London Hospitals NHS Foundation Trust Research Articles

Safety and Efficacy of Anakinra in Haemophagocytic Lymphohistiocytosis Associated with Acute Leukaemia

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition in which immune hyperactivation and dysregulation results in a cytokine storm. It may be primary or secondary to infection, autoimmune disorders or malignancies (HLH-M). Lymphoma is the most widely described association in HLH-M; there is very limited data linking acute leukaemia and HLH. Current recommended treatments for HLH-M include steroids, IVIG and etoposide-containing regimens. In contrast, the recommended treatment in HLH- Macrophage activation syndrome is anti-IL1 directed therapy such as anakinra. In 2021 NHS England approved the use of anakinra to treat HLH of any cause, but the safety and efficacy data of anakinra in HLH-M is limited. We report a retrospective review of all patients diagnosed with HLH and acute leukaemia (AML) or acute lymphoblastic leukaemia (ALL) in a single London tertiary referral centre (University College London Hospitals NHS Foundation Trust (UCLH)), between 1 January2019 and 31 December 2022. We analysed electronic health records (EHR) of all patients diagnosed with ALL or AML and cross-referenced this with records of all patients referred to the UCLH HLH MDT. This identified 468 patients with acute leukaemia, of whom 13 (2.8%) were diagnosed with HLH. For diagnostic purposes, we utilised H scores (comprising laboratory and clinical parameters providing an HLH probability for each patient) using clinical and laboratory data collected from the EHR. HLH was diagnosed in patients with a clinical suspicion of HLH and an H score of >169. Patients were treated with various types of immunosuppressive therapy (IST). Twelve (92%) received anakinra, three (17%) of whom had anakinra monotherapy whilst the remainder had anakinra with steroids (38%), steroids and IVIG (15%), or steroids, IVIG and etoposide (8%). Anakinra was given intravenously in eleven patients and subcutaneously in one, with a mean daily dose of 4.6mg/kg. All patients required critical care input during their HLH treatment. Eight (62%) were admitted to intensive care unit (ICU) on diagnosis with HLH and required ventilatory and vasopressor support; the remainder were reviewed by critical care outreach. 92% patients had an initial rapid clinicopathological response following IST, becoming afebrile, reduction in oxygen requirement and haemodynamic stability seen within 24-72 hours. One patient (8%) had an initial clinical response to anakinra, methylprednisolone and IVIG triple therapy, but displayed subsequent rapid deterioration in the context of pseudomonal infection and died of multiorgan failure. Nine patients (69%) had no clinicopathological recurrence of HLH following initial treatment. Three (23%) had an initial clinical response to IST but had subsequent biochemical and clinical relapse of HLH. These patients all had relapsed/refractory disease on HLH recurrence. Only one (8%) patient died from HLH. Eight (62%) remain in remission from leukaemia at the end of the study period. Three patients (23%) died of refractory leukaemia, whilst a fourth patient is receiving palliative care for refractory disease. Although the link between HLH and lymphoma is well characterised, there is limited data on HLH in the context of acute leukaemia. In this case series, 2.8% of the patients treated with acute leukaemia developed HLH, which is comparable to the 3% for lymphoma quoted elsewhere. Although 92% of patients had microbiological or radiological evidence of infection on HLH diagnosis, many infections involved organisms not classically associated with HLH e.g. rhinovirus, indicating that the underlying leukaemia may play a central role in HLH-M pathogenesis. This is highlighted by the relapse of HLH which occurred alongside leukaemia relapse in three patients. Treatment responses and outcomes were favourable compared to the existing literature. Tamamyan et al reported an overall survival rate of 15% in 13 patients with HLH-M. Delavigne et al reported a three-month mortality rate of 36% in AML patients presenting with HLH during induction, compared to our figure of 23% for this time period and our overall survival rate of 62%. We believe this is the first case series demonstrating the effectiveness and high overall survival of HLH-M patients with concurrent leukaemia diagnosis using anakinra. Early treatment with anakinra alongside other immunosuppression may explain the trend towards improved outcomes in our cohort.

Editorial introductions.

Editorial introductions.

The role of the electroencephalogram (EEG) in determining the aetiology of catatonia: a systematic review and meta-analysis of diagnostic test accuracy

Catatonia is a psychomotor syndrome that has a wide range of aetiologies. Determining whether catatonia is due to a medical or psychiatric cause is important for directing treatment but is clinically challenging. We aimed to ascertain the performance of the electroencephalogram (EEG) in determining whether catatonia has a medical or psychiatric cause, conventionally defined. In this systematic review and meta-analysis of diagnostic test accuracy (PROSPERO CRD42021239027), Medline, EMBASE, PsycInfo, and AMED were searched from inception to May 11, 2022 for articles published in peer-reviewed journals that reported EEG findings in catatonia of a medical or psychiatric origin and were reported in English, French, or Italian. Eligible study types were clinical trials, cohort studies, case-control studies, cross-sectional studies, case series, and case reports. The reference standard was the final clinical diagnosis. Data extraction was conducted using individual patient-level data, where available, by two authors. We prespecified two types of studies to overcome the limitations anticipated in the data: larger studies (n≥5), which were suitable for formal meta-analytic methods but generally lacked detailed information about participants, and smaller studies (n<5), which were unsuitable for formal meta-analytic methods but had detailed individual patient level data, enabling additional sensitivity analyses. Risk of bias and applicability were assessed with the QUADAS-2 tool for larger studies, and with a published tool designed for case reports and series for smaller studies. The primary outcomes were sensitivity and specificity, which were derived using a bivariate mixed-effects regression model. 355 studies were included, spanning 707 patients. Of the 12 larger studies (5 cohort studies and 7 case series), 308 patients were included with a mean age of 48.2 (SD=8.9) years. 85 (52.8%) were reported as male and 99 had catatonia due to a general medical condition. In the larger studies, we found that an abnormal EEG predicted a medical cause of catatonia with a sensitivity of 0.82 (95% CI 0.67-0.91) and a specificity of 0.66 (95% CI 0.45-0.82) with an I 2 of 74% (95% CI 42-100%). The area under the summary ROC curve offered excellent discrimination (AUC=0.83). The positive likelihood ratio was 2.4 (95% CI 1.4-4.1) and the negative likelihood ratio was 0.28 (95% CI 0.15-0.51). Only 5 studies had low concerns in terms of risk of bias and applicability, but a sensitivity analysis limited to these studies was similar to the main analysis. Among the 343 smaller studies, 399 patients were included, resulting in a sensitivity of 0.76 (95% CI 0.71-0.81), specificity of 0.67 (0.57-0.76) and AUC=0.71 (95% CI 0.67-0.76). In multiple sensitivity analyses, the results were robust to the exclusion of reports of studies and individuals considered at high risk of bias. Features of limbic encephalitis, epileptiform discharges, focal abnormality, or status epilepticus were highly specific to medical catatonia, but features of encephalopathy had only moderate specificity and occurred in 23% of the cases of psychiatric catatonia in smaller studies. In cases of diagnostic uncertainty, the EEG should be used alongside other investigations to ascertain whether the underlying cause of catatonia is medical. The main limitation of this review is the differing thresholds for considering an EEG abnormal between studies. Wellcome Trust, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust.

Working in a UK national proton radiotherapy facility: the therapeutic radiographer perspective

Abstract The first national UK proton beam therapy centre opened at The Christie NHS Foundation Trust in 2018, which alongside University College London Hospitals NHS Foundation Trust (UCLH) proton beam therapy centre, is expected to treat approximately seven-hundred and fifty patients per year at service ramp up. The aim of this editorial is to share with a wider audience the role of a Band 6 proton senior treatment radiographer working in a national NHS service and future developments of the service. Prior to the service being clinical, a range of processes were followed, including the creation of quality documents, departmental training and end-to-end testing, with the first patient receiving treatment in December 2018. Proton senior radiographers are responsible for the delivery of safe and accurate radiotherapy and ensuring a smooth patient pathway, through a multi-collaborative team approach. Although there are key differences between proton and photon radiotherapy, the fundamental aspects, including radiation principles, governance and patient advice are the same. The training package for proton senior radiographers includes an individual local induction as part of the proton education and competency framework, which incorporates practical learning, including clinical supervision and workshops, plus audio-visual presentations and workbooks to complete. Future developments of proton beam therapy include proton arc therapy and flash therapy, alongside educational developments, such as training the future workforce and advanced practice consultant radiographer roles. Shared learning through multi-collaboration of international proton beam therapy centres is crucial to improve care for future service users.

Editorial introductions.

Editorial introductions.

Editorial introductions.

Editorial introductions.

Providing support and raising awareness of a delicate subject.

Clare Akers, Clinical Nurse Practitioner, University College London Hospitals NHS Foundation Trust, was runner up in the urology nurse of the year category in the BJN Awards 2020.

Safety and Immunogenicity Report from the Com-COV Study – a Single-Blind Randomised&amp;nbsp;Non-Inferiority&amp;nbsp;Trial&amp;nbsp;Comparing&amp;nbsp;Heterologous&amp;nbsp;And Homologous&amp;nbsp;Prime-Boost Schedules with An Adenoviral Vectored and mRNA COVID-19 Vaccine

Safety and Immunogenicity Report from the Com-COV Study – a Single-Blind Randomised&amp;nbsp;Non-Inferiority&amp;nbsp;Trial&amp;nbsp;Comparing&amp;nbsp;Heterologous&amp;nbsp;And Homologous&amp;nbsp;Prime-Boost Schedules with An Adenoviral Vectored and mRNA COVID-19 Vaccine

Mohankumar Adiseshiah

Born in Chennai, the son of the renowned UNESCO educationalist, Malcolm Adiseshiah, Mo graduated from Westminster Hospital Medical School with the surgery prize Mo trained in the heyday of invasive...

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

SummaryBackgroundBefore the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19.MethodsIn this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I2 statistics, and assessment of study quality.Findings1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5–36·0] of 129 patients), depressed mood (42 [32·6%; 24·7–40·9] of 129), anxiety (46 [35·7%; 27·6–44·2] of 129), impaired memory (44 [34·1%; 26·2–42·5] of 129), and insomnia (54 [41·9%; 22·5–50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5–14·1] of 332 patients), insomnia (34 [12·1%; 8·6–16·3] of 280), anxiety (21 [12·3%; 7·7–17·7] of 171), irritability (28 [12·8%; 8·7–17·6] of 218), memory impairment (44 [18·9%; 14·1–24·2] of 233), fatigue (61 [19·3%; 15·1–23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9–37·3] of 181) and sleep disorder (14 [100·0%; 88·0–100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7–42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1–18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1–19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1–84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality.InterpretationIf infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term.FundingWellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.

Experience from the first UK inter-regional specialist multidisciplinary meeting in the diagnosis and management of IgG4-related disease

Immunoglobulin G4-related disease (IgG4-RD) is a complex multisystem fibro-inflammatory disorder, requiring diagnostic differentiation from malignancy and other immune-mediated conditions, and careful management to minimise glucocorticoid-induced toxicity and prevent progressive organ dysfunction. We describe the experience of the first inter-regional specialist IgG4-RD multidisciplinary team meeting (MDM) incorporating a broad range of generalists and specialists, held 6-weekly via web-link between Oxford University Hospitals NHS Foundation Trust and University College London Hospitals NHS Foundation Trust. Over 3 years, there were 206 discussions on 156 patients. Of these, 97 (62%) were considered to have definite or possible IgG4-RD; 67% had multi-organ involvement and 23% had a normal serum IgG4. The average number of specialist opinions sought prior to MDM was four per patient. Management was changed in the majority of patients (74%) with the treatment escalation recommended in 61 cases, including 19 for rituximab. Challenges arose from delays and misdiagnosis, cross-specialty presentation and the management of sub-clinical disease. Our cross-discipline IgG4-RD MDM enabled important diagnostic and management decisions in this complex multisystem disorder, and can be used as a model for other centres in the UK.

Activities of daily living in myotonic dystrophy type 1.

The objective of this cross-sectional, observational study was to investigate performance of activities of daily living in patients with myotonic dystrophy type 1 (DM1). Adults with genetically confirmed DM1 were recruited from Newcastle University (Newcastle upon Tyne, UK) and University College London Hospitals NHS Foundation Trust (London, UK). Data on activities of daily living were recorded through the DM1-ActivC (scale scores range between 0 and 100, where a higher/lower score indicates a higher/lower ability). Our sample comprised 192 patients with DM1 (mean age: 46years; 51% female). Patients reported most difficulties with running, carrying and putting down heavy objects, and standing on one leg, and least difficulties with eating soup, washing upper body, and taking a shower. Irrespective of the disease duration (mean: 20years), most patients were able to perform basic and instrumental activities of daily living (eg personal hygiene and grooming, showering, eating, cleaning and shopping), with the exception of functional mobility/transfer tasks (eg walking uphill and running). The mean DM1-ActivC total score was estimated at 71 (95% CI: 68-74). Estimated progenitor cytosine-thymine-guanine repeat length and age explained 27% of the variance in DM1-ActivC total scores (P<.001). We show that DM1 impairs performance of activities of daily living, in particular those requiring a high degree of muscle strength, stability and coordination. Yet, across the evolution of the disease, the majority of patients will still be able to independently perform most basic and instrumental activities of daily living.

CN47 - Young people’s experiences when active cancer treatment ends

BackgroundThe end of active treatment is known to be a period of high stress in young people’s cancer timeline but little is known about young people’s experiences in this transition phase. This study aimed to understand the experiences and needs of young people at the end of treatment (EoT), how these are currently being met, and how best to provide support to young people. MethodsThis was a multi-stage, mixed methods study, conducted from January to December 2018, exploring the EoT experience from the perspectives of young people and healthcare professionals caring for them. This paper reports on the EoT experiences of young people (n=11), all within 12 months of EoT, who participated in semi-structured telephone or face-to-face interviews. Interviews were transcribed and analysed using thematic analysis. ResultsThree key themes emerged from the data relating to young people’s experience of ending active treatment: 1) Challenges with social reintegration; 2) Expectations versus the reality of ending treatment; 3) Sudden loss of the safe “bubble” of treatment. Some young people reported feeling isolated from their peers after they finished treatment, feeling they no longer belonged to previous peer groups. Young people reported challenges in managing both their own expectations and expectations of others about how they would feel at the end of treatment, versus the reality of how they actually felt both physically and psychosocially. They did not expect to experience onerous ongoing physical issues including pain, nausea and fatigue. Additionally, young people experienced a range of conflicting emotions: excitement, happiness, nerves, fear, shock, surprise and uncertainty. They described realising they were no longer regularly surrounded by healthcare professionals, and feared the loss of the familiar routine of regular hospital visits. ConclusionsEnd of treatment is a transition that results in changed relationships, routines, assumptions and roles. Young people often lacked awareness of and were under prepared for this. Having a better understanding of the unpredictable and ongoing nature of both physical and psychosocial issues they may face at the EoT would be beneficial, as would reassurance that challenges during this transition period are both acceptable and expected. Legal entity responsible for the studyUniversity College London Hospitals NHS Foundation Trust. FundingTeenage Cancer Trust. DisclosureAll authors have declared no conflicts of interest.

Nosocomial transmission of influenza: A retrospective cross-sectional study using next generation sequencing at a hospital in England (2012-2014).

BackgroundThe extent of transmission of influenza in hospital settings is poorly understood. Next generation sequencing may improve this by providing information on the genetic relatedness of viral strains.ObjectivesWe aimed to apply next generation sequencing to describe transmission in hospital and compare with methods based on routinely‐collected data.MethodsAll influenza samples taken through routine care from patients at University College London Hospitals NHS Foundation Trust (September 2012 to March 2014) were included. We conducted Illumina sequencing and identified genetic clusters. We compared nosocomial transmission estimates defined using classical methods (based on time from admission to sample) and genetic clustering. We identified pairs of cases with space‐time links and assessed genetic relatedness.ResultsWe sequenced influenza sampled from 214 patients. There were 180 unique genetic strains, 16 (8.8%) of which seeded a new transmission chain. Nosocomial transmission was indicated for 32 (15.0%) cases using the classical definition and 34 (15.8%) based on genetic clustering. Of the 50 patients in a genetic cluster, 11 (22.0%) had known space‐time links with other cases in the same cluster. Genetic distances between pairs of cases with space‐time links were lower than for pairs without spatial links (P < .001).ConclusionsGenetic data confirmed that nosocomial transmission contributes significantly to the hospital burden of influenza and elucidated transmission chains. Prospective next generation sequencing could support outbreak investigations and monitor the impact of infection and control measures.

Qualitative study to identify issues affecting quality of life in adults with craniofacial anomalies

Our objective was to identify key issues that affect the quality of life (QoL) of adult patients with craniofacial anomalies. This was a qualitative prospective study using in-depth, semi-structured interviews. Ten patients who fulfilled the inclusion criteria were recruited during their attendance at the Adult Craniofacial Clinic at the Eastman Dental Hospital, University College London Hospitals NHS Foundation Trust. Interviews ceased when no new themes arose. A framework method of analysis was used to identify themes that related to QoL. Opinions varied and, although some were positive, the eight main themes that emerged were mainly negative. One of the main themes was that of emotional issues. Within this theme, subthemes included teasing, bullying and abuse, as well as low mood, anxiety, depression, and self-harm. Participants experienced a range of feelings as a result of their craniofacial conditions and expressed the need for further support. Healthcare professionals involved in the treatment of these patients, should be aware of these issues and give advice about how to access further support.

Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study.

Men with suspected prostate cancer usually undergo transrectal ultrasound (TRUS)-guided prostate biopsy. TRUS-guided biopsy can cause side effects and has relatively poor diagnostic accuracy. Multiparametric magnetic resonance imaging (mpMRI) used as a triage test might allow men to avoid unnecessary TRUS-guided biopsy and improve diagnostic accuracy. To (1) assess the ability of mpMRI to identify men who can safely avoid unnecessary biopsy, (2) assess the ability of the mpMRI-based pathway to improve the rate of detection of clinically significant (CS) cancer compared with TRUS-guided biopsy and (3) estimate the cost-effectiveness of a mpMRI-based diagnostic pathway. A validating paired-cohort study and an economic evaluation using a decision-analytic model. Eleven NHS hospitals in England. Men at risk of prostate cancer undergoing a first prostate biopsy. Participants underwent three tests: (1) mpMRI (the index test), (2) TRUS-guided biopsy (the current standard) and (3) template prostate mapping (TPM) biopsy (the reference test). Diagnostic accuracy of mpMRI, TRUS-guided biopsy and TPM-biopsy measured by sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using primary and secondary definitions of CS cancer. The percentage of negative magnetic resonance imaging (MRI) scans was used to identify men who might be able to avoid biopsy. Diagnostic study - a total of 740 men were registered and 576 underwent all three tests. According to TPM-biopsy, the prevalence of any cancer was 71% [95% confidence interval (CI) 67% to 75%]. The prevalence of CS cancer according to the primary definition (a Gleason score of ≥ 4 + 3 and/or cancer core length of ≥ 6 mm) was 40% (95% CI 36% to 44%). For CS cancer, TRUS-guided biopsy showed a sensitivity of 48% (95% CI 42% to 55%), specificity of 96% (95% CI 94% to 98%), PPV of 90% (95% CI 83% to 94%) and NPV of 74% (95% CI 69% to 78%). The sensitivity of mpMRI was 93% (95% CI 88% to 96%), specificity was 41% (95% CI 36% to 46%), PPV was 51% (95% CI 46% to 56%) and NPV was 89% (95% CI 83% to 94%). A negative mpMRI scan was recorded for 158 men (27%). Of these, 17 were found to have CS cancer on TPM-biopsy. Economic evaluation - the most cost-effective strategy involved testing all men with mpMRI, followed by MRI-guided TRUS-guided biopsy in those patients with suspected CS cancer, followed by rebiopsy if CS cancer was not detected. This strategy is cost-effective at the TRUS-guided biopsy definition 2 (any Gleason pattern of ≥ 4 and/or cancer core length of ≥ 4 mm), mpMRI definition 2 (lesion volume of ≥ 0.2 ml and/or Gleason score of ≥ 3 + 4) and cut-off point 2 (likely to be benign) and detects 95% (95% CI 92% to 98%) of CS cancers. The main drivers of cost-effectiveness were the unit costs of tests, the improvement in sensitivity of MRI-guided TRUS-guided biopsy compared with blind TRUS-guided biopsy and the longer-term costs and outcomes of men with cancer. The PROstate Magnetic resonance Imaging Study (PROMIS) was carried out in a selected group and excluded men with a prostate volume of > 100 ml, who are less likely to have cancer. The limitations in the economic modelling arise from the limited evidence on the long-term outcomes of men with prostate cancer and on the sensitivity of MRI-targeted repeat biopsy. Incorporating mpMRI into the diagnostic pathway as an initial test prior to prostate biopsy may (1) reduce the proportion of men having unnecessary biopsies, (2) improve the detection of CS prostate cancer and (3) increase the cost-effectiveness of the prostate cancer diagnostic and therapeutic pathway. The PROMIS data set will be used for future research; this is likely to include modelling prognostic factors for CS cancer, optimising MRI scan sequencing and biomarker or translational research analyses using the blood and urine samples collected. Better-quality evidence on long-term outcomes in prostate cancer under the various management strategies is required to better assess cost-effectiveness. The value-of-information analysis should be developed further to assess new research to commission. Current Controlled Trials ISRCTN16082556 and NCT01292291. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 39. See the NIHR Journals Library website for further project information. This project was also supported and partially funded by the NIHR Biomedical Research Centre at University College London (UCL) Hospitals NHS Foundation Trust and UCL and by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research Biomedical Research Centre and was co-ordinated by the Medical Research Council's Clinical Trials Unit at UCL (grant code MC_UU_12023/28). It was sponsored by UCL. Funding for the additional collection of blood and urine samples for translational research was provided by Prostate Cancer UK.

Editorial introductions

Editorial introductions

Nurses' and midwives' revalidation preparation experiences at one NHS trust.

Since 1 April 2016, UK nurses and midwives have been required to undertake revalidation to maintain their registration with the Nursing and Midwifery Council. This article reports the results of a service evaluation to identify the revalidation preparation experiences of nurses and midwives at University College London Hospitals NHS Foundation Trust (UCLH). Findings suggest that the revalidation preparation process at UCLH supports staff to seek opportunities continually for practice feedback, reflect on their everyday experiences and link their learning to ongoing professional development.

Novel diagnostic technologies for clinical and frontline use: Advanced diagnostics based on molecular markers and analysis technologies has been improving diagnosis across a wide range of diseases.

Misdiagnosis is a major problem at all levels of health care causing unnecessary pain or even death as it prevents efficient, timely, and adequate treatment. In the case of infectious diseases, for instance, identification of the wrong pathogen might lead to incorrect prescription of antibiotics. While reliable data on the full extent of misdiagnosis are elusive, some evidence of the problem's scale came from a meta‐analysis of deaths within US intensive care units (ICUs), which found that 40,500 adult patients in the USA may die each year as a result of a misdiagnosis [1]. An earlier, more comprehensive, study based on searching the MEDLINE (1950–2007) and EMBASE (1980–2007) electronic databases for articles about diagnostic error or delay in primary care also found that misdiagnosis was a significant issue, although the reasons varied with each condition [2]. Moreover, many diseases, in particular rare diseases, are hard to diagnose as physicians are often unfamiliar with the symptoms; alternatively, the symptoms might be vague or untypical, as can happen with some autoimmune disorders. Many cancers in their early stages do not even show any symptoms, which prevents timely and effective treatment. There are also complex disorders that present highly varied symptoms that can lead doctors in the wrong direction, at least at first. Not surprisingly, there is an immense interest in molecular‐level diagnostics that promise to deliver far more accurate and rapid diagnoses without relying on interpreting symptoms. While this can raise new challenges, such as poor‐quality samples or analyzing complex data sets, molecular diagnostics has made progress across a range of clinical conditions, including infectious diseases and some cancers, through identification of characteristic molecular markers. A wide variety of diseases could also be diagnosed using next‐generation sequencing (NGS), including solid cancers or rare diseases of genetic origin. NGS …

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

SummaryBackgroundStatin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.MethodsIn this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FindingsData were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30).InterpretationPCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FundingBritish Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.