Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase 1/2 Multicenter Study (HORIZON): 24-Month Safety and Efficacy Results: Subretinal Gene Therapy AGTC-501 for XLRP Ph 1/2 24M Results.

Purpose: To evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa (XLRP).

Design: Phase 1/2, open-label, dose-escalation study.

Methods: Setting: Four centers in the United States.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

Background: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed.

Aims: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.

Safety and Effectiveness of Rivaroxaban Versus Warfarin Across GFR Levels in Atrial Fibrillation: A Population-Based Study in Australia and Canada.

Rationale & Objective: The benefit-risk profile of rivaroxaban versus warfarin for atrial fibrillation (AF) in patients with chronic kidney disease is uncertain. We compared rivaroxaban with warfarin across the range of kidney function in adults with AF.

Study Design: Multicenter retrospective cohort.

AAV Gene Augmentation of Truncated Complement Factor H Differentially Rescues Ocular Complement Dysregulation in a Mouse Model.

Purpose: Complement dysregulation in the eye has been implicated in the pathogenesis of age-related macular degeneration (AMD), and genetic variants of complement factor H (CFH) are strongly associated with AMD risk. We therefore aimed to untangle the role of CFH and its splice variant, factor H-like 1 (FHL-1), in ocular complement regulation derived from local versus circulating sources. We assessed the therapeutic efficacy of adeno-associated viruses (AAVs) expressing human FHL-1 and a truncated version of CFH (tCFH), which retains the functional N- and C-terminal ends of the CFH protein, in restoring the alternative complement pathway in Cfh-/- mouse eyes and plasma.

Preclinical studies in support of phase I/II clinical trials to treat -associated Leber congenital amaurosis.

Mutations in are associated with severe early-onset retinal dystrophy, Leber congenital amaurosis type 1 (LCA1), a leading cause of blindness in children. Despite a high degree of visual disturbance stemming from photoreceptor dysfunction, patients with LCA1 largely retain normal photoreceptor structure, suggesting that they are good candidates for gene replacement therapy. The purpose of this study was to conduct the preclinical and IND-enabling experiments required to support clinical application of AAV5-hGRK1- in patients harboring biallelic recessive mutations in .

Kidney function and the comparative effectiveness and safety of direct oral anticoagulants vs. warfarin in adults with atrial fibrillation: a multicenter observational study.

Aims: The aim of this study was to determine the comparative effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin in adults with atrial fibrillation (AF) by level of kidney function.

Methods And Results: We pooled findings from five retrospective cohorts (2011-18) across Australia and Canada of adults with; a new dispensation for a DOAC or warfarin, an AF diagnosis, and a measure of baseline estimated glomerular filtration rate (eGFR). The outcomes of interest, within 1 year from the cohort entry date, were: (1) the composite of all-cause death, first hospitalization for ischaemic stroke, or transient ischaemic attack (effectiveness), and (2) first hospitalization for major bleeding defined as an intracranial, upper or lower gastrointestinal, or other bleeding (safety).

Patient factors associated with dermatology outpatient non-attendance: An analysis of racial and ethnic diversity.

Non-attendance to dermatology outpatient appointments is a risk factor for poorer patient outcomes. The culturally and linguistically diverse (CALD) communities in Australia have been identified as at risk of poorer health outcomes, but there is a paucity of data assessing patient factors that may increase outpatient non-attendance. To investigate this, we performed a retrospective cross-sectional study of dermatology appointments from patients attending a tertiary, referral public hospital located in one of Australia's most racially and ethnically diverse communities.

Improved CRISPR genome editing using small highly active and specific engineered RNA-guided nucleases.

Streptococcus pyogenes (Spy) Cas9 has potential as a component of gene therapeutics for incurable diseases. One of its limitations is its large size, which impedes its formulation and delivery in therapeutic applications. Smaller Cas9s are an alternative, but lack robust activity or specificity and frequently recognize longer PAMs.

An Internet-Based Intervention for Cardiovascular Disease Management Integrated With Primary Care Electronic Health Records: Mixed Methods Evaluation of Implementation Fidelity and User Engagement.

Background: Growing evidence supports the benefits of eHealth interventions to increase patient engagement and improve outcomes for a range of conditions. However, ineffective program delivery and usage attrition limit exposure to these interventions and may reduce their effectiveness.

Objective: This study aims to evaluate the delivery fidelity of an eHealth intervention, describe use patterns, compare outcomes between low and high users, and identify mediating factors on intervention delivery and receipt.

The effect of low-dose corticosteroids and theophylline on the risk of acute exacerbations of COPD: the TASCS randomised controlled trial.

Background: The highest burden of chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries. Low-cost oral medications, if effective, could enable affordable, accessible COPD treatment.

Methods: In this randomised, three-arm, double-blind, double-dummy, placebo-controlled study conducted in 37 centres in China, symptomatic patients with moderate to very severe COPD were randomised 1:1:1 to placebo twice daily plus placebo once daily, low-dose theophylline 100 mg twice daily plus placebo once daily or low-dose theophylline 100 mg twice daily plus low-dose oral prednisone 5 mg once daily for 48 weeks.

Risk factors for incident kidney disease in older adults: an Australian prospective population-based study.

Background And Aim: To determine risk factors for incident chronic kidney disease (CKD) in a large population-based cohort.

Methods: This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly sampled from the Services Australia database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely collected databases. The primary outcome was the development of incident CKD, defined as eGFR < 60 mL/min/1.

A digital health intervention for cardiovascular disease management in primary care (CONNECT) randomized controlled trial.

Digital health applications (apps) have the potential to improve health behaviors and outcomes. We aimed to examine the effectiveness of a consumer web-based app linked to primary care electronic health records (EHRs). CONNECT was a multicenter randomized controlled trial involving patients with or at risk of cardiovascular disease (CVD) recruited from primary care (Clinical Trial registration ACTRN12613000715774).

Predictors of Change in Left-Ventricular Structure and Function in a Trial of Extended Hours Hemodialysis.

Background: Myocardial pathology is common in patients undergoing hemodialysis. To explore the effects of differing aspects of dialysis treatment on its evolution, we examined the impact of change in markers of volume status, hemodynamics and solute clearance on left ventricular (LV) parameters in a randomized trial of extended hours dialysis.

Methods And Results: A Clinical Trial of IntensiVE (ACTIVE) Dialysis randomized 200 patients undergoing hemodialysis to extended dialysis hours (≥ 24 hours/week) or standard hours (12-18 hours/week) for 12 months.

Effect of extended hours dialysis on markers of chronic kidney disease-mineral and bone disorder in the ACTIVE Dialysis study.

Background: Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD) is a significant cause of morbidity among haemodialysis patients and is associated with pathological changes in phosphate, calcium and parathyroid hormone (PTH). In the ACTIVE Dialysis study, extended hours dialysis reduced serum phosphate but did not cause important changes in PTH or serum calcium. This secondary analysis aimed to determine if changes in associated therapies may have influenced these findings and to identify differences between patient subgroups.

Medication non-adherence in a cohort of chronically ill Australians: A case of missed opportunities.

Background And Objectives: This study investigated the effect of management - including home medicines reviews and chronic disease management plans funded through the Medicare Benefits Schedule - on self-reported medication non-adherence.

Method: An observational cohort study including 244 individuals with an exacerbation of chronic illness enrolled into the Care Navigation randomised controlled trial of integrated care. Non-adherence was measured using the Morisky-Greene-Levine self-reported adherence tool.

Rationally designed AAV2 and AAVrh8R capsids provide improved transduction in the retina and brain.

The successful application of adeno-associated virus (AAV) gene delivery vectors as a therapeutic paradigm will require efficient gene delivery to the appropriate cells in affected organs. In this study, we utilized a rational design approach to introduce modifications to the AAV2 and AAVrh8R capsids and the resulting variants were evaluated for transduction activity in the retina and brain. The modifications disrupted either capsid/receptor binding or altered capsid surface charge.

Universal Method for the Purification of Recombinant AAV Vectors of Differing Serotypes.

The generation of clinical good manufacturing practices (GMP)-grade adeno-associated virus (AAV) vectors requires purification strategies that support the generation of vectors of high purity, and that exhibit a good safety and efficacy profile. To date, most reported purification schemas are serotype dependent, requiring method development for each AAV gene therapy product. Here, we describe a platform purification process that is compatible with the purification of multiple AAV serotypes.

Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial.

Background: Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration.

Methods: This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA.

AAVS1-Targeted Plasmid Integration in AAV Producer Cell Lines.

Adeno-associated virus (AAV) producer cell lines are created via transfection of HeLaS3 cells with a single plasmid containing three components (the vector sequence, the AAV rep and cap genes, and a selectable marker gene). As this plasmid contains both the cis (Rep binding sites) and trans (Rep protein encoded by the rep gene) elements required for site-specific integration, it was predicted that plasmid integration might occur within the AAVS1 locus on human chromosome 19 (chr19). The objective of this study was to investigate whether integration in AAVS1 might be correlated with vector yield.