Use of statistical process control in quality improvement projects in abdominal surgery: a PRISMA systematic review.

BACKGROUND: The use of quality improvement methodology has increased in recent years due to a perceived benefit in effectively reducing morbidity, mortality and length of stay. Statistical process control (SPC) is an important tool to evaluate these actions, but its use has been limited in abdominal surgery. Previous systematic reviews have examined the use of SPC in healthcare, but relatively few surgery-related articles were found at that time. OBJECTIVE: To perform a systematic review (SR) to evaluate the application of SPC on abdominal surgery specialties between 2004 and 2019. METHODS: An SR following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram was completed using Embase and Ovid Medline with terms related to abdominal surgery and SPC. RESULTS: A total of 20 articles were selected after applying the exclusion criteria. Most of the articles came from North America, Europe and Australia, and half have been published in the last 5 years. The most common outcome studied was surgical complications. Urology, colorectal and paediatric surgery made up most of the articles. Articles show the application of SPC in various outcomes and the use of different types of graphs, demonstrating flexibility in using SPC. However, some studies did not use SPC in a robust way and these studies were of variable quality. CONCLUSION: This study shows that SPCs are being applied increasingly for most surgical specialties; however, it is still less used than in other fields, such as anaesthesia. We identified conceptual errors in several studies, such as issues with the design or incorrect data analysis. SPCs can be used to increase the quality of surgical care; the use should increase, but critically, the analysis needs to improve to prevent erroneous conclusions being drawn.

Vancomycin use for haemodialysis patients-Development of a new dosing protocol.

AIM: To develop a dosing and monitoring protocol to achieve therapeutic vancomycin levels on intermittent haemodialysis. METHODS: We identified 15 vancomycin treatment courses received by patients on intermittent haemodialysis at a district health board in Auckland, New Zealand. Demographic, biochemical and clinical parameters were gathered from their health records. We subsequently devised and implemented a new vancomycin protocol consisting of weight-based loading dose, and subsequent dose titration according to same-day measured pre-dialysis levels. We then re-audited 16 vancomycin treatment courses to assess the performance of the protocol. RESULTS: A significantly higher proportion of vancomycin levels were within the target range (15-20 mg/L) following the implementation of protocol, from 23% to 46% (p < .005). Additionally, a greater proportion of treatment courses had >50% of pre-dialysis levels within the target range, rising from 13% to 56% (p < .01). In the pre-protocol group, 19 out of 117 doses of vancomycin were withheld during treatment, compared to 1 out of 118 doses in the post-protocol group. A total of 62% of total maintenance doses were administered in adherence to protocol. Length of hospital stay and number of positive blood cultures while on treatment were reduced. CONCLUSIONS: Our initial audit revealed deficiencies in our clinical practice in the absence of a local vancomycin protocol for patients receiving intermittent haemodialysis. Following the implementation of our novel protocol, there was an improvement in therapeutic levels and fewer doses were withheld. Our sample size was too small to allow for interpretation of clinical outcome data.

Extensive aortic thrombosis and testicular infarction - a rare complication of biventricular cardiac thrombi.

Heart failure is a heterogenous syndrome which is increasing in prevalence, with a prognosis worse than many malignancies. Morbidity and mortality most commonly occur secondary to pump failure or ventricular arrhythmias; however, a more infrequently seen complication is the formation of mural thrombi. More commonly seen within the left ventricle, thrombi can embolize leading to stroke or end organ infarction. We present the case of a male who presented with decompensated heart failure. The presence of biventricular thrombi was found on echocardiography and subsequent cross-sectional imaging revealed these had embolized resulting in the rare complication of extensive abdominal aortic thrombosis with renal and testicular infarction. Biventricular thrombi are rare but high risk due to the potential for embolization as demonstrated in this case. Prompt recognition and management with anti-coagulation are essential, followed by treatment of the underlying pathology, which resulted in the formation of thrombi to prevent recurrence.

A rare case of pulmonary mucormycosis complicated by hydropneumothorax, successfully treated with non-surgical therapies.

Pulmonary mucormycosis (PM) is a rare but rapidly progressive fungal infection associated with high mortality. A review of the literature suggests that pleural effusions and pneumothoraces are uncommon manifestations associated with distant dissemination. Combined surgical interventions and prolonged antifungal therapy constitute the standard first-line management, with significantly poorer outcomes seen in patients managed with medical therapy alone. Here, we report an unusual case of PM complicated by hydropneumothorax in an immunocompromised patient, in whom comorbidities and disease burden precluded surgical debridement. His disease was ultimately treated with intravenous amphotericin B and maintenance posaconazole after adjunctive drainage. This clinical experience highlights the efficacy of antifungal therapy alone in the treatment of potentially fatal cases of PM unsuitable for surgery.

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.

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.

Time trends in autism diagnosis over 20 years: a UK population-based cohort study.

BACKGROUND: Autism spectrum disorder is a diagnosis that is increasingly applied; however, previous studies have conflicting findings whether rates of diagnosis rates continue to grow in the UK. This study tested whether the proportion of people receiving a new autism diagnosis has been increasing over a twenty-year period, both overall and by subgroups. METHOD: Population-based study utilizing the Clinical Practice Research Datalink (CPRD) primary care database, which contains patients registered with practices contributing data to the CPRD between 1998 and 2018 (N = 6,786,212 in 1998 to N = 9,594,598 in 2018). 65,665 patients had a diagnosis of autism recorded in 2018. Time trend of new (incident) cases of autism diagnosis was plotted for all, and stratified by gender, diagnostic subtypes, and developmental stage: infancy and preschool, 0-5 years old; childhood, 6-11 years old; adolescence, 12-19 years old; adults, over 19 years old. RESULTS: There was a 787%, exponential increase in recorded incidence of autism diagnoses between 1998 and 2018; R2 = 0.98, exponentiated coefficient = 1.07, 95% CI [1.06, 1.08], p < .001. The increase in diagnoses was greater for females than males (exponentiated interaction coefficient = 1.02, 95% CI [1.01, 1.03], p < .001) and moderated by age band, with the greatest rises in diagnostic incidence among adults (exponentiated interaction coefficient = 1.06, 95% CI [1.04, 1.07], p < .001). CONCLUSIONS: Increases could be due to growth in prevalence or, more likely, increased reporting and application of diagnosis. Rising diagnosis among adults, females and higher functioning individuals suggest augmented recognition underpins these changes.

Enzyme-linked immunosorbent assays for monitoring TNF-alpha inhibitors and antibody levels in people with rheumatoid arthritis: a systematic review and economic evaluation.

BACKGROUND: Rheumatoid arthritis is a chronic autoimmune disease that primarily causes inflammation, pain and stiffness in the joints. People with severe disease may be treated with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor-α inhibitors, but the efficacy of these drugs is hampered by the presence of anti-drug antibodies. Monitoring the response to these treatments typically involves clinical assessment using response criteria, such as Disease Activity Score in 28 joints or European League Against Rheumatism. Enzyme-linked immunosorbent assays can also be used to measure drug and antibody levels in the blood. These tests may inform whether or not adjustments to treatment are required or help clinicians to understand the reasons for treatment non-response or a loss of response. METHODS: Systematic reviews were conducted to identify studies reporting on the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assays to measure drug and anti-drug antibody levels to monitor the response to tumour necrosis factor-α inhibitors [adalimumab (Humira®; AbbVie, Inc., North Chicago, IL, USA), etanercept (Enbrel®; Pfizer, Inc., New York, NY, USA), infliximab (Remicade®, Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia®; UCB Pharma Limited, Slough, UK) and golimumab (Simponi®; Merck Sharp & Dohme Limited)] in people with rheumatoid arthritis who had either achieved treatment target (remission or low disease activity) or shown primary or secondary non-response to treatment. A range of bibliographic databases, including MEDLINE, EMBASE and CENTRAL (Cochrane Central Register of Controlled Trials), were searched from inception to November 2018. The risk of bias was assessed using the Cochrane ROBINS-1 (Risk Of Bias In Non-randomised Studies - of Interventions) tool for non-randomised studies, with adaptations as appropriate. Threshold and cost-utility analyses that were based on a decision tree model were conducted to estimate the economic outcomes of adding therapeutic drug monitoring to standard care. The costs and resource use were considered from the perspective of the NHS and Personal Social Services. No discounting was applied to the costs and effects owing to the short-term time horizon of 18 months that was adopted in the economic analysis. The impact on the results of variations in testing and treatment strategies was explored in numerous clinically plausible sensitivity analyses. RESULTS: Two studies were identified: (1) a non-randomised controlled trial, INGEBIO, that compared standard care with therapeutic drug monitoring using Promonitor® assays [Progenika Biopharma SA (a Grifols-Progenika company), Derio, Spain] in Spanish patients receiving adalimumab who had achieved remission or low disease activity; and (2) a historical control study. The economic analyses were informed by INGEBIO. Different outcomes from INGEBIO produced inconsistent results in both threshold and cost-utility analyses. The cost-effectiveness of therapeutic drug monitoring varied, from the intervention being dominant to the incremental cost-effectiveness ratio of £164,009 per quality-adjusted life-year gained. However, when the frequency of testing was assumed to be once per year and the cost of phlebotomy appointments was excluded, therapeutic drug monitoring dominated standard care. LIMITATIONS: There is limited relevant research evidence and much uncertainty about the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assay-based testing for therapeutic drug monitoring in rheumatoid arthritis patients. INGEBIO had serious limitations in relation to the National Institute for Health and Care Excellence scope: only one-third of participants had rheumatoid arthritis, the analyses were mostly not by intention to treat and the follow-up was 18 months only. Moreover, the outcomes might not be generalisable to the NHS. CONCLUSIONS: Based on the available evidence, no firm conclusions could be made about the cost-effectiveness of therapeutic drug monitoring in England and Wales. FUTURE WORK: Further controlled trials are required to assess the impact of using enzyme-linked immunosorbent assays for monitoring the anti-tumour necrosis factors in people with rheumatoid arthritis. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018105195. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 8. See the NIHR Journals Library website for further project information.

Rheumatoid arthritis is a long-term condition that causes pain, swelling and stiffness in the joints. People with severe disease may be treated with drugs called tumour necrosis factor-α inhibitors [adalimumab (Humira^®; AbbVie Inc., North Chicago, IL, USA), etanercept (Enbrel^®; Pfizer, Inc., New York, NY, USA), infliximab (Remicade^®; Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia^®; UCB Pharma Limited, Slough, UK) and golimumab (Simponi^®; Merck Sharp & Dohme Limited)]. Some people taking these drugs find that their disease improves, whereas others do not respond to the treatment or improve initially and then experience loss of response. One cause of lost response is that individuals develop antibodies (i.e. protective proteins) against the drug, which hamper the effect of treatment. Various tests have been developed to measure the level of drugs and antibodies against these drugs in patient's blood samples. This kind of monitoring would allow treatment to be adjusted in response to the test outcomes to optimise benefit for the patient, and help clinicians to better understand the reasons for an absence or a loss of response to treatment. The aim of this study was to find out whether or not it would be clinically effective (i.e. good for patients) and cost-effective (i.e. a good use of NHS resources) to use these tests for monitoring drug and antibody levels, as a means of assessing treatment response in rheumatoid arthritis patients who are controlled, have not responded or have lost response. Results from a systematic review showed that, because of the limited and poor-quality evidence, there was much uncertainty in the clinical effectiveness of testing. A simple mathematical model drew on evidence from one poorly reported study, which was heavily supplemented by data from other studies and expert advice. Results from the model were inconclusive and suggest that there is considerable uncertainty in the cost-effectiveness of testing. Therefore, the results presented here should be considered with caution. Further studies are needed to assess the impact of tumour necrosis factor testing in patients with rheumatoid arthritis.

Citrate Coordination and Bridging of Gold Nanoparticles: The Role of Gold Adatoms in AuNP Aging.

Gold nanoparticles used in many types of nanostructure are mostly stabilized by citrate ligands. Fully understanding their dynamic surface chemistry is thus essential for applications, particularly since aging is frequently a problem. Using surface-enhanced Raman spectroscopy in conjunction with density functional theory calculations, we are able to determine Au-citrate coordination in liquid with minimal invasiveness. We show that citrate coordination is mostly bidentate and simply controlled by its protonation state. More complex binding motifs are caused by interfering chloride ions and gold adatoms. With increasing age of stored gold nanoparticle suspensions, gold adatoms are found to move atop the Au facets and bind to an additional terminal carboxylate of the citrate. Aged nanoparticles are fully refreshed by removing these adatoms, using etching and subsequent boiling of the gold nanoparticles.

Light-Induced Coalescence of Plasmonic Dimers and Clusters.

The properties of nanoplasmonic structures depend strongly on their geometry, creating the need for high-precision control and characterization. Here, by exploiting the low activation energy of gold atoms on nanoparticle surfaces, we show how laser irradiation reshapes nanoparticle dimers. Time-course dark-field microspectroscopy allows this process to be studied in detail for individual nanostructures. Three regimes are identified: facet growth, formation of a conductive bridge between particles, and bridge growth. Electromagnetic simulations confirm the growth dynamics and allow measurement of bridge diameter, found to be highly reproducible and also self-limiting. Correlations in spectral resonances for the initial and final states give insight into the energy barriers for bridge growth. Dark-field microscopy shows that coalescence of multiple gaps in nanoparticle clusters can be digitally triggered, with each gap closing after discrete increases in irradiation power. Such control is important for light-induced nanowire formation or trimming of electronic and optoelectronic devices.

Pregabalin induced visual hallucinations - a rare adverse reaction.

BACKGROUND: Pregabalin is an anticonvulsive, analgesic and anxiolytic medication. The typical side effects include dizziness, somnolence and weight gain. Few studies or case reports have demonstrated psychiatric side effects resulting from its use. CASE PRESENTATION: We present a patient who suffered visual hallucinations and agitation associated with an increase in pregabalin dose, resolving completely after pregabalin discontinuation. CONCLUSIONS: Acute visual hallucinations should be considered in the clinical spectrum of very rare side effects of pregabalin use, especially at higher doses. Tapered discontinuation of the medication can improve and resolve symptoms.

Successful treatment of carbapenemase producing Enterobacteriaceae peritonitis: 'Old therapy for a new bug'.

Multidrug-resistant organisms cause significant morbidity and mortality. Infections due to resistant gram-negative bacilli are increasingly being reported. For years, carbapenem antibiotics have been successfully used to treat infections due to resistant Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, including those producing extended spectrum ß-lactamases, a subset of ß-lactamase enzymes that confer broad resistance to penicillins and cephalosporins. More recently, carbapenem-resistant Enterobacteriaceae have emerged as pathogenic organisms, which confer broad resistance to most ß-lactam antibiotics including 'last-line' carbapenems. However, different types of carbapenemases confer diverse spectra of antibiotic resistance. Here, we describe the case of an 84-year-old lady on peritoneal dialysis (PD) for 3 years who, on developing carbapenem-resistant Klebsiella pneumoniae PD peritonitis, was successfully treated with colistin, an antimicrobial agent first used in the 1950s.

Use of patient-reported outcome measures and patient-reported experience measures in renal units in Australia and New Zealand: A cross-sectional survey study.

AIM: Patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) are increasingly used in research to quantify how patients feel and function, and their experiences of care, however, knowledge of their utilization in routine nephrology is limited. METHODS: The Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) PROMs working group conducted a prospective cross-sectional survey of PROMs/PREMs use among renal 'parent hospitals'. One survey per hospital was completed (August-November 2017). Descriptive statistics reported type and frequency of measures used and purpose of use. RESULTS: Survey response rate was 100%. Fifty-five of 79 hospitals (70%) used at least one PROMs or PREMs for specific patient groups. PROMs were more likely to be collected from patients receiving comprehensive conservative care (45% of hospitals) than dialysis patients (32%, 31% and 28% of hospitals for home haemodialysis, peritoneal dialysis and facility dialysis, respectively). Few renal transplanting hospitals (3%) collected PROMs. The Integrated Palliative Outcome Scale-Renal (IPOS-Renal) (40% of units), and the Euro-Qol (EQ-5D-5 L) (25%), were most frequently used. The main reason for collecting PROMs was to inform clinical care (58%), and for PREMs was to fulfil private dialysis/hospital provider requirements (25%). The most commonly reported reason for not using PROMs in 24 hospitals was insufficient staff resources (79%). Sixty-two hospitals (78%) expressed interest in participating in a registry-based PROMs trial. CONCLUSION: Many renal hospitals in Australia and New Zealand collect PROMs and/or PREMs as part of clinical care with use varying by treatment modality. Resources are a key barrier to PROMs use.

Can clinical audits be enhanced by pathway simulation and machine learning? An example from the acute stroke pathway.

OBJECTIVE: To evaluate the application of clinical pathway simulation in machine learning, using clinical audit data, in order to identify key drivers for improving use and speed of thrombolysis at individual hospitals. DESIGN: Computer simulation modelling and machine learning. SETTING: Seven acute stroke units. PARTICIPANTS: Anonymised clinical audit data for 7864 patients. RESULTS: Three factors were pivotal in governing thrombolysis use: (1) the proportion of patients with a known stroke onset time (range 44%-73%), (2) pathway speed (for patients arriving within 4 hours of onset: per-hospital median arrival-to-scan ranged from 11 to 56 min; median scan-to-thrombolysis ranged from 21 to 44 min) and (3) predisposition to use thrombolysis (thrombolysis use ranged from 31% to 52% for patients with stroke scanned with 30 min left to administer thrombolysis). A pathway simulation model could predict the potential benefit of improving individual stages of the clinical pathway speed, whereas a machine learning model could predict the benefit of 'exporting' clinical decision making from one hospital to another, while allowing for differences in patient population between hospitals. By applying pathway simulation and machine learning together, we found a realistic ceiling of 15%-25% use of thrombolysis across different hospitals and, in the seven hospitals studied, a realistic opportunity to double the number of patients with no significant disability that may be attributed to thrombolysis. CONCLUSIONS: National clinical audit may be enhanced by a combination of pathway simulation and machine learning, which best allows for an understanding of key levers for improvement in hyperacute stroke pathways, allowing for differences between local patient populations. These models, based on standard clinical audit data, may be applied at scale while providing results at individual hospital level. The models facilitate understanding of variation and levers for improvement in stroke pathways, and help set realistic targets tailored to local populations.

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy.

Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes-induced glomerular albumin solute permeability (Ps'alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps'alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.

Case finding and therapy for chronic viral hepatitis in primary care (HepFREE): a cluster-randomised controlled trial.

BACKGROUND: The prevalence of viral hepatitis (hepatitis B virus and hepatitis C virus) in migrants is higher than among the general population in many high-income countries. We aimed to determine whether incentivising and supporting primary-care physicians in areas with a high density of migrants increases the numbers of adult migrants screened for viral hepatitis. METHODS: HepFREE was a multicentre, open, cluster-randomised controlled trial in general practices in areas of the UK with a high density of migrants (Bradford, Yorkshire, and northeast and southeast London). Participants were adult patients (aged 18 years or older) in primary care, who had been identified as a first or second generation migrant from a high-risk country. General practices were randomly assigned (1:2:2:2:2) to an opportunistic screening (control) group or to one of four targeted screening (interventional) groups: standard (ie, hospital-based) care and a standard invitation letter; standard care and an enhanced invitation letter; community care and a standard invitation letter; or community care and an enhanced invitation letter. In control screening, general practitioners (GPs) were given a teaching session on viral hepatitis and were asked to test all registered migrants. In the intervention, GPs were paid a nominal sum for setting up searches of records, reimbursed for signed consent forms, and supported by a dedicated clinician. Patients who were eligible for testing and tested positive for viral hepatitis in the intervention groups were eligible to enrol in a second embedded trial of community versus hospital based care. The primary outcomes were the proportion of patients eligible for screening, the proportion of those eligible who were sent an invitation letter in the intervention groups, the uptake of viral hepatitis screening (in the intention-to-treat population), the proportion of patients who tested positive for viral hepatitis, the proportion who complied with treatment, and the cost-effectiveness of the intervention. This trial is registered with ISRCTN, number ISRCTN54828633. FINDINGS: Recruitment and testing ran from Oct 31, 2013, to Feb 4, 2017, and each practice recruited for 18 consecutive calendar months. We approached 70 general practices in three areas with a high density of migrants, of which 63 general practices agreed to participate. Five practices withdrew and 58 practices were randomly assigned: eight to control and 50 to an intervention. In control practices, 26 046 (38·4%) of 67 820 patients who were initially registered were eligible for testing, as were 152 321 (43·3%) of 351 710 patients in the interventional groups in London and Bradford. Of 51 773 randomly selected eligible patients in the intervention groups in London and Bradford, letters were sent to 43 585 (84·2%) patients. In the eight control general practices, screening was taken up by 543 (1·7%) of 31 738 eligible participants, which included 5692 newly registered patients. However, in the 50 general practices that used the intervention, screening was taken up by 11 386 (19·5%) of 58 512 eligible participants (including 6739 newly registered patients; incidence rate ratio 3·70, 95% CI 1·30-10·51; p=0·014) and this intervention was cost-effective. 720 (4·5%) of 15 844 patients who received a standard letter versus 1032 (3·7%) of 28 095 patients who received the enhanced letter were tested (0·70, 0·38-1·31; p=0·26). In the control group, 17 patients tested positive for viral hepatitis, as did 220 patients (one with a co-infection) in the intervention groups. In the embedded study, 220 patients were randomly assigned to either hospital-based care or community care; 80 (87·9%) of 91 patients in the hospital setting complied with treatment versus 105 (81·4%) of 129 patients in the community setting. The intervention was cost-effective at willingness to pay thresholds in excess of £8540. One serious adverse event (thyroiditis) was noted. INTERPRETATION: Screening migrants for viral hepatitis in primary care is effective if doctors are incentivised and supported. Community care is expensive and there is no evidence that this offers benefits in this setting or that bespoke invitation letters add value. We suggest that bespoke invitation letters should not be used, and we suggest that outreach, community-based services for migrants should not be developed. FUNDING: National Institute for Health Research.

Novel hemodynamic structures in the human glomerulus.

To investigate human glomerular structure under conditions of physiological perfusion, we have analyzed fresh and perfusion-fixed normal human glomeruli at physiological hydrostatic and oncotic pressures using serial resin section reconstruction, confocal, multiphoton, and electron microscope imaging. Afferent and efferent arterioles (21.5 ± 1.2 µm and 15.9 ± 1.2 µm diameter), recognized from vascular origins, lead into previously undescribed wider regions (43.2 ± 2.8 µm and 38.4 ± 4.9 µm diameter) we have termed vascular chambers (VCs) embedded in the mesangium of the vascular pole. Afferent VC (AVC) volume was 1.6-fold greater than efferent VC (EVC) volume. From the AVC, long nonbranching high-capacity conduit vessels ( n = 7) (Con; 15.9 ± 0.7 µm diameter) led to the glomerular edge, where branching was more frequent. Conduit vessels have fewer podocytes than filtration capillaries. VCs were confirmed in fixed and unfixed specimens with a layer of banded collagen identified in AVC walls by multiphoton and electron microscopy. Thirteen highly branched efferent first-order vessels (E1; 9.9 ± 0.4 µm diameter) converge on the EVC, draining into the efferent arteriole (15.9 ± 1.2 µm diameter). Banded collagen was scarce around EVCs. This previously undescribed branching topology does not conform to the branching of minimum energy expenditure (Murray's law), suggesting that even distribution of pressure/flow to the filtration capillaries is more important than maintaining the minimum work required for blood flow. We propose that AVCs act as plenum manifolds possibly aided by vortical flow in distributing and balancing blood flow/pressure to conduit vessels supplying glomerular lobules. These major adaptations to glomerular capillary structure could regulate hemodynamic pressure and flow in human glomerular capillaries.

Assessing health risks from multiple environmental stressors: Moving from G×E to I×E.

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.

A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli.

Increased urinary albumin excretion is a key feature of glomerular disease but has limitations as a measure of glomerular permeability. Here we describe a novel assay to measure the apparent albumin permeability of single capillaries in glomeruli, isolated from perfused kidneys cleared of red blood cells. The rate of decline of the albumin concentration within the capillary lumen was quantified using confocal microscopy and used to calculate apparent permeability. The assay was extensively validated and provided robust, reproducible estimates of glomerular albumin permeability. These values were comparable with previous in vivo data, showing this assay could be applied to human as well as rodent glomeruli. To confirm this, we showed that targeted endothelial glycocalyx disruption resulted in increased glomerular albumin permeability in mice. Furthermore, incubation with plasma from patients with post-transplant recurrence of nephrotic syndrome increased albumin permeability in rat glomeruli compared to remission plasma. Finally, in glomeruli isolated from rats with early diabetes there was a significant increase in albumin permeability and loss of endothelial glycocalyx, both of which were ameliorated by angiopoietin-1. Thus, a glomerular permeability assay, producing physiologically relevant values with sufficient sensitivity to measure changes in glomerular permeability and independent of tubular function, was developed and validated. This assay significantly advances the ability to study biology and disease in rodent and human glomeruli.