and state legislatures should apply a public health framework and consider the possible downstream effects of marijuana policy change on paediatric health.

Western Australia Atropine for the Treatment of Myopia (WA-ATOM) study: Rationale, methodology and participant baseline characteristics.

IMPORTANCE: Atropine eyedrops are a promising treatment for slowing myopia progression in East Asian children. However, its effects on children in Australia, including those of non-Asian background, have not been well-studied. BACKGROUND: The Western Australia Atropine for the Treatment of Myopia (WA-ATOM) study aims to determine the efficacy and long-term effects of low-dose atropine eyedrops in myopia control. This paper describes the study rationale, methodology and participant baseline characteristics. DESIGN: Single-centre, double-masked, randomized controlled trial. PARTICIPANTS: Children (6-16 years) with spherical equivalent ≤-1.50 D in each eye, astigmatism ≤1.50 D and myopia progression by ≥0.50 D/year. METHODS: Enrolled children were randomly assigned 2:1 to receive 0.01% atropine or placebo eyedrops. Participants are examined every 6 months during first 3 years of the study (2-year treatment phase followed by a 1-year washout phase), and then at a 5-year follow-up (2 years after the end of the washout phase). MAIN OUTCOME MEASURES: Annual progression rate of myopia and axial length, tolerability to eyedrops and incidence and severity of unwanted effects. RESULTS: Out of 311 children who were referred, 242 were suitable for study participation, and 153 were subsequently enrolled. The baseline characteristics of enrolled participants are presented. CONCLUSIONS AND RELEVANCE: Outcomes of the WA-ATOM study will inform on the efficacy, tolerability, safety and long-term effects of low-dose atropine eyedrops in myopia control in Australian children. The impact of ocular sun exposure, iris colour and parental myopia on the efficacy of low-dose atropine will also be assessed.

Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration: Evidence from the EYE-RISK and European Eye Epidemiology Consortia.

PURPOSE: Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. DESIGN: Pooled analysis of cross-sectional data. PARTICIPANTS: Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. METHODS: AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. MAIN OUTCOME MEASURES: AMD features and stage; lipid measurements. RESULTS: HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10-7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10-6 and P = 1.6 × 10-4). CONCLUSIONS: Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.