Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway.

The complement alternative pathway (AP) is implicated in numerous diseases affecting many organs, ranging from the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH), to the common blinding disease age-related macular degeneration (AMD). Critically, the AP amplifies any activating trigger driving a downstream inflammatory response; thus, components of the pathway have become targets for drugs of varying modality. Recent validation from clinical trials using drug modalities such as inhibitory antibodies has paved the path for gene targeting of the AP or downstream effectors. Gene targeting in the complement field currently focuses on supplementation or suppression of complement regulators in AMD and PNH, largely because the eye and liver are highly amenable to drug delivery through local (eye) or systemic (liver) routes. Targeting the liver could facilitate treatment of numerous diseases as this organ generates most of the systemic complement pool. This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA-targeting therapeutics ALN-CC5, ARO-C3, and IONIS-FB-LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years.

Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.

Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.

Comprehensive functional characterization of Complement factor I rare variant genotypes identified in the SCOPE Geographic Atrophy cohort.

Rare variants (RVs) in the gene encoding the regulatory enzyme complement factor I (CFI; FI) that reduce protein function or levels increase age-related macular degeneration (AMD) risk. A total of 3357 subjects underwent screening in the SCOPE natural history study for Geographic Atrophy (GA) secondary to AMD, including CFI sequencing followed by serum FI measurement. Eleven CFI RV genotypes that were challenging to categorise as Type I (low serum level) or Type II (normal serum level but reduced enzymatic function) were characterized in the context of pure FI protein in C3b and C4b fluid phase cleavage assays and a novel bead-based functional assay (BBFA) of surface-bound C3b cleavage. A further 4 variants predicted or previously characterized as benign, were analysed using the BBFA to add confidence to their classification. In all, 3 variants [W51S, C67R, I370T] resulted in low expression. A further 4 variants [P64L, R339Q, G527V and P528T] were identified as being highly deleterious with IC50s for C3b breakdown >1 log increased vs the WT protein, while 2 variants [K476E and R474Q] were ∼1 log reduced in function. Meanwhile, 6 variants [P50A, T203I, K441R, E548Q, P553S, S570T] had IC50s similar to wild-type (WT). Odds ratios (ORs) and BBFA IC50s were positively correlated (r=0.76, P<0.01), whilst ORs vs combined annotation dependent depletion (CADD) scores were not (r=0.43, P=0.16). Overall, 15 CFI RVs were functionally characterized which may aid future patient stratification approaches for complement-targeted therapies. Pure protein in vitro analysis remains the gold standard for determining the functional consequence of CFI RVs.

Parents' and nurses' perceptions and behaviours of family-centred care during periods of busyness.

PURPOSE: Busyness as a construct within modern healthcare is complex and multidimensional. To date, few studies have sought to explore how busyness influences family-centred care. This study explored the influence of busyness on the delivery of family-centred care for nurses and parents. DESIGN AND METHOD: Ethnography was selected as the research design. The study site was a metropolitan tertiary hospital inpatient paediatric unit in Sydney, Australia. Semi-structured interview and non-participant observation techniques were used for data collection. Ten paediatric nurses and 10 parents were interviewed and 40 h of non-participant observations were undertaken. The COREQ was used to report the study. RESULTS: The findings are presented as three key themes: (i) 'Supporting family-centred care' in which participants detail beliefs about the nurse-parent relationships and how despite busyness nurses sought out moments to engage with parents; (ii) 'Being present at the bedside' identified the challenges in optimising safety and how parents adapted their way of being and interacting on the unit; and (iii) 'The emotional cost of busyness' and how this influenced nurse-parent interactions, care delivery and family-centred care. CONCLUSIONS: The ethnography has given shape to social understandings of busyness, the complexities of paediatric nursing and family-centred care. The culture of care changed in moments of busyness and transformed parent and nursing roles, expectations and collaborative care that at time generated internal emotional conflict and tension. PRACTICE IMPLICATIONS: Given the increasing work demands across health systems, new agile ways of working need to ensure maintenance of a family-centred approach. Strategies need to be developed during periods of busyness to better support collaborative connections and the well-being of paediatric nurses and parents. At an organisational level, fostering a positive workplace culture that shares a vision for family-centred care and collaboration is essential. PATIENT OR PUBLIC CONTRIBUTION: Parents of sick children admitted to an acute paediatric inpatient ward were invited to be a participant in a single interview. Parents were aware of the study through ward advertisement and informal discussions with the researchers or senior clinical staff. Engagement with parents was important as healthcare delivery in paediatrics is focused on the delivery of family-centred care. To minimise the risk of child distress and separation anxiety, children were present during the parent interview. Whist children and young people voices were not silenced during the interview process, for this study the parent's voice remained the focus. While important, due to limited resources, parents were not involved in the design analysis or interpretation of the data or in the preparation of this manuscript. DATA SHARING: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19.

Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade is considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in COVID-19 to date, comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalized COVID-19 patients collected across the hospitalization period as part of the UK ISARIC4C (International Acute Respiratory and Emerging Infection Consortium) study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to healthy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples were associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention.

2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases.

OBJECTIVES: Fatigue is prevalent in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and recognised as one of the most challenging symptoms to manage. The existence of multiple factors associated with driving and maintaining fatigue, and the evidence about what improves fatigue has led to a multifaceted approach to its management. However, there are no recommendations for fatigue management in people with I-RMDs. This lack of guidance is challenging for those living with fatigue and health professionals delivering clinical care. Therefore, our aim was to develop EULAR recommendations for the management of fatigue in people with I-RMDs. METHODS: A multidisciplinary taskforce comprising 26 members from 14 European countries was convened, and two systematic reviews were conducted. The taskforce developed the recommendations based on the systematic review of evidence supplemented with taskforce members' experience of fatigue in I-RMDs. RESULTS: Four overarching principles (OAPs) and four recommendations were developed. OAPs include health professionals' awareness that fatigue encompasses multiple biological, psychological and social factors which should inform clinical care. Fatigue should be monitored and assessed, and people with I-RMDs should be offered management options. Recommendations include offering tailored physical activity and/or tailored psychoeducational interventions and/or, if clinically indicated, immunomodulatory treatment initiation or change. Patient-centred fatigue management should consider the individual's needs and preferences, their clinical disease activity, comorbidities and other psychosocial and contextual factors through shared decision-making. CONCLUSIONS: These 2023 EULAR recommendations provide consensus and up-to-date guidance on fatigue management in people with I-RMDs.

Barriers and enablers for safe medication administration in adult and neonatal intensive care units mapped to the behaviour change wheel.

BACKGROUND: Intensive care settings have high rates of medication administration errors. Medications are often administered by nurses and midwives using a specified process (the '5 rights'). Understanding where medication errors occur, the contributing factors and how best practice is delivered may assist in developing interventions to improve medication safety. AIMS: To identify medication administration errors and context specific barriers and enablers for best practice in an adult and a neonatal intensive care unit. Secondary aims were to identify intervention functions (through the Behaviour Change Wheel). STUDY DESIGN: A dual methods exploratory descriptive study was conducted (May to June 2021) in a mixed 56-bedded adult intensive care unit and a 6-bedded neonatal intensive care unit in Sydney, Australia. Incident monitoring data were examined. Direct semi-covert observational medication administration audits using the 5 rights (n = 39) were conducted. Brief interviews with patients, parents and nurses were conducted. Data were mapped to the Behaviour Change Wheel. RESULTS: No medication administration incidents were recorded. Audits (n = 3) for the neonatal intensive care unit revealed no areas for improvement. Adult intensive care unit nurses (n = 36) performed checks for the right medication 35 times (97%) and patient identity 25 times (69%). Sixteen administrations (44%) were interrupted. Four themes were synthesized from the interview data: Trust in the nursing profession; Availability of policies and procedures; Adherence to the '5 rights' and departmental culture; and Adequate staffing. The interventional functions most likely to bring about behaviour change were environmental restructuring, enablement, restrictions, education, persuasion and modelling. CONCLUSIONS: This study reveals insights about the medication administration practices of nurses in intensive care. Although there were areas for improvement there was widespread awareness among nurses regarding their responsibilities to safely administer medications. Interview data indicated high levels of trust among patients and parents in the nurses. RELEVANCE TO CLINICAL PRACTICE: This novel study indicated that nurses in intensive care are aware of their responsibilities to safely administer medications. Mapping of contextual data to the Behaviour Change Wheel resulted in the identification of Intervention functions most likely to change medication administration practices in the adult intensive care setting that is environmental restructuring, enablement, restrictions, education, persuasion and modelling.

DetectIS: a pipeline to rapidly detect exogenous DNA integration sites using DNA or RNA paired-end sequencing data.

MOTIVATION: Recombinant DNA technology is widely used for different applications in biology, medicine and bio-technology. Viral transduction and plasmid transfection are among the most frequently used techniques to generate recombinant cell lines. Many of these methods result in the random integration of the plasmid into the host genome. Rapid identification of the integration sites is highly desirable in order to characterize these engineered cell lines. RESULTS: We developed detectIS: a pipeline specifically designed to identify genomic integration sites of exogenous DNA, either a plasmid containing one or more transgenes or a virus. The pipeline is based on a Nextflow workflow combined with a Singularity image containing all the necessary software, ensuring high reproducibility and scalability of the analysis. We tested it on simulated datasets and RNA-seq data from a human sample infected with Hepatitis B virus. Comparisons with other state of the art tools show that our method can identify the integration site in different recombinant cell lines, with accurate results, lower computational demand and shorter execution times. AVAILABILITY AND IMPLEMENTATION: The Nextflow workflow, the Singularity image and a test dataset are available at https://github.com/AstraZeneca/detectIS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Visualization for epidemiological modelling: challenges, solutions, reflections and recommendations.

We report on an ongoing collaboration between epidemiological modellers and visualization researchers by documenting and reflecting upon knowledge constructs-a series of ideas, approaches and methods taken from existing visualization research and practice-deployed and developed to support modelling of the COVID-19 pandemic. Structured independent commentary on these efforts is synthesized through iterative reflection to develop: evidence of the effectiveness and value of visualization in this context; open problems upon which the research communities may focus; guidance for future activity of this type and recommendations to safeguard the achievements and promote, advance, secure and prepare for future collaborations of this kind. In describing and comparing a series of related projects that were undertaken in unprecedented conditions, our hope is that this unique report, and its rich interactive supplementary materials, will guide the scientific community in embracing visualization in its observation, analysis and modelling of data as well as in disseminating findings. Equally we hope to encourage the visualization community to engage with impactful science in addressing its emerging data challenges. If we are successful, this showcase of activity may stimulate mutually beneficial engagement between communities with complementary expertise to address problems of significance in epidemiology and beyond. See https://ramp-vis.github.io/RAMPVIS-PhilTransA-Supplement/. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

FAIR data pipeline: provenance-driven data management for traceable scientific workflows.

Modern epidemiological analyses to understand and combat the spread of disease depend critically on access to, and use of, data. Rapidly evolving data, such as data streams changing during a disease outbreak, are particularly challenging. Data management is further complicated by data being imprecisely identified when used. Public trust in policy decisions resulting from such analyses is easily damaged and is often low, with cynicism arising where claims of 'following the science' are made without accompanying evidence. Tracing the provenance of such decisions back through open software to primary data would clarify this evidence, enhancing the transparency of the decision-making process. Here, we demonstrate a Findable, Accessible, Interoperable and Reusable (FAIR) data pipeline. Although developed during the COVID-19 pandemic, it allows easy annotation of any data as they are consumed by analyses, or conversely traces the provenance of scientific outputs back through the analytical or modelling source code to primary data. Such a tool provides a mechanism for the public, and fellow scientists, to better assess scientific evidence by inspecting its provenance, while allowing scientists to support policymakers in openly justifying their decisions. We believe that such tools should be promoted for use across all areas of policy-facing research. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Targeted CHO cell engineering approaches can reduce HCP-related enzymatic degradation and improve mAb product quality.

Host cell proteins (HCP) that co-purify with biologics produced in Chinese hamster ovary cells have been shown to impact product quality through proteolytic degradation of recombinant proteins, leading to potential product losses. Several problematic HCPs can remain in the final product even after extensive purification. Each recombinant cell line has a unique HCP profile that can be determined by numerous upstream and downstream factors, including clonal variation and the protein sequence of the expressed therapeutic molecule. Here, we worked with recombinant cell lines with high levels of copurifying HCPs, and showed that in those cell lines even modest downregulation (≤50%) of the difficult to remove HCP Cathepsin D, through stable short hairpin RNA interference or monoallelic deletion of the target gene using CRISPR-Cas9, is sufficient to greatly reduce levels of co-purifying HCP as measured by high throughput targeted LC-MS. This reduction led to improved product quality by reducing fragmentation of the drug product in forced degradation studies to negligible levels. We also show the potential of cell engineering to target other undesired HCPs and relieve the burden on downstream purification.

Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy.

BACKGROUND: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants. RESULTS: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10-8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10-8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. CONCLUSIONS: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

Antimicrobial use in UK long-term care facilities: results of a point prevalence survey.

BACKGROUND: The majority of people in long-term care facilities (LTCFs) are aged 65 years and older, and most of their care needs are provided by the LTCF staff. Provision of healthcare services for residents in LTCFs is variable and can result in disjointed care between carers and NHS healthcare professionals. OBJECTIVES: Our aim was to understand the use of antibiotics in LTCFs across the UK and to identify potential gaps in knowledge and support for carers and residents when using antibiotics, in order to determine how community pharmacy teams can provide additional support. METHODS: A point prevalence survey (PPS) was conducted by community pharmacists (n = 57) when they carried out visits to LTCFs across the UK between 13 November and 12 December 2017. Anonymized data were recorded electronically by the individual pharmacists. RESULTS: Data were analysed for 17909 residents in 644 LTCFs across the UK. The mean proportion of residents on antibiotics on the day of the visit was as follows: 6.3% England (536 LTCFs), 7.6% Northern Ireland (35 LTCFs), 8.6% Wales (10 LTCFs) and 9.6% Scotland (63 LTCFs). The percentage of antibiotics prescribed for prophylactic use was 25.3%. Antibiotic-related training was reported as being available for staff in 6.8% of LTCFs and 7.1% of LTCFs reported use of a catheter passport scheme. Pharmacists conducting the PPS intervened during the survey for 9.5% of antibiotic prescription events; 53.4% of interventions were for clinical reasons and 32.2% were for administration reasons. CONCLUSIONS: This survey identified high prophylactic use of antibiotics. There are opportunities for community pharmacy teams to improve antimicrobial stewardship in LTCF settings, including workforce education.

Characterizing a pH-switch anti-C5 antibody as a tool for human and mouse complement C5 purification and cross-species inhibition of classical and reactive lysis.

C5 plays a major role in complement activation; C5 convertase cleaves C5 into the pro-inflammatory C5a, and C5b, the nidus for the formation of the lytic membrane attack complex. C5 is a major target for anti-complement drugs, necessitating better methods for the study of C5 function. Purification of C5 is complicated; classical methods involve precipitation or pH shifts that result in functional loss and low yield. We here present a method for C5 purification using a novel anti-C5 monoclonal antibody (mAb); RO7112689 (C5i mAb, SKY59), pH-switch engineered to induce antibody-antigen dissociation in the acidic endosome (~ pH 5·5). RO7112689 was bound on an affinity column; applied serum was completely depleted of C5. Elution at pH 5 produced fully active C5 at 98% yield. The mAb also bound C5b in the C5b6 complex, preventing C5b6 binding to target membranes and enabling purification of C5b6 from activated serum. RO7112689 inhibited C5 in mouse serum and efficiently purified mouse C5. Used as capture, RO7112689 produced sensitive and specific assays for human and mouse C5. This novel antibody enables efficient production of intact, fully active, pure human and mouse C5, and quantification of C5 in these species. The demonstration that RO7112689 binds C5b6 adds an additional mechanism of membrane attack complex inhibition by this mAb.

Rituximab induction therapy for de novo ANCA associated vasculitis in pregnancy: a case report.

BACKGROUND: The diagnosis of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is rare in pregnancy but potentially life threatening. There are no randomized controlled trials to guide the management of AAV in pregnancy and fetal safety data remains limited. Rituximab administration, a treatment for AAV, has been reported in pregnant women with reassuring fetal outcomes in the oncology and rheumatology literature; however, no published reports describe its use in AAV. CASE PRESENTATION: We present a case of de novo myeloperoxidase positive (MPO) AAV diagnosed at 22 weeks gestation. Clinical presentation included elevated serum creatinine at 177 µmol/L, hematuria and nephrotic range proteinuria along with high-titre MPO. Diagnosis was confirmed by renal biopsy. Patient was treated with methylprednisolone IV followed by oral prednisone 70 mg daily and Rituximab 650 mg IV weekly for four weeks followed by azathioprine maintenance therapy and prednisone taper. Delivery occurred at 29 weeks gestation via cesarean section for maternal neurologic symptoms concerning for preeclampsia. Maternal and fetal CD + 19 cells were depleted at time of delivery with associated fetal lymphopenia in the absence of infection or other complications related to Rituximab use. The patient experienced a reduction in proteinuria and inflammatory markers following Rituximab therapy; however, serum creatinine increased to 375 µmol/L by 11 weeks post-partum. CONCLUSION: We report the first use, to our knowledge, of Rituximab with corticosteroids for induction therapy of AAV in pregnancy.

Sustainability in Health care by Allocating Resources Effectively (SHARE) 11: reporting outcomes of an evidence-driven approach to disinvestment in a local healthcare setting.

BACKGROUND: This is the final paper in a thematic series reporting a program of Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. The SHARE Program was established to explore a systematic, integrated, evidence-based organisation-wide approach to disinvestment in a large Australian health service network. This paper summarises the findings, discusses the contribution of the SHARE Program to the body of knowledge and understanding of disinvestment in the local healthcare setting, and considers implications for policy, practice and research. DISCUSSION: The SHARE program was conducted in three phases. Phase One was undertaken to understand concepts and practices related to disinvestment and the implications for a local health service and, based on this information, to identify potential settings and methods for decision-making about disinvestment. The aim of Phase Two was to implement and evaluate the proposed methods to determine which were sustainable, effective and appropriate in a local health service. A review of the current literature incorporating the SHARE findings was conducted in Phase Three to contribute to the understanding of systematic approaches to disinvestment in the local healthcare context. SHARE differed from many other published examples of disinvestment in several ways: by seeking to identify and implement disinvestment opportunities within organisational infrastructure rather than as standalone projects; considering disinvestment in the context of all resource allocation decisions rather than in isolation; including allocation of non-monetary resources as well as financial decisions; and focusing on effective use of limited resources to optimise healthcare outcomes. CONCLUSION: The SHARE findings provide a rich source of new information about local health service decision-making, in a level of detail not previously reported, to inform others in similar situations. Multiple innovations related to disinvestment were found to be acceptable and feasible in the local setting. Factors influencing decision-making, implementation processes and final outcomes were identified; and methods for further exploration, or avoidance, in attempting disinvestment in this context are proposed based on these findings. The settings, frameworks, models, methods and tools arising from the SHARE findings have potential to enhance health care and patient outcomes.

Sustainability in Health care by Allocating Resources Effectively (SHARE) 8: developing, implementing and evaluating an evidence dissemination service in a local healthcare setting.

BACKGROUND: This is the eighth in a series of papers reporting Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. The SHARE Program was a systematic, integrated, evidence-based program for disinvestment within a large Australian health service. One of the aims was to explore methods to deliver existing high quality synthesised evidence directly to decision-makers to drive decision-making proactively. An Evidence Dissemination Service (EDS) was proposed. While this was conceived as a method to identify disinvestment opportunities, it became clear that it could also be a way to review all practices for consistency with current evidence. This paper reports the development, implementation and evaluation of two models of an in-house EDS. METHODS: Frameworks for development of complex interventions, implementation of evidence-based change, and evaluation and explication of processes and outcomes were adapted and/or applied. Mixed methods including a literature review, surveys, interviews, workshops, audits, document analysis and action research were used to capture barriers, enablers and local needs; identify effective strategies; develop and refine proposals; ascertain feedback and measure outcomes. RESULTS: Methods to identify, capture, classify, store, repackage, disseminate and facilitate use of synthesised research evidence were investigated. In Model 1, emails containing links to multiple publications were sent to all self-selected participants who were asked to determine whether they were the relevant decision-maker for any of the topics presented, whether change was required, and to take the relevant action. This voluntary framework did not achieve the aim of ensuring practice was consistent with current evidence. In Model 2, the need for change was established prior to dissemination, then a summary of the evidence was sent to the decision-maker responsible for practice in the relevant area who was required to take appropriate action and report the outcome. This mandatory governance framework was successful. The factors influencing decisions, processes and outcomes were identified. CONCLUSION: An in-house EDS holds promise as a method of identifying disinvestment opportunities and/or reviewing local practice for consistency with current evidence. The resource-intensive nature of delivery of the EDS is a potential barrier. The findings from this study will inform further exploration.

An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice.

Activation of complement is a key determinant of neuropathology and disability after traumatic brain injury (TBI), and inhibition is neuroprotective. However, systemic complement is essential to fight infections, a critical complication of TBI. We describe a targeted complement inhibitor, comprising complement receptor of the Ig superfamily (CRIg) fused with complement regulator CD59a, designed to inhibit membrane attack complex (MAC) assembly at sites of C3b/iC3b deposition. CRIg and CD59a were linked via the IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited MAC formation and prevented complement-mediated lysis in vitro. CD59-2a-CRIg dimer bound C3b-coated surfaces with submicromolar affinity (KD). In experimental TBI, CD59-2a-CRIg administered posttrauma homed to sites of injury and significantly reduced MAC deposition, microglial accumulation, mitochondrial stress, and axonal damage and enhanced neurologic recovery compared with placebo controls. CD59-2a-CRIg inhibited MAC-induced inflammasome activation and IL-1ß production in microglia. Given the important anti-infection roles of complement opsonization, site-targeted inhibition of MAC should be considered to promote recovery postneurotrauma.