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IntroductionStructured medication reviews (SMRs), introduced in the United Kingdom (UK) in 2020, aim to enhance shared decision-making in medication optimisation, particularly for patients with multimorbidity and polypharmacy. Despite its potential, there is limited empirical evidence on the implementation of SMRs, and the challenges faced in the process. This study is part of a larger DynAIRx (Artificial Intelligence for dynamic prescribing optimisation and care integration in multimorbidity) project which aims to introduce Artificial Intelligence (AI) to SMRs and develop machine learning models and visualisation tools for patients with multimorbidity. Here, we explore how SMRs are currently undertaken and what barriers are experienced by those involved in them.MethodsQualitative focus groups and semi-structured interviews took place between 2022-2023. Six focus groups were conducted with doctors, pharmacists and clinical pharmacologists (n = 21), and three patient focus groups with patients with multimorbidity (n = 13). Five semi-structured interviews were held with 2 pharmacists, 1 trainee doctor, 1 policy-maker and 1 psychiatrist. Transcripts were analysed using thematic analysis.ResultsTwo key themes limiting the effectiveness of SMRs in clinical practice were identified: 'Medication Reviews in Practice' and 'Medication-related Challenges'. Participants noted limitations to the efficient and effectiveness of SMRs in practice including the scarcity of digital tools for identifying and prioritising patients for SMRs; organisational and patient-related challenges in inviting patients for SMRs and ensuring they attend; the time-intensive nature of SMRs, the need for multiple appointments and shared decision-making; the impact of the healthcare context on SMR delivery; poor communication and data sharing issues between primary and secondary care; difficulties in managing mental health medications and specific challenges associated with anticholinergic medication.ConclusionSMRs are complex, time consuming and medication optimisation may require multiple follow-up appointments to enable a comprehensive review. There is a need for a prescribing support system to identify, prioritise and reduce the time needed to understand the patient journey when dealing with large volumes of disparate clinical information in electronic health records. However, monitoring the effects of medication optimisation changes with a feedback loop can be challenging to establish and maintain using current electronic health record systems.

Purpose: To conduct a costing study comparing orthoptist-led with consultant-led clinics screening for optic pathway gliomas (OPGs) in children with neurofibromatosis Type 1 (NF1) attending the Royal Children’s Hospital (RCH), Melbourne. Methods: Patients with NF1 examined in the orthoptist-led NF1 screening clinic and/or consultant-led clinics during the study period were identified. The workflow management software Q-Flow 6® provided data documenting patient’s time spent with the orthoptist, nurse, and ophthalmologist. Time points were converted into minutes and multiplied by the cost-per-minute for each profession. A bottom-up micro-costing approach was used to estimate appointment level costs. Bootstrap simulations with 1000 replications were used to estimate 95% confidence intervals (CIs) for the difference in mean appointment time and cost between clinics. Results: Data for 130 consultant-led clinic appointments and 234 orthoptist-led clinic appointments were extracted for analysis. The mean time per appointment for the consultant-led clinic was 45.11 minutes, and the mean time per appointment for the orthoptist-led clinic was 25.85 minutes. The mean cost per appointment for the consultant-led clinic was A $84.15 (GBP £39.60) compared to the orthoptist-led clinic at A $20.40 (GBP £9.60). This represents a mean reduction of 19.25 minutes per appointment (95% CI, –24.85 to –13.66) and a mean reduction of A $63.75 (GBP £30.00) per appointment (95% CI, (A $-75.40 to $-52.10 [GBP £ -35.48 to £ -24.52]). Conclusion: An orthoptist-led clinic screening for OPGs in patients with NF1 can be a more cost-efficient model of care for ophthalmic screening in this patient group.

The reliable operation of an integrated circuit can be affected by environmental changes, such as of multiple frequency electromagnetic (EM) disturbances and temperature variations. This paper compares the performance of two oscillator circuits, namely a current-starved voltage controlled oscillator and a ring oscillator integrated into a chip, in terms of their immunity to multitone direct power injection while under the influence of thermal stress. The objective is to demonstrate by the means of measurements the synergistic effect caused by multitone EM disturbances in a test chip, in contrast to the conventional single-tone EM disturbances. Moreover, the multitone immunity levels of integrated blocks with different architectures but similar functionality are analyzed at extreme temperature deviations. Bayesian networks (BN) are applied in order to visualize the probability of circuit failure due to multitone disturbances and temperature influence. Additionally, noisy-OR and improved-adaptive-recursive-noisy-OR (I-ARNOR) probabilistic models are implemented to identify the types of causal interactions (i.e. inhibition and positive causality) between multitone disturbances and to predict the probability of failure due to higher order multitone disturbances, respectively.

Background Structured Medication Reviews (SMRs) are intended to help deliver the NHS Long Term Plan for medicines optimisation in people living with multiple long-term conditions and polypharmacy. It is challenging to gather the information needed for these reviews due to poor integration of health records across providers and there is little guidance on how to identify those patients most urgently requiring review. Objective To extract information from scattered clinical records on how health and medications change over time, apply interpretable artificial intelligence (AI) approaches to predict risks of poor outcomes and overlay this information on care records to inform SMRs. We will pilot this approach in primary care prescribing audit and feedback systems, and co-design future medicines optimisation decision support systems. Design DynAIRx will target potentially problematic polypharmacy in three key multimorbidity groups, namely, people with (a) mental and physical health problems, (b) four or more long-term conditions taking ten or more drugs and (c) older age and frailty. Structured clinical data will be drawn from integrated care records (general practice, hospital, and social care) covering an ∼11m population supplemented with Natural Language Processing (NLP) of unstructured clinical text. AI systems will be trained to identify patterns of conditions, medications, tests, and clinical contacts preceding adverse events in order to identify individuals who might benefit most from an SMR. Discussion By implementing and evaluating an AI-augmented visualisation of care records in an existing prescribing audit and feedback system we will create a learning system for medicines optimisation, co-designed throughout with end-users and patients.

Glaucoma is a highly heritable disease that is a leading cause of blindness worldwide. Here, we identified heterozygous thrombospondin 1 (THBS1) missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma, a severe form of glaucoma affecting children. Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure. Extracellular matrix (ECM) proteins, especially fibronectin, which bind to THBS1, also accumulated within THBS1 deposits. These results show that missense variants altering THBS1 p.Arg1034 can cause elevated IOP through a mechanism involving impaired TM fluid outflow in association with accumulation of aggregated THBS1 in the ECM of juxtacanalicular meshwork with altered morphology.

Objectives Missing data is the most common data quality issue in electronic health records (EHRs). Missing data checks implemented in common analytical software are typically limited to counting the number of missing values in individual fields, but researchers and organisations also need to understand multifield missing data patterns to better inform advanced missing data strategies for which counts or numerical summaries are poorly suited. This study shows how set-based visualisation enables multifield missing data patterns to be discovered and investigated.Design Development and evaluation of interactive set visualisation techniques to find patterns of missing data and generate actionable insights. The visualisations comprised easily interpretable bar charts for sets, heatmaps for set intersections and histograms for distributions of both sets and intersections.Setting and participants Anonymised admitted patient care health records for National Health Service (NHS) hospitals and independent sector providers in England. The visualisation and data mining software was run over 16 million records and 86 fields in the dataset.Results The dataset contained 960 million missing values. Set visualisation bar charts showed how those values were distributed across the fields, including several fields that, unexpectedly, were not complete. Set intersection heatmaps revealed unexpected gaps in diagnosis, operation and date fields because diagnosis and operation fields were not filled up sequentially and some operations did not have corresponding dates. Information gain ratio and entropy calculations allowed us to identify the origin of each unexpected pattern, in terms of the values of other fields.Conclusions Our findings show how set visualisation reveals important insights about multifield missing data patterns in large EHR datasets. The study revealed both rare and widespread data quality issues that were previously unknown, and allowed a particular part of a specific hospital to be pinpointed as the origin of rare issues that NHS Digital did not know exist.

Objective Paediatric (childhood or congenital) cataract is an opacification of the normally clear lens of the eye and has a genetic basis in at least 18% of cases in Australia. This study aimed to replicate clinical gene screening to identify variants likely to be causative of disease in an Australian patient cohort.Methods and analysis Sixty-three reported isolated cataract genes were screened for rare coding variants in 37 Australian families using genome sequencing.Results Disease-causing variants were confirmed in eight families with variant classification as ‘likely pathogenic’. This included novel variants PITX3 p.(Ter303LeuextTer100), BFSP1 p.(Glu375GlyfsTer2), and GJA8 p.(Pro189Ser), as well as, previously described variants identified in genes GJA3, GJA8, CRYAA, BFSP1, PITX3, COL4A1 and HSF4. Additionally, eight variants of uncertain significance with evidence towards pathogenicity were identified in genes: GJA3, GJA8, LEMD2, PRX, CRYBB1, BFSP2, and MIP.Conclusion These findings expand the genotype–phenotype correlations of both pathogenic and benign variation in cataract-associated genes. They further emphasise the need to develop additional evidence such as functional assays and variant classification criteria specific to paediatric cataract genes to improve interpretation of variants and molecular diagnosis in patients.

Abstract Background Secondary use of data via integrated health information technology is fundamental to many healthcare policies and processes worldwide. However, repurposing data can be problematic and little research has been undertaken into the everyday practicalities of inter-system data sharing that helps explain why this is so, especially within (as opposed to between) organisations. In response, this article reports one of the most detailed empirical examinations undertaken to date of the work involved in repurposing healthcare data for National Clinical Audits. Methods Fifty-four semi-structured, qualitative interviews were carried out with staff in five English National Health Service hospitals about their audit work, including 20 staff involved substantively with audit data collection. In addition, ethnographic observations took place on wards, in ‘back offices’ and meetings (102 h). Findings were analysed thematically and synthesised in narratives. Results Although data were available within hospital applications for secondary use in some audit fields, which could, in theory, have been auto-populated, in practice staff regularly negotiated multiple, unintegrated systems to generate audit records. This work was complex and skilful, and involved cross-checking and double data entry, often using paper forms, to assure data quality and inform quality improvements. Conclusions If technology is to facilitate the secondary use of healthcare data, the skilled but largely hidden labour of those who collect and recontextualise those data must be recognised. Their detailed understandings of what it takes to produce high quality data in specific contexts should inform the further development of integrated systems within organisations.

Abstract\nPLAIN LANGUAGE SUMMARYHigher education leaders sometimes transgress norms of political involvement. Despite some norm-violating behaviors, legal consequences are sparse. Some argue that this is based on concerns over taxpayers impugning regulators’ motives as partisan. Public skepticism is warranted, especially as university officials engage in unlawful forms of political activism that can go unenforced. What explains citizens’ tolerance for norm-violating political activities within higher education institutions? Furthermore, what drives citizens to blame some leaders for engaging in legally precarious political behaviors while providing more latitude for others who act similarly? Drawing from research on citizen accountability as well as partisan cue-led attitudes, authors argue that tolerance for political involvement in higher education contexts is explained by an institutional leader’s partisanship and sectoral type, that is, private versus public institution. To test these claims, authors fielded a survey experiment drawing on a Lucid panel. Findings show evidence that a leader’s partisanship and the institution’s sectoral type influence individuals’ acceptance or rejection of a university president’s endorsement of a political candidate, dependent upon the respondent’s partisan characteristics. Findings also confirm the emerging politicization of higher educational spaces, highlighting the implications for understanding public perceptions of higher education leaders’ political involvement and the impact on the sector.College and university presidents may become involved in politics in ways that may not follow the law or fall in line with norms. Often leaders who cross the line are not punished or held accountable, potentially because punishment may look politically biased. While there are times when public doubt is justified, there are also times when college and university leaders push political agendas without consequences. Why do citizens sometimes ignore these transgressions? Why do citizens criticize some college and university leaders for political actions but not others? The answer might have to do with the leaders’ political affiliations and whether a private or public institution is connected to a scandal. To better understand this phenomenon, authors conducted a survey experiment with 1,403 participants. Results showed that citizens’ reactions to a university president supporting a political candidate are influenced by both the leader’s and the participant’s political affiliations as well as whether the institution is private or public. This research supports the idea that politics is becoming more prominent in higher education and that enforcement of laws is a difficult challenge. [ABSTRACT FROM AUTHOR]

Abstract Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed. Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.

In addition to other assessments, the EFSA bee guidance document (2013) requires the risk assessment of plant protection products on honey bee larvae. At the time the EFSA GD was finalized, no data on honey bee larvae were available due to absence of suitable methods. That is why in 2013 the European Crop Protection Association (ECPA) perfomed an impact analysis of the new EFSA risk assessment, using extrapolated endpoints derived from acute oral honey bee endpoints. Today, a number of honey bee larvae toxicity studies (138 active substances or formulated products) have been conducted according to the newly developed testing methods for single exposure (OECD TG 237) repeated exposure studies until the end of the larval development (D7/D8) and repeated exposure testing (OECD GD 239) until adult hatch (D22). These experimental data have been used to determine the ‘pass rates’ for 215 worst case uses (72 fungicide spray and solid uses, 91 herbicide spray uses, incl. 8 PGR uses and in total 52 insecticide spray and solid uses, incl. 2 nematicide and 3 IGR uses) according to the EFSA Bee GD and to compare with the original ECPA impact analysis. As standardized test methods for non- Apis bees larvae were not available, risk assessment according to EFSA for bumblebees and solitary bees based on the honey bee endpoint as surrogate corrected by a safety factor of 10. Morevoer, the sensitivity of the NOEDs at D8 and D22 in repeated exposure (D 22) studies were analysed. Overall, the toxicity of fungicides and herbicides to honey bee larvae (expressed as means and medians of NOED and LD50 values) was moderate to low, while insecticides as expected displayed stronger toxicity. Moreover, the endpoints for herbicides were on average a factor of 2 higher than fungicides which ranges within the normal biological variability (factor of 3). In addition, it is unclear, if the difference is related to a slightly higher toxicity or other factors like different physical chemical properties (e.g. lower solubility). For insecticides, toxicity was about 125 (based on medians) and 6 to 8 (based on means) times higher than herbicides. In the screening risk assessment according to EFSA Bee GD the majority of fungicide (83.3%) and herbicide (95.6%) uses passed the risk assessment for larvae; whereas, for all insecticide uses thr pass rate was about 29%. In the Tier 1 risk assessment, these pass rates slightly increased and were even higher in the ‘treated crop’ and ‘weed in the field’ scenarios for fungicide and herbicide uses, almost being 100%. Pass rates for insecticide uses did not improve very much and amounted to be about 42% for both scenarios. When basing the risk assessment of bumblebee and solitary bee larvae on 1/10th of the honey bee larval endpoint, the majority of active substances and their respective products will fail the screening (overall about 96%) and Tier 1 risk assessment (overall about 90%). Alternative risk assessment approaches proposed by ECPA (e.g. following the EPPO approach; ECPA Option 1 using refinement options and more representative assumptions) or comparing an assummed exposure concentration to the NOEC (ECPA Option 2) led to a slight increase (Option 1) or even no differences in the pass rates (Option 2a) compared to EFSA Tier 1 risk assessment. Thus both, the standard risk assessment according to the EFSA Bee GD as well as the alternative ECPA Option 1 and 2 result in a clear distinction between products with high toxicity (insecticides) vs. non-toxic products (herbicides and fungicides) for the honey bee risk assessment. The sensitivity analysis of repeated exposure studies according OECD GD 239 indicated that in most cases toxicity did not increase during the pupation period between D8 and D22. Thus, the larval growing period between D3 and D8 represents the most sensitive period of the pre-imaginal development.

Background: National audits aim to reduce variations in quality by stimulating quality improvement. However, varying provider engagement with audit data means that this is not being realised. Aim: The aim of the study was to develop and evaluate a quality dashboard (i.e. QualDash) to support clinical teams’ and managers’ use of national audit data. Design: The study was a realist evaluation and biography of artefacts study. Setting: The study involved five NHS acute trusts. Methods and results: In phase 1, we developed a theory of national audits through interviews. Data use was supported by data access, audit staff skilled to produce data visualisations, data timeliness and quality, and the importance of perceived metrics. Data were mainly used by clinical teams. Organisational-level staff questioned the legitimacy of national audits. In phase 2, QualDash was co-designed and the QualDash theory was developed. QualDash provides interactive customisable visualisations to enable the exploration of relationships between variables. Locating QualDash on site servers gave users control of data upload frequency. In phase 3, we developed an adoption strategy through focus groups. ‘Champions’, awareness-raising through e-bulletins and demonstrations, and quick reference tools were agreed. In phase 4, we tested the QualDash theory using a mixed-methods evaluation. Constraints on use were metric configurations that did not match users’ expectations, affecting champions’ willingness to promote QualDash, and limited computing resources. Easy customisability supported use. The greatest use was where data use was previously constrained. In these contexts, report preparation time was reduced and efforts to improve data quality were supported, although the interrupted time series analysis did not show improved data quality. Twenty-three questionnaires were returned, revealing positive perceptions of ease of use and usefulness. In phase 5, the feasibility of conducting a cluster randomised controlled trial of QualDash was assessed. Interviews were undertaken to understand how QualDash could be revised to support a region-wide Gold Command. Requirements included multiple real-time data sources and functionality to help to identify priorities. Conclusions: Audits seeking to widen engagement may find the following strategies beneficial: involving a range of professional groups in choosing metrics; real-time reporting; presenting ‘headline’ metrics important to organisational-level staff; using routinely collected clinical data to populate data fields; and dashboards that help staff to explore and report audit data. Those designing dashboards may find it beneficial to include the following: ‘at a glance’ visualisation of key metrics; visualisations configured in line with existing visualisations that teams use, with clear labelling; functionality that supports the creation of reports and presentations; the ability to explore relationships between variables and drill down to look at subgroups; and low requirements for computing resources. Organisations introducing a dashboard may find the following strategies beneficial: clinical champion to promote use; testing with real data by audit staff; establishing routines for integrating use into work practices; involving audit staff in adoption activities; and allowing customisation. Limitations: The COVID-19 pandemic stopped phase 4 data collection, limiting our ability to further test and refine the QualDash theory. Questionnaire results should be treated with caution because of the small, possibly biased, sample. Control sites for the interrupted time series analysis were not possible because of research and development delays. One intervention site did not submit data. Limited uptake meant that assessing the impact on more measures was not appropriate. Future work: The extent to which national audit dashboards are used and the strategies national audits use to encourage uptake, a realist review of the impact of dashboards, and rigorous evaluations of the impact of dashboards and the effectiveness of adoption strategies should be explored. Study registration: This study is registered as ISRCTN18289782. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 12. See the NIHR Journals Library website for further project information.

BackgroundDashboards can support data-driven quality improvements in health care. They visualize data in ways intended to ease cognitive load and support data comprehension, but how they are best integrated into working practices needs further investigation. ObjectiveThis paper reports the findings of a realist evaluation of a web-based quality dashboard (QualDash) developed to support the use of national audit data in quality improvement. MethodsQualDash was co-designed with data users and installed in 8 clinical services (3 pediatric intensive care units and 5 cardiology services) across 5 health care organizations (sites A-E) in England between July and December 2019. Champions were identified to support adoption. Data to evaluate QualDash were collected between July 2019 and August 2021 and consisted of 148.5 hours of observations including hospital wards and clinical governance meetings, log files that captured the extent of use of QualDash over 12 months, and a questionnaire designed to assess the dashboard’s perceived usefulness and ease of use. Guided by the principles of realist evaluation, data were analyzed to understand how, why, and in what circumstances QualDash supported the use of national audit data in quality improvement. ResultsThe observations revealed that variation across sites in the amount and type of resources available to support data use, alongside staff interactions with QualDash, shaped its use and impact. Sites resourced with skilled audit support staff and established reporting systems (sites A and C) continued to use existing processes to report data. A number of constraints influenced use of QualDash in these sites including that some dashboard metrics were not configured in line with user expectations and staff were not fully aware how QualDash could be used to facilitate their work. In less well-resourced services, QualDash automated parts of their reporting process, streamlining the work of audit support staff (site B), and, in some cases, highlighted issues with data completeness that the service worked to address (site E). Questionnaire responses received from 23 participants indicated that QualDash was perceived as useful and easy to use despite its variable use in practice. ConclusionsWeb-based dashboards have the potential to support data-driven improvement, providing access to visualizations that can help users address key questions about care quality. Findings from this study point to ways in which dashboard design might be improved to optimize use and impact in different contexts; this includes using data meaningful to stakeholders in the co-design process and actively engaging staff knowledgeable about current data use and routines in the scrutiny of the dashboard metrics and functions. In addition, consideration should be given to the processes of data collection and upload that underpin the quality of the data visualized and consequently its potential to stimulate quality improvement. International Registered Report Identifier (IRRID)RR2-10.1136/bmjopen-2019-033208

Introduction: Structured medication reviews (SMRs), introduced in the United Kingdom (UK) in 2020, aim to enhance shared decision-making in medication optimisation, particularly for patients with multimorbidity and polypharmacy. Despite its potential, there is limited empirical evidence on the implementation of SMRs, and the challenges faced in the process. This study is part of a larger DynAIRx (Artificial Intelligence for dynamic prescribing optimisation and care integration in multimorbidity) project which aims to introduce Artificial Intelligence (AI) to SMRs and develop machine learning models and visualisation tools for patients with multimorbidity. Here, we explore how SMRs are currently undertaken and what barriers are experienced by those involved in them. Methods: Qualitative focus groups and semi-structured interviews took place between 2022–2023. Six focus groups were conducted with doctors, pharmacists and clinical pharmacologists (n = 21), and three patient focus groups with patients with multimorbidity (n = 13). Five semi-structured interviews were held with 2 pharmacists, 1 trainee doctor, 1 policy-maker and 1 psychiatrist. Transcripts were analysed using thematic analysis. Results: Two key themes limiting the effectiveness of SMRs in clinical practice were identified: 'Medication Reviews in Practice' and 'Medication-related Challenges'. Participants noted limitations to the efficient and effectiveness of SMRs in practice including the scarcity of digital tools for identifying and prioritising patients for SMRs; organisational and patient-related challenges in inviting patients for SMRs and ensuring they attend; the time-intensive nature of SMRs, the need for multiple appointments and shared decision-making; the impact of the healthcare context on SMR delivery; poor communication and data sharing issues between primary and secondary care; difficulties in managing mental health medications and specific challenges associated with anticholinergic medication. Conclusion: SMRs are complex, time consuming and medication optimisation may require multiple follow-up appointments to enable a comprehensive review. There is a need for a prescribing support system to identify, prioritise and reduce the time needed to understand the patient journey when dealing with large volumes of disparate clinical information in electronic health records. However, monitoring the effects of medication optimisation changes with a feedback loop can be challenging to establish and maintain using current electronic health record systems. [ABSTRACT FROM AUTHOR]

Introduction Voretigene neparvovec-rzyl (Luxturna) was approved by the Australian Therapeutic Goods Administration on 4 August 2020 for the treatment of biallelic mutations in the RPE65 gene, a rare cause of congenital and adult-onset retinal dystrophy (predominantly Leber congenital amaurosis). Previous studies have shown that individuals who might participate in gene therapy trials overestimate clinical effect and underestimate risks. However, little is known about the perspectives of patients who may be offered approved gene therapy treatment for ocular conditions (as distinct from participating in clinical trials of gene therapy). The main objective of this study is to develop a tool to assess knowledge, attitudes and perceptions of approved and future genetic therapies among potential recipients of ocular gene therapy. In addition, we aim to assess the quality of life, attitudes towards clinical trials and vision-related quality of life among this cohort.Methods and analysis A new ‘Attitudes to Gene Therapy for the Eye’ tool will be developed following consultation with people with inherited retinal disease (IRD) and content matter experts. Australians with IRD or their guardians will be asked to complete an internet-based survey comprising existing quality of life and visual function instruments and items for the newly proposed tool. We expect to recruit 500 survey participants from patient support groups, the practices of Australian ophthalmologists who are specialists in IRD and Australian ophthalmic research institutions. Launch is anticipated early 2021. Responses will be analysed using item response theory methodology.Ethics and dissemination This study has received ethics approval from the University of Melbourne (#2057534). The results of the study will be published in a peer-reviewed journal and will be presented at relevant conferences. Organisations involved in recruitment, and the Patient Engagement Advisory committee will assist the research team with dissemination of the study outcomes.

Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed-some animals exhibited large fluctuations in viral load after cART cessation-the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.

Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis.