Cambridge University Hospitals Research Articles

P1792SUCCESSFUL TRANSPLANTATION OF STEM CELLS AND KIDNEY IN REFRACTORY LUPUS NEPHRITIS: REMOTE OUTCOMES

Abstract Background and Aims Lupus nephritis is a common part of systemic lupus erythematosus (SLE), severe autoimmune disease that affects multiple organ systems and associated with pure prognosis. Patients with lupus nephritis who experience persisted disease activity despite conventional immunosuppression are at high risk of early death. Re-setting of the immune system and self-tolerance by high-dose immunosuppressive therapy with autologous stem cell transplantation (ASCT) is a new approach in the treatment of refractory SLE. Remote outcomes of this method and effectiveness relapse treatment are still unclear and were the aims of this study. Method We report a sick woman 39 years old, with refractory severe lupus nephritis. Standard therapy was ineffective, SLEDAI score remains 22 so patient was underwent high dose immunosuppressive therapy with ASCT and included in European Group for Blood and Marrow Transplantation European League against Rheumatism (EBMT/EULAR) registry on 53 pts who received ASCT for SLE between 1996 and 2005. Ethical approval was obtained for this study from Cambridge University Hospital Ethics Committee. Results The ASCT induced complete clinical and serological remission (SLEDAI score was 0) for 3 years. Than relapse with nephritic syndrome and anti-dsDNA positivity occurred and caused renal failure, creatinine clearance decreased to 21. Despite therapy including prednisolone, 45 mg daily, and mycophenolate mofetil, 2000 mg daily, disease activity persisted, creatinine clearance remained decreasing and 3 years later became 15 ml/min. During 1 year patient was on regular hemodialysis, then renal transplantation performed. Now, follow up is 15 years after ASCT and 8 years after kidney transplantation. Patient received a standard post-transplant immunosuppression with prednisolone, 5 mg daily, tacrolimus, 2.5 mg daily, and azathioprine, 100 mg daily, and her conditions remains stable, she has functioning renal allograft, SLEDAI score is 2 (anti-dsDNA positivity in low titer). Conclusion We present the successful remote outcomes of first case of immunoablation and double transplantation of autologous stem cells and allogeneic kidney in severe refractory to conventional immunosuppression SLE with lupus nephritis.

Novel Approach to Imaging Active Takayasu Arteritis Using Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging

Novel Approach to Imaging Active Takayasu Arteritis Using Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging

Utilisation of Antimicrobial Stewardship (AMS) Electronic Interventions (i-Vents) as a metric of pharmacy AMS at Cambridge University Hospitals (CUH) NHS Foundation Trust

Background: The aim of the project was to identify the contribution clinical pharmacists make to antimicrobial stewardship (AMS) at CUH. The EPIC e-hospital system in place allows pharmacists to record interventions (i-Vents) electronically; these can be used as a metric of pharmacist AMS. Method:A bespoke electronic report of all AMS i-Vents which occurred in April 2018 was generated using EPIC.Each i-Vent was categorised by type, clinical speciality, grade of pharmacist making the i-Vent and whether the i-Vent was following on from a previous one. The antimicrobials(s) mentioned in each i-Vent were also recorded. Results:During April 2018 554 pharmacist i-Vents were recorded. I-Vent types included therapeutic drug monitoring (31%), dose optimisation (22%), course length optimisation (12%), interaction and contraindication management (2%) and patient counselling (0.2%). AMS i-Vents were recorded for patients under the care of 42 clinical specialties including neonatology (12%), diabetes and endocrinology (11%) and respiratory (8%). I-vent numbers increased with seniority of pharmacist with band 8 pharmacists making the most interventions (44%) and band 6 pharmacists making the fewest (16%). There were 645 separate references to a total of 53 individual antimicrobial agents. The top three drugs mentioned in i-Vents were vancomycin (30%), gentamicin (12%), and ciprofloxacin (8%). Follow-up i-Vents constituted 111 (20%) of all recorded i-Vents. Conclusion:Our findings demonstrate that pharmacists contribute significantly to AMS at CUH, especially on therapeutic drug monitoring and dose-optimisation issues.We suggest that AMS i-Vents are a reliable metric for monitoring AMS pharmacist activities, related directly to patient care.

A large-scale pragmatic automated audit of the appropriateness of antibiotics initiated for presumed community-acquired pneumonia using a novel algorithmic approach

Background Audit is a fundamental part of antimicrobial stewardship, but this has traditionally been labour-intensive. The advent of fully electronic records (EPIC) at Cambridge University Hospitals (CUH) presents novel opportunities for large-scale automated data analyses and feedback. We developed and validated an algorithm to audit the appropriateness of prescriptions initiated for presumed community-acquired pneumonia (CAP). Methods We developed an algorithm that extracts prescription and clinical data from EPIC, calculates CURB-65 scores, and assesses the appropriateness of antibiotics with an indication of CAP against Trust guidelines based on predefined rules. Clinical data included age, gender, blood results, vital signs, NEWS-2 score, MRSA status, penicillin allergy and pregnancy status. Prescriptions were limited to 48 hours from admission. The accuracy of the algorithm was validated in a representative sample of 30 patients. We present data on all prescriptions initiated for CAP admitted to CUH between September 2018 and June 2019. Results On validation, the algorithm calculated the CURB-65 score with an accuracy of 97% and correctly categorised antibiotic appropriateness in 98.5% of cases. Only 15% of patients had a CURB-65 score documented in the notes. The algorithm evaluated 4,307 prescriptions in 2,198 patients. Appropriateness was significantly better in CURB-65 scores of 2-5 (83.7%) versus 0-1 (33.5%) largely due to over-prescription of co-amoxiclav in the latter. Conclusion This algorithm enables large-scale analysis of prescriptions initiated for CAP with high accuracy automating the audit cycle. An automatically calculated CURB-65 score has the potential to reduce over-prescribing of co-amoxiclav and should be evaluated in the future.

P505 Different failure rates after non-medical switching of 744 patients from adalimumab originator to 2 different adalimumab biosimilars at Cambridge University Hospitals, UK: real-world experience

Abstract Background Biosimilar adalimumab became available in the UK in October 2018, with payers introducing a series of measures to drive the adoption of the ‘best value’ adalimumab.1 Consideration of value should include risk of loss of efficacy and adverse reactions, which might drive further biologic switches or ‘reverse switches’ to originator. Managing potential ‘nocebo effect’ requires high levels of patient engagement, whilst the presence or absence of citrate buffer may affect patient-reported discomfort, hence patient treatment perceptions. Methods Patients were switched to 2 different biosimilar adalimumabs, one buffered with citrate (ADA1) and one in a citrate-free buffer (ADA2). The choice of adalimumab biosimilar was made for clinical and economic reasons. Patients were informed of the switch to either ADA1 or ADA2 in advance via letter and at clinic visits. Patients who reported problems after switching were reviewed. Results A total of 744 patients were switched from originator adalimumab (ADA0) to ADA1 or ADA2. Rheumatology and dermatology patients were switched to ADA1, whilst gastroenterology patients were switched to ADA2, except for those with a latex allergy, where ADA1 was used (or ADA2 in a latex-free syringe). A total of 49 (6.6%) patients reported problems and a further switch of drug was judged necessary in 48 (Table 1). Switch failure was significantly more likely with ADA1 than ADA2 (7.7% vs. 1.8%; p = 0.006). The median time to switch failure was 97 days (range 5–196 days). The commonest reason for switch failure was disease flare (23 patients, 48%), followed by injection site pain or reaction (21 patients, 44%). Disease flare and injection site problems were more likely to be reported with ADA1 than ADA2 (flare: 23/583 vs. 0/161, p = 0.008; injection site pain 20/583 vs. 1/161, p = 0.06). For patients reporting disease flare, clinicians tended to select a reverse switch to ADA0, whilst for those with injection site problems, a further switch to a different biosimilar was the preferred approach; both strategies were effective at recapture. Conclusion In the context of an effective patient communication strategy, adalimumab biosimilar switching was associated with overall low rates of patient-reported problems in a large cohort. Despite an identical communication strategy, significantly higher rates of injection site problems and disease flares were seen between 2 different biosimilars, reflected in a higher need for further switches. These differences may impact the cost-effectiveness of any chosen strategy. Reference

ActivPAL and ActiGraph Assessed Sedentary Behavior and Cardiometabolic Health Markers.

To establish whether associations between sedentary behavior and cardiometabolic health differ when assessed by thigh-worn and waist-worn accelerometry. Participants were recruited from several areas in the United Kingdom. Sedentary behavior was assessed using the activPAL worn on the thigh and ActiGraph worn on the waist. Average total (TST), prolonged (bouts ≥30 min; PST) and breaks (BST) in sedentary time were calculated. Cardiometabolic health markers included: adiposity (body fat) and surrogate markers of adiposity ((waist circumference, body mass index [BMI]), lipids (total, low density lipoprotein, and high-density lipoprotein [HDL] cholesterol, triglycerides), blood pressure, and glucose (fasting, 2 h and glycated hemoglobin A1c). A clustered cardiometabolic risk score was calculated. Linear regression analysis examined the associations with cardiometabolic health. There were 1457 participants (mean age [± standard deviation], 59.38 ± 11.85 yr; 51.7% male; mean BMI, 30.19 ± 5.59 kg·m) included in the analyses. ActivPAL and ActiGraph sedentary variables were moderately correlated (0.416-0.511, P < 0.01); however, all variables were significantly different from each other (P < 0.05). Consistency was observed across devices in the direction and magnitude of associations of TST and PST with adiposity, surrogate markers of adiposity, HDL, triglycerides, and cardiometabolic risk score and for BST with adiposity, surrogate markers of adiposity, and cardiometabolic risk. Differences across devices were observed in associations of TST and PST with diastolic blood pressure, for TST with 2-h glucose and for BST with HDL. No other associations were observed for any other health marker for either device. Results suggest that associations with cardiometabolic health are largely comparable across the two common assessments of sedentary behavior but some small differences may exist for certain health markers.

Minimally Invasive Pancreatic Necrosectomy: A step-up approach towards ultra-low mortality in 103 consecutive procedures

Background: Infected pancreatic necrosis carries up to 70% risk of mortality. Open necrosectomy, previously regarded as standard treatment, carries very high risk of morbidity and mortality. Step-up management with percutaneous drainage followed by minimally invasive pancreatic necrosectomy (MIPN) has shown improved outcomes. We report the outcomes of the protocol developed at Cambridge of ‘early’ percutaneous drainage followed by ‘delayed’ MIPN. Materials and Methods: Cambridge University Hospital is a tertiary referral centre for pancreatic surgery including complicated pancreatitis. Retrospective analysis of all MIPNs between December 2009 and October 2018. Demographics, morbidity and mortality outcomes were reported. Results: During the 9-year period, 103 MIPNs were performed in 86 patients, with 12 (13.9%) needing multiple procedures. The mean age was 58 ±15 years, with 74.4% (n=64) being male gender and 50.0% (n=43) with BMI >30 Kg/m2.Thirty patients (34.9%) had required preoperative ITU admission for multi-organ support due to infected necrosis. The median time for insertion of percutaneous drain was 28 days (range 1-99). The median time of the MIPN from acute episode was 45 days (range 4-307). Thirteen patients (15.1%) required admission to ITU after MIPN with a median stay of 22 days (range 1-104). Complications of MIPN (n=29, 33.7%) included bleeding requiring intervention (n=5), pancreatic fistula (n=5) and multi-organ failure (n=19), which was considered as the morbidity rate. 30-day and 90-day mortality following MIPN was 2.3% (n=2) and 5.8% (n=5). All deaths were due to sepsis and multi-organ failure. Conclusions: This is the lowest reported mortality rate for patients with infected pancreatic necrosis. Minimally invasive management with early percutaneous drain insertion followed by delayed MIPN is associated with ultra-low mortality. Management of complicated necrotizing pancreatitis almost invariably requires tertiary referral expertise as it involves multimodal approaches, complex medical and ITU care, multiple procedures, prolonged admissions and long-term follow-up.

Is seniority of emergency physician associated with the weekend mortality effect? An exploratory analysis of electronic health records in the UK

ObjectiveAdmission to hospital over a weekend is associated with increased mortality, but the underlying causes of the weekend effect are poorly understood. We explore to what extent differences in emergency...

British Society for Gene and Cell Therapy Annual Conference Wednesday 19th June – Friday 21st June 2019 University of Sheffield, Sheffield, UK www.bsgct.org

British Society for Gene and Cell Therapy Annual Conference Wednesday 19th June – Friday 21st June 2019 University of Sheffield, Sheffield, UK www.bsgct.org

Modelling outcomes after paediatric brain injury with admission laboratory values: a machine-learning approach.

Severe traumatic brain injury (TBI) is a leading cause of mortality in children, but the accurate prediction of outcomes at the point of admission remains very challenging. Admission laboratory results are a promising potential source of prognostic data, but have not been widely explored in paediatric cohorts. Herein, we use machine-learning methods to analyse 14 different serum parameters together and develop a prognostic model to predict 6-month outcomes in children with severe TBI. A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between 2009 and 2013 with a TBI. The data for 14 admission serum parameters were recorded. Logistic regression and a support vector machine (SVM) were trained with these data against dichotimised outcomes from the recorded 6-month Glasgow Outcome Scale. Ninety-four patients were identified. Admission levels of lactate, H+, and glucose were identified as being the most informative of 6-month outcomes. Four different models were produced. The SVM using just the three most informative parameters was the best able to predict favourable outcomes at 6 months (sensitivity = 80%, specificity = 99%). Our results demonstrate the potential for highly accurate outcome prediction after severe paediatric TBI using admission laboratory data.

Urology general practitioner advice and guidance: A service evaluation of its effectiveness

Objective: This study aims to assess the effectiveness of the Urology Advice and Guidance (A&amp;G) referral pathway within the National Health Service (NHS). It seeks to identify whether the A&amp;G system helps to prevent unnecessary referrals to secondary care services and endeavours to see whether there is any variability in consultant responses to A&amp;G queries, and whether this affects how patients are subsequently managed. Patients and methods: This study uses patient data collected by Cambridge University Hospitals NHS Foundation Trust over a six-month period between 2016 and 2017. The correspondence from 192 A&amp;G referrals was analysed to extract 11 data points from each referral to help analyse the aims of the study. Results: The results showed that almost half of all A&amp;G referrals could be avoided if general practitioners made better use of the urology guidelines made available to them. The results also demonstrated that A&amp;G referrals were more appropriately managed when guidance was given by a consultant with subspecialty interests in line with the referral. Conclusion: The aims of this study were appropriately met, and the study outlines how improvements in the A&amp;G service could offer both financial and clinical benefits to primary and secondary care services alike. Level of evidence: 3b

Hemoglobin Video Imaging Provides Novel In Vivo High-Resolution Imaging and Quantification of Human Aqueous Outflow in Patients with Glaucoma

PurposeNoninvasive, detailed measurement of the dynamics of human aqueous outflow is difficult to achieve with currently available clinical tools. We used hemoglobin video imaging (HVI) to develop a technique to image and quantify human aqueous outflow noninvasively and in real time.DesignA prospective observational study to describe characteristics of aqueous veins and a pilot prospective interventional feasibility study to develop quantification parameters.ParticipantsPatients were recruited from the Cambridge University Hospitals NHS Foundation Trust Glaucoma clinic. The observational study included 30 eyes, and the pilot interventional feasibility study was performed on 8 eyes undergoing selective laser trabeculoplasty (SLT). Our SLT protocol also included the installation of pilocarpine and apraclonidine eye drops.MethodsParticipants underwent HVI alongside their usual clinic visit.Main Outcome MeasuresThe change in cross-sectional area (CSA) of the aqueous column within episcleral veins was correlated with intraocular pressure (IOP) reduction and change in visual field mean deviation (MD) before and after intervention. Fluctuations in contrast and pixel intensity of red blood cells in an aqueous vein were calculated to compare the flow rate before and after intervention using autocorrelation analysis.ResultsHemoglobin video imaging enables the direct observation of aqueous flow into the vascular system. Aqueous is seen to centralize within a laminar venous column. Flow is pulsatile, and fluctuations of flow through globe pressure or compression of the aqueous vein are observed. There was a significant increase in the aqueous column after the administration of our SLT protocol (n = 13; P < 0.05). This correlated with the degree of IOP reduction (n = 13; Pearson’s correlation coefficient 0.7; P = 0.007) and the improvement in MD observed postintervention (n = 8; Pearson’s correlation coefficient 0.75; P = 0.03). Autocorrelation analysis demonstrated a faster rate of decay in an aqueous vein after intervention, indicating an increase in flow rate.ConclusionsHemoglobin video imaging can be incorporated into a routine clinic slit-lamp examination to allow a detailed assessment and quantification of aqueous outflow in real time. It has the potential to be used to help target therapeutic interventions to improve aqueous outflow and further advance our understanding of aqueous outflow dysregulation in the pathogenesis of glaucoma.

Thresholds for identifying pathological intracranial pressure in paediatric traumatic brain injury

Intracranial pressure (ICP) monitoring forms an integral part of the management of severe traumatic brain injury (TBI) in children. The prediction of elevated ICP from imaging is important when deciding on whether to implement invasive ICP monitoring for a patient. However, the radiological markers of pathologically elevated ICP have not been specifically validated in paediatric studies. Here in, we describe an objective, non-invasive, quantitative method of stratifying which patients are likely to require invasive monitoring. A retrospective review of patients admitted to Cambridge University Hospital’s Paediatric Intensive Care Unit between January 2009 and December 2016 with a TBI requiring invasive neurosurgical monitoring was performed. Radiological biomarkers of TBI (basal cistern volume, ventricular volume, volume of extra-axial haematomas) from CT scans were measured and correlated with epochs of continuous high frequency variables of pressure monitoring around the time of imaging. 38 patients were identified. Basal cistern volume was found to correlate significantly with opening ICP (r = −0.53, p < 0.001). The optimal threshold of basal cistern volume for predicting high ICP (ge 20 mmHg) was a relative volume of 0.0055 (sensitivity 79%, specificity 80%). Ventricular volume and extra-axial haematoma volume did not correlate significantly with opening ICP. Our results show that the features of pathologically elevated ICP in children may differ considerably from those validated in adults. The development of quantitative parameters can help to predict which patients would most benefit from invasive neurosurgical monitoring and we present a novel radiological threshold for this.

Minimally Invasive Pancreatic Necrosectomy: A step-up approach towards ultra-low mortality in 103 consecutive procedures

Introduction: Infected pancreatic necrosis carries up to 70% risk of mortality. Open necrosectomy, previously regarded as standard treatment, carries very high risk of morbidity and mortality. Step-up management with percutaneous drainage followed by minimally invasive pancreatic necrosectomy (MIPN) has shown improved outcomes. We report the outcomes of the protocol developed at Cambridge of ‘early’ percutaneous drainage followed by ‘delayed’ MIPN. Method: Cambridge University Hospital is a tertiary referral centre for pancreatic surgery including complicated pancreatitis. Retrospective analysis of all MIPNs between December 2009 and October 2018. Demographics, morbidity and mortality outcomes are reported. Result: During the 9-year period, 103 MIPNs were performed in 86 patients, with 12 (13.9%) needing multiple procedures. The mean age was 58 ±15 years, with 74.4% (n=64) being male gender and 50.0% (n=43) with BMI more than 30 Kg/m2.Thirty (34.9%) patients had required preoperative ITU admission for multi-organ support related to infected necrosis. The mean time for insertion of percutaneous drain was 28 days (range 1-99). The mean time of the MIPN from acute episode was 45 days (range 4-307). Thirteen patients (15.1%) required admission to ITU after MIPN with a mean stay of 22 days (range 1-104). Composite endpoint for complications including bleeding needing intervention (n=5), multi-organ failure (19) and fistula (5) were 29 (33.7%), which was considered as the morbidity rate. 30-day and 90-day mortality following MIPN was 2.3% (n=2) and 5.8% (n=5), all deaths were due to sepsis and multi-organ failure. Conclusion: This is the lowest reported mortality rate for patients with infected pancreatic necrosis. Minimally invasive management with early percutaneous drain insertion followed by delayed MIPN is associated with ultra-low mortality. Management of complicated necrotizing pancreatitis almost invariably requires tertiary referral expertise as multimodal approaches, complex medical and ITU involvement, multiple procedures, prolonged admissions and long-term follow-up.

A Cross-Sectional Questionnaire Study of Tinnitus Awareness and Impact in a Population of Adult Cochlear Implant Users.

The primary aim was to identify the proportion of individuals within the adult cochlear implant population who are aware of tinnitus and those who report a negative impact from this perception, using a bespoke questionnaire designed to limit bias. A secondary aim was to use qualitative analysis of open-text responses to identify themes linked to tinnitus perception in this population. A cross-sectional questionnaire study of a large clinical population who received an implant from Cambridge University Hospitals, United Kingdom. Seventy-five percent of respondents reported tinnitus awareness. When impact scores for six areas of difficulty were ranked, 13% of individuals ranked tinnitus their primary concern and nearly a third ranked tinnitus in the top two positions. Tinnitus impact was not found to reduce with duration since implantation. The most common open-text responses were linked to a general improvement postimplantation and acute tinnitus alleviation specific to times when the device was in use. Tinnitus is a problem for a significant proportion of individuals with a cochlear implant. Clinicians, scientists, and cochlear implant manufacturers should be aware that management of tinnitus may be a greater priority for an implantee than difficulties linked to speech perception. Where a positive effect of implantation was reported, there was greater evidence for masking of tinnitus via the implant rather than reversal of maladaptive plasticity.

Persistence of Imported Malaria Into the United Kingdom: An Epidemiological Review of Risk Factors and At-risk Groups.

BackgroundThe United Kingdom documented a decline of >30% in imported cases of malaria annually between 1996 and 2003; however, there are still approximately 1700 cases and 5–10 deaths each year. Prophylaxis health messages focus on families returning to their country of origin.MethodsWe reviewed 225 records of patients seen in Cambridge University Hospital Foundation Trust [CUHFT], a tertiary referral center in Cambridge, England. All records of patients seen in CUHFT between 2002–2016 were analyzed in the context of national figures from Public Health England.ResultsBetween 2004–2016, there was no decrease in imported cases of malaria locally or nationally. Plasmodium falciparum remains responsible for most imported infections (66.7%); Plasmodium vivax contributed 15.1%, Plasmodium malariae 4%, and Plasmodium ovale 6.7%; 7.5% (17/225) of patients had an incomplete record. Most cases were reported in people coming from West Africa. Sierra Leone and the Ivory Coast had the highest proportions of travelers being infected at 8 and 7 per 1000, respectively. Visiting family in the country of origin (27.8%) was the commonest reason for travel. However, this was exceeded by the combined numbers traveling for business and holidays (22.5% and 20.1%, respectively). Sixty percent of patients took no prophylaxis. Of those who did, none of the patients finished their chemoprophylaxis regimen.ConclusionsSignificant numbers of travelers to malarious countries still take no chemoprophylaxis. Health advice about prophylaxis before travel should be targeted not only at those visiting family in their country of origin but also to those traveling for holiday and work.

The Cambridge experience with buried bumpers

AimBuried Bumper (BB) is a complication of percutaneous endoscopic gastrostomy (PEG) that leads to tube dysfunction and major morbidity. Although many techniques have been described to manage BB, none are universally adopted, and laparotomy remains the mainstay. We introduce a novel endoscopic technique in paediatric surgery that avoids laparotomy. MethodsA retrospective review of medical records of patients who presented with BB to Cambridge University Hospital, UK, between January 2012 and June 2018 was done. Data collected included: demographics, tube size and type, interval between insertion and diagnosis of BB, hospital stay, technique used, and postoperative complications. The technique involved using an endoscopic snare passed from inside the stomach lumen through the PEG lumen to the outside, guided if required by a stiff nylon thread if no part of the PEG was visible, grasping the PEG tube externally after cutting it short, followed by a retrograde pull to remove the buried tube via the mouth. Main resultsFifteen BBs were found in ten patients. Median patient age was 5.25 years (1.2–16.6). Median time between gastrostomy insertion and diagnosis of BB was 9 months (1–32). Twelve BBs were removed endoscopically with no postoperative complications. Patients had a replacement inserted through the original track and were discharged within 24 h. Two underwent laparotomies performed by surgeons unfamiliar with endoscopic technique, and one was converted to laparotomy owing to inability to transverse an encrusted and closed PEG tube lumen. ConclusionEndoscopic retrograde BB removal is a safe, easy, and quick technique with minimal complications. We strongly advocate widespread adoption of the technique before considering a laparotomy. Level of evidenceTreatment study: Level IV.

Whole Genome Sequence Analysis of Intensively Ill Children: A Prospective Study of Parent-Child Trios in the UK

Background: Each year 95,000 neonates are admitted to intensive care units (ICU) in the UK. With growing evidence that Mendelian diseases present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist with acute care decisions and long-term planning within a national health care system. Methods: We performed trio whole genome sequence analysis (WGS) on a prospective cohort of 159 families recruited from neonatal and paediatric intensive care units (NICU and PICU) in the UK over a period of 18 months. We developed a research pipeline in collaboration with the National Health Service (NHS) to deliver validated pertinent pathogenic findings from WGS within 2-3 weeks of recruitment. Findings: 48% of families approached consented to the study and 87% of those recruited provided parental samples for trio analysis. Overall, ~20% received a molecular genetic diagnosis. The phenotypic description of the child was a poor predictor of the gene identified in 87% of cases. The diagnosis affected clinical management in >75% of cases including modification of treatments, initiating new specialist care pathways and/or informing palliative care decisions. A 2-3 week turnaround was sufficient for clinical decision making. Interpretation: The use of WGS in intensively ill children is acceptable to parents and trio analysis facilitates diagnoses. A trio gene agnostic analysis was highly effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. Scale up of this process will support NHS commissioning of WGS for first line management of intensively ill children. Funding Statement: The study was supported by the Rosetrees Trust, Cambridge Biomedical Research Centre (FLR and DHR) and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966). Declaration of Interests: The authors state: none declared. Ethics Approval Statement: Participants for this study were recruited through NHS Cambridge University Hospitals Foundation Trust under NRES Cambridge South Research Ethics Committee approval 13/EE/0325.

Editor's Choice – Mid-term Migration and Device Failure Following Endovascular Aneurysm Sealing with the Nellix Stent Graft System – a Single Centre Experience

Endovascular aneurysm sealing (EVAS) with the Nellix stent graft system is a novel concept in the management of abdominal aortic aneurysm (AAA) that aims to reduce the prevalence of all endoleaks following endovascular repair. There are few data describing the longer-term durability of this approach. The aim was to report the longer-term outcomes following EVAS in a single centre. This is a retrospective review of all patients that underwent Nellix at Cambridge University Hospitals Foundation Trust. Factors that are described as device failure include secondary sac rupture, graft explantation, further surgical procedures for Type 1 endoleak, or major migration of the stent grafts with pressurisation of the aortic sac. A total of 161 patients have been treated with Nellix. The indications included primary AAA (n=115), ruptured AAA (n=4), salvage of other aortic grafts (n=18), primary iliac aneurysm (n=6), and chimney EVAS (ChEVAS) for pararenal AAA (n=18). In total there have been 42 graft failures in patients treated with EVAS for primary AAA. The 4 year freedom from graft failure was 42% in patients treated for primary AAA. Failures mostly occurred more than 2 years post-Nellix implant. There were eight secondary sac ruptures (incidence 2.4 per 100 person years) and there have been 14 graft explants. Failure of aneurysm sealing following treatment with Nellix has been more common than anticipated and can cause aortic rupture. Post-operative surveillance of Nellix stent grafts is crucial to identify features of failure.

Care home residents admitted to hospital through the emergency pathway: characteristics and associations with inpatient mortality.

Routinely collected hospital information could help to understand the characteristics and outcomes of care home residents admitted to hospital as an emergency. This retrospective 2-year service evaluation included first emergency admissions of any older adult (≥75 years) presenting to Cambridge University Hospital. Routinely collected patient variables were captured by an electronic patient record system. Care home status was established using an official register of care homes. 7.7% of 14,777 admissions were care home residents. They were older, frailer, more likely to be women and have cognitive impairment than those admitted from their own homes. Additionally, 42% presented with an Emergency Department Modified Early Warning Score above the threshold triggering urgent review, compared to 26% of older adults from their own homes. Admission from a care home was associated with higher 30-day inpatient mortality (11.1 vs 5.7%), which persisted after multivariable adjustment (hazard ratio: 1.42; 95% confidence interval: 1.09-1.83; p=0.008). Care home residents admitted to hospital as an emergency have high illness acuity and inpatient mortality.