A small molecule chaperone rescues keratin-8 mediated trafficking of misfolded podocin to correct genetic Nephrotic Syndrome.

Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum. Here, we provide evidence that podocin R138Q (but not wild-type podocin) complexes with the intermediate filament protein keratin 8 (K8) thereby preventing its correct trafficking to the plasma membrane. We have also identified a small molecule (c407), a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator protein defect, that interrupts this complex and rescues mutant protein mistrafficking. This results in both the correct localization of podocin at the plasma membrane and functional rescue in both human patient R138Q mutant podocyte cell lines, and in a mouse inducible knock-in model of the R138Q mutation. Importantly, complete rescue of proteinuria and histological changes was seen when c407 was administered both via osmotic minipumps or delivered orally prior to induction of disease or crucially via osmotic minipump two weeks after disease induction. Thus, our data constitute a therapeutic option for patients with NS bearing a podocin mutation, with implications for other misfolding protein disorders. Further studies are necessary to confirm our findings.

Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.

BACKGROUND: Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined. METHODS: In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized to investigate the impact of endothelial cell surface (i.e., endothelial glycocalyx) heparan sulphate loss on microvascular barrier function. Endothelial glycocalyx changes were measured using fluorescence microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2D, db/db) mouse model was used to determine the therapeutic potential of preventing heparan sulphate damage using treatment with a novel heparanase inhibitor, OVZ/HS-1638. Endothelial glycocalyx changes were measured as above, and microvascular barrier function assessed by albumin extravasation in the eye and a glomerular permeability assay in the kidney. RESULTS: In both models of heparan sulphate depletion, endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permeability was increased. T2D mice treated with OVZ/HS-1638 had improved endothelial glycocalyx measurements compared to vehicle treated T2D mice and were simultaneously protected from microvascular permeability changes associated with DR and DKD. CONCLUSION: We demonstrate that endothelial glycocalyx heparan sulphate plays a common mechanistic role in microvascular barrier function in the eye and kidney. Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor OVZ/HS-1638, effectively prevents microvascular permeability changes associated with DR and DKD, demonstrating a novel systemic approach to address diabetic microvascular complications.

Codesign of Lynch ChoicesTM : Using implementation science to create a clinically deliverable patient decision support website to transform cancer genetics care pathways.

BACKGROUND: Resources including Patient Decision Aids (PtDA) are useful and valued by patients and clinicians to provide information and complement shared decision-making. Despite their promise, few PtDA exist for patients with genetic cancer susceptibility facing difficult decisions about risk management. We aimed to fill this gap, partnering with patients to codesign Lynch ChoicesTM , a PtDA website for families with Lynch Syndrome. In addition to a Patient Reference Panel, we purposively invited an international stakeholder panel including charities, public bodies, clinical and academic experts. Implementation strategies and frameworks were employed to optimise translation of research findings to improve care. METHODS: Patient/stakeholder suggestions were incorporated in a transparent Table of Changes and prioritised using the Person-Based Approach throughout planning and codesign of Lynch ChoicesTM . An interactive stakeholder meeting was convened to identify barriers and facilitators to clinical implementation of the PtDA. RESULTS: Patient and stakeholder partnerships drove the direction of the research throughout codesign, resulting in several iterative refinements to the PtDA prior to roll out including the addition of illustrations/videos, clearer presentation of cancer risks and increased accessibility for lower literacy. Barriers and facilitators identified from stakeholders were used to create an implementation process map. CONCLUSIONS: Creating an effective, engaging PtDA is not enough. Systematic uptake in real world clinical practice, with its resource limitations, is needed to optimise benefit to patients and clinicians. Assessment of speed and breadth of dissemination and usage will be collected to further evidence the benefit of embedding implementation science methods from the outset to translate research findings into clinical practice.

'I Live With Lynch. Cancer Worry Ebbs Into the Background, Then Something Brings It to the Fore.' A Qualitative Interview Study Exploring How Lynch Syndrome Carriers Make Sense of Their Cancer Risks and Implications to Support Decision Making.

BACKGROUND: Lynch syndrome carriers ('carriers') are presented with complex, emotionally laden choices regarding management of increased genetic cancer risks. Decision aids encourage active involvement in values-based health decisions. This paper aimed to address the research question: How do Lynch syndrome carriers make sense of their chances of developing cancer, and what are the implications for providing support with decision making about genetic cancer risk management? METHODS: Adult carriers were recruited through a genetics service or involvement with Lynch Syndrome UK. Semi-structured interviews explored lived experiences of carriers' access to care with a focus on decision support. Themes were constructed using framework analysis. These were developed into a conceptual model with recommendations for codevelopment of improved information and support including a tailored decision aid to complement integrated healthcare. RESULTS: Twenty participants included 12 women and eight men, half with a history of cancer. Six overarching themes were: (1) finding balance with Lynch; (2) living 'on higher alert'; (3) managing uncertainty: 'I've thought about it a lot'; (4) burden of responsibility: 'It's on me'; (5) access to joined-up care and support: 'There's something missing'; and (6) influence/pressure from others. CONCLUSIONS: This qualitative interview study provided in-depth insights from Lynch syndrome carriers about their lived experiences, informed by their values. Recommendations to empower carriers to make sense of genetic cancer risks and support decisions included accessible, trusted information, educated healthcare professionals, shared decision making, and joined-up integrated care pathways complemented by tailored decision aids.

The unique structural and functional characteristics of glomerular endothelial cell fenestrations and their potential as a therapeutic target in kidney disease.

Glomerular endothelial cell (GEnC) fenestrations are a critical component of the glomerular filtration barrier. Their unique nondiaphragmed structure is key to their function in glomerular hydraulic permeability, and their aberration in disease can contribute to loss of glomerular filtration function. This review provides a comprehensive update of current understanding of the regulation and biogenesis of fenestrae. We consider diseases in which GEnC fenestration loss is recognized or may play a role and discuss methods with potential to facilitate the study of these critical structures. Literature is drawn from GEnCs as well as other fenestrated cell types such as liver sinusoidal endothelial cells that most closely parallel GEnCs.

Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events.

About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS. Here, the role of PAR-1 was studied in human podocytes in vitro, and using a mouse model with developmental or inducible expression of podocyte-specific constitutively active PAR-1, and using biopsies from patients with nephrotic syndrome. In vitro podocyte PAR-1 activation caused a pro-migratory phenotype with phosphorylation of the kinase JNK, VASP protein and docking protein Paxillin. This signaling was mirrored in podocytes exposed to patient relapse-derived NS plasma and in patient disease biopsies. Both developmental and inducible activation of transgenic PAR-1 (NPHS2 Cre PAR-1Active+/-) caused early severe nephrotic syndrome, FSGS, kidney failure and, in the developmental model, premature death. We found that the non-selective cation channel protein TRPC6 could be a key modulator of PAR-1 signaling and TRPC6 knockout in our mouse model significantly improved proteinuria and extended lifespan. Thus, our work implicates podocyte PAR-1 activation as a key initiator of human NS circulating factor and that the PAR-1 signaling effects were partly modulated through TRPC6.

Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations.

BACKGROUND: Glomerular endothelial cell (GEnC) fenestrations are recognized as an essential component of the glomerular filtration barrier, yet little is known about how they are regulated and their role in disease. METHODS: We comprehensively characterized GEnC fenestral and functional renal filtration changes including measurement of glomerular Kf and GFR in diabetic mice (BTBR ob-/ob- ). We also examined and compared human samples. We evaluated Eps homology domain protein-3 (EHD3) and its association with GEnC fenestrations in diabetes in disease samples and further explored its role as a potential regulator of fenestrations in an in vitro model of fenestration formation using b.End5 cells. RESULTS: Loss of GEnC fenestration density was associated with decreased filtration function in diabetic nephropathy. We identified increased diaphragmed fenestrations in diabetes, which are posited to increase resistance to filtration and further contribute to decreased GFR. We identified decreased glomerular EHD3 expression in diabetes, which was significantly correlated with decreased fenestration density. Reduced fenestrations in EHD3 knockdown b.End5 cells in vitro further suggested a mechanistic role for EHD3 in fenestration formation. CONCLUSIONS: This study demonstrates the critical role of GEnC fenestrations in renal filtration function and suggests EHD3 may be a key regulator, loss of which may contribute to declining glomerular filtration function through aberrant GEnC fenestration regulation. This points to EHD3 as a novel therapeutic target to restore filtration function in disease.

Projected health and economic outcomes of extending public funding of pharmacy services to include administration of Pneu23 and Td/Tdap immunizations by pharmacy practitioners in New Brunswick.

Background: Although legislation permits New Brunswick pharmacy professionals to administer a wide range of immunizations, public funding for these services is currently limited to immunizations against influenza and COVID-19 and was recently extended to include pneumococcal immunization (Pneu23) in individuals aged 65 years or older. We used administrative data to project health and economic outcomes associated with the current Pneu23 program and with extension of public funding to include: 1) younger adults aged 19 years or older in the Pneu23 program, and 2) tetanus boosters (Td/Tdap). Methods: Two model scenarios were compared: a Physician-Only model in which physicians remain the only practitioners to administer publicly funded Pneu23 and Td/Tdap, and a Blended model in which this service is also provided by pharmacy professionals. Immunization rates by practitioner type were projected based on physician billing data accessed via the New Brunswick Institute for Research, Data and Training in conjunction with trends observed with influenza immunization by pharmacists. These projections were used along with published data to estimate health and economic outcomes under each model. Results: Public funding of Pneu23 (65+), Pneu23 (19+) and Td/Tdap (19+) administration by pharmacy professionals is projected to yield increased immunization rates and physician time savings compared with the Physician-Only model. Public funding of Pneu23 and Td/Tdap administration by pharmacy professionals in those aged ≥19 years would result in cost savings, owing primarily to productivity losses avoided in the working age population. Discussion: Increased immunization rates, physician time savings and cost savings may be realized if public funding were extended to include administration of Pneu23 in younger adults and Td/Tdap, by pharmacy practitioners.

Endothelial glycocalyx is damaged in diabetic cardiomyopathy: angiopoietin 1 restores glycocalyx and improves diastolic function in mice.

AIMS/HYPOTHESIS: Diabetic cardiomyopathy (DCM) is a serious and under-recognised complication of diabetes. The first sign is diastolic dysfunction, which progresses to heart failure. The pathophysiology of DCM is incompletely understood but microcirculatory changes are important. Endothelial glycocalyx (eGlx) plays multiple vital roles in the microcirculation, including in the regulation of vascular permeability, and is compromised in diabetes but has not previously been studied in the coronary microcirculation in diabetes. We hypothesised that eGlx damage in the coronary microcirculation contributes to increased microvascular permeability and hence to cardiac dysfunction. METHODS: We investigated eGlx damage and cardiomyopathy in mouse models of type 1 (streptozotocin-induced) and type 2 (db/db) diabetes. Cardiac dysfunction was determined by echocardiography. We obtained eGlx depth and coverage by transmission electron microscopy (TEM) on mouse hearts perfusion-fixed with glutaraldehyde and Alcian Blue. Perivascular oedema was assessed from TEM images by measuring the perivascular space area. Lectin-based fluorescence was developed to study eGlx in paraformaldehyde-fixed mouse and human tissues. The eGlx of human conditionally immortalised coronary microvascular endothelial cells (CMVECs) in culture was removed with eGlx-degrading enzymes before measurement of protein passage across the cell monolayer. The mechanism of eGlx damage in the diabetic heart was investigated by quantitative reverse transcription-PCR array and matrix metalloproteinase (MMP) activity assay. To directly demonstrate that eGlx damage disturbs cardiac function, isolated rat hearts were treated with enzymes in a Langendorff preparation. Angiopoietin 1 (Ang1) is known to restore eGlx and so was used to investigate whether eGlx restoration reverses diastolic dysfunction in mice with type 1 diabetes. RESULTS: In a mouse model of type 1 diabetes, diastolic dysfunction (confirmed by echocardiography) was associated with loss of eGlx from CMVECs and the development of perivascular oedema, suggesting increased microvascular permeability. We confirmed in vitro that eGlx removal increases CMVEC monolayer permeability. We identified increased MMP activity as a potential mechanism of eGlx damage and we observed loss of syndecan 4 consistent with MMP activity. In a mouse model of type 2 diabetes we found a similar loss of eGlx preceding the development of diastolic dysfunction. We used isolated rat hearts to demonstrate that eGlx damage (induced by enzymes) is sufficient to disturb cardiac function. Ang1 restored eGlx and this was associated with reduced perivascular oedema and amelioration of the diastolic dysfunction seen in mice with type 1 diabetes. CONCLUSIONS/INTERPRETATION: The association of CMVEC glycocalyx damage with diastolic dysfunction in two diabetes models suggests that it may play a pathophysiological role and the enzyme studies confirm that eGlx damage is sufficient to impair cardiac function. Ang1 rapidly restores the CMVEC glycocalyx and improves diastolic function. Our work identifies CMVEC glycocalyx damage as a potential contributor to the development of DCM and therefore as a therapeutic target.

Modifiable pre-treatment factors are associated with quality of life in women with gynaecological cancers at diagnosis and one year later: Results from the HORIZONS UK national cohort study.

OBJECTIVE: Personalised care requires the identification of modifiable risk factors so that interventions can be implemented rapidly following a gynaecological cancer diagnosis. Our objective was to determine what pre-treatment factors are associated with quality of life (QOL) at baseline (pre-treatment) and 12 months. METHODS: 1222 women with a confirmed diagnosis of endometrial, ovarian, cervical or vulvar cancer from 82 UK NHS hospitals agreed to complete questionnaires at baseline, three and 12 months. Questionnaires included measures of QOL, health, lifestyle, support and self-management. The primary outcome measure was QOL as measured by Quality of Life in Adult Cancer Survivors (QLACS). Sites provided clinical data at baseline, six and 12 months. Linear regression models were constructed to examine the association between baseline characteristics and QOL outcomes. RESULTS: QOL declined between baseline and 3 months, followed by an improvement at 12 months. Baseline (pre-treatment) factors associated with worse QOL at both baseline and 12 months were depression, anxiety, living in a more deprived area and comorbidities which limit daily activities, whereas higher self-efficacy and age of 50+ years were associated with better QOL. CONCLUSIONS: Depression, anxiety and self-efficacy are modifiable risk factors that can impact on QOL. Screening for these, and assessment of whether comorbidities limit daily activities, should be incorporated in a holistic needs assessment and interventions to improve self-efficacy should be made available. Care can then be personalised from the outset to enable all women with a gynaecological cancer the opportunity to have the best QOL.

'Why would we not want to keep everybody safe?' The views of family members of people who use drugs on the implementation of drug consumption rooms in Scotland.

BACKGROUND: People who use drugs in Scotland are currently experiencing disproportionately high rates of drug-related deaths. Drug consumption rooms (DCRs) are harm reduction services that offer a safe, hygienic environment where pre-obtained drugs can be consumed under supervision. The aim of this research was to explore family member perspectives on DCR implementation in Scotland in order to inform national policy. METHODS: Scotland-based family members of people who were currently or formerly using drugs were invited to take part in semi-structured interviews to share views on DCRs. An inclusive approach to 'family' was taken, and family members were recruited via local and national networks. A convenience sample of 13 family members were recruited and interviews conducted, audio-recorded, transcribed, and analysed thematically using the Structured Framework Technique. RESULTS: Family members demonstrated varying levels of understanding regarding the existence, role, and function of DCRs. While some expressed concern that DCRs would not prevent continued drug use, all participants were in favour of DCR implementation due to a belief that DCRs could reduce harm, including saving lives, and facilitate future recovery from drug use. Participants highlighted challenges faced by people who use drugs in accessing treatment/services that could meet their needs. They identified that accessible and welcoming DCRs led by trusting and non-judgemental staff could help to meet unmet needs, including signposting to other services. Family members viewed DCRs as safe environments and highlighted how the existence of DCRs could reduce the constant worry that they had of risk of harm to their loved ones. Finally, family members emphasised the challenge of stigma associated with drug use. They believed that introduction of DCRs would help to reduce stigma and provide a signal that people who use drugs deserve safety and care. CONCLUSIONS: Reporting the experience and views of family members makes a novel and valuable contribution to ongoing public debates surrounding DCRs. Their views can be used to inform the implementation of DCRs in Scotland but also relate well to the development of wider responses to drug-related harm and reduction of stigma experienced by people who use drugs in Scotland and beyond.

Assessing the feasibility, acceptability and accessibility of a peer-delivered intervention to reduce harm and improve the well-being of people who experience homelessness with problem substance use: the SHARPS study.

BACKGROUND: For people experiencing homelessness and problem substance use, access to appropriate services can be challenging. There is evidence that the development of trusting relationships with non-judgemental staff can facilitate service engagement. Peer-delivered approaches show particular promise, but the evidence base is still developing. METHODS: The study used mixed methods to assess the feasibility, acceptability and accessibility of a peer-delivered, relational intervention to reduce harms and improve health/well-being, quality of life and social functioning, for people experiencing homelessness and problem substance use. Four Peer Navigators were employed to support individuals (n = 68 total, intervention participants). They were based in outreach services and hostels in Scotland and England. Qualitative interviews were conducted with intervention participants, Peer Navigators and staff in services, and observations were conducted in all settings. Quantitative outcomes relating to participants' substance use, physical and mental health, and quality of the Peer Navigator relationship, were measured via a 'holistic health check' with six questionnaires completed at two time-points. RESULTS: The intervention was found to be acceptable to, and feasible and accessible for, participants, Peer Navigators, and service staff. Participants reported improvements to service engagement, and feeling more equipped to access services independently. The lived experience of the Peer Navigators was highlighted as particularly helpful, enabling trusting, authentic, and meaningful relationships to be developed. Some challenges were experienced in relation to the 'fit' of the intervention within some settings. Among participants there were reductions in drug use and risky injecting practices. There were increases in the number of participants receiving opioid substitution therapy. Overall, the intervention was positively received, with collective recognition that the intervention was unique and highly valuable. While most of the measures chosen for the holistic health check were found to be suitable for this population, they should be streamlined to avoid duplication and participant burden. CONCLUSIONS: The study established that a peer-delivered, relational harm reduction intervention is acceptable to, and feasible and accessible for, people experiencing homelessness and problem substance use. While the study was not outcomes-focused, participants did experience a range of positive outcomes. A full randomised controlled trial is now required to assess intervention effectiveness. TRIAL REGISTRATION: Study registered with ISRCTN: 15900054.

The Pathological Relevance of Increased Endothelial Glycocalyx Permeability.

The endothelial glycocalyx is a vital regulator of vascular permeability. Damage to this delicate layer can result in increased protein and water transit. The clinical importance of albuminuria as a predictor of kidney disease progression and vascular disease has driven research in this area. This review outlines how research to date has attempted to measure the contribution of the endothelial glycocalyx to vessel wall permeability. We discuss the evidence for the role of the endothelial glycocalyx in regulating permeability in discrete areas of the vasculature and highlight the inherent limitations of the data that have been produced to date. In particular, this review emphasizes the difficulties in interpreting urinary albumin levels in early disease models. In addition, the research that supports the view that glycocalyx damage is a key pathologic step in a diverse array of clinical conditions, including diabetic complications, sepsis, preeclampsia, and atherosclerosis, is summarized. Finally, novel methods are discussed, including an ex vivo glomerular permeability assay that enhances the understanding of permeability changes in disease.

The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.

Psychological, educational, and social late effects in adolescent survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.

OBJECTIVE: To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor. METHODS: Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis. RESULTS: Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40). CONCLUSIONS: Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.

Quantifying prescribed high dose opioids in the community and risk of overdose.

BACKGROUND: Opioid prescribing for a range of health issues is increasing globally. The risk of fatal and non-fatal overdose is increased among people prescribed strong opioids: in high doses in the context of polypharmacy (the use of multiple medications at the same time), especially with other sedatives; and among people with multiple morbidities including cardiorespiratory, hepatic and renal conditions. This study described and quantified the prescribing of strong opioids, comorbidities and other overdose risk factors among those prescribed strong opioids, and factors associated with high/very high opioid dosage in a regional health authority in Scotland as part of a wider service improvement exercise. METHODS: Participating practices ran searches to identify patients prescribed strong opioids and their characteristics, polypharmacy, and other overdose risk factors. Data were anonymised before being analysed at practice and patient-level. Morphine Equivalent Doses were calculated for patients based on drug/dose information and classed as Low/Medium/High/Very High. Descriptive statistics were generated on the strong opioid patient population and overdose risk factors. The relationship between the prescribing of strong opioids and practice/patient-level factors was investigated using linear and logistic regression models. RESULTS: Eighty-five percent (46/54) of GP practices participated. 12.4% (42,382/341,240) of individuals in participating practices were prescribed opioids and, of these, one third (14,079/42,382) were prescribed strong opioids. The most common comorbidities and overdose risk factors among strong opioid recipients were pain (67.2%), cardiovascular disease (43.2%), and mental health problems (39.3%). There was a positive significant relationship between level of social deprivation among practice caseload and level of strong opioid prescribing (p < 0.001). People prescribed strong opioids tended to be older (mean 59.7 years) and female (8638, 61.4%) and, among a subset of patients, age, gender and opioid drug class were significantly associated with prescribing of High/Very High doses. CONCLUSIONS: Our findings have identified a large population at potential risk of prescription opioid overdose. There is a need to explore pragmatic models of tailored interventions which may reduce the risk of overdose within this group and clinical practice may need to be tightened to minimise overdose risk for individuals prescribed high dose opioids.

Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease.

The endothelial glycocalyx is a key component of the glomerular filtration barrier. We have shown that matrix metalloproteinase (MMP)-mediated syndecan 4 shedding is a mechanism of glomerular endothelial glycocalyx damage in vitro, resulting in increased albumin permeability. Here we sought to determine whether this mechanism is important in early diabetic kidney disease, by studying streptozotocin-induced type 1 diabetes in DBA2/J mice. Diabetic mice were albuminuric, had increased glomerular albumin permeability and endothelial glycocalyx damage. Syndecan 4 mRNA expression was found to be upregulated in isolated glomeruli and in flow cytometry-sorted glomerular endothelial cells. In contrast, glomerular endothelial luminal surface syndecan 4 and Marasmium oreades agglutinin lectin labelling measurements were reduced in the diabetic mice. Similarly, syndecan 4 protein expression was significantly decreased in isolated glomeruli but increased in plasma and urine, suggesting syndecan 4 shedding. Mmp-2, 9 and 14 mRNA expression were upregulated in isolated glomeruli, suggesting a possible mechanism of glycocalyx damage and albuminuria. We therefore characterised in detail the activity of MMP-2 and 9 and found significant increases in kidney cortex, plasma and urine. Treatment with MMP-2/9 inhibitor I for 21 days, started six weeks after diabetes induction, restored endothelial glycocalyx depth and coverage and attenuated diabetes-induced albuminuria and reduced glomerular albumin permeability. MMP inhibitor treatment significantly attenuated glomerular endothelial and plasma syndecan 4 shedding and inhibited plasma MMP activity. Thus, our studies confirm the importance of MMPs in endothelial glycocalyx damage and albuminuria in early diabetes and demonstrate that this pathway is amenable to therapeutic intervention. Hence, treatments targeted at glycocalyx protection by MMP inhibition may be of benefit in diabetic kidney disease.

Provision of peer support at the intersection of homelessness and problem substance use services: a systematic 'state of the art' review.

BACKGROUND: Peer support refers to a process whereby individuals with lived experience of a particular phenomenon provide support to others by explicitly drawing on their personal experience. It has been adopted in a variety of service contexts including homelessness, substance use, mental and physical health. Those who experience homelessness have some of the most complex intersecting health and social challenges. This 'state of the art' review provides a systematic search and synthesis of literature examining use of peer support models within services for people impacted by homelessness and problem substance use. METHODS: A systematic search using six databases (CINAHL, SocINDEX, PsycINFO, MEDLINE, Scopus and Web of Knowledge) was conducted in August 2019 and identified 2248 papers published in English after the year 2000. After de-duplication and scanning titles/abstracts, 61 papers were deemed relevant. Three more papers (including one grey literature report) were identified via references, but two papers were later excluded due to relevance. The final 62 papers included studies conducted in five countries. A thematic analysis approach was used to compare and contrast the study findings and provide a synthesis of the main learning points. RESULTS: In recent years there has been a substantial increase in research examining the utility of peer support yet there is significant variation across this field. Alongside profiling the range of settings, aims, populations, and main outcomes of these studies, this paper also provides an overview of overarching themes: the overall effectiveness and impact of peer-staffed or peer-led interventions; and challenges commonly faced in these roles. Five themes relating to the challenges faced by peers were identified: vulnerability, authenticity, boundaries, stigma, and lack of recognition. CONCLUSIONS: While our findings provide support for current efforts to involve individuals with lived experience in providing peer support to those experiencing concurrent problem substance use and homelessness, they also urge caution because of common pitfalls that can leave those providing the support vulnerable. We conclude that peers should be respected, valued, supported, and compensated for their work which is often profoundly challenging. Suggested guidelines for the implementation of peer involvement in research studies and service delivery are presented.

Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.

Aldosterone contributes to end-organ damage in heart failure and chronic kidney disease. Mineralocorticoid-receptor inhibitors limit activation of the receptor by aldosterone and slow disease progression, but side effects, including hyperkalemia, limit their clinical use. Damage to the endothelial glycocalyx (a luminal biopolymer layer) has been implicated in the pathogenesis of endothelial dysfunction and albuminuria, but to date no one has investigated whether the glomerular endothelial glycocalyx is affected by aldosterone. In vitro, human glomerular endothelial cells exposed to 0.1 nM aldosterone and 145 mMol NaCl exhibited reduced cell surface glycocalyx components (heparan sulfate and syndecan-4) and disrupted shear sensing consistent with damage of the glycocalyx. In vivo, administration of 0.6 µg/g/d of aldosterone (subcutaneous minipump) and 1% NaCl drinking water increased glomerular matrix metalloproteinase 2 activity, reduced syndecan 4 expression, and caused albuminuria. Intravital multiphoton imaging confirmed that aldosterone caused damage of the glomerular endothelial glycocalyx and increased the glomerular sieving coefficient for albumin. Targeting matrix metalloproteinases 2 and 9 with a specific gelatinase inhibitor preserved the glycocalyx, blocked the rise in glomerular sieving coefficient, and prevented albuminuria. Together these data suggest that preservation of the glomerular endothelial glycocalyx may represent a novel strategy for limiting the pathological effects of aldosterone.