Progression of diabetic retinopathy in women with pregestational diabetes during pregnancy and postpartum.

BACKGROUND: Diabetic retinopathy (DR) may worsen during pregnancy, but its course in the postpartum remains poorly understood. Understanding the natural history of DR during and after pregnancy can help determine when sight-threatening DR treatment should be administered. METHODS: A prospective longitudinal cohort study recruited pregnant women with pre-existing type 1 (T1D) or type 2 diabetes from two tertiary Diabetes Antenatal Clinics in Melbourne, Australia. Eye examination results in early pregnancy, late pregnancy, and up to 12-months postpartum were compared to determine DR changes. Two-field fundus photographs and optical coherence tomography scans were used to assess DR severity. RESULTS: Overall, 105 (61.4%) women had at least two eye examinations during the observation period. Mean age was 33.5 years (range 19-51); 54 women (51.4%) had T1D; 63% had HbA1c <7% in early pregnancy. DR progression rate was 23.8% (95% CI 16.4-32.6). Having T1D (RR 4.96, 95% CI 1.83-13.46), pre-existing DR in either eye (RR 4.54, 95% CI 2.39-8.61), and elevated systolic blood pressure (adjusted RR 2.49, 95% CI 1.10-5.66) were associated with increased risk of progression. Sight-threatening progression was observed in 9.5% of women. Among the 19 eyes with progression during pregnancy, 15 eyes remained stable, three eyes progressed, and only one eye regressed in the postpartum. CONCLUSIONS: Nearly 1 in 4 women had DR progression from conception through to 12-months postpartum; almost half of these developing sight-threatening disease. DR progression occurring during pregnancy was found to predominantly remain unchanged, or worsen, after delivery, with very few eyes spontaneously improving postpartum.

Can clinician's risk assessments distinguish those who disclose suicidal ideation from those who attempt suicide?

Participants were 85 individuals who made suicide attempts within two years of their Improving Access to Psychological Therapies (IAPT) assessment, identified using record linkage. Two comparison groups, non-suicidal controls (n = 1416) and (ideators, n = 743) were compared on variables extracted from the standardized IAPT risk assessment interview. Disclosure of a historical suicide attempt or non-suicidal self-injury (NSSI) distinguished those making an attempt from those with suicidal ideation only, but suicidal intent did not. A third of the participants concealed a historical suicide attempt. The IAPT Phobia Scale classified 49.30% of attempters with 100% specificity. The IAPT Phobia Scale may have clinical value in assessing risk but requires validation. Past suicide attempt and NSSI have better clinical risk assessment utility than current suicidal ideation intensity. Risk assessment relying on disclosure is likely to be flawed and risks support being withheld from those assumed to be at lower risk.

Prevalence of diabetic retinopathy in women with pregestational diabetes during pregnancy and the postpartum.

BACKGROUND: Diabetic retinopathy (DR) may be affected by pregnancy. The majority of prevalence data regarding DR in pregnancy predate the advent of contemporary guidelines for diabetes management during pregnancy. This study reports DR prevalence and associated risk factors in women with pregestational diabetes during pregnancy and the postpartum in Australia. METHODS: A total of 172 pregnant women with type 1 (T1DM) or type 2 diabetes diagnosed pre-pregnancy were prospectively recruited from two obstetrics hospitals in Melbourne (November 2017-March 2020). Eye examinations were scheduled in each trimester, at 3-, 6-, and 12-months postpartum. DR severity was graded from two-field fundus photographs by an independent grader utilising the Airlie House Classification. Sight-threatening DR (STDR) was defined as the presence of diabetic macular oedema or proliferative DR. RESULTS: Overall, 146 (84.9%) women had at least one eye examination during pregnancy. The mean age was 33.8 years (range 19-51), median diabetes duration was 7.0 years (IQR 3.0-17.0), 71 women (48.6%) had T1DM. DR and STDR prevalence during pregnancy per 100 eyes was 24.3 (95% CI 19.7-29.6) and 9.0 (95% CI 6.1-12.9); while prevalence in the postpartum was 22.2 (95% CI 16.5-29.3) and 10.0 (95% CI 5.4-17.9), respectively. T1DM, longer diabetes duration, higher HbA1c in early pregnancy, and pre-existing nephropathy were significant risk factors. CONCLUSIONS: The prevalence of DR in pregnant women was similar to the non-pregnant diabetic population in Australia. One in nine participants had STDR during pregnancy and the postpartum, highlighting the need to optimise DR management guidelines in pregnancy given the significant risk of vision loss.

The association between intravitreal ranibizumab therapy and serum cytokine concentrations in patients with diabetic macular edema.

Aim: To investigate the association between intravitreal ranibizumab therapy and serum cytokine concentrations in patients with diabetic macular edema (DME). Methods: Twenty-five patients with center-involved DME were recruited prospectively. Serum samples were collected from the patients before and 4 weeks after two ranibizumab injections. The levels of 32 cytokines at these two time points were assessed using a multiplex array assay. Results: Following two ranibizumab injections, there was a statistically significant decrease in the median [interquartile range] levels of Interleukin 1-1beta (IL-1ß) from 5.56 [3.6, 8.75] to 2.33 [1.51, 2.89], Interleukin 13 (IL-13) from 4.30 [1.84, 18.55] to 0.38 [0.38, 0.78], granulocyte-colony stimulating factor (G-CSF) from 64.65 [42.9, 108] to 37.8 [27.3, 46.37], Interferon gamma (IFN-γ) from 241 [103.33, 753.4] to 94.4626 [42.04, 118.58], Interferon gamma-induced protein 10 (IP-10) from 234.68 [144.16, 285.98] to 158.73 [94.71, 198.64], Macrophage Inflammatory Protein-1 alpha (MIP-1α) from 3.65 [2.62, 11.02] to 1.41 [0.94, 1.88], and Tumor necrosis factor- alpha (TNF-α) from 131.09 [100.68,28 240.27] to 45.19 [24.04, 68.55]. There was a statistically significant increase in the levels of Interleukin 9 (IL-9) from 0.76 [0.76, 7.03] to 19.67 [5.36 27.76], Macrophage Inflammatory Protein-1 beta (MIP-1ß) from 0.28 [0.28, 30 0.28] to 6.79 [I3.74, 14.16], Vascular endothelial growth factor (VEGF) from 2.55 [2.55, 2.55] to 25.24 [14.51, 41.73], and soluble vascular endothelial growth factor -1 (sVEGFR-1) from 333.92 [204.99, 440.43] to 500.12 [38.7, 786.91]. A Bonferroni-corrected p value of 0.00156 was considered statistically significant. Conclusions: In patients with DME, intravitreal ranibizumab therapy appears to influence the serum levels of a range of cytokines. After two injections, intravitreal ranibizumab therapy appears to be associated with a significant decrease in inflammatory mediators and a rise in VEGF and sVEGFR1.

Patterns of Vitamin D Levels and Exposures in Active and Inactive Noninfectious Uveitis Patients.

PURPOSE: To compare serum vitamin D levels and patterns of ultraviolet light and dietary exposure among patients with active and inactive noninfectious uveitis and population controls. DESIGN: Prospective case-control study. All participants (n = 151) underwent serum 25-hydroxy vitamin D measurement and completed a questionnaire on vitamin D intake and ultraviolet light exposure. Serum 25-hydroxy vitamin D levels were compared between active and inactive uveitis groups and with local population estimates. PARTICIPANTS: Adult patients with active and inactive noninfectious uveitis were recruited from 2 Victorian tertiary hospitals and 1 private ophthalmic practice. METHODS: Serum 25-hydroxy vitamin D levels were compared between patients with active and inactive uveitis and population-based estimates of serum 25-hydroxy vitamin D levels, stratified by geographic region and season. Vitamin D intakes and exposures based on questionnaire results, including vitamin D supplementation and sunlight exposures on weekdays and weekends, were compared between active and inactive uveitis groups. MAIN OUTCOME MEASURES: Serum vitamin D levels, intake of vitamin D, and exposure to sources of vitamin D. RESULTS: The median level of serum vitamin D in those with active uveitis (n = 74) was 46 nmol/l (interquartile range [IQR], 29-70 nmol/l), significantly lower than in the inactive control group (n = 77) at 64 nmol/l (IQR, 52-79 nmol/l; P < 0.001). The active uveitis group also showed lower median serum vitamin D levels than the local population median of 62 nmol/l (IQR, 46-77 nmol/l). Vitamin D supplementation also was associated significantly with uveitis inactivity (P = 0.026, Kendall's τ test). In a subanalysis of vitamin D-deficient participants, sun exposure was associated significantly with uveitis inactivity (P = 0.014 for weekday and weekend analyses). CONCLUSIONS: Participants with active uveitis showed significantly lower serum 25-hydroxy vitamin D levels than inactive uveitis patients and local population-based estimates. Vitamin D supplementation was found to be associated with decreased uveitis activity, as was sun exposure in those with vitamin D deficiency. These results suggest that vitamin D supplementation should be studied as an option for the prevention of uveitis relapse in at-risk patients.

Response to correspondence from Koerner and colleagues concerning our paper entitled: The effect of diluting povidone-iodine on bacterial growth associated with speech.

Clinicians adopt varying strategies for antisepsis with PI, which to this day remains efficient, economical and effective. Clinicians should prudently consider effective PI application, and we thank Koerner and Grzybowski for encouraging debate and raising the profile of this issue.

Epidemiology of episcleritis and scleritis in urban Australia.

IMPORTANCE: The epidemiology of episcleritis and scleritis in Australia is largely unknown. BACKGROUND: To determine the incidence, prevalence and clinical characteristics of episcleritis and scleritis in Melbourne. DESIGN: Retrospective longitudinal study. PARTICIPANTS: Patients aged ≥18 years with episcleritis or scleritis seen at the Royal Victorian Eye and Ear Hospital from November 2014 to October 2015. METHODS: Medical record review confirmed clinical diagnosis and characteristics. Incidence and prevalence were calculated using estimates of the adult population in areas of Melbourne with ≥30 ocular presentations/year to the emergency department. MAIN OUTCOME MEASURES: Diagnosis of active episcleritis or scleritis, aetiology, ocular complications and treatments. RESULTS: From a general population of 3 408 068, we confirmed 149 new and 23 pre-existing cases of active episcleritis, and 35 new and 23 pre-existing cases of active scleritis. Incidence per 100 000 person-years was 4.4 (95% confidence interval [CI] 3.7-5.1) for episcleritis and 1.0 (95% CI 0.7-1.4) for scleritis, while 12-month prevalence was 5.1 (95% CI 4.3-5.9) and 1.7 (1.3-2.2) per 100 000 persons, respectively. Systemic disease was associated with 10% of episcleritis compared with 34% of scleritis (P < .001). Ocular complications were seen in 3% (6/184) of episcleritis eyes and 44% (32/72) of scleritis eyes, with the commonest being anterior uveitis (12/72) and ocular hypertension (14/72). At presentation, scleritis patients were commonly treated with oral non-steroidal anti-inflammatory drugs (60%) and prednisolone (19%). By 12 months, 24% of scleritis patients required immunosuppressants. CONCLUSIONS AND RELEVANCE: Rates of episcleritis and scleritis in our single-centre Australian study were low. Episcleritis was usually benign, whereas scleritis had increased ocular complications and systemic disease.

Diabetic retinopathy progression 6 months post-cataract surgery with intravitreous bevacizumab vs triamcinolone: A secondary analysis of the DiMECAT trial.

IMPORTANCE: Diabetic retinopathy (DR) may progress following cataract surgery due to surgery-induced inflammation. The effect of intravitreal bevacizumab (BVB) and triamcinolone acetonide (TCA), which have differing anti-inflammatory properties, on DR progression following cataract surgery has not been reported. BACKGROUND: To report the progression of DR in diabetic patients undergoing cataract extraction treated with intravitreal BVB or TCA during the surgery. DESIGN: Post hoc analysis of 6-month data from a prospective, randomized, double-masked clinical trial. PARTICIPANTS: Diabetic patients with clinically significant cataract and fovea involving diabetic macular oedema (DME), or a recent history of DME. METHODS: Participants were randomly allocated 1:1 to receive intravitreal BVB 1.25 mg or TCA 4 mg during and post-cataract surgery as needed. The rate of DR progression between groups was compared. MAIN OUTCOME MEASURES: DR progression. RESULTS: There were 61 eyes included. Patients receiving BVB were older than those receiving TCA (70.2 vs 64.3 years; P < .05). Three participants (10.7%) in the BVB and three (9.09%) in the TCA group had a one-step progression, while none in BVB and only one (3%) in the TCA group demonstrated two-step DR progression. In the majority of these patients, DR progression was from mild to moderate non-proliferative diabetic retinopathy. CONCLUSION AND RELEVANCE: In this study, BVB and TCA groups had a similar, and lower rate of DR progression compared to previous studies where no adjunctive treatment was administered, suggesting that patients with DME may benefit from either intraoperative intravitreous BVB or TCA injection to reduce the risk of DR progression following cataract surgery.

The effect of diluting povidone-iodine on bacterial growth associated with speech.

BACKGROUND: Povidone-Iodine (PI) may be diluted when used as an antiseptic prior to an intravitreal injection in an attempt to decrease patient discomfort. This study aims to investigate the effect of diluting povidone-iodine (PI) on bacterial growth from bacterial droplet dispersal associated with speech. METHODS: Participants read a standardised script for 5 min over a blood agar plate positioned at 20 cm in a simulated position of an intravitreal injection procedure. The blood agar plates were subject to a randomised pre-application of 1% PI; 2.5% PI; 5% PI and no pre-application (control). The plates were incubated at 37 °C for 72 h and the number of Colony Forming Units (CFUs) was determined. CFUs were summarised as median and interquartile range (IQR). Wilcoxon rank sum test was used to assess pairwise comparisons of the various PI concentrations to the control group. Any trend across PI concentration was assessed using Kendall's tau rank correlation. RESULTS: Twenty-one subjects participated. Control plates had a median growth of 25 CFUs (interquartile range [IQR]:15-40), 1% PI plates had a median growth of 30 CFUs (IQR:15-82), 2.5% PI had a median growth of 18 CFUs (IQR:10-32) and 5% PI had a median growth of 2 CFUs (IQR:0-5). There was significantly less bacterial growth with 5% PI compared to control (P < 0.001). Bacterial growth at 2.5% PI and 1% PI did not differ significantly from control. There was a statistically significant trend for decreasing colony count as PI concentration increased (P < 0.001). CONCLUSIONS: PI concentrations less than 5% are not effective at reducing bacterial growth from bacterial droplet dispersal associated with speech. When using PI for pre-injection antisepsis, concentrations below 5% should be avoided.

Differences in practice of ophthalmology by gender in Australia.

IMPORTANCE: The number of females practising ophthalmology is rising. It is known that practice patterns between female and male ophthalmologists differ. Understanding the differences will help to inform future workforce planning. BACKGROUND: To investigate the differences in clinical practice between female and male ophthalmologists in Australia. DESIGN: Cross-sectional study. PARTICIPANTS: Ophthalmologists participating in the Royal Australian & New Zealand College of Ophthalmologists workforce survey, and/or Medicine in Australia: Balancing Employment and Life survey, and those who made claims from Medicare Benefits Schedule Australia. METHODS: Combined analysis of de-identified 2014 data from the surveys and Medicare Benefits Schedule. MAIN OUTCOME MEASURES: Hours worked, service provision, remuneration and social circumstances. RESULTS: Female ophthalmologists provided 35% fewer services per ophthalmologist per year (2834 vs 4328) than male ophthalmologists. Female ophthalmologists received approximately half the annual income of male ophthalmologists; median self-reported net personal annual income was AUD122 500 (interquartile range [IQR] 96 000-225 000) for females compared to AUD245 000 (IQR 180 000-365 000) for males (P = .01). The median self-reported hours worked per week was 35.0 (IQR 28.0-46.0) for females and 41.8 (IQR 36.5-48.5) for males (P = 0.04). A higher proportion of females practise in medical subspecialties, while a higher proportion of males practise in surgical subspecialties. CONCLUSIONS AND RELEVANCE: Female ophthalmologists earn less compared to male ophthalmologists after accounting for lower service provision and hours worked. Difference in income may be partially accounted for by higher total number of services and procedural services provided by male ophthalmologists. Understanding differences between female and male ophthalmologists will help to inform future medical workforce planning.

Epidemiology of uveitis in urban Australia.

IMPORTANCE: Few prior studies have described the epidemiology of uveitis in the Australian population. BACKGROUND: To report the incidence and period prevalence of active uveitis in Melbourne and detail their subtypes and aetiologies. DESIGN: Cross-sectional study using retrospective medical record review in a tertiary hospital. PARTICIPANTS: Patients with a coded diagnosis of uveitis who attended the emergency department or specialist ocular immunology clinic at the Royal Victorian Eye and Ear Hospital between November 2014 through October 2015 (N = 1752). METHODS: Medical records were reviewed to confirm the date of diagnosis and subtype of uveitis. Incidence and prevalence rates were calculated utilizing estimates of the adult population residing in areas of greater Melbourne with more than 30 ocular-related presentations to the emergency department annually. MAIN OUTCOMES AND MEASURES: Presence and date of onset, anatomical distribution and aetiology of uveitis. RESULTS: During the study period, 734 new cases of uveitis and 502 cases of pre-existing uveitis requiring active treatment were confirmed. These figures yielded an incidence of 21.54 (CI 20.03, 23.15) per 100 000 person-years and a period prevalence of 36.27 (CI 34.30, 38.35) per 100 000 persons. The distribution of prevalent uveitis cases was anterior (75%), intermediate (6%), posterior (15%) and panuveitis (4%). An infectious aetiology accounted for 13.4% of cases, a systemic associated disease for 26.4% of cases, and no cause was identified in 60.2% of cases. CONCLUSION AND RELEVANCE: The incidence and prevalence rates of uveitis in urban Australia were lower than recent studies from the United States and Europe.

Proteomic profiling of cellular steatosis with concomitant oxidative stress in vitro.

BACKGROUND: Nutrient excess underpins the development of nonalcoholic fatty liver disease (NAFLD). The ensuing metabolic derangement is characterised by increased cellular respiration, oxidative stress and mitochondrial impairment. We have previously recapitulated these events in an in vitro cellular steatosis model. Here, we examined the distinct patterns of protein expression involved using a proteomics approach. METHODS: Human hepatoblastoma C3A cells were treated with a combination of energy substrates; lactate (L), pyruvate (P), octanoate (O) and ammonia (N). Proteins extracts were trypsinized and analyzed on a capillary HPLC OrbitrapXL mass spectrometer. Proteins were quantified using a label-free intensity based approach. Functional enrichment analysis was performed using ToppCluster via Gene Ontology (GO) database. RESULTS: Of the 1327 proteins identified, 104 were differentially expressed between LPON and untreated cells (defined as: ≥2 peptides; fold change ≥1.5; p-value <0.05). Seventy of these were upregulated with LPON. Functional enrichment analysis revealed enhanced protein biosynthesis accompanied by downregulation of histones H2A type 1-A, H1.2, H1.5 and H1.0I in LPON cells. Lipid binding annotations were also enriched as well as proteins involved in cholesterol synthesis, uptake and efflux. Increased expression of aldo-keto reductase family 1, member C1 and C3 suggests enhanced sterol metabolism and increased ROS-mediated lipid peroxidation. CONCLUSIONS: The surge of energy substrates diverts free fatty acid metabolism towards pathways that can mitigate lipotoxicity. The histones depletion may represent an adaptation to increased protein synthesis. However, this can also expose DNA to oxidative stress thus should be explored further in the context of NAFLD progression.

Diabetic Macular Edema at the time of Cataract Surgery trial: a prospective, randomized clinical trial of intravitreous bevacizumab versus triamcinolone in patients with diabetic macular oedema at the time of cataract surgery - preliminary 6 month results.

BACKGROUND: To compare visual and anatomical outcomes between intravitreous bevacizumab (BVB, Avastin) and triamcinolone (TA, Triesence) when administered at the time of cataract surgery in patients with diabetic macular oedema (DME). DESIGN: Prospective, single-masked, randomized clinical trial at The Royal Victorian Eye and Ear Hospital, Melbourne. PARTICIPANTS: Patients with clinically significant cataract and either centre-involving DME or DME treated within the previous 24 months. METHODS: Participants were randomized 1:1 to receive intravitreous BVB 1.25 mg or TA 4 mg during cataract surgery, and at subsequent review if required over 6 months. MAIN OUTCOME MEASURES: Change in central macular thickness (CMT) and best corrected visual acuity at 6 months. RESULTS: Forty-one patients (mean age 66.4 years, 73.2% male) were recruited. Visual acuity and CMT were similar between groups at baseline (P > 0.2).After six months, both groups gained vision (mean +21.4 letters in TA group P < 0.0001, +12.5 letters in BVB, P = 0.002), with no significant difference between groups (P = 0.085). In addition, 60.9% of eyes receiving TA achieved a VA of ≥6/12 compared to 73.3% in the BVB group (P = 0.501). However, only TA was associated with a sustained reduction in CMT (-43.8-µm reduction TA vs. +37.3-µm increase BVB, P = 0.006 over 6 months). Following surgery, additional injections were required in 70.6% of participants in the BVB group, compared to 16.7% in the TA group (P < 0.0001). Three patients in the TA group experienced a rise of IOP over 21 mmHg (12.5%) during the 6-month follow-up; BVB had no cases (P = 0.130). There were no cases of endophthalmitis in either group. CONCLUSIONS: When administered at the time of cataract surgery in patients with DME, at 6 months both TA and BVB improve visual acuity; however, only TA results in a sustained reduction in CMT. Further follow-up will determine whether this translates into better long-term visual outcomes in the TA group.

Fibrinogen production is enhanced in an in-vitro model of non-alcoholic fatty liver disease: an isolated risk factor for cardiovascular events?

BACKGROUND: Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the individual contribution of NAFLD to CVD risk factors in the absence of pathogenic influences from other comorbidities often found in NAFLD patients, by using an established in-vitro model of hepatic steatosis. METHODS: Histopathological events in non-alcoholic fatty liver disease were recapitulated by focused metabolic nutrient overload of hepatoblastoma C3A cells, using oleate-treated-cells and untreated controls for comparison. Microarray and proteomic data from cell culture experiments were integrated into a custom-built systems biology database and proteogenomics analysis performed. Candidate genes with significant dysregulation and concomitant changes in protein abundance were identified and STRING association and enrichment analysis performed to identify putative pathogenic pathways. RESULTS: The search strategy yielded 3 candidate genes that were specifically and significantly up-regulated in nutrient-overloaded cells compared to untreated controls: fibrinogen alpha chain (2.2 fold), fibrinogen beta chain (2.3 fold) and fibrinogen gamma chain (2.1 fold) (all rank products pfp <0.05). Fibrinogen alpha and gamma chain also demonstrated significant concomitant increases in protein abundance (3.8-fold and 2.0-fold, respectively, p <0.05). CONCLUSIONS: In-vitro modelling of NAFLD and reactive oxygen species formation in nutrient overloaded C3A cells, in the absence of pathogenic influences from other comorbidities, suggests that NAFLD is an isolated determinant of CVD. Nutrient overload-induced up-regulation of all three fibrinogen component subunits of the coagulation cascade provides a possible mechanism to explain the excess CVD mortality observed in NAFLD patients.

Drug Retention Time of Immunosuppressive Therapy in Behcet's Uveitis.

PURPOSE: Behcet's Disease is a chronic multisystem vasculitis associated with a blinding uveitis. Few comparative studies exist between conventional disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs in Behcet's uveitis (BU). We therefore used drug retention time (DRT), an accepted surrogate measure of pharmacological efficacy and tolerability, to compare these treatments in patients with BU. METHODS: Retrospective chart review of patients who met the revised International Criteria for Behcet's Disease (ICBD) treated at the Royal Victorian Eye and Ear Hospital, Australia, between 1985-2021. DRT was analysed with Kaplan-Meier plots and defined as total time on drug in the first medication-period for each DMARD in each patient. RESULTS: Forty-eight patients (37 males) with median age of 28.6 years were followed-up for a median of 8.0 years. At initial presentation, half had bilateral disease and median logMAR visual acuity was 0.176 (Snellen 6/9) in 62 uveitic eyes (16 anterior uveitis, 11 intermediate, 2 posterior, and 33 panuveitis). Thirty-three patients met ICBD initially. Prescribed corticosteroid-sparing agents were Cyclosporin (N = 24), Mycophenolate (N = 22), Azathioprine (N = 22), Methotrexate (N = 16), and Adalimumab (N = 15). Median DRT was 14.0, 27.4, 8.3, 24.0, and 52.0 months, respectively. DMARDs were discontinued 116 times and adverse effects (N = 37) were the main reason for cessation. Over time, patients were switched from Cyclosporin to Adalimumab earlier in the disease course due to poorer tolerance of adverse events. CONCLUSION: Adalimumab's drug retention time was found to be similar to and possibly better than cDMARDs in patients with BU, who often suffer from vision-threatening disease at first presentation.

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles.

The serotonin 2 receptor (5HT2R) agonist psilocybin displays rapid and persistent therapeutic efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. A single dose of psilocybin induced ensemble turnover between fear learning and extinction days while oppositely modulating activity in fear- and extinction- active neurons. The acute suppression of fear-active neurons and delayed recruitment of extinction-active neurons were predictive of psilocybin-enhanced fear extinction. A computational model revealed that acute inhibition of fear-active neurons by psilocybin is sufficient to explain its neural and behavioral effects days later. These results align with our hypothesis and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.

Reduction in Herpes Zoster Antiviral Use Since the Introduction of the Live-Attenuated Zoster Vaccine on Australia's National Immunisation Program: A Population-Based Study from 1994 to 2019.

INTRODUCTION: Zostavax, the live-attenuated vaccine used to prevent herpes zoster (HZ), has been available to individuals aged 70 and 71-79 years (phased catch-up) via Australia's National Immunisation Program (NIP) since 2016. There are limited data characterising the incidence of HZ at the level of the Australian population. National prescription data for antivirals used to treat HZ may be used as a proxy for HZ incidence. We aimed to examine trends in antiviral prescriptions supplied for the treatment of HZ in Australia pre- and post-2016, and to assess whether Zostavax's inclusion on the NIP correlated with a reduction in HZ antiviral prescription rates. METHODS: Using the Australian Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme prescribing data, we analysed antiviral prescriptions supplied for the treatment of HZ Australia-wide between 1994 and 2019. Annual prescription rates were calculated, and trends and changes in HZ antiviral use were explored descriptively and using Poisson models. RESULTS: HZ antiviral prescription rates increased 2.6-fold (160%) between 1995 and 2015 [25.4 (95% CI 25.2, 25.6) and 65.3 (95% CI 64.9, 65.6) prescriptions per 10,000 people, respectively], and then decreased 0.45-fold (55%) between 2016 and 2018 [60.9 (95% CI 60.6, 61.2) and 27.5 (95% CI 27.3, 27.9) prescriptions per 10,000 people, respectively]. The prescription rate for the antiviral famciclovir restricted specifically for treating HZ in immunocompromised individuals increased 8.5-fold (750%) between 2006 (year first listed) and 2019 [0.3 (95% CI 0.3, 0.3) and 2.5 (95% CI 2.4, 2.6) prescriptions per 10,000 people, respectively]. CONCLUSION: The introduction of the live-attenuated HZ vaccine on Australia's formal national vaccination program was associated with a reduction in HZ antiviral prescription rates within the Australian population. The data suggest that the introduction of Shingrix, the non-live subunit zoster vaccine, may also be associated with a similar reduction in HZ antiviral prescriptions used to treat the immunocompromised, as well as the general population, given its accepted greater efficacy over Zostavax.

Variation of Practice in Prophylactic Protocol to Reduce Prosthetic Joint Infection in Primary Hip and Knee Arthroplasty: A National Survey in the United Kingdom.

Purpose: Prosthetic joint infection (PJI) has an enormous physiological and psychological burden on patients. Surgeons rightly wish to minimise this risk. It has been shown that a standardised, evidence-based approach to perioperative care leads to better patient outcomes. A review of current practice was conducted using a cross-sectional survey among surgeons at multiple centers nationwide. Materials and Methods: An 11-question electronic survey was circulated to hip and knee arthroplasty consultants nationally via the BOA (British Orthopaedic Association) e-newsletter. Results: The respondents included 56 consultants working across 19 different trusts. Thirty-four (60.7%) screen patients for asymptomatic bacteriuria (ASB) preoperatively, with 19 (55.9%) would treating with antibiotics. Fifty-six (100%) screen for methicillin-resistant Staphylococcus aureus and treat if positive. Only 15 (26.8%) screen for methicillin-sensitive S. aureus (MSSA) or empirically eradicate. Zero (0%) routinely catheterise patients perioperatively. Forty-one (73.2%) would give intramuscular or intravenous gentamicin for a perioperative catheterisation. All surgeons use laminar flow theatres. Twenty-six (46.4%) use only an impervious gown, 6 (10.7%) exhaust pipes, and 24 (42.3%) surgical helmet system. Five different antimicrobial prophylaxis regimens are used 9 (16.1%) cefuroxime, 2 (3.6%) flucloxacillin, 19 (33.9%) flucloxacillin and gentamicin, 10 (17.9%) teicoplanin, 16 (28.6%) teicoplanin and gentamicin. Twenty-two (39.3%) routinely give further doses. Conclusion: ASB screening, treatment and intramuscular gentamicin for perioperative catheterisation is routinely practiced despite no supporting evidence base. MSSA screening and treatment is underutilised. Multiple antibiotic regimens exist despite little variation in organisms in PJI. Practice varies between surgeons and centers, we should all be practicing evidence-based medicine.

Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to µ-opioidergic cell types.

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene (mMORp) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp (hMORp) efficiently transduced macaque cortical OPRM1+ cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.

Global Estimates of Diabetic Retinopathy Prevalence and Progression in Pregnant Women With Preexisting Diabetes: A Systematic Review and Meta-analysis.

Importance: Diabetic retinopathy (DR) may be worsened by pregnancy in pregnant women with preexisting type 1 diabetes (T1D) or type 2 diabetes (T2D). Conflicting findings from previous studies have resulted in inconsistencies in guidelines regarding DR management in pregnancy. Global estimates of DR prevalence and progression in pregnancy are therefore required to provide clearer information about the overall true burden of DR in this population. Objective: To estimate the prevalence of DR and its progression rate in pregnant women with preexisting T1D or T2D diagnosed before pregnancy. Data Sources: For this systematic review and meta-analysis, conducted from November 27, 2018, to June 29, 2021, a systematic literature search was conducted in MEDLINE/Ovid, Embase/Ovid, and Scopus databases to identify English-language articles that were published from inception through October 2020. Study Selection: Observational studies that reported on DR and its changes in pregnant women with preexisting T1D and T2D. Data Extraction and Synthesis: Two independent reviewers extracted relevant data from each included study. Data were pooled using a random-effects model with the Freeman-Tukey double arcsine transformation. This study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Main Outcomes and Measures: Prevalence of any DR, proliferative DR (PDR), and DR progression rates. Results: A total of 18 observational studies involving 1464 pregnant women with T1D and 262 pregnant women with T2D were included in the analysis. The pooled prevalence of any DR and PDR in early pregnancy was 52.3 (95% CI, 41.9-62.6) and 6.1 (95% CI, 3.1-9.8) per 100 pregnancies, respectively. The pooled progression rate per 100 pregnancies for new DR development was 15.0 (95% CI, 9.9-20.8), worsened nonproliferative DR was 31.0 (95% CI, 23.2-39.2), progression from nonproliferative DR to PDR was 6.3 (95% CI, 3.3-10.0), and worsened PDR was 37.0 (95% CI, 21.2-54.0). DR progression rates per 100 pregnancies were similar between the T1D and T2D groups, except for the development of new DR (T1D groups: 15.8; 95% CI, 10.5-21.9; T2D groups: 9.0; 95% CI, 4.9-14.8). A global trend toward a lower DR progression rate was observed after the 1989 St Vincent Declaration. Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that women with T1D and T2D had a similar risk of DR progression during pregnancy. Despite improvements in the management of diabetes and diabetes during pregnancy, DR prevalence and progression in pregnant women with diabetes remains higher than the nonpregnant population with diabetes, highlighting the need to improve DR management in pregnancy.