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Abstract The utilization of kidneys from donors with acute kidney injury (AKI) is often limited by unpredictable post-transplantation outcomes. The aim of our study was to identify protein mediators implicated in either recovery or failure of these organs. Forty kidney biopsies from donors with (20) and without AKI (20) were selected and then subdivided according to the post-transplant outcome defined as a threshold of 45 ml/min for the eGFR at 1 year from transplantation. Tissue homogenates were analysed by western blot to assess how the levels of 17 pre-selected proteins varied across the four groups. Samples from AKI kidneys with a poor outcome showed a fourfold increase in the levels of PPARg and twofold reduction of STAT1 compared to the other groups (p

Renal transplantation is common worldwide, with >25,000 procedures performed in 2022. Usage of prophylactic perinephric drains is variable in renal transplantation; drains are associated with risks, and there is a lack of consensus regarding benefit of routine drain placement in these patients. This meta-analysis assessed whether prophylactic drainage reduced need for reintervention postoperatively. This systematic review and meta-analysis was carried out using the Preferred Reporting Items in Systematic Reviews and Meta-Analysis, and prospectively registered on PROSPERO. Summary statistics for outcomes of interest underwent meta-analyses to a confidence interval (CI) of 95% and are presented as Forest Plots for Odds Ratio (OR). A systematic literature search in June 2023 revealed 1,540 unique articles across four databases. Of these, four retrospective cohort studies were selected. Meta-analysis of three studies showed no significant reduction in reintervention rate with pre-emptive drain placement, OR = 0.59 (95% CI: 0.16–2.23), p = 0.44. Meta-analysis did not show a significant reduction in perinephric collections with prophylactic drain insertion OR = 0.55 (95% CI: 0.13–2.37), p = 0.42. Finally, there is not good evidence that drain placement reduces superficial wound complications or improves 12-month graft survival. Further work is needed, including well-designed, prospective studies to assess the risks and benefits of drain placement in these patients.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023422685, Identifier PROSPERO CRD42021255795.

Background Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure. Objective To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency. Design A prospective multicentre observational cohort study (the ‘SONAR’ study). Setting Seventeen haemodialysis centres in the UK. Participants Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created. Intervention Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings. Main outcome measures Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months. Results A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas’ non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset (n = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data. Conclusions Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit. Trial Registration This trial is registered as ISRCTN36033877 and ISRCTN17399438. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information. Plain language summary What was the problem? For people with advanced kidney disease, haemodialysis is best provided by an ‘arteriovenous fistula’, which is created surgically by joining a vein onto an artery at the wrist or elbow. However, these take about 2 months to develop fully (‘mature’), and as many as 3 out of 10 fail to do so. What was the question? We asked whether we could use early ultrasound scanning of the fistula to identify those that are unlikely to mature. This would allow us to decide whether it would be practical to run a large, randomised trial to find out if using early ultrasound allows us to ‘rescue’ fistulas that would otherwise fail. What did we do? We invited adults to undergo serial ultrasound scanning of their fistula in the first few weeks after it was created. We then analysed whether we could use the data from the early scans to identify those fistulas that were not going to mature by week 10. What did we find? Of the 333 fistulas that were created, about two-thirds reached maturity by week 10. We found that an ultrasound scan 4 weeks after fistula creation could reliably identify those fistulas that were going to mature. However, of those fistulas predicted to fail, about one-third did eventually mature without further intervention, and even without knowing what the early scans showed, another third were successfully rescued by surgery or X-ray-guided treatment at a later stage. What does this mean? Performing an early ultrasound scan on a fistula can provide reassurance that it will mature and deliver trouble-free dialysis. However, because scans are poor at identifying fistulas that are unlikely to mature, we would not recommend their use to justify early surgery or X-ray-guided treatment in the expectation that this will improve outcomes. Scientific summary Background Because of their favourable durability and low infection rates, arteriovenous fistulas (AVFs) are considered the best option for provision of haemodialysis, and they offer survival advantages compared to dialysis through a central venous catheter (CVC). Upon surgical creation, AVFs undergo a period of ‘maturation’, wherein the transit of high-pressure arterial flow through the anastomosis triggers compensatory dilatation and thickening of the draining fistula vein, with marked increases in blood flow through the AVF. This maturation, which generally takes about 2 months, is required to achieve functionality and enables the AVF to be used for dialysis. The main drawback with AVFs is that a large proportion (in excess of 30% in some series) do not develop fully, and either thrombose or remain patent in an immature state. This necessitates further surgical or radiological interventions to aid maturation, or formation of an entirely new fistula, thus potentially prolonging the requirement for dialysis through a CVC. Strategies to increase maturation rates and early patency of AVFs may therefore make a substantial difference to patient outcomes. In this respect, widespread patient and clinician consultation, supported by the James Lind Alliance, has identified the question, ‘What can be done to make fistulas or grafts last as long as possible?’ as one of the top 10 research priorities in vascular access provision. One possible approach to counter early fistula loss from non-maturation/thrombosis is to use Doppler ultrasound (US) surveillance in the first few weeks after creation to identify at-risk fistulas and to inform early radiological or surgical intervention, in anticipation that this improves longer-term fistula patency. This has, however, not yet been tested. The SONAR consortium, representing 17 UK centres that provide vascular access surgery, was established to test the hypothesis: Doppler US surveillance of AVFs immediately after creation improves longer-term AVF patency, by directing early and effective surgical or radiological salvage of those AVFs at risk of failing or not maturing. Objectives In considering the above hypothesis, several conditions must be met if US-guided early salvage intervention is to improve outcomes following AVF creation: that US can effectively distinguish those newly formed fistulas that are unlikely to mature that maturity failure occurs commonly enough that clinically meaningful improvements in fistula outcomes by early identification of at-risk fistulas are plausible that salvage interventions performed on those ‘at-risk’ fistulas are effective and improve fistula patency. The SONAR study thus aimed to address the following objectives sequentially, over a 5-year window: Run an observational cohort study in which consenting participants undergo serial US assessment of their AVF in the first 3 months after its formation (phase 1). Model whether features on early US can reliably identify those fistulas that will not mature or will fail early. Assess from the observational cohort study whether a randomised controlled trial (RCT) evaluating early US-guided salvage intervention is feasible. Run a multicentre RCT in which 1-year fistula patency in a treatment group receiving early US surveillance of their developing fistula is compared against standard care: monitoring of fistula maturation by clinical assessment only (phase 2). Progression to the phase 2 study depended upon accomplishing the first three objectives and, in particular, demonstrating that US surveillance could accurately predict fistula non-maturation. This manuscript will thus focus on the phase 1 study set-up and outcomes. Methods A prospective multicentre observational cohort study of adult patients undergoing formation of AVF for haemodialysis was performed to test the hypothesis: Doppler US surveillance early after AVF creation can reliably identify those AVFs that will not mature or will fail early. Criteria for participation were as follows: Adult, aged 16 years or older. The participant had end-stage renal disease and was either already established on haemodialysis or likely to start imminently. The participant was due creation of an arm AVF (either wrist or elbow) including the following types of fistula: radiocephalic, ulnobasilic, brachiocephalic and brachiobasilic (one- or two-stage) fistula, with a minimal acceptable threshold of 2 mm venous diameter at whatever site was chosen. Full informed consent to participate was provided. Consenting participants underwent serial US scanning at weeks 2, 4, 6 and 10 after fistula formation in addition to standard care (such as regular clinical assessment) as per local centre policy. Fistula flow rates, fistula venous diameter and resistance index were recorded, according to a standard study protocol, with clinical teams blinded to the US findings, unless a scan was simultaneously requested on clinical grounds or the scan confirmed thrombosis of the fistula. The primary outcome measure was fistula maturation at 10 weeks. To encompass participants who remained pre-dialysis, along with clinical examination, maturation was assessed at 10 weeks according to accepted surrogate US parameters: wrist fistula: representative venous diameter ≥ 4 mm, with flow > 400 ml/minute elbow fistula: representative venous fistula diameter ≥ 5 mm, with flow > 500 ml/minute. Three distinct outcomes defined fistula non-maturation: a fistula occlusion/thrombosis within the study period (76 days post AVF creation) fistula abandonment within the study period due to failure to mature or due to thrombosis/occlusion failure to achieve (either reported at the week 10 scan or imputed) maturation, according to the preset US parameters. The following secondary outcome measures were also recorded: for those patients established on dialysis, successful use of the fistula for dialysis on three successive occasions clinical suitability for dialysis 10 weeks after fistula creation based on examination alone according to local practice formation of a new fistula (including fashioning of proximal neoanastomosis) or radiological salvage procedure fistula thrombosis secondary fistula patency patient acceptability, based on the proportion of patients that complete their scans. Assuming that early US surveillance predicts fistula non-maturation/failure in 25% of AVFs, a total of 347 fistulas were required to achieve precision of ± 10% for an estimated 72% positive predictive value (PPV) for detecting non-maturation/failure. The total sample size allows for 10% dropout. Mixed multivariable logistic regression (binary-data population-average model with exchangeable correlation structure) of the early US scan data was then used to build separate models for wrist and elbow AVF that contained the minimum number of measurements required to predict AVF non-maturation by 10 weeks. Receiver operating characteristic curves of the developed risk scores were analysed to determine when surgical or radiological intervention on the developing AVF could be considered. The PPV and negative predictive value (NPV; the probability of AVF maturation given that the model predicts maturation) were calculated alongside a 95% confidence interval (CI) for the chosen risk-score cut-off. Additional modelling was then performed on a subset (n = 192) of the original SONAR cohort available for follow-up, to assess whether fistula failure at 6 and 12 months could be identified by analysis of early US characteristics. The primary outcome measure for the longer-term follow-up was primary fistula patency at 6 months, defined as ‘the interval between access creation to the earliest time of fistula thrombosis, abandonment (except abandonment because of steal), intervention on the fistula (to re-establish or maintain patency) or the time of measurement of patency’. Secondary outcome measures included assisted primary patency (the interval from access creation until access thrombosis or the time of measurement of patency, including any interventions to maintain patency) and secondary patency (the interval from access creation to time of measurement of patency or to abandonment of the fistula). Similar binary-data population-average modelling was performed as for predicting 10-week non-maturation, aiming to build parsimonious models that contained the minimum number of variables from one scan time point (at either week 4 or week 6) to effectively predict primary fistula non-patency at 6 months. Results Of 347 consents to participation (median age 65 years; interquartile range 52–74 years; 64.8% male; 43.2% diabetic; 55.0% pre-dialysis), 333 underwent AVF creation during the study window (47.7% wrist, 52.3% elbow fistula). Early failure before the first US scan occurred in 37 (11.1%) AVFs, but by 10 weeks, 219 of 333 (65.8%) created AVFs had reached maturity (67.2% elbow, 60.4% wrist). Of the remainder, by week 10 a further 20 had failed (57 failures in total; 17.1%), 29 (8.7%) remained patent but not mature and the status of 28 (8.4%) was unknown. Excluding those failures occurring within the first 2 weeks (because it would be impractical to organise salvage so quickly) results in a fistula maturation rate of 74.0% at 10 weeks. Serial US scanning revealed that maturation occurred rapidly (the vast majority of AVFs that were mature by 10 weeks had reached maturation by 2 weeks). Comparison of the early scan data in those AVFs that had matured by week 10 against those AVFs that remained immature (see Figure 4) revealed consistently lower fistula flow rates and fistula vein diameter in the latter. For example, the median blood flow at 2 weeks was 1135.5 and 691.0 ml/minute in those elbow and wrist fistulas, respectively, that reached maturation by week 10, whereas week 2 flows of 349.0 and 395.5 ml/minute were recorded in those elbow and wrist fistulas that did not reach maturation at week 10. Modelling to predict AVF non-maturation at week 10 was optimally built on the week 4 scan data but required separate algorithms for wrist and elbow fistulas, with fistula venous diameter and flow rate at week 4 identified as the most significant variables in explaining wrist fistula maturity failure (PPV 60.6%, 95% CI 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow fistula maturity failure (PPV 66.7%, 95% CI 48.9% to 84.4%). Diagnostic tests for model fit and influential observations were run on the optimum models for wrist and elbow AVFs, with both performing well, with area under the curve values of at least 0.90. Conversely, both models could predict fistula maturation much more reliably [NPVs of 95.4% (91.0–99.8) and 95.6% (91.8–99.4) for wrist and elbow, respectively]. Additional modelling was then performed on a subset (n = 192) of the original SONAR cohort available for follow-up, to assess whether fistula failure at 6 and 12 months could be identified by analysis of early US characteristics. Primary, assisted primary and secondary patency AVF rates at 6 months were 76.5%, 80.7% and 83.3%, respectively, and at 12 months were 68.3%, 74.1% and 79.5%, respectively. Broadly similar US characteristics (fistula vein size, flow rate and resistance index) were identified as the most significant variables predicting primary patency failure at 6 months, with similar predictive power as for 10-week AVF maturity failure, but with wide CIs (wrist AVF: PPV 72.7%, 95% CI 46.4% to 99.0%; elbow AVF: 57.1%, 95% CI 20.5% to 93.8%). Moreover, the models performed very poorly at identifying assisted primary and secondary patency failure, likely because a subset of those identified as liable to fail were instead successfully salvaged by radiological or surgical intervention. Conclusions Although early US can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those unlikely to mature or to fail within 6 months. Allied to the better than expected fistula patency rate achieved by the SONAR consortium (that is further improved by successful radiological or survival salvage without recourse to the early US data), we estimate that a prospective randomised trial comparing early US-guided intervention against standard care (observation only) would require at least 1300 fistulas and would only achieve a minimally clinically important difference in the intervention arm if virtually every intervention were successful in maintaining/restoring fistula patency. Limitations The US scan findings were generally not made available to the clinical teams, so as to avoid their influencing participant management. However, scan results were revealed to the responsible clinical team on 98 occasions (10.7% of all scans), either because an early US scan was standard care for that unit (76 occasions) or because unblinding was requested because of clinical concern relating to the fistula’s maturation. It is therefore possible that in a small number of cases, the study US scans triggered salvage procedures that would not otherwise have been performed on clinical grounds alone. This is particularly problematic for the 12-month follow-up study, because the intervention would mark the end of primary patency – the primary outcome measure for the 6-month analysis – and it would therefore provide false support for the statistical modelling. However, in the majority of cases, unblinding did not prompt further intervention (simply instead confirming fistula maturation), and thus is unlikely to have compromised the statistical modelling. Similarly, to include pre-dialysis patients in the study, it was necessary to adopt surrogate US markers to define fistula maturation, and it is perhaps not ideal to be using the same modality to delineate the maturation process as one uses to define maturation, particularly because fistula maturation is principally a functional concern relating to whether the fistula can be used to provide adequate dialysis. Repeat US was not performed at 6 months for the follow-up study, and the analysis of fistula patency, rather than maturation status, provides a better reflection of fistula functionality. This may partly explain the differences in the modelling findings between the 10-week and 6-month studies. Trial registration The SONAR study was approved by the Cambridgeshire and Hertfordshire Research Ethics Committee and by the Health Research Authority (REC 18/EE/0234) and assigned ISRCTN36033877. The SONAR-12M study was approved by the West Midlands – Edgbaston Research Ethics Committee (REC 20/WM/0331) and assigned ISRCTN17399438. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.

Abstract Objective To perform a molecular screening to detect infections by the mayaro virus and possible coinfections with Chikungunya during an outbreak in the state of Tocantins/Brazil in 2017. Results Of a total 102 samples analyzed in this study, 6 cases were identified with simultaneous infection between mayaro and chikungunya viruses (5.88%). In these 6 samples, the mean Cycle threshold (Ct) for CHIKV was 26.87 (SD ± 10.54) and for MAYV was 29.58 (SD ± 6.34). The mayaro sequences generated showed 95–100% identity to other Brazilian sequences of this virus and with other MAYV isolates obtained from human and arthropods in different regions of the world. The remaining samples were detected with CHIKV monoinfection (41 cases), DENV monoinfection (50 cases) and coinfection between CHIKV/DENV (5 cases). We did not detect MAYV monoinfections.

IntroductionCurrently there is an urgent need to translate interventions that may be beneficial to marginal donor kidneys prior to transplant, to improve their quality from bench to bedside. This project investigated the effects of CC-4066, a potent dual inhibitor of cyclophilin proteins A and D, treatment during static cold storage (SCS) in a porcine model of renal ischemia-reperfusion injury (IRI) using Normothermic Reperfusion (NR).Materials and methodsPorcine kidneys and autologous blood were retrieved in pairs from a local abattoir (n = 7). One kidney from each pair was randomly allocated to treatment and one allocated to control and flushed with preservation solution containing CC-4066 or vehicle. After 7 h of SCS kidneys underwent 3 h Normothermic Reperfusion (NR) with autologous whole blood while perfusion characteristics and samples were collected.ResultsPerfusion and metabolic parameters showed similar trends and no statistical differences were observed between the groups. IL-6 showed a significant increase over time but no significant difference between groups (p-value 0.009 and 0.14 respectively, two-way ANOVA). Oxygen consumption and lactate levels were similar between groups but there was increased vacuolation on histology in the control group.ConclusionsThe addition of CC-4066 during SCS of kidneys is safe and feasible and has no adverse or detrimental effects on perfusion during assessment on NR. There was no difference in cytokine levels although there was a trend towards less vacuolation on histology in the treatment group.

Introduction Cardiovascular events are a major cause of mortality following successful kidney transplantation.Arteriovenous fistulas (AVFs) are considered the best option for haemodialysis, but may contribute to this excess mortality because they promote adverse cardiac remodelling and ventricular hypertrophy. This raises the question whether recipients with a well-functioning kidney transplant should undergo elective AVF ligation.Methods and analysis The COBALT feasibility study is a multicentre interventional randomised controlled trial (RCT) that will randomise renal transplant patients with stable graft function and a working AVF on a 1:1 basis to standard care (continued conservative management) or to AVF ligation. All patients will perform cardiopulmonary exercise testing (CPET) on recruitment and 6 months later. Daily functioning and quality of life will be additionally assessed by questionnaire completion and objective measure of physical activity. The primary outcome—the proportion of approached patients who complete the study (incorporating rates of consent, receipt of allocated intervention and completion of both CPETs without withdrawal)—will determine progression to a full-scale RCT. Design of the proposed RCT will be informed by an embedded qualitative assessment of participant and healthcare professional involvement.Ethics and dissemination This study has been approved by the East Midlands—Derby Research Ethics Committee (22/EM/0002) and the Health Research Authority. The results of this work will be disseminated academically through presentation at national and international renal meetings and via open access, peer-reviewed outputs. Existing networks of renal patient groups will also be used to disseminate the study findings to other key stakeholders.Trial registration number ISRCTN49033491.

Abstract DNA methylation is one of the epigenetic modifications that configures gene transcription programs. This study describes the DNA methylation profile of HIV-infected individuals with distinct characteristics related to natural and artificial viremia control. Sheared DNA from circulating mononuclear cells was subjected to target enrichment bisulfite sequencing designed to cover CpG-rich genomic regions. Gene expression was assessed through RNA-seq. Hypermethylation in virologic responders was highly distributed closer to Transcription Start Sites (p-value = 0.03). Hyper and hypomethylation levels within TSS adjacencies varied according to disease progression status (Kruskal–Wallis, p

Abstract Background The co-circulation of types of arbovirus in areas where they are endemic increased the risk of outbreaks and limited the diagnostic methods available. Here, we analyze the epidemiological profile of DENV, CHIKV and ZIKV at the serological and molecular level in patients with suspected infection with these arboviruses in the city of Juazeiro do Norte, Ceará, Brazil. Methods In 2016, the Central Public Health Laboratory (LACEN) of Juazeiro do Norte received 182 plasma samples from patients who visited health facilities with symptoms compatible with arbovirus infection. The LACEN performed serological tests for detection of IgM/IgG to DENV and CHIKV. They then sent these samples to the Retrovirology Laboratory of the Federal University of São Paulo and Faculty of Medical of the ABC where molecular analyses to confirm the infection by DENV, ZIKV and CHIKV were performed. The prevalence of IgM/IgG antibodies and of infections confirmed by RT-qPCR were presented with 95% confidence interval. Results In serologic analysis, 125 samples were positive for antibodies against CHIKV and all were positive for antibodies against DENV. A higher prevalence of IgG against CHIKV (63.20% with 95% CI: 45.76–70.56) than against DENV (95.05% with 95% CI: 78.09–98.12) was observed. When the samples were submitted to analysis by RT-qPCR, we observed the following prevalence: mono-infection by ZIKV of 19.23% (95% CI: 14.29–34.82) patients, mono-infection by CHIKV of 3.84% (95% CI: 2.01–5.44) and co-infection with ZIKV and CHIKV of 1.09% (95% CI: 0.89–4.56). Conclusion The serologic and molecular tests performed in this study were effective in analyzing the epidemiological profile of DENV, CHIKV and ZIKV in patients with suspected infection by these arboviruses in the city of Juazeiro do Norte, Ceará/Brazil.

Abstract Expected crime rates that enable police forces to contrast recorded and anticipated spatial patterns of crime victimisation offer a valuable tool in evaluating the under-reporting of crime and inform/guide crime reduction initiatives. Prior to this study, police forces had no access to expected burglary maps at the neighbourhood level covering all parts of England and Wales. Drawing on analysis of the Crime Survey for England and Wales and employing a population terrain modelling approach, this paper utilises household and area characteristics to predict the mean residential burglary incidences per 1000 population across all neighbourhoods in England and Wales. The analysis identifies distinct differences in recorded and expected neighbourhood burglary incidences at the Output Area level, providing a catalyst for stimulating further reflection by police officers and crime analysts.

Ischaemia–reperfusion injury (IRI) is an inevitable process in transplantation and results in inflammation and immune system activation. Alpha-1 antitrypsin (AAT) has anti-inflammatory properties. Normothermic machine perfusion (NMP) can be used to deliver therapies and may help in assessing the effects of IRI and immunity. This study investigated the effects of AAT on IRI and inflammation in pig kidneys when administered during preservation, followed by normothermic reperfusion (NR) with autologous whole blood, as a surrogate for transplant. Two different models were used to deliver AAT or placebo to paired slaughterhouse pig kidneys: Model 1: 7-h static cold storage (SCS) + 3-h NR (n = 5 pairs), where either AAT (10 mg/ml) or placebo was delivered in the flush following retrieval; Model 2: 4-h SCS + 3-h NMP + 3-h NR (n = 5 pairs), where either AAT or placebo was delivered during NMP. Injury markers and cytokines levels were analysed in the perfusate, and heat shock protein 70 KDa (HSP-70) was analysed in biopsies. AAT delivered to kidneys showed no adverse effects on perfusion parameters. HSP-70 fold changes were significantly lower in the AAT group during NMP (P < 0.01, paired t-test) but not during NR. Interleukin-1 receptor antagonist (IL-1ra) fold changes were significantly higher in the AAT group during NR model 1 (p < 0.05, two-way ANOVA). In contrast to the AAT group, significant upregulation of interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) between t = 90 min and t = 180 min and interleukin-8 (IL-8) between baseline and t = 90 min was observed in the control group in NR model 2 (p < 0.05, Tukey’s multiple comparison test). However, overall inflammatory cytokines and injury markers showed similar levels between groups. Delivery of AAT to pig kidneys was safe without any detrimental effects. NMP and NR provided excellent methods for comparison of inflammation and immune activation in the delivery of a novel therapy.

Background: The co-circulation of Chikungunya (CHIKV), Dengue (DENV) and Zika (ZIKV) viruses increased the risk of outbreaks and coinfections among them. Here, we report cases of coinfection in clinical samples from state of Tocantins, Brazil. Methods: In 2017, the Central Public Health Laboratory (LACEN) received samples of patients who consulted health units with symptoms compatible with arboviral infections. A total of 102 samples were sent to the Retrovirology Laboratory at the Federal University of São Paulo, where they were tested by RT-qPCR to confirm DENV, ZIKV and CHIKV infections and to detect coinfected patients. Results: We identified with CHIKV monoinfection (52), DENV serotypes 1 (28) and serotypes 2 (22). We did not detect ZIKV. Five patients were characterized with coinfection involving CHIKV and DENV serotype 2. Conclusions: The presence of co-circulating arboviruses increases the chance of coinfection and demonstrates the importance of differential diagnosis and vector control. Keywords: Arbovirus, RT-qPCR, Coinfection, Chikungunya, Dengue

Background: Latent HIV-1 is a major hurdle in obtaining HIV-1 sustained virological remission (SVR). Here we explored histone deacetylation inhibition property of nicotinamide (NAM; n = 17) for the first time in comparison to a combination of methyltransferase inhibitors (MTIs; Chaetocin and BIX01294; n = 25) to reactivate latent HIV ex vivo in CD8-depleted PBMCs from antiretroviral treated aviremic individuals. Results: NAM reactivated HIV-1 from 13/17 (76.4%) samples compared to 20/25 (80.0%) using MTIs with mean viral load (VLs) of 4.32 and 3.22 log10 RNA copies/mL, respectively (p = 0.004). Mean purging time after NAM and MTIs stimulation was 5.1 and 6.75 days, respectively (p = 0.73). Viral purging in autologous cultures exhibited blunted HIV recovery with fluctuating VLs followed by a complete viral extinction when expanded in allogenic system. Electron microscopy from five supernatants revealed anomalous viral particles, with lack of complete viral genomes when characterized by ultradeep sequencing through metagenomics approach (n = 4). Conclusion: NAM alone was more potent HIV-1 activator than combination of MTIs, with potential of clinical use.

In response to anthropogenic threats, conservation translocations are increasingly used to combat species' population and range declines. However, moving animals outside of their current distribution can mean introducing them to novel conditions, even in the case of reintroductions to formerly inhabited areas due to ecosystem changes following extirpation. This exposure to novel conditions introduces uncertainty that can undermine decision making for species conservation. Here we propose two strategies, which we define as conservative and extrapolative, for approaching and managing novelty and the resulting uncertainty in conservation translocations. Conservative strategies are characterised by the avoidance and removal of novel conditions as much as possible, whereas extrapolative strategies are more experimental, allowing exposure to novel conditions and monitoring outcomes to increase understanding of a species' ecology. As each strategy carries specific risks and opportunities, they will be applicable in different scenarios. Extrapolative strategies suit species in recovery which can afford some experimental management, or species facing novel and emerging threats which require less traditional translocations, such as assisted colonisations. We provide examples, applying our framework to two endemic New Zealand species with long histories of translocation management: tuatara (Sphenodon punctatus), a reptile and takahē (Porphyrio hochstetteri), a flightless bird.

Several studies of patients with COVID-19 have evaluated biological markers for predicting outcomes, most of them retrospectively and with a wide scope of clinical severity. We followed a prospective cohort of patients admitted in hospital wards with moderate COVID-19 disease, including those with a history of kidney transplantation, and examined the ability of changes in routine hematologic laboratory parameters to predict and mirror the patients’ clinical course regarding the severity of their condition (classified as critical vs. non-critical) and in-hospital mortality or hospital discharge. Among the 68 patients, 20 (29%) were kidney transplanted patients (KT), and they had much higher mortality than non-kidney transplanted patients in this cohort (40% X 8.3%). Lymphocytes, neutrophils and neutrophils/lymphocytes ratio (NLR) at admission and platelets as well as the red blood cells parameters hemoglobin, hematocrit, and RDW by the time of hospital discharge or death clearly differentiated patients progressing to critical disease and those with clinical recovery. Patients with deteriorating clinical courses presented elevated and similar NLRs during the first week of hospitalization. However, they were dramatically different at hospital discharge, with a decrease in the survivors (NLR around 5.5) and sustained elevation in non-survivors (NLR around 21). Platelets also could distinguish survivors from non-survivors among the critical patients. In conclusion, routine hematologic tests are useful to monitor the clinical course of COVID-19 patients admitted with moderate disease. Unexpectedly, changes in hematologic tests, including lymphopenia, were not predictive of complicated outcomes among KT recipients.

BackgroundTreatment-resistant schizophrenia is a major disabling illness which often proves challenging to manage in a secondary care setting. The National Psychosis Unit (NPU) is a specialised tertiary in-patient facility that provides evidence-based, personalised, multidisciplinary interventions for complex treatment-resistant psychosis, in order to reduce the risk of readmission and long-term care costs.AimsThis study aimed to assess the long-term effectiveness of treatment at the NPU by considering naturalistic outcome measures.MethodUsing a mirror image design, we compared the numbers of psychiatric and general hospital admissions, in-patient days, acuity of placement, number of psychotropic medications and dose of antipsychotic medication prescribed before and following NPU admission. Data were obtained from the Clinical Records Interactive Search system, an anonymised database sourced from the South London and Maudsley NHS Trust electronic records, and by means of anonymous linkage to the Hospital Episode Statistics system.ResultsCompared with the 2 years before NPU admission, patients had fewer mental health admissions (1.65 ± 1.44 v. 0.87 ± 0.99, z = 5.594, P < 0.0001) and less mental health bed usage (335.31 ± 272.67 v. 199.42 ± 261.96, z = 5.195 P < 0.0001) after NPU admission. Total in-patient days in physical health hospitals and total number of in-patient days were also significantly reduced (16.51 ± 85.77 v. 2.83 ± 17.38, z = 2.046, P = 0.0408; 351.82 ± 269.09 v. 202.25 ± 261.05, z = 5.621, P < 0.0001). The reduction in level of support required after treatment at the NPU was statistically significant (z = −8.099, P < 0.0001).ConclusionsThis study demonstrates the long-term effectiveness of a tertiary service specialising in treatment-resistant psychosis.

INTRODUCTION:To be eligible for government-provided treatment in Brazil, all HCV-infected individuals are required to be genotyped shortly after diagnosis. We describe the HCV genotype (G) profiles by geographic region, gender, age and HIV co-infection. METHODS:We assessed 29,071 genotypes collected from HCV-infected individuals from March 2016 to March 2018 (Abbott Real-Time HCV Genotype). We randomly selected 12,336 samples for HIV co-infection testing using an EIA rapid test kit (TR DPP HIV 1/2 Bio-Manguinhos). Descriptive statistical analyses were performed using R. RESULTS:Overall, HCV genotype distribution was 40.9% G1A, 30.2% G1B, 23.8% G3, 3.8% G2, 0.7% G4, 0.1% G5 and 0.6% with multiples genotypes. G1A prevalence was 44.4% among males and 35.8% among females. G1B and G2 were more prevalent in older individuals than G1A and G3. G3 was more prevalent in the South region. Of samples tested for HIV co-infection, 15% were HIV+. Median age among HCV/HIV co-infected individuals was 50 years old compared to 57 years old among mono-infected individuals. Distinct HCV genotype prevalence between HCV/HIV co-infected and HCV mono-infected individuals were respectively: G1A 60.6% versus 37.8%, G1B 15.2% versus 32.9%, and G3 18.9% versus 24.7%. G4 was detected among co-infected young men (3.5% versus 0.2% among mono-infected). CONCLUSION:The increasing prevalence of G3, as inferred by the younger ages of the HCV-infected individuals, poses an extra challenge with regards to disease progression. Distinct genotypical profiles between HCV mono-infection and HCV/HIV co-infection warrant future research in order to better understand and help mitigate HCV chains of transmission.

Background. This pilot study aimed to maintain acceptable animal welfare in the development of a porcine autotransplantation model with severe and incremental renal ischemic injury, a model for usage in future intervention studies. Secondary aims were to develop and test methods to collect blood and urine without the need to restrain or use sedative and avoid transportation to optimize welfare of the pig. Methods. Kidneys from 7 female pigs were subjected to incremental durations of warm ischemia (WI) 30, 45, or 75 minutes by left renal artery and vein clamping. After static cold storage, contralateral nephrectomy was performed, and the injured graft was autotransplanted and animals observed for 14 days. Animal welfare was assessed and recorded using a structured scoring sheet before and 4 days after the kidney autotransplantation. Furthermore, blood samples were drawn daily the first week and every second day the following week using a semi-central venous catheter. An ostomy bag around the genitals was tested for urine collection. Measured glomerular filtration rate was calculated using renal clearance of chromium-51-labeled ethylenediamine tetraacetic acid on day 14. Results. None of the 7 animals died during the follow-up. The animal welfare was moderately affected when applying 75 minutes of WI (n = 2), and for that reason WI was not further increased. Pigs with lower WI had no observed welfare issues. With 75 minutes of WI peak, plasma creatinine was 1486 and 1317 µmol/L, reached on day 4. Lowest glomerular filtration rate levels were observed in the pigs with 75 minutes of WI. Conclusions. WI up to 75 minutes caused the intended severely impaired renal function without significantly compromising animal welfare. Blood and urine was collected postoperatively without sedation of the pigs or use of a metabolic cage.

Introduction Arteriovenous fistulas (AVFs) are considered the best and safest modality for providing haemodialysis in patients with end-stage renal disease. Only 20% of UK centres achieve the recommended 80% target for achieving dialysis of the prevalent dialysis population via permanent access (as opposed to a central venous catheter). This is partly due to the relatively poor maturation rate of newly created fistulas, with as many as 50% of fistulas failing to mature.The Surveillance Of arterioveNous fistulAe using ultRasound study will examine whether a protocolised programme of Doppler ultrasound (US) surveillance can identify, early after creation, potentially correctable problems in those AVFs that subsequently fail to mature.Methods and analysis This is a multicentre observational study that will assess newly created AVFs by Doppler US performed at 2, 4, 6 and 10 weeks after creation. The primary outcome measure will be primary fistula patency at week 10. Secondary outcome measures include: successful use of the fistula; clinical suitability for dialysis; creation of new fistula or radiological salvage; fistula thrombosis; secondary fistula patency rate and patient acceptability.Ethics and dissemination The study has been approved by the Cambridgeshire and Hertfordshire Research Ethics Committee and by the Health Research Authority (REC 18/EE/0234). The results generated from this work will be published as open access, within 3 years of trial commencement. We will also present our findings at key national/international renal meetings, as well as support volunteers at renal patient groups to disseminate the trial outcome.Trial registration number ISRCTN36033877

Ex-situ normothermic machine perfusion (NMP) of transplant kidneys allows assessment of kidney quality and targeted intervention to initiate repair processes prior to transplantation. Mesenchymal stromal cells (MSC) have been shown to possess the capacity to stimulate kidney repair. Therefore, the combination of NMP and MSC therapy offers potential to repair transplant kidneys. It is however unknown how NMP conditions affect MSC. In this study the effect of NMP perfusion fluid on survival, metabolism and function of thawed cryopreserved human (h)MSC and porcine (p)MSC in suspension conditions was studied. Suspension conditions reduced the viability of pMSC by 40% in both perfusion fluid and culture medium. Viability of hMSC was reduced by suspension conditions by 15% in perfusion fluid, whilst no differences were found in survival in culture medium. Under adherent conditions, survival of the cells was not affected by perfusion fluid. The perfusion fluid did not affect survival of fresh MSC in suspension compared to the control culture medium. The freeze-thawing process impaired the survival of hMSC; 95% survival of fresh hMSC compared to 70% survival of thawed hMSC. Moreover, thawed MSC showed increased levels of reactive oxygen species, which indicates elevated levels of oxidative stress, and reduced mitochondrial activity, which implies reduced metabolism. The adherence of pMSC and hMSC to endothelial cells was reduced after the thawing process, effect which was particularly profound in in the perfusion fluid. To summarize, we observed that conditions required for machine perfusion are influencing the behavior of MSC. The freeze-thawing process reduces survival and metabolism and increases oxidative stress, and diminishes their ability to adhere to endothelial cells. In addition, we found that hMSC and pMSC behaved differently, which has to be taken into consideration when translating results from animal experiments to clinical studies.

This paper presents a literature review on techniques related to the computed tomography procedure that incorporate automation elements in their research investigations or industrial applications. Computed tomography (CT) is a non-destructive testing (NDT) technique in that the imaging and inspection are performed without damaging the sample, allowing for additional or repeated analysis if necessary. The reviewed literature is organized based on the steps associated with a general NDT task in order to define an end-to-end computed tomography automation architecture. The process steps include activities prior to image collection, during the scan, and after the data are collected. It further reviews efforts related to repeating this process based on a previous scan result. By analyzing the multiple existing but disparate efforts found in the literature, we present a framework for fully automating NDT procedures and discuss the remaining technical gaps in the developed framework.

As work continues in neutron computed tomography, at Los Alamos Neutron Science Center (LANSCE) and other locations, source reliability over the long imaging times is an issue of increasing importance. Moreover, given the time commitment involved in a single neutron image, it is impractical to simply discard a scan and restart in the event of beam instability. In order to mitigate the cost and time associated with these options, strategies are presented in the current work to produce a successful reconstruction of computed tomography data from an unstable source. The present work uses a high energy neutron tomography dataset from a simulated munition collected at LANSCE to demonstrate the method, which is general enough to be of use in conjunction with unstable X-ray computed tomography sources as well.

The mechanisms underlying host HIV control hold much promise in the search for a functional HIV cure. We investigated the host genomic signatures in elite controllers or rapid progressors following recent infection and the correlates of immune reconstitution during combination antiretroviral therapy. We characterized the HIV-specific longitudinal host transcriptional response of peripheral blood mononuclear cells from elite controllers, rapid progressors, immune responders and non-responders using a RT-qPCR array in a cohort of recently HIV-infected Brazilian individuals. The elite controllers expressed unique transcripts early in infection that were closely associated with specialized cross-presentation between XCR1+ DCs and antigen-specific CD8+ T cells (XCL1). The natural suppression of HIV was also associated with the highly functional co-expression of cytokines and chemokines (CCL2, TNF and IL-10) concomitant with the maintenance of important anti-inflammatory and anticoagulant properties (Antithrombin III). Immune responders exhibited exclusively upregulated mRNAs possibly related to stem cell mobilization before combination antiretroviral therapy (neutrophil elastase). Our longitudinal approach to gene expression permitted us to discover previously unrecognized determinants that contribute to natural or antiretroviral-mediated HIV-1 immune control.

The process of engaging students in the negotiation of their place in historical landscapes is vitalized through the development of historical consciousness as a pedagogical tool for instruction in social studies. This study uses student reflection collected from a graduate course to examine how historical consciousness is understood and expressed through experiential interaction with historical sites and the role of people, places, and historical events in the creation of social history. The participants in the study reflected on how public memory is constructed and individualized within grand and personal narratives of their chosen area of commemoration. The study’s participants showed an eagerness to incorporate interactive technology to express their understanding of historical events, further highlighting technology’s role in democratizing information through digital historical narratives. The student-participants also internalized and articulated their experiences with history through artistic means, which permitted a free expression across multiple media. As prospective educators, the participants negotiated the role of historical consciousness in the development and extension of curricular practices, including the critical examination of official narratives in favour of a socialized history.

A floristic survey was undertaken in mountains forest of West Sumbawa and some surrounding lower forests, an area of Indonesia receiving limited biological study. Three hundred sixteen species of Angiosperms and ferns were collected from this area in 2004 and 2005. The collection represents 101 families and 234 genera.

Immunological and virological status of HIV-infected individuals entering the Brazilian public system over time was analyzed. We evaluated the impact of ART on virological, immunological and antiretroviral resistance over time.CD4+ T cell counts, viral loads and genotypes from patients over 13 years old from 2001-2011 were analyzed according to demographic data. We compared groups using parametric t-tests and linear regression analysis in the R statistical software language.Mean baseline CD4+ T cell counts varied from 348 (2003) to 389 (2009) and was higher among women (p = 1.1 x 10(-8)), lower in older patients (p< 1 x 10(-8)) and lower in less developed regions (p = 1.864 x 10(-5)). Percentage of treated patients with undetectable viral loads increased linearly from 46% (2001) to 77% (2011), was lower among women (p = 2.851 x 10(-6)), younger ages (p = 1 x 10(-3)), and in less developed regions (p = 1.782 x 10(-4)). NRTI acquired resistance was 86% in 2001-3 and decreased over time. NNRTI resistance increased from 2001-3(50%) to 2006-9 (60%), PI resistance decreased from 2001-3 (60%) to 2009 (40%), and 3-class resistance was stable over time around 25%. Subtype prevalence comprised B (75.3%), B/F recombinants (12.2%), C (5.7%), F (5.3%) and B/C recombinants (1.5%), with regional variations. Three-class resistance was 26.5% among Bs, 22.4% among Fs and 17.2% among Cs.HIV diagnosis occurs late, especially among elderly Brazilians. Younger individuals need special attention due to poor virological response to treatment. Antiretroviral Resistance profile is subtype related.