CLADIN- CLADribine and INnate immune response in multiple sclerosis - A phase IV prospective study.

Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ 'non-classical' monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.

A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. METHODS: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use. RESULTS: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]. CONCLUSIONS: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.

P2X7 receptor antagonism by AZ10606120 significantly depletes glioblastoma cancer stem cells in vitro.

Glioblastoma is the most aggressive and lethal primary brain malignancy with limited treatment options and poor prognosis. Self-renewing glioblastoma cancer stem cells (GSCs) facilitate tumour progression, resistance to conventional treatment and tumour recurrence. GSCs are resistant to standard treatments. There is a need for novel treatment alternatives that effectively target GSCs. The purinergic P2X receptor 7 (P2X7R) is expressed in glioblastomas and has been implicated in disease pathogenesis. However, the roles of P2X7R have not been comprehensively elucidated in conventional treatment-resistant GSCs. This study characterised P2X7R channel and pore function and investigated the effect of pharmacological P2X7R inhibition in GSCs. Immunofluorescence and live cell fluorescent dye uptake experiments revealed P2X7R expression, and channel and pore function in GSCs. Treatment of GSCs with the P2X7R antagonist, AZ10606120 (AZ), for 72 hours significantly reduced GSC numbers, compared to untreated cells. When compared with the effect of the first-line conventional chemotherapy, temozolomide (TMZ), GSCs treated with AZ had significantly lower cell numbers than TMZ-treated cultures, while TMZ treatment alone did not significantly deplete GSC numbers compared to the control. AZ treatment also induced significant lactate dehydrogenase release by GSCs, indicative of treatment-induced cytotoxic cell death. There were no significant differences in the expression of apoptotic markers, Annexin V and cleaved caspase-3, between AZ-treated cells and the control. Collectively, this study reveals for the first time functional P2X7R channel and pore in GSCs and significant GSC depletion following P2X7R inhibition by AZ. These results indicate that P2X7R inhibition may be a novel therapeutic alternative for glioblastoma, with effectiveness against GSCs resistant to conventional chemotherapy.

Myopia progression following 0.01% atropine cessation in Australian children: Findings from the Western Australia - Atropine for the Treatment of Myopia (WA-ATOM) study.

BACKGROUND: A rebound in myopia progression following cessation of atropine eyedrops has been reported, yet there is limited data on the effects of stopping 0.01% atropine compared to placebo control. This study tested the hypothesis that there is minimal rebound myopia progression after cessation of 0.01% atropine eyedrops, compared to a placebo. METHODS: Children with myopia (n = 153) were randomised to receive 0.01% atropine eyedrops or a placebo (2:1 ratio) daily at bedtime during the 2-year treatment phase of the study. In the third year (wash-out phase), all participants ceased eyedrop instillation. Participants underwent an eye examination every 6 months, including measurements of spherical equivalent (SphE) after cycloplegia and axial length (AL). Changes in the SphE and AL during the wash-out phase and throughout the 3 years of the study (treatment + wash-out phase) were compared between the treatment and control groups. RESULTS: During the 1-year wash-out phase, SphE and AL progressed by -0.41D (95% CI = -0.33 to -0.22) and +0.20 mm (95% CI = -0.46 to -0.36) in the treatment group compared to -0.28D (95% CI = 0.11 to 0.16) and +0.13 mm (95% CI = 0.18 to 0.21) in the control group. Progression in the treatment group was significantly faster than in the control group (p = 0.016 for SphE and <0.001 for AL). Over the 3-year study period, the cumulative myopia progression was similar between the atropine and the control groups. CONCLUSIONS: These findings showed evidence of rapid myopia progression following cessation of 0.01% atropine. Further investigations are warranted to ascertain the long-term effects of atropine eyedrops.

Risk of Cervical Abnormalities for Women With Multiple Sclerosis Treated With Moderate-Efficacy and High-Efficacy Disease-Modifying Therapies.

BACKGROUND AND OBJECTIVES: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs). METHODS: This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects. RESULTS: We included 248 wwMS. The incidence of abnormal CSTs was lower (p < 0.001) for women not exposed to moderate-high-efficacy therapy (10.2 per 1,000 patient-years [95% confidence interval (CI) 5.5-14.9]), compared with those exposed (36.6 per 1,000 patient-years [95% CI 21.7-51.6]). Exposure to higher efficacy treatment was associated with a 3.79-fold increased hazard (95% CI 2.02-7.08, p < 0.001) of developing a cervical abnormality relative to those not exposed. When adjusted for vaccination status, smoking, hormonal contraceptive use, and socioeconomic status, the risk remained elevated at 3.79 (95% CI 1.99-7.21, p < 0.001). Marginal hazard ratios declined over time, ranging from 3.90 (95% CI 2.09-7.27) at 20 years of age to 2.06 (95% CI 1.14-3.73) at 70 years of age. DISCUSSION: A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.

Distribution of Axial Length in Australians of Different Age Groups, Ethnicities, and Refractive Errors.

Purpose: Treatments are available to slow myopic axial elongation. Understanding normal axial length (AL) distributions will assist clinicians in choosing appropriate treatment for myopia. We report the distribution of AL in Australians of different age groups and refractive errors. Methods: Retrospectively collected spherical equivalent refraction (SER) and AL data of 5938 individuals aged 5 to 89 years from 8 Australian studies were included. Based on the SER, participants were classified as emmetropes, myopes, and hyperopes. Two regression model parameterizations (piece-wise and restricted cubic splines [RCS]) were applied to the cross-sectional data to analyze the association between age and AL. These results were compared with longitudinal data from the Raine Study where the AL was measured at age 20 (baseline) and 28 years. Results: A piece-wise regression model (with 1 knot) showed that myopes had a greater increase in AL before 18 years by 0.119 mm/year (P < 0.001) and after 18 years by 0.011 mm/year (P < 0.001) compared to emmetropes and hyperopes, with the RCS model (with 3 knots) showing similar results. The longitudinal data from the Raine Study revealed that, when compared to emmetropes, only myopes showed a significant change in the AL in young adulthood (by 0.016 mm/year, P < 0.001). Conclusions: The AL of myopic eyes increases more rapidly in childhood and slightly in early adulthood. Further studies of longitudinal changes in AL, particularly in childhood, are required to guide myopia interventions. Translational Relevance: The axial length of myopic eyes increases rapidly in childhood, and there is a minimal increase in the axial length in non-myopic eyes after 18 years of age.

P2X7 receptor antagonism by AZ10606120 significantly reduced in vitro tumour growth in human glioblastoma.

Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14-18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.

Benefits of a Laser Chorioretinal Anastomosis Plus Ranibizumab vs Ranibizumab Alone for Central Retinal Vein Occlusion: 4-Year Results.

PURPOSE: To evaluate what clinical gains can be achieved over conventional treatment with ranibizumab alone for central retinal vein occlusion (CRVO) when causal pathology is additionally addressed successfully with a laser-induced chorio-retinal anastomosis (L-CRA). DESIGN: Two-year extension of prospective, randomized controlled clinical trial. METHODS: A total of 58 patients with macular edema secondary to CRVO were randomized 1:1 to receive either an L-CRA (n = 29) or sham procedure (n = 29) at baseline and then monthly intravitreal ranibizumab 0.5 mg. Outcomes (best corrected visual acuity [BCVA], central subfield thickness [CST], injection requirements) were monitored in the monthly pro re nata (PRN) ranibizumab phase from months 7 to 48. RESULTS: Injection requirements for patients with a functioning L-CRA (24 of 29) during the monthly PRN period from 7 to 24 months were a mean (95% CI) of 2.18 (1.57, 2.78) injections compared to 7.07 (6.08, 8.06) (P < .0001) for control (ranibizumab alone). These decreased further over the next 2 years to 0.29 (0.14, 0.61) compared to 2.20 (1.68, 2.88) (P < .001) for the third year and 0.25 (0.11, 0.56) and 1.84 (1.34, 2.54) for the fourth year (P < .001). Mean BCVA was statistically different at all follow-up time points from month 7 through month 48 for the group with the functioning L-CRA compared to the control monotherapy group. This improved to 14.06 letters at month 48 (P = .009). There was no difference in CST between any of the groups over the 48 months of follow-up. CONCLUSION: For CRVO patients, addressing causal pathology in addition to conventional therapy improves BCVA and reduces injection requirements.

Predictors of cognitive functioning in presentations to a community-based specialist addiction neuropsychology service.

INTRODUCTION: Cognitive impairment is common in individuals presenting to alcohol and other drug (AOD) settings and the presence of biopsychosocial complexity and health inequities can complicate the experience of symptoms and access to treatment services. A challenge for neuropsychologists in these settings is to evaluate the likely individual contribution of these factors to cognition when providing an opinion regarding diagnoses such as acquired brain injury (ABI). This study therefore aimed to identify predictors of cognitive functioning in AOD clients attending for neuropsychological assessment. METHODS: Clinical data from 200 clients with AOD histories who attended for assessment between 2014 and 2018 were analysed and a series of multiple regressions were conducted to explore predictors of cognitive impairment including demographic, diagnostic, substance use, medication, and mental health variables. RESULTS: Regression modelling identified age, gender, years of education, age of first use, days of abstinence, sedative load, emotional distress and diagnoses of ABI and developmental disorders as contributing to aspects of neuropsychological functioning. Significant models were obtained for verbal intellectual functioning (Adj R2 = 0.19), nonverbal intellectual functioning (Adj R2 = 0.10), information processing speed (Adj R2 = 0.20), working memory (Adj R2 = 0.05), verbal recall (Adj R2 = 0.08), visual recall (Adj R2 = 0.22), divided attention (Adj R2 = 0.14), and cognitive inhibition (Adj R2 = 0.07). CONCLUSIONS: These findings highlight the importance of careful provision of diagnoses in clients with AOD histories who have high levels of unmet clinical needs. They demonstrate the interaction of premorbid and potentially modifiable comorbid factors such as emotional distress and prescription medication on cognition. Ensuring that modifiable risk factors for cognitive impairment are managed may reduce experiences of cognitive impairment and improve diagnostic clarity.

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.

The Relationship Between Fetal Growth and Retinal Nerve Fiber Layer Thickness in a Cohort of Young Adults.

Purpose: To explore relationships between patterns of fetal anthropometric growth, as reflective of fetal wellbeing, and global retinal nerve fiber layer (RNFL) thickness measured in young adulthood. Methods: Participants (n = 481) from within a Western Australian pregnancy cohort study underwent five serial ultrasound scans during gestation, with fetal biometry measured at each scan. Optic disc parameters were measured via spectral-domain optical coherence tomography imaging at a 20-year follow-up eye examination. Generalized estimating equations were used to evaluate differences in global RNFL thickness between groups of participants who had undergone similar growth trajectories based on fetal head circumference (FHC), abdominal circumference (FAC), femur length (FFL), and estimated fetal weight (EFW). Results: Participants with consistently large FHCs throughout gestation had significantly thicker global RNFLs than those with any other pattern of FHC growth (P = 0.023), even after adjustment for potential confounders (P = 0.037). Based on model fit statistics, FHC growth trajectory was a better predictor of global RNFL thickness than birth weight or head circumference at birth. RNFL thickness did not vary significantly between groups of participants with different growth trajectories based on FAC, FFL, or EFW. Conclusions: FHC growth is associated with RNFL thickness in young adulthood and, moreover, is a better predictor than either birth weight or head circumference at birth. Translational Relevance: This research demonstrates an association between intrauterine growth and long-term optic nerve health, providing a basis for further exploring the extent of the influence of fetal wellbeing on clinical conditions linked to RNFL thinning.

Choroidal Thickening During Young Adulthood and Baseline Choroidal Thickness Predicts Refractive Error Change.

Purpose: The purpose of this study was to explore the age-related change in choroidal thickness (ChT) and test the hypothesis that baseline ChT is predictive of refractive error change in healthy young adults. Methods: Participants underwent spectral-domain optical coherence tomography (SD-OCT) imaging and autorefraction at 20 (baseline) and 28 years old. The enhanced depth imaging mode on the SD-OCT was used to obtain images of the choroid. Scans were exported from the SD-OCT and analyzed with a custom software that automatically measures the central ChT. The longitudinal change in subfoveal ChT and association between baseline subfoveal ChT and 8-year change in refractive error (spherical equivalent) were determined using linear mixed models. Results: In total, 395 eyes of 198 participants (44% men; 18-22 years at baseline) were included. Over 8 years, mean spherical equivalent decreased by 0.25 diopters (D) and axial length increased by 0.09 mm. Subfoveal choroid thickened by 1.3 µm/year (95% confidence interval [CI] = 0.6-2.0), but this was reduced by 0.9 µm/year (95% CI = 1.6-0.2) for every 1 mm increase in axial length. For every 10 µm increase in baseline ChT, average annual change in spherical equivalent and axial length reduced by 0.006 D/year and 0.003 mm/year, respectively. Conclusions: In a community-based cohort of young adults, the choroid continued to change during early adulthood. Choroidal thickening was less in eyes that were longer at baseline, and the choroid thinned in eyes that showed myopia progression. The association between baseline ChT and longitudinal changes in spherical equivalent and axial length supports the hypothesis that ChT may be predictive of refractive error development and/or myopia progression.

The effect of transverse ocular magnification adjustment on macular thickness profile in different refractive errors in community-based adults.

PURPOSE: Changes in retinal thickness are common in various ocular diseases. Transverse magnification due to differing ocular biometrics, in particular axial length, affects measurement of retinal thickness in different regions. This study evaluated the effect of axial length and refractive error on measured macular thickness in two community-based cohorts of healthy young adults. METHODS: A total of 2160 eyes of 1247 community-based participants (18-30 years; 23.4% myopes, mean axial length = 23.6mm) were included in this analysis. Macular thickness measurements were obtained using a spectral-domain optical coherence tomography (which assumes an axial length of 24.385mm). Using a custom program, retinal thickness data were extracted at the 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) regions with and without correction for transverse magnificent effects, with the corrected measurements adjusting according to the participant's axial length. Linear mixed models were used to analyse the effect of correction and its interaction with axial length or refractive group on retinal thickness. RESULTS: The raw measures (uncorrected for axial length) underestimated the true retinal thickness at the central macula, while overestimating at most non-central macular regions. There was an axial length by correction interaction effect in all but the nasal regions (all p<0.05). For each 1mm increase in axial length, the central macular thickness is overestimated by 2.7-2.9µm while thicknesses at other regions were underestimated by 0.2-4.1µm. Based on the raw thickness measurements, myopes have thinner retinas than non-myopes at most non-central macular. However, this difference was no longer significant when the corrected data was used. CONCLUSION: In a community-based sample, the raw measurements underestimate the retinal thickness at the central macula and overestimate the retinal thickness at non-central regions of the ETDRS grid. The effect of axial length and refractive error on retinal thickness is reduced after correcting for transverse magnification effects resulting from axial length differences.

Incidence and Progression of Myopia in Early Adulthood.

IMPORTANCE: Myopia incidence and progression has been described extensively in children. However, few data exist regarding myopia incidence and progression in early adulthood. OBJECTIVE: To describe the 8-year incidence of myopia and change in ocular biometry in young adults and their association with the known risk factors for childhood myopia. DESIGN, SETTING, AND PARTICIPANTS: The Raine Study is a prospective single-center cohort study. Baseline and follow-up eye assessments were conducted from January 2010 to August 2012 and from March 2018 to March 2020. The data were analyzed from June to July 2021. A total of 1328 participants attended the baseline assessment, and 813 participants attended the follow-up assessment. Refractive information from both visits was available for 701 participants. Participants with keratoconus, previous corneal surgery, or recent orthokeratology wear were excluded. EXPOSURES: Participants' eyes were examined at ages 20 years (baseline) and 28 years. MAIN OUTCOMES AND MEASURES: Incidence of myopia and high myopia; change in spherical equivalent (SE) and axial length (AL). RESULTS: A total of 516 (261 male [50.6%]) and 698 (349 male [50.0%]) participants without myopia or high myopia at baseline, respectively, were included in the incidences analyses, while 691 participants (339 male [49%]) were included in the progression analysis. The 8-year myopia and high myopia incidence were 14.0% (95% CI, 11.5%-17.4%) and 0.7% (95% CI, 0.3%-1.2%), respectively. A myopic shift (of 0.50 diopters [D] or greater in at least 1 eye) occurred in 261 participants (37.8%). Statistical significance was found in longitudinal changes in SE (-0.04 D per year; P < .001), AL (0.02 mm per year; P <.001), and lens thickness (0.02 mm per year; P < .001). Incident myopia was associated with self-reported East Asian vs White race (odds ratio [OR], 6.13; 95% CI, 1.06-35.25; P = .04), female vs male sex (OR, 1.81; 95% CI, 1.02-3.22; P = .04), smaller conjunctival ultraviolet autofluorescence area (per 10-mm2 decrease, indicating less sun exposure; OR, 9.86; 95% CI, 9.76-9.97; P = <.009), and parental myopia (per parent; OR, 1.57; 95% CI, 1.03-2.38; P = <.05). Rates of myopia progression and axial elongation were faster in female participants (estimate: SE, 0.02 D per year; 95 % CI, 0.01-0.02 and AL, 0.007 mm per year, 95 % CI, 0.00.-0.011; P ≤ .001) and those with parental myopia (estimate per parent: SE, 0.01 D per year; 95% CI, 0.00-0.02 and AL, 95% CI, 0.002-0.008; P ≤ .001). Education level was not associated with myopia incidence or progression. CONCLUSIONS AND RELEVANCE: These findings suggest myopia progression continues for more than one-third of adults during the third decade of life, albeit at lower rates than during childhood. The protective effects of time outdoors against myopia may continue into young adulthood.

In Utero Exposure to Smoking and Alcohol, and Passive Smoking during Childhood: Effect on the Retinal Nerve Fibre Layer in Young Adulthood.

PURPOSE: In utero exposure to cigarette smoke has been suggested to result in thinner retinal nerve fibre layer (RNFL). However, the potential cofounding effects of in utero alcohol exposure and passive smoking during childhood had not been considered. We explored RNFL thickness in young adults in relation to these early life factors. METHODS: In 1989-1991, pregnant women completed questionnaires on their current smoking and alcohol drinking patterns. Following the birth of their offspring, information on household smokers was obtained between the 1- and 13-year follow-ups. At the 20-year follow-up, these offspring underwent an eye examination including optical coherence tomography imaging of the RNFL. RESULTS: Participants (n = 1,287) were 19-22 years old at time of eye examination. Most participants (77%) had no in utero exposure to cigarette smoke; 1.3% were initially exposed but not after 18 weeks' gestation, while 21% had continual in utero smoking exposure. Half of the mothers never consumed alcohol or only consumed alcohol once during their pregnancies. After correcting for potential confounders, including in utero alcohel exposure and childhood passive smoking, participants who had continued in utero exposure to >10 cigarettes/day and ≤10 cigarettes/day had thinner RNFLs by 6.6 (95% confidence interval [CI] = 4.4-8.7) and 3.7 µm (95%[CI] = 2.3-5.5), respectively, than those with no exposure (p < .001). In utero alcohol exposure and childhood passive smoking were not significantly associated with RNFL thickness after accounting for in utero exposure to smoking. CONCLUSIONS: In utero exposure to cigarette smoke is associated with thinner RFNL in young adulthood, independent of other early life environmental factors.

Startle-elicited Event-Related Potentials to Affective Stimuli are Associated with Recent Illicit Opioid use among Patients Receiving Opioid Agonist Treatment.

Opioid use disorder (OUD) has been linked to exaggerated attentional, affective, and arousal responses to opioid-related stimuli, as well as altered responses to other affective (eg, naturally rewarding or aversive) stimuli, particularly blunted responses to pleasant/rewarding stimuli. Both exaggerated responses to drug-related stimuli and reduced response to pleasant stimuli may influence the course of OUD and its treatment, however interpretation of studies thus far is limited by methodological issues. In the present study, we examined subjective ratings, and attenuation of the P3 component of the acoustic startle-evoked event-related potential (as a measure of attention), while viewing neutral, pleasant, unpleasant, and drug-related images. Participants prescribed opioid agonist treatment (OAT) for OUD (n = 82) were compared to a carefully-matched control group (n = 33) and to recently-abstinent participants with OUD (n = 22). Relative to controls, participants prescribed OAT gave higher positive valence ratings of drug images, and blunted valence responses to other affective images, but groups did not differ in terms of arousal ratings or P3 amplitude. Within the OAT group, linear modeling of associations between frequency of recent illicit opioid use and startle P3 amplitude found an association between increased recent illicit opioid use and reduced attention to pleasant, relative to unpleasant, images. The latter finding may have implications for interventions targeting cognitive biases in people with substance use disorder. In particular, they suggest that enhancing attention to pleasant stimuli may be as, if not more important, than the typical approach of trying to reduce attentional bias to drug-related stimuli.

Functional benefits of a chorioretinal anastomosis at 2 years in eyes with a central retinal vein occlusion treated with ranibizumab compared with ranibizumab monotherapy.

OBJECTIVE: To evaluate the functional benefits (best corrected visual acuity (BCVA), central subfield thickness, injection loads, central venous pressure (CVP)) of a laser-induced chorioretinal anastomosis (L-CRA) in patients with central retinal vein occlusion (CRVO) treated with ranibizumab compared with ranibizumab monotherapy. METHODS AND ANALYSIS: This is a post-hoc analysis of the 2-year randomised ranibizumab plus L-CRA for CRVO trial. Twenty-four patients (82.5%) developed a functioning or successful L-CRA; outcome effects were monitored in the monthly as-needed ranibizumab phase from months 7 to 24 and compared with the ranibizumab monotherapy group (n=29). RESULTS: From months 7 to 24, the mean (95% CI) injection load for the functioning L-CRA group was 2.18 (1.57 to 2.78) compared with 7.07 (6.08 to 8.06) for the control group (p<0.0001). The mean BCVA was averaged across all timepoints between the control and functioning L-CRA groups (average difference=11.46 (3.16 to 19.75) letters, p=0.01). At 2 years, there was an 82.5% reduction in the odds of high CVP (greater or equal to central retinal artery diastolic pressure) for those with a successful L-CRA compared with controls (p<0.0001). CONCLUSION: For patients with CRVO, adding L-CRA as a causal-based treatment to conventional therapy reduced CVP and injection loads and offered improved BCVA.Trial registration number ACTRN12612000004864.

Time spent outdoors through childhood and adolescence - assessed by 25-hydroxyvitamin D concentration - and risk of myopia at 20 years.

PURPOSE: To investigate the relationship between time spent outdoors, at particular ages in childhood and adolescence, and myopia status in young adulthood using serum 25-hydroxyvitamin D [25(OH)D] concentration as a biomarker of time spent outdoors. METHODS: Participants of the Raine Study Generation 2 cohort had 25(OH)D concentrations measured at the 6-, 14-, 17- and 20-year follow-ups. Participants underwent cycloplegic autorefraction at age 20 years, and myopia was defined as a mean spherical equivalent -0.50 dioptres or more myopic. Logistic regression was used to analyse the association between risk of myopia at age 20 years and age-specific 25(OH)D concentrations. Linear mixed-effects models were used to analyse trajectory of 25(OH)D concentrations from 6 to 20 years. RESULTS: After adjusting for sex, race, parental myopia, body mass index and studying status, myopia at 20 years was associated with lower 25(OH)D concentration at 20 years (per 10 nmol/L decrease, odds ratio (aOR)=1.10, 95% CI: 1.02, 1.18) and a low vitamin D status [25(OH)D < 50 nmol/L] at 17 years (aOR = 1.71, 95% CI: 1.06, 2.76) and 20 years (aOR = 1.71, 95% CI: 1.14, 2.56), compared to those without low vitamin D status. There were no associations between 25(OH)D at younger ages and myopia. Individuals who were myopic at 20 years had a 25(OH)D concentration trajectory that declined, relative to non-myopic peers, with increasing age. Differences in 25(OH)D trajectory between individuals with and without myopia were greater among non-Caucasians compared to Caucasians. CONCLUSIONS: Myopia in young adulthood was most strongly associated with recent 25(OH)D concentrations, a marker of time spent outdoors.

Protocol for the methamphetamine approach-avoidance training (MAAT) trial, a randomised controlled trial of personalised approach bias modification for methamphetamine use disorder.

BACKGROUND: Globally, methamphetamine use has increased in prevalence in recent years. In Australia, there has been a dramatic increase in numbers of people seeking treatment, including residential rehabilitation, for methamphetamine use disorder (MUD). While residential rehabilitation is more effective for MUD than withdrawal treatment (i.e. "detoxification") alone, relapse rates remain high, with approximately half of rehabilitation clients using methamphetamine within 3 months of rehabilitation. "Approach bias modification" (ABM) is a computerised cognitive training approach that aims to dampen automatically triggered impulses to approach drugs and drug-related stimuli. ABM has been demonstrated to reduce alcohol relapse rates, but no randomised controlled trials of ABM for MUD have yet been conducted. We aim to test whether a novel "personalised" form of ABM, delivered during rehabilitation, reduces post-treatment methamphetamine use, relative to a sham-training control condition. Secondary outcomes will include dependence symptoms, cravings, and approach bias. METHODS: We aim to recruit 100 participants attending residential rehabilitation for MUD at 3 sites in the Melbourne metropolitan area. Participants will complete baseline measures of methamphetamine use, craving, dependence severity, and approach bias before being randomised to receiving 6 sessions of ABM or "sham" training. In the active condition, ABM will be personalised for each participant, using those methamphetamine images that they rate as most relevant to their recent methods of methamphetamine use as "avoidance" images and using positive images representing their goals or healthy sources of pleasure as "approach" images. Approach bias and craving will be re-assessed following completion of training, and methamphetamine use, dependence, and craving will be assessed 4 weeks and 3 months following discharge from residential treatment. DISCUSSION: This study is the first randomised controlled trial of ABM for MUD and also the first ABM study to test using a personalised set of both approach and avoid images for ABM training. If effective, the low cost and easy implementation of ABM means it could be widely implemented as a standard part of MUD treatment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620000072910. Registered on 30 January 2020 (prospectively registered): https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378804&isReview=true.

Neurocognitive functioning among people accessing an addiction neuropsychology clinic with and without a history of offending behaviour.

Effectiveness of interventions for violent behaviour may be undermined by the presence of neurocognitive impairment, which is known to be common among alcohol and other drug (AOD) users and violent offenders. The current study aimed to examine whether the cognitive functioning of individuals with AOD histories presenting to a specialist addiction neuropsychology service differed according to their offending history (i.e. non-offending, non-violent offending and violent offending), using a retrospective case file audit design. Data were extracted from 190 clients. Tests assessed a breadth of cognitive domains. Violent offenders demonstrated the lowest premorbid IQ out of the three groups, and a significantly higher proportion of violent offenders presented with impaired divided attention and impaired cognitive inhibition compared to non-violent offenders. Rates of impairment across groups were well beyond those expected within the general population. Delivery of both AOD and violence interventions should be adapted to accommodate individuals' cognitive difficulties.