The Minimisation of Cardiovascular Disease Screening for Kidney Transplant Candidates.

Background: There is increasing evidence that cardiac screening prior to kidney transplantation does not improve its outcomes. However, risk aversion to perioperative events means that, in practice, testing remains common, limiting the availability of 'real-world' data to support any change. Our objective was to assess perioperative and 1-year post-transplant cardiovascular events in a kidney transplant candidate cohort who received minimal cardiovascular screening. Methods: The retrospective cohort study included all adult kidney-only transplant recipients in a single UK region between January 2015 and December 2021. Kidney transplant recipients asymptomatic of cardiac disease, even those with established risk factors, did not receive cardiac stress testing. The perioperative and 1-year post-transplant cardiovascular event incidences were examined. Logistic regression was used to identify variables of statistical significance that predicted cardiovascular or cerebrovascular events. Results: A total of 895 recipients fulfilled the inclusion criteria. Prior to transplantation, 209 (23%) recipients had an established cardiac diagnosis, and 193 (22%) individuals had a diagnosis of diabetes. A total of 18 (2%) patients had a perioperative event, and there was a 5.7% incidence of cardiovascular events 1 year post-transplantation. The cardiovascular mortality rate was 0.0% perioperatively, 0.2% at 3 months post-transplant, and 0.2% at 1 year post-transplant. Conclusions: This study demonstrates comparable rates of cardiovascular events despite reduced screening in asymptomatic recipients. It included higher risk individuals who may, on the basis of screening results, have been excluded from transplantation in other programmes. It provides further evidence that extensive cardiac screening prior to kidney transplantation is unlikely to be offset by reduced rates of cardiovascular events.

Proteomic analysis investigating kidney transplantation outcomes- a scoping review.

BACKGROUND: Kidney transplantation is the optimal treatment option for most patients with end-stage kidney disease given the significantly lower morbidity and mortality rates compared to remaining on dialysis. Rejection and graft failure remain common in transplant recipients with limited improvement in long-term transplant outcomes despite therapeutic advances. There is an unmet need in the development of non-invasive biomarkers that specifically monitor graft function and predict transplant pathologies that affect outcomes. Despite the potential of proteomic investigatory approaches, up to now, no candidate biomarkers of sufficient sensitivity or specificity have translated into clinical use. The aim of this review was to collate and summarise protein findings and protein pathways implicated in the literature to date, and potentially flag putative biomarkers worth validating in independent patient cohorts. METHODS: This review followed the Joanna Briggs' Institute Methodology for a scoping review. MedlineALL, Embase, Web of Science Core Collection, Scopus and Google Scholar databases were searched from inception until December 2022. Abstract and full text review were undertaken independently by two reviewers. Data was collated using a pre-designed data extraction tool. RESULTS: One hundred one articles met the inclusion criteria. The majority were single-centre retrospective studies of small sample size. Mass spectrometry was the most used technique to evaluate differentially expressed proteins between diagnostic groups and studies identified various candidate biomarkers such as immune or structural proteins. DISCUSSION: Putative immune or structural protein candidate biomarkers have been identified using proteomic techniques in multiple sample types including urine, serum and fluid used to perfuse donor kidneys. The most consistent findings implicated proteins associated with tubular dysfunction and immunological regulatory pathways such as leukocyte trafficking. However, clinical translation and adoption of candidate biomarkers is limited, and these will require comprehensive evaluation in larger prospective, multicentre trials.

Management of an aneurysmal arteriovenous fistula in kidney transplant recipients.

Aneurysms remain the most common complication of an arteriovenous fistula created for dialysis access. The management of an aneurysmal arteriovenous fistula (AAVF) in kidney transplant recipients remains contentious with a lack of clear clinical guidelines. Recipients of a functioning graft do not require the fistula for dialysis access, however risk of graft failure and needing the access at a future date must be considered. In this review we outline the current evidence in the assessment and management of a transplant recipient with an AAVF. We will describe our recommended five-step approach to assessing an AAVF in transplant patients; 1.) Define AAVF 2.) Risk assess AAVF 3.) Assess transplant graft function and future graft failure risk 4.) Consider future renal replacement therapy options 5.) Vascular mapping to assess future vascular access options. Then we will describe the current therapeutic options and when they would most appropriately be employed.

Patient education interventions for adolescent and young adult kidney transplant recipients- a scoping review.

BACKGROUND: Adolescence and young adulthood are high risk periods for kidney transplant recipients. The reasons for this are complex; but are predominantly thought to be due to poor adherence to immunosuppressive medications. Patient education can help support young recipients to reduce their risk of behaviour-related transplant loss. The aim of this review was to understand what is known about education interventions targeted at adolescent and young adult kidney transplant recipients. METHODS: Systematic scoping review methodology was utilised. Six online databases were searched for suitable articles. Articles were selected for full text review following title and abstract screening. Articles deemed eligible to be included in the review had data extracted, which were qualitatively analysed using thematic analysis. Findings were validated through a consultation exercise with both young recipients and healthcare professionals. RESULTS: 29 studies were eligible for inclusion in the review. There was a high level of heterogeneity in the content, mode, design, and measurement of efficacy of interventions in the selected studies. Traditional face-to-face education and transition clinics were the most common educational interventions. Using technology to enhance patient education was also a major theme identified. Few studies reported using educational theory or involving patients in intervention design. DISCUSSION: Four key research gaps were identified. 1.) Lack of educational theory in intervention design 2.) Lack of patient/ stakeholder involvement 3.) Identifying best way to measure efficacy 4.) identifying novel future research questions within already well established paediatric and educational frameworks. Addressing these gaps in future research will help inform best-practice in this vulnerable population.

A Service Reconfiguration Bundle for Expanding Access to Peritoneal Dialysis Including for Older Frailer Patients.

INTRODUCTION: Rates of peritoneal dialysis (PD) have been traditionally low in Northern Ireland. With rising numbers of patients reaching end-stage kidney disease, PD is a more cost-effective treatment than haemodialysis and aligns with international goals to increase home-based dialysis options. The aim of our study was to highlight how a service reconfiguration bundle expanded access to PD in Northern Ireland. METHODS: The service reconfiguration bundle consisted of the appointment of a surgical lead, a dedicated interventional radiologist for fluoroscopically guided PD catheter insertion, and a nephrology-led ultrasound-guided PD catheter insertion service in an area of particular need. All patients in Northern Ireland who had a PD catheter inserted in the year following service reconfigurations were included and prospectively followed up for one-year. Patient demographics, PD catheter insertion technique, setting of procedure, and outcome data were summarised. RESULTS: The number of patients receiving PD catheter insertion doubled to 66 in the year following service reconfigurations. The range of approaches to PD catheter insertion (laparoscopic n = 41, percutaneous n = 24 and open n = 1) allowed a wide range of patients to benefit from PD. Six patients had emergency PD catheter insertion, with four receiving urgent or early start PD. Nearly half (48%, 29/60) of the PD catheters inserted electively were in smaller elective hubs rather than the regional unit. A total of 97% of patients successfully started PD. Patients who experienced percutaneous PD catheter insertion were older [median age 76 (range 37-88) vs. 56 (range 18-84), p < 0.0001] and had less previous abdominal surgery than patients who experienced laparoscopic PD catheter insertion (25%, 6/24 vs. 54%, 22/41, p = 0.05). DISCUSSION: Through a service reconfiguration bundle, we were able to double our annual incident PD population. This study highlights how flexible models of service delivery introduced as a bundle can quickly deliver expanded access to PD and home therapy.

The Educational Needs of Adolescent and Young Adult Renal Transplant Recipients-A Scoping Review.

Renal transplantation is the gold-standard treatment for adolescents and young adults with end-stage renal disease. Despite enjoying excellent short-term outcomes, they suffer the worst rates of premature transplant function loss. Health behaviors: such as lack of adherence to immunosuppressive medications, are felt to be the major contributory factor. Understanding the educational needs of young renal transplant recipients allows healthcare practitioners to better support patients in managing their chronic disease. The aim of this scoping review was to understand what is known about their educational needs. A scoping review methodology was followed. Following an online search, study titles, and abstracts were screened for eligibility, followed by full-text assessment and data extraction. Data were qualitatively analyzed using thematic analysis. A total of 29 studies were included in the scoping review. In young people who struggled with self-management, three themes were identified (1) the Needs of the disrupted youth, (2) the Needs of the disorganized youth (3) the Needs of the distressed youth. There was a paucity of research to identify the protective factors that enable young recipients to successfully manage their health. This review outlines current knowledge of the patient education needs of young transplant recipients. It also highlights remaining research gaps that will need to be addressed with future research.

A decade of arteriovenous fistula creations in the ⩾75 years population: Equal opportunity or sub-optimal use of resources.

BACKGROUND: The optimal vascular access in the elderly remains contentious in the context of increasingly limited resources and anticipated survival on hemodialysis. Research focus has shifted to include the impact of vascular access on quality of life. This study explored clinical outcomes in individuals aged ⩾75 years who had an arteriovenous fistula (AVF) created in a single center over a 10-year period. MATERIALS AND METHODS: Demographic and clinical data concerning AVFs created January 2009-December 2019 were identified from a prospective database for retrospective analysis. Outcome measures were AVF patency and failure to mature rates plus overall patient and vascular access survival. The Vascular Access Specific Quality of life measure (VASQoL) was completed in a contemporary cohort aged ⩾75 years established on HD in October 2021. RESULTS: AVF outcomes were available for 272 patients (93%). The failure to mature (FTM) rate was 36% with the significant predictors of AVF FTM being the creation of a radiocephalic AVF (OR 8.13, 95% CI 8.02-8.52, p < 0.01), female gender (OR 4.84, 95% CI 4.70-5.41, p < 0.01), and a history of peripheral vascular disease (OR 5.25, 95% CI 5.22-6.00, p value = 0.02). Functional patency was associated with a median 12-month survival benefit compared to those whose fistula FTM (p < 0.01). The median patency duration for a functionally patent AVF was 3 years. Elderly patients with a fistula reported a lower quality of life in VASQoL scoring than those with central venous catheters. CONCLUSIONS: In this cohort, AVF creation in individuals aged ⩾75 years AVFs was associated with comparable AVF patency rates to younger patients. AVF functional patency was associated with superior patient survival compared to those with AVF FTM. A multi-disciplinary surveillance program may help reduce AVF loss. Further work on how vascular access choice impacts quality of life in elderly patients is required.

Identifying classification systems regarding vascular access for haemodialysis: protocol for a scoping review.

INTRODUCTION: Classifications are important clinical tools that enable data arrangement, patient categorisation and comparative research. The care of patients with end-stage renal disease who have vascular access requires collaboration of several specialists. In such a field, where several different specialties overlap, strong evidence and well-grounded recommendations for good practice are essential. In this protocol, we aim to search the literature to identify classification systems regarding vascular access for haemodialysis. This protocol serves as a pragmatic tool for setting a systematic approach using scoping review methodology. It also aims to make the study transparent and avoid potential duplication. METHODS AND ANALYSIS: We will follow the Joanna Briggs Institute methodology for the conduct of scoping reviews during the course of the proposed review. Scopus, Web of Science, PubMed, Google Scholar and the ClinicalTrials.gov registry will be searched by two researchers. Titles and abstracts will be screened and articles featuring classifications regarding vascular access for haemodialysis will be eligible for full-text analysis. There will be no age, sex or race limitation for the study populations. The title and abstract (if abstract available) must be in English but there will be no language restrictions for full-text review. Databases will be searched from inception to the date of search. All patients indicated for creation or placement of vascular access will be eligible, as well as patients with already existing vascular access. Classifications regarding preprocedural assessment, vascular access insertion or creation, complications and their management will be included in the study. Classifications regarding peritoneal dialysis will not be eligible. A comprehensive summary of the available evidence will be presented. ETHICS AND DISSEMINATION: The protocol and the review are exempt from ethical approval as there is no direct patient involvement and the review will summarise data from already published literature. The final article will be submitted to a peer-reviewed scientific journal.

The psychosocial needs of adolescent and young adult kidney transplant recipients, and associated interventions: a scoping review.

BACKGROUND: Renal transplantation is considered the gold standard treatment for end-stage kidney disease. Adolescent and young adult kidney transplant recipients have the highest rate of graft loss amongst transplanted patients. It is largely accepted this is due to psychosocial and behavioural difficulties, which impact adherence to prescribed therapies. This phenomenon is not isolated to a particular healthcare system having been observed in multiple countries across different continents. It is a global issue of concern. We sought to review the psychosocial needs of these patients, and the interventions designed to meet these needs. METHODS: A scoping review was conducted based on Arksey and O'Malley's six-stage framework. Eligibility criteria included primary studies of any type that investigated the psychosocial needs of adolescent and/or young adult renal transplant recipients or studies which examined interventions designed to address these needs. Search strategies were developed and conducted on PsycINFO, PubMed, Embase, and CINAHL. Articles meeting the inclusion criteria were critically reviewed using a descriptive-analytical narrative method. RESULTS: Thirty-nine studies met our inclusion criteria, 30 of which related to psychosocial needs, and the remainder examined psychosocial interventions. Four main themes were derived from our analysis of psychosocial needs literature, as follows: the need for (1) emotional support, (2) acceptance, (3) direction, (4) equality in healthcare. 2 main themes emerged from analysis of psychosocial intervention literature, namely: psychosocial (1) capability, (2) assessment. Despite the evidence that graft health is strongly associated with psychosocial wellbeing, findings revealed a significant lack of literature investigating how best to meet psychosocial needs. Trends were observed amongst intervention studies, namely interventions of novel and non-evidenced based design, with the aim of improving medication adherence through organisational strategies and education. However, literature regarding psychosocial needs showed non-adherence to therapies was not simply a result of disorganisation or lack of understanding, but rather, was founded on a recipient's idiosyncratic relationship with their prescribed therapies e.g., psychological, social or financial reasons for non-adherence. CONCLUSIONS: Future research should be directed at investigating the efficacy of evidence-based interventions that empower the individual patient to overcome their specific barrier to an optimal relationship with their therapies.

Diagnostic value of mid-regional pro-Adrenomedullin as a biomarker of invasive bacterial infection in children: a systematic review.

BACKGROUND: Invasive bacterial infections (IBI) in children present a difficult clinical challenge. They are often life-threatening, however in the early stages they can be hard to differentiate from benign viral infections. This leaves clinicians with the risk of missing a serious IBI diagnosis or inappropriately using antimicrobials in a child with a viral infection- contributing to the ongoing development of increased antimicrobial resistance. Hence, biomarkers which could aid in early detection of IBI and differentiation from viral infections are desirable. Mid-Regional pro-Adrenomedullin (MR-proADM) is a biomarker which has been associated with IBI. The aim of this systematic review was to determine its diagnostic accuracy in identifying children with IBI. METHODS: A strategy was devised to search online databases MEDLINE, Embase, Web of Science and Scopus for human clinical trials reporting the accuracy of MR-proADM in children. Against predesigned inclusion and exclusion criteria full texts were selected for inclusion and data extraction. True positives, false positives, true negatives and false negatives were extracted from each included study to fill 2 × 2 tables. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool methodological quality of each study was assessed. RESULTS: A total of 501 articles were initially identified. After the removal of duplicates and abstract screening 11 texts were fully reviewed and four texts (totaling 1404 patients) were included in the systematic analysis. Only one study was of a high quality and that study accounted for the vast majority of patients. A single study reported the diagnostic accuracy of MR-proADM for invasive bacterial infection reporting an Area under the Curve of 0.69. The paucity of available studies made meta-analysis and studies of heterogeneity impossible. CONCLUSION: There is a paucity of research regarding the diagnostic accuracy of MR-proADM in the diagnosis of invasive bacterial infections in children. Initial results would suggest that MR-proADM testing alone is poor at identifying IBI in young children. It remains unclear if MR-proADM performs differently in older children or in children with signs and symptoms of IBI. TRIAL REGISTRATION: PROSPERO CRD42018096295 .

Validating clinical practice guidelines for the management of children with non-blanching rashes in the UK (PiC): a prospective, multicentre cohort study.

BACKGROUND: No previous studies have validated current clinical practice guidelines for the management of non-blanching rashes in children who have received meningococcal B and C vaccinations. The aim of this study was to evaluate the performance of existing clinical practice guidelines in the diagnosis of invasive meningococcal disease in children presenting with a fever and non-blanching rash in the UK. METHODS: The Petechiae in Children (PiC) study was a prospective, multicentre cohort study involving children (aged <18 years) presenting to 37 paediatric emergency departments in the UK with a fever (≥38°C) and a new-onset non-blanching rash or features suggestive of meningococcal infection. Children with pre-existing haematological conditions (ie, haematological malignancy, idiopathic thrombocytopenic purpura, or coagulopathy) or an existing diagnosis of Henoch-Schonlein purpura were excluded. Invasive meningococcal disease was confirmed by positive culture or a quantitative PCR test for Neisseria meningitidis from either blood or cerebrospinal fluid samples. The primary outcome was the performance of six tailored clinical practice guidelines from participating centres (London, Nottingham, Newcastle-Birmingham-Liverpool, Glasgow, Chester, and Bristol) and two clinical practice guidelines from the National Institutes for Health and Care Excellence (NICE; CG102 and NG51) in identifying children with invasive meningococcal disease, assessed by the sensitivity and specificity of each clinical practice guideline. This study is registered with ClinicalTrials.gov, NCT03378258. FINDINGS: Between Nov 9, 2017, and June 30, 2019, 1513 patients were screened, of whom 1329 were eligible and were included in the analysis. The median age of patients was 24 months (IQR 12-48). 1137 (86%) of 1329 patients had a blood test and 596 (45%) received parenteral antibiotics. 19 (1%) patients had confirmed meningococcal disease. All eight clinical practice guidelines had a sensitivity of 1·00 (95% CI 0·82-1·00) for identifying meningococcal disease. The specificities of NICE guidelines CG102 (0·01 [95% CI 0·01-0·02]) and NG51 (0·00 [0·00-0·00]) for identifying meningococcal disease were significantly lower than that of tailored clinical practice guidelines (p<0·0001). The best performing clinical practice guidelines for identifying meningococcal disease were the London (specificity 0·36 [0·34-0·39]) and Nottingham (0·34 [0·32-0·37]) clinical practice guidelines. INTERPRETATION: Invasive meningococcal disease is a rare cause of non-blanching rashes in children presenting to the emergency department in the UK. Current NICE guidelines perform poorly when compared with tailored clinical practice guidelines. These findings suggest that UK national guidance could be improved by shifting towards a tailored approach. FUNDING: Public Health Agency.

Seroprevalence of SARS-CoV-2 antibodies in children: a prospective multicentre cohort study.

BACKGROUND: Studies based on molecular testing of oral/nasal swabs underestimate SARS-CoV-2 infection due to issues with test sensitivity, test timing and selection bias. The objective of this study was to report the presence of SARS-CoV-2 antibodies, consistent with previous infection. DESIGN: This multicentre observational cohort study, conducted between 16 April to 3 July 2020 at 5 UK sites, recruited children of healthcare workers, aged 2-15 years. Participants provided blood samples for SARS-CoV-2 antibody testing and data were gathered regarding unwell contacts and symptoms. RESULTS: 1007 participants were enrolled, and 992 were included in the final analysis. The median age of participants was 10·1 years. There were 68 (6.9%) participants with positive SARS-CoV-2 antibody tests indicative of previous SARS-CoV-2 infection. Of these, 34/68 (50%) reported no symptoms prior to testing. The presence of antibodies and the mean antibody titre was not influenced by age. Following multivariable analysis four independent variables were identified as significantly associated with SARS-CoV-2 seropositivity: known infected household contact OR=10.9 (95% CI 6.1 to 19.6); fatigue OR=16.8 (95% CI 5.5 to 51.9); gastrointestinal symptoms OR=6.6 (95% CI 3.0 to 13.8); and changes in sense of smell or taste OR=10.0 (95% CI 2.4 to 11.4). DISCUSSION: Children demonstrated similar antibody titres in response to SARS-CoV-2 irrespective of age. Fatigue, gastrointestinal symptoms and changes in sense of smell or taste were the symptoms most strongly associated with SARS-CoV-2 antibody positivity. TRIAL REGISTRATION NUMBER: NCT0434740.

Diagnostic test accuracy of point-of-care procalcitonin to diagnose serious bacterial infections in children.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) have called for research into the role of biomarkers, and specifically procalcitonin (PCT), for the early diagnosis of serious bacterial infections (SBI) in children. The aim of this study was to compare the diagnostic test accuracy of C-reactive protein (CRP) and PCT for the diagnosis of SBI in children. METHODS: Data was collected prospectively from four UK emergency departments (ED) between November 2017 and June 2019. Consecutive children under 18 years of age with fever and features of possible sepsis and/or meningitis were eligible for inclusion. The index tests were PCT and CRP and the reference standard was the confirmation of SBI. RESULTS: 213 children were included in the final analysis. 116 participants (54.5%) were male, and the median age was 2 years, 9 months. Parenteral antibiotics were given to 100 (46.9%), three (1.4%) were admitted to a paediatric intensive care unit and there were no deaths. There were ten (4.7%) confirmed SBI. The area under the curve for PCT and CRP for the detection of SBI was identical at 0.70. CONCLUSIONS: There was no difference in the performance of PCT and CRP for the recognition of SBI in this cohort. TRIAL REGISTRATION: Registered at https://www.clinicaltrials.gov (trial registration: NCT03378258 ) on the 19th of December 2017.

Loop-mediated isothermal amplification for the early diagnosis of invasive meningococcal disease in children.

BACKGROUND: Rapid molecular diagnostic testing has the potential to improve the early recognition of meningococcal disease (MD). The aim of this study was to report on the diagnostic test accuracy of point-of-care loop-mediated isothermal amplification (LAMP) in the diagnosis of MD. DESIGN: Data were collected prospectively from three UK emergency departments (ED) between November 2017 and June 2019. Consecutive children under 18 years of age attending the ED with features of MD were eligible for inclusion. The meningococcal LAMP test (index test) was performed on a dry swab of the child's oropharynx. Reference standard testing was the confirmation of invasive MD defined as positive N. meningitidis culture or PCR result from a sterile body site (blood or cerebrospinal fluid). RESULTS: There were 260 children included in the final analysis. The median age was 2 years 11 months and 169 (65%) children were aged 5 years or younger. The LAMP test was negative in 246 children and positive in 14 children. Of the 14 children with positive LAMP tests, there were five cases of invasive MD. Of the 246 children with negative LAMP tests, there were no cases of invasive MD. The sensitivity of LAMP testing was 1.00 and the specificity was 0.97. The negative and positive predictive values were 1.00 and 0.36, respectively. The positive likelihood ratio was 28.3. DISCUSSION: Non-invasive LAMP testing using oropharyngeal swabs provided an accurate fast and minimally invasive mechanism for predicting invasive MD in this study. TRIAL REGISTRATION NUMBER: NCT03378258.

A protocol for a systematic review and meta-analysis of the diagnostic accuracy of mid-regional pro-adrenomedullin in predicting invasive bacterial infection in children.

BACKGROUND: The early recognition of invasive bacterial infections (IBI) in children can be difficult. Clinically it is often challenging to differentiate between the early stages of an IBI and a benign self-limiting viral infection. These challenges mandate a cautious approach resulting in the overuse of antimicrobial drugs with resultant antimicrobial resistance. Due to these challenges, there is growing research into the role of biomarkers for the early identification of children with IBI. Earlier and more accurate diagnoses may lead to improved clinical outcomes for children and reduced antimicrobial resistance. Mid-regional pro-adrenomedullin (MR-proADM) is a biomarker that has been shown to be elevated in patients with IBI. The aim of this systematic review is to determine the diagnostic accuracy of MR-proADM at identifying children with IBI. METHODS: To identify relevant studies we will search MEDLINE, Embase, Web of Science and Scopus from 1980 to the present day for all human clinical trials involving children that report the test accuracy of MR-proADM. We will include case-control studies, cohort studies and randomised control trials reported in any language. In addition, we will hand-search reference lists and grey literature including conference abstracts and web searches. Two reviewers will independently screen study titles and abstracts for eligibility followed by full-text assessment and data extraction including population, setting, timing and use of index test and reference standard used. Methodological quality will be assessed, by two authors, according to the revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2), any discrepancies will be resolved by a third author. The following test characteristics will be extracted into 2 × 2 tables for all included studies: true positives, false positives, true negatives and false negatives. Study-specific estimates of sensitivity and specificity with 95% confidence intervals will be displayed in forest plots. DISCUSSION: This review will report the normal ranges for MR-proADM in health and the diagnostic accuracy of MR-proADM at identifying children with IBI. The review will help to define where in the diagnostic pathway MR-proADM could be useful including potential as a point-of-care test for children at first presentation with IBI. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018096295.

Protective effects of intermedin/adrenomedullin-2 in a cellular model of human pulmonary arterial hypertension.

Proliferation of pulmonary fibroblasts (PF) and distal migration of smooth muscle cells (PSM) are hallmarks of pulmonary arterial hypertension (PAH). Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the Calcitonin Gene-Related Peptide (CGRP)/Adrenomedullin (AM) superfamily. These peptides act via Calcitonin-Like Receptors (CLR) combined with one of three Receptor activity-modifying proteins (RAMPs). IMD/AM2 is a potent pulmonary vasodilator in animal studies. The aim was to describe expression of IMD/AM2, AM and receptor components in human pulmonary vascular cells and to elucidate effects of IMD/AM2 on human PSM migration and PF proliferation. Gene expression was detected by immunofluorescence, immunoblotting and qRT-PCR. Normotension and hypertension were simulated by applying pulsatile mechanical stretch (Flexcell® apparatus). Viable cell numbers were determined by dye exclusion. PSM chemotaxis was measured via Dunn chamber. IMD/AM2 protein was co-expressed with AM and their receptor components in pulmonary artery and microvascular endothelial (PAEC, PMVEC) and non-endothelial cells (PF, PSM), and localised to vesicles. IMD/AM2 was secreted under basal conditions, most abundantly from PF and PMVEC. Secretion from PF and PSM was enhanced by stretch. IMD/AM2 mRNA expression increased in response to hypertensive stretch of PSM. IMD/AM2 inhibited PDGF (10-7 M)-mediated PSM migration maximally at 3 × 10-10 M and PF proliferation maximally at 3 × 10-9 M. Angiotensin II (5 × 10-8 M), normotensive and hypertensive stretch augmented PF proliferation. IMD/AM2 (10-9 M) abolished the proliferative effects of Angiotensin II and normotensive stretch and attenuated the proliferative effect of hypertensive stretch alone and combined with angiotensin II. These findings indicate an important counter-regulatory role for IMD/AM2 in PAH.

Fifteen-minute consultation: Symptoms and signs of meningococcal disease.

Meningococcal disease remains a leading cause of meningitis, sepsis and death in children worldwide and in the UK. Successful vaccination programmes in the UK have, however, significantly reduced the burden of disease in children. Unfortunately, despite vaccination, a significant number of children are still diagnosed with invasive meningococcal disease each year.As the prevalence of meningococcal disease falls, it is important that we maintain awareness of the symptoms and signs of meningococcal disease because the prompt recognition of this life-threatening infection improves outcomes.In this article we discuss the pathology, epidemiology and recognition of invasive meningococcal disease in children. The aim is to maintain awareness of this rare but life-threatening infection.

Seroprevalence of SARS-CoV-2 antibodies in children of United Kingdom healthcare workers: a prospective multicentre cohort study protocol.

BACKGROUND: A novel coronavirus SARS-CoV-2 has been responsible for a worldwide pandemic. Children typically have very mild, or no, symptoms of infection. This makes estimations of seroprevalence in children difficult. Research is therefore required to determine the seroprevalence of SARS-CoV-2 antibodies in children. The primary objective of this study is to report the seroprevalence of SARS-CoV-2 IgM and/or IgG antibodies in healthy children at baseline, 2 months and 6 months. This is the only longitudinal UK study of seroprevalence in an exclusively paediatric population. Determining the changing seroprevalence is of vital public health importance and can help inform decisions around the lifting of paediatric specific social distancing measures such as school closures and the cancellation of routine paediatric hospital services. METHODS AND ANALYSIS: 1000 healthy children of healthcare workers aged between 2 and 15 years will be recruited from five UK sites (Belfast, Cardiff, Glasgow, London and Manchester). The children will undergo phlebotomy at baseline, 2 months and 6 months to measure IgM and/or IgG positivity to SARS-CoV-2. A sample size of 675 patients is required to detect a 5% change in seroprevalence at each time point assuming an alpha of 0.05 and a beta of 0.2. Adjusted probabilities for the presence of IgG and/or IgM antibodies and of SARS-CoV-2 infection will be reported using logistic regression models where appropriate. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London - Chelsea Research Ethics Committee (REC Reference-20/HRA/1731) and the Belfast Health & Social Care Trust Research Governance (Reference 19147TW-SW). Results of this study will be made available as preprints and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT0434740; Results.

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds.

Understanding olfaction at the molecular level is challenging due to the lack of crystallographic models of odorant receptors (ORs). To better understand the molecular mechanism of OR activation, we focused on chiral (R)-muscone and other musk-smelling odorants due to their great importance and widespread use in perfumery and traditional medicine, as well as environmental concerns associated with bioaccumulation of musks with estrogenic/antiestrogenic properties. We experimentally and computationally examined the activation of human receptors OR5AN1 and OR1A1, recently identified as specifically responding to musk compounds. OR5AN1 responds at nanomolar concentrations to musk ketone and robustly to macrocyclic sulfoxides and fluorine-substituted macrocyclic ketones; OR1A1 responds only to nitromusks. Structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics (QM/MM) hybrid methods were validated through direct comparisons with activation profiles from site-directed mutagenesis experiments and analysis of binding energies for 35 musk-related odorants. The experimentally found chiral selectivity of OR5AN1 to (R)- over (S)-muscone was also computationally confirmed for muscone and fluorinated (R)-muscone analogs. Structural models show that OR5AN1, highly responsive to nitromusks over macrocyclic musks, stabilizes odorants by hydrogen bonding to Tyr260 of transmembrane α-helix 6 and hydrophobic interactions with surrounding aromatic residues Phe105, Phe194, and Phe207. The binding of OR1A1 to nitromusks is stabilized by hydrogen bonding to Tyr258 along with hydrophobic interactions with surrounding aromatic residues Tyr251 and Phe206. Hydrophobic/nonpolar and hydrogen bonding interactions contribute, respectively, 77% and 13% to the odorant binding affinities, as shown by an atom-based quantitative structure-activity relationship model.

Fluorinated Musk Fragrances: The CF2 Group as a Conformational Bias Influencing the Odour of Civetone and (R)-Muscone.

The difluoromethylene (CF2 ) group has a strong tendency to adopt corner over edge locations in aliphatic macrocycles. In this study, the CF2 group has been introduced into musk relevant macrocyclic ketones. Nine civetone and five muscone analogues have been prepared by synthesis for structure and odour comparisons. X-ray studies indeed show that the CF2 groups influence ring structure and they give some insight into the preferred ring conformations, triggering a musk odour as determined in a professional perfumery environment. The historical conformational model of Bersuker and co-workers for musk fragrance generally holds, and structures that become distorted from this consensus, by the particular placement of the CF2 groups, lose their musk fragrance and become less pleasant.