Systemic Inflammation, the Peripheral Blood Transcriptome, and Primary Melanoma.

Peripheral blood transcriptomes from 383 patients with newly diagnosed melanoma were subjected to differential gene expression analysis. The hypotheses were that impaired systemic immunity is associated with poorer prognosis (thicker tumors and fewer tumor-infiltrating lymphocytes) and evidence of systemic inflammation (high-sensitivity CRP and fibrinogen levels). Higher fibrinogen levels were associated with thicker primary tumors. In single-gene analysis, high-sensitivity CRP levels were significantly associated with higher blood CD274 expression (coding for PD-L1), but each was independently prognostic, with high-sensitivity CRP associated with increased mortality and higher CD274 protective, independent of age. Pathway analysis identified downregulation of immune cell signaling pathways in the blood of people with thicker tumors and notable upregulation of signal transducer and activator of transcription 1 gene STAT1 in people with brisk tumor-infiltrating lymphocytes. Transcriptomic data provided evidence for increased NF-kB signaling with higher inflammatory markers but with reduction in expression of HLA class II molecules and higher CD274, suggesting that aberrant systemic inflammation is a significant mediator of reduced immune function in melanoma. In summary, transcriptomic data revealed evidence of reduced immune function in patients with thicker tumors and fewer tumor-infiltrating lymphocytes at diagnosis. Inflammatory markers were associated with thicker primaries and independently with death from melanoma, suggesting that systemic inflammation contributes to that reduced immune function.

Computed tomography-based radiomic markers are independent prognosticators of survival in advanced laryngeal cancer: a pilot study.

OBJECTIVE: Advanced laryngeal cancers are clinically complex; there is a paucity of modern decision-making models to guide tumour-specific management. This pilot study aims to identify computed tomography-based radiomic features that may predict survival and enhance prognostication. METHODS: Pre-biopsy, contrast-enhanced computed tomography scans were assembled from a retrospective cohort (n = 72) with advanced laryngeal cancers (T3 and T4). The LIFEx software was used for radiomic feature extraction. Two features: shape compacity (irregularity of tumour volume) and grey-level zone length matrix - grey-level non-uniformity (tumour heterogeneity) were selected via least absolute shrinkage and selection operator-based Cox regression and explored for prognostic potential. RESULTS: A greater shape compacity (hazard ratio 2.89) and grey-level zone length matrix - grey-level non-uniformity (hazard ratio 1.64) were significantly associated with worse 5-year disease-specific survival (p < 0.05). Cox regression models yielded a superior C-index when incorporating radiomic features (0.759) versus clinicopathological variables alone (0.655). CONCLUSIONS: Two radiomic features were identified as independent prognostic biomarkers. A multi-centre prospective study is necessary for further exploration. Integrated radiomic models may refine the treatment of advanced laryngeal cancers.

Study of How Adiposity in Pregnancy has an Effect on outcomeS (SHAPES): protocol for a prospective cohort study.

INTRODUCTION: Maternal obesity increases the risk of multiple maternal and infant pregnancy complications, such as gestational diabetes and pre-eclampsia. Current UK guidelines use body mass index (BMI) to identify which women require additional care due to increased risk of complications. However, BMI may not accurately predict which women will develop complications during pregnancy as it does not determine amount and distribution of adipose tissue. Some adiposity measures (eg, waist circumference, ultrasound measures of abdominal visceral fat) can better identify where body fat is stored, which may be useful in predicting those women who need additional care. METHODS AND ANALYSIS: This prospective cohort study (SHAPES, Study of How Adiposity in Pregnancy has an Effect on outcomeS) aims to evaluate the prognostic performance of adiposity measures (either alone or in combination with other adiposity, sociodemographic or clinical measures) to estimate risk of adverse pregnancy outcomes. Pregnant women (n=1400) will be recruited at their first trimester ultrasound scan (11+2-14+1 weeks') at Newcastle upon Tyne National Health Service Foundation Trust, UK. Early pregnancy adiposity measures and clinical and sociodemographic data will be collected. Routine data on maternal and infant pregnancy outcomes will be collected from routine hospital records. Regression methods will be used to compare the different adiposity measures with BMI in terms of their ability to predict pregnancy complications. If no individual measure performs better than BMI, multivariable models will be developed and evaluated to identify the most parsimonious model. The apparent performance of the developed model will be summarised using calibration, discrimination and internal validation analyses. ETHICS AND DISSEMINATION: Ethical favourable opinion has been obtained from the North East: Newcastle & North Tyneside 1 Research Ethics Committee (REC reference: 22/NE/0035). All participants provide informed consent to take part in SHAPES. Planned dissemination includes peer-reviewed publications and additional dissemination appropriate to target audiences, including policy briefs for policymakers, media/social-media coverage for public and conferences for research TRIAL REGISTRATION NUMBER: ISRCTN82185177.

Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study.

Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.

Current practices in studies applying the target trial emulation framework: a protocol for a systematic review.

INTRODUCTION: Observational studies represent an alternative to estimate real-world causal effects in the absence of available randomised controlled trials (RCTs). Target trial emulation is a framework for the application of RCT design principles to emulate a hypothetical open-label RCT (the hypothetical target trial) using existing observational data as the primary data source as opposed to the prospective recruitment and measurement of randomised units. The aim of this systematic review is to investigate the practices of studies applying the target trial emulation framework to evaluate the effectiveness of interventions. METHODS AND ANALYSIS: We will systematically search in Medline (via Ovid), Embase (via Ovid, entries from medRxiv are included), PsycINFO (via Ovid), SCOPUS, Web of Science, Cochrane Library, the ISRCTN registry and ClinicalTrials.gov for all study reports and protocols which used the trial emulation framework (without time restriction). We will extract information concerning study design, data source, analysis, results, interpretation and dissemination. Two reviewers will perform study selection, data extraction and quality assessment. Disagreements between reviewers will be resolved by a third reviewer. A narrative approach will be used to synthesise and report qualitative and quantitative data. Reporting of the review will be informed by Preferred Reporting Items for Systematic Review and Meta-Analysis guidance (PRISMA). ETHICS AND DISSEMINATION: Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations.

Maternal age and the prevalence of congenital heart defects in Europe, 1995-2015: A register-based study.

BACKGROUND: Evidence on the direction and strength of association between maternal age and the prevalence of congenital heart defects (CHD) in different age group categories is conflicting. Some studies have illustrated different trends with an increase in prevalence in younger and older age groups while other studies have reported a linear relationship. Given the increase in maternal age over recent years, it is important to study the CHD prevalence by maternal age. OBJECTIVES: To examine the association between maternal age and the prevalence of CHD in Europe between 1995 and 2015 using population-based data from 24 registries belonging to the European Surveillance of Congenital Anomalies (EUROCAT) network. METHODS: Associations over time of all nonsyndromic CHD according to maternal age category and for three CHD severity groupings (severity group I: very severe; severity group II: severe; severity group III: less severe) were examined using Bayesian multilevel Poisson regression modeling. Further subgroup analyses were undertaken within four maternal age-bands: ≤24, 25-29, 30-34 and 35-44 years. Descriptive summaries are also presented. RESULTS: There were 51,608 nonsyndromic CHD cases in Europe over the 20-year study period. Total prevalence for all CHD combined was increased for younger mothers (≤24 years) and for mothers 35-44 years of age when compared with mothers aged 25-29 years (reference group) (IRR: 1.05, 95% CI: 1.02, 1.07). The total prevalence was increased for severity group I (very severe) only for younger mothers compared to those aged 25-29 years (IRR: 1.14, 95% CI: 1.04, 1.23). We found an increased prevalence of the following CHD subtypes: double outlet right ventricle (IRR:1.33, 95% CI: 1.09, 1.60), hypoplastic left heart syndrome (IRR: 1.18, 95% CI: 1.05, 1.32), hypoplastic right heart syndrome (IRR: 1.41, 95% CI: 1.05, 1.84), atrioventricular septal defect (IRR: 1.15, 95% CI: 1.01, 1.32), coarctation of aorta (IRR: 1.15, 95% CI: 1.03, 1.28) and atrial septal defect (IRR: 1.08, 95% CI: 1.02, 1.13). For older mothers (35-44 years) compared to the reference category, we observed an increased risk in the prevalence for severity group II (IRR: 1.09, 95% CI: 1.03, 1.14), severity group III (IRR: 1.05, 95% CI: 1.01, 1.08) and an increased prevalence of the CHD subtypes: Pulmonary valve stenosis (IRR: 1.22, 95% CI: 1.09, 1.34), ASD (IRR: 1.07, 95% CI: 1.02, 1.13), CoA (IRR: 1.18, 95% CI: 1.06, 1.32) and Tetralogy of Fallot (IRR: 1.14, 95% CI: 1.01, 1.28). Finally, for all age categories compared to the reference category, different associations of ASD and an increased prevalence of CoA was also observed. CONCLUSIONS: Based on data for cases of CHD from 24 European population-based registries, evidence of a positive association between maternal age and the total prevalence of CHD for younger (≤24 years old) and older (35-44 years old) mothers was observed. The results suggest that young maternal age (≤24 years old) is a factor associated with severe CHD phenotypes while a positive association between advanced maternal age (35-44 years old) and mild CHD phenotypes was observed.

Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy.

BACKGROUND: Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to 15,000 adults (and a similar number of children) in the UK. Mitochondrial disease manifests multisystem and isolated organ involvement, commonly affecting those tissues with high energy demands, such as skeletal muscle. Myopathy manifesting as fatigue, muscle weakness and exercise intolerance is common and debilitating in patients with mitochondrial disease. Currently, there are no effective licensed treatments and consequently, there is an urgent clinical need to find an effective drug therapy. AIM: To investigate the efficacy of 12-week treatment with acipimox on the adenosine triphosphate (ATP) content of skeletal muscle in patients with mitochondrial disease and myopathy. METHODS: AIMM is a single-centre, double blind, placebo-controlled, adaptive designed trial, evaluating the efficacy of 12 weeks' administration of acipimox on skeletal muscle ATP content in patients with mitochondrial myopathy. Eligible patients will receive the trial investigational medicinal product (IMP), either acipimox or matched placebo. Participants will also be prescribed low dose aspirin as a non-investigational medical product (nIMP) in order to protect the blinding of the treatment assignment. Eighty to 120 participants will be recruited as required, with an interim analysis for sample size re-estimation and futility assessment being undertaken once the primary outcome for 50 participants has been obtained. Randomisation will be on a 1:1 basis, stratified by Fatigue Impact Scale (FIS) (dichotomised as < 40, ≥ 40). Participants will take part in the trial for up to 20 weeks, from screening visits through to follow-up at 16 weeks post randomisation. The primary outcome of change in ATP content in skeletal muscle and secondary outcomes relating to quality of life, perceived fatigue, disease burden, limb function, balance and walking, skeletal muscle analysis and symptom-limited cardiopulmonary fitness (optional) will be assessed between baseline and 12 weeks. DISCUSSION: The AIMM trial will investigate the effect of acipimox on modulating muscle ATP content and whether it can be repurposed as a new treatment for mitochondrial disease with myopathy. TRIAL REGISTRATION: EudraCT2018-002721-29 . Registered on 24 December 2018, ISRCTN 12895613. Registered on 03 January 2019, https://www.isrctn.com/search?q=aimm.

Neuropsychiatric Inventory domains cluster into neuropsychiatric syndromes in Alzheimer's disease: A systematic review and meta-analysis.

BACKGROUND: Studies of patients with Alzheimer's disease (AD) have observed that neuropsychiatric symptoms (NPS) tend to co-occur as neuropsychiatric syndromes and have generally shown mixed results regarding the number and composition of syndromes. We systematically reviewed how neuropsychiatric syndromes in AD have been defined and compared the different published definitions in a pooled sample of AD patients using meta-analytic structural equation modeling (MASEM). METHODS: Studies examining the factor structure of the Neuropsychiatric Inventory (NPI) and published from 1994 to 2021 were included. We contacted the corresponding authors of eligible studies for correlation coefficients between NPI items. We pooled correlations under a random effects MASEM model and fitted and compared measurement models from published studies to identify a best-fitting model. RESULTS: Twenty-five studies were included in the systematic review, and correlations were obtained from seven studies for MASEM. For the NPI-10 (seven studies, n = 5185), a five-factor structure was found to have a good fit to the data. For the NPI-12 (four studies, n = 2397), we were unable to identify a factor structure that displayed a good model fit. CONCLUSION: This systematic review and meta-analysis contribute to the development of a theoretical model of neuropsychiatric syndromes in AD and reveals the barriers that accompany MASEM methodology.

Association between maternal adiposity measures and infant health outcomes: A systematic review and meta-analysis.

Maternal obesity increases risks of adverse fetal and infant outcomes. Guidelines use body mass index to diagnose maternal obesity. Evidence suggests body fat distribution might better predict individual risk, but there is a lack of robust evidence during pregnancy. We explored associations between maternal adiposity and infant health. Searches included six databases, references, citations, and contacting authors. Screening and quality assessment were carried out by two authors independently. Random effects meta-analysis and narrative synthesis were conducted. We included 34 studies (n = 40,143 pregnancies). Meta-analysis showed a significant association between maternal fat-free mass and birthweight (average effect [AE] 18.07 g, 95%CI 12.75, 23.38) but not fat mass (AE 8.76 g, 95%CI -4.84, 22.36). Women with macrosomic infants had higher waist circumference than controls (mean difference 4.93 cm, 95% confidence interval [CI] 1.05, 8.82). There was no significant association between subcutaneous fat and large for gestational age (odds ratio 1.06 95% CI 0.91, 1.25). Waist-to-hip ratio, neck circumference, skinfolds, and visceral fat were significantly associated with several infant outcomes including small for gestational age, preterm delivery, neonatal morbidity, and mortality, although meta-analysis was not possible for these variables. Our findings suggest that some measures of maternal adiposity may be useful for risk prediction of infant outcomes. Individual participant data meta-analysis could overcome some limitations in our ability to pool published data.

Association between maternal adiposity measures and adverse maternal outcomes of pregnancy: Systematic review and meta-analysis.

Maternal obesity increases pregnancy-related risks. Women with a body mass index (BMI) ≥ 30 kg/m2 are considered to be at risk and should receive additional care, although approximately half will have uncomplicated pregnancies. This systematic review aimed to identify early pregnancy measures of adiposity associated with adverse maternal health outcomes. Searches included six databases, reference lists, citations, and contacting authors. Screening and quality assessment were carried out by two authors independently. Random effects meta-analysis and narrative synthesis were conducted. Seventy studies were included with a pooled sample of 89,588 women. Meta-analysis showed significantly increased odds of gestational diabetes mellitus (GDM) with higher waist circumference (WC) categories (1.40, 95% confidence interval [CI] 1.04, 1.88) and per unit increase in WC (1.31, 95% CI 1.03, 1.67). Women with GDM had higher WC than controls (mean difference [MD] 6.18 cm, 95% CI 3.92, 8.44). WC was significantly associated with hypertensive disorders, delivery-related outcomes, metabolic syndrome, and composite pregnancy outcomes. Waist to hip ratio was significantly associated with GDM, hypertensive disorders, and delivery-related outcomes. Fat mass, neck circumference, skinfolds, and visceral fat were significantly associated with adverse outcomes, although limited data were available. Our findings identify the need to explore how useful adiposity measures are at predicting risk in pregnancy, compared with BMI, to direct care to women with the greatest need.

Sequential multiple assignment randomized trial studies should report all key components: a systematic review.

OBJECTIVE: Sequential Multiple Assignment Randomized Trial (SMART) designs allow multiple randomizations of participants; this allows assessment of stage-specific questions (individual randomizations) and adaptive interventions (i.e. treatment strategies). We assessed the quality of reporting of the information required to design SMART studies. STUDY DESIGN AND SETTING: We systematically searched four databases (PubMed, Ovid, Web of Science and Scopus) for all trial reports, protocols, reviews, and methodological papers which mentioned SMART designs up to June 15, 2020. RESULTS: Of the 157 selected records, 12 (7.64%) were trial reports, 24 (15.29%) were study protocols, 91 (58%) were methodological papers, and 30 (19.1%) were review papers. All these trials were powered using stage-specific aims. Only four (33.33%) of these trials reported parameters required for sample size calculations. A small number of the trials (16.67 %) were interested in determining the best embedded adaptive interventions. Most of the trials did not report information about multiple testing adjustment. Furthermore, most of records reported designs that were mainly focused on stage-specific aims. CONCLUSIONS: Some features of SMART designs are seldomly reported and/or used. Furthermore, studies using this design tend to not adequately report information about all the design parameters, limiting their transparency and interpretability.

Innovative trial approaches in immune-mediated inflammatory diseases: current use and future potential.

BACKGROUND: Despite progress that has been made in the treatment of many immune-mediated inflammatory diseases (IMIDs), there remains a need for improved treatments. Randomised controlled trials (RCTs) provide the highest form of evidence on the effectiveness of a potential new treatment regimen, but they are extremely expensive and time consuming to conduct. Consequently, much focus has been given in recent years to innovative design and analysis methods that could improve the efficiency of RCTs. In this article, we review the current use and future potential of these methods within the context of IMID trials. METHODS: We provide a review of several innovative methods that would provide utility in IMID research. These include novel study designs (adaptive trials, Sequential Multi-Assignment Randomised Trials, basket, and umbrella trials) and data analysis methodologies (augmented analyses of composite responder endpoints, using high-dimensional biomarker information to stratify patients, and emulation of RCTs from routinely collected data). IMID trials are now well-placed to embrace innovative methods. For example, well-developed statistical frameworks for adaptive trial design are ready for implementation, whilst the growing availability of historical datasets makes the use of Bayesian methods particularly applicable. To assess whether and how these innovative methods have been used in practice, we conducted a review via PubMed of clinical trials pertaining to any of 51 IMIDs that were published between 2018 and 20 in five high impact factor clinical journals. RESULTS: Amongst 97 articles included in the review, 19 (19.6%) used an innovative design method, but most of these were relatively straightforward examples of innovative approaches. Only two (2.1%) reported the use of evidence from routinely collected data, cohorts, or biobanks. Eight (9.2%) collected high-dimensional data. CONCLUSIONS: Application of innovative statistical methodology to IMID trials has the potential to greatly improve efficiency, to generalise and extrapolate trial results, and to further personalise treatment strategies. Currently, such methods are infrequently utilised in practice. New research is required to ensure that IMID trials can benefit from the most suitable methods.

Antibiotic-loaded bone cement is associated with a lower risk of revision following primary cemented total knee arthroplasty: an analysis of 731,214 cases using National Joint Registry data.

AIMS: Antibiotic-loaded bone cements (ALBCs) may offer early protection against the formation of bacterial biofilm after joint arthroplasty. Use in hip arthroplasty is widely accepted, but there is a lack of evidence in total knee arthroplasty (TKA). The objective of this study was to evaluate the use of ALBC in a large population of TKA patients. MATERIALS AND METHODS: Data from the National Joint Registry (NJR) of England and Wales were obtained for all primary cemented TKAs between March 2003 and July 2016. Patient, implant, and surgical variables were analyzed. Cox proportional hazards models were used to assess the influence of ALBC on risk of revision. Body mass index (BMI) data were available in a subset of patients. RESULTS: Of 731 214 TKAs, 15 295 (2.1%) were implanted with plain cement and 715 919 (97.9%) with ALBC. There were 13 391 revisions; 2391 were performed for infection. After adjusting for other variables, ALBC had a significantly lower risk of revision for any cause (hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77 to 0.93; p < 0.001). ALBC was associated with a lower risk of revision for all aseptic causes (HR 0.85, 95% CI 0.77 to 0.95; p < 0.001) and revisions for infection (HR 0.84, 95% CI 0.67 to 1.01; p = 0.06). The results were similar when BMI was added into the model, and in a subanalysis where surgeons using only ALBC over the entire study period were excluded. Prosthesis survival at ten years for TKAs implanted with ALBC was 96.3% (95% CI 96.3 to 96.4) compared with 95.5% (95% CI 95.0 to 95.9) in those implanted with plain cement. On a population level, where 100 000 TKAs are performed annually, this difference represents 870 fewer revisions at ten years in the ALBC group. CONCLUSION: After adjusting for a range of variables, ALBC was associated with a significantly lower risk of revision in this registry-based study of an entire nation of primary cemented knee arthroplasties. Using ALBC does not appear to increase midterm implant failure rates. Cite this article: Bone Joint J 2019;101-B:1331-1347.

Medication errors and adverse drug events in a UK hospital during the optimisation of electronic prescriptions: a prospective observational study.

BACKGROUND: WHO's Third Global Patient Safety Challenge, Medication Without Harm, focused on reducing the substantial burden of iatrogenic harm associated with medications by 50% in the next 5 years. We aimed to assess whether the number and type of medication errors changed as an electronic prescribing system was optimised over time in a UK hospital. METHODS: We did a prospective observational study at a tertiary-care teaching hospital. Eight senior clinical pharmacists reviewed patients' records and collected data across four adult wards (renal, cardiology, general medical, and orthopaedic surgical) over a 2-year period (from Sept 29, 2014, to June 9, 2016). All medication errors and potential and actual adverse drug events were documented and the number of medication errors measured over the course of four time periods 7-10 weeks long. Pharmacists also recorded instances where the electronic prescribing system contributed to an error (system-related errors). A negative-binomial model and a Poisson model were used to identify factors related to medication error rates. FINDINGS: 5796 primary errors were recorded over the four time periods (period 1, 47 days [Sep 29-Dec 2, 2014]; period 2, 38 days [April 20-June 12, 2015, for the renal, medical, and surgical wards and April 20-June 15, 2015, for the cardiology ward]; period 3, 35 days [Sep 28-Nov 27, 2015] for the renal ward, 37 days [Sep 28-Nov 23, 2015] for the medical ward, and 40 days [Sep 28-Nov 20, 2015] for the cardiology and surgical wards; and period 4, 37 days [Feb 22-April 15, 2015] for the renal and medical wards and 39 days for the cardiology [April 13-June 7, 2015] and surgery [April 18-June 9, 2015] wards; unanticipated organisational factors prevented data collection on some days during each time period). There was no change in the rate of primary medication errors per admission over the observation periods: 1·53 medication errors in period 1, 1·44 medication errors in period 2, 1·70 medication errors in period 3, and 1·43 medication errors in period 4, per admission. By contrast, the overall rate of different types of medication errors decreased over the four periods. The most common types of error were medicine-reconciliation, dose, and avoidable delay-of-treatment errors. Some types of errors appeared to reduce over time (eg, dose errors [from 52 errors in period 1 to 19 errors in period 4, per 100 admissions]), whereas others increased (eg, inadequate follow-up of therapy [from 12 errors in period 1 to 24 errors in period 4, per 100 admissions]). We also found a reduction in the rates of potential adverse drug events between the first three periods and period 4. 436 system-related errors were recorded over the study period. INTERPRETATION: Although the overall rates of primary medication errors per admission did not change, we found a reduction in some error types and a significant decrease in the rates of potential adverse drug events over a 2-year period, during which system optimisation occurred. Targeting some error types could have the added benefit of reducing others, which suggests that system optimisation could ultimately help improve patient safety and outcomes. FUNDING: No funding.

Inequity of care provision and outcome disparity in autoimmune hepatitis in the United Kingdom.

BACKGROUND: Treatment paradigms in autoimmune hepatitis (AIH) have remained largely unchanged for decades. Studies report ≤20% of patients have sub-optimal treatment response with most requiring long-term therapy. AIM: The United Kingdom Autoimmune Hepatitis (UK-AIH) study was established to evaluate current treatment practice and outcomes, determine the unmet needs of patients, and develop and implement improved treatment approaches. METHODS: The United Kingdom Autoimmune Hepatitis study is a cross-sectional cohort study examining secondary care management of prevalent adult patients with a clinical diagnosis of autoimmune hepatitis. Enrolment began in March 2014. Prevalent cases were defined as having been diagnosed and treated for >1 year. Demographic data, biochemistry, treatment history and response, and care location were collected. RESULTS: In total, 1249 patients were recruited; 635 were cared for in transplant units and 614 in non-transplant centres (81% female with median age at diagnosis 50 years). Overall, 29 treatment regimens were reported and biochemical remission rate was 59%. Remission rates were significantly higher in transplant compared to non-transplant centres (62 vs 55%, P = 0.028). 55% have ongoing corticosteroid exposure; 9% are receiving prednisolone monotherapy. Those aged ≤20 years at diagnosis were more likely to develop cirrhosis and place of care was associated with an aggressive disease phenotype. CONCLUSIONS: There are significant discrepancies in the care received by patients with autoimmune hepatitis in the UK. A high proportion remains on corticosteroids and there is significant treatment variability. Patients receiving care in transplant centres were more likely to achieve and maintain remission. Overall poor remission rates suggest that there are significant unmet therapeutic needs for patients with autoimmune hepatitis.

Can testing clinical significance reduce false positive rates in randomized controlled trials? A snap review.

OBJECTIVE: The use of minimum clinically important difference in the hypothesis formulation for superiority trials is similar in principle to the concept of non-inferiority or equivalence trial. However, most clinical trials are analysed testing zero clinical difference. Since the minimum clinically important difference is pre-defined for power calculation, it is important to incorporate it in both the hypothesis testing and the interpretation of findings from clinical trials. RESULTS: We reviewed a set of 50 publications (25 with binary outcome, and 25 with survival time outcome). 20% of the 50 published trials that were statistically significant, were also clinically significant based on the minimum clinically important risk differences (or hazard ratio) used for their power calculations. This snap review seems to suggest that most published trials with statistically significant results were less likely to be clinically significant, which may partly explain the high false positive findings associated with findings from superiority trials. Furthermore, none of the reviewed publications explicitly used minimum clinically important difference in the interpretation of their findings. However, a systematic review is needed to critically appraise the impact of the current practice on false positive rate in published trials with significant findings.

Detection of Lung Cancer through Metabolic Changes Measured in Blood Plasma.

INTRODUCTION: Low-dose computed tomography, the currently used tool for lung cancer screening, is characterized by a high rate of false-positive results. Accumulating evidence has shown that cancer cell metabolism differs from that of normal cells. Therefore, this study aims to evaluate whether the metabolic phenotype of blood plasma allows detection of lung cancer. METHODS: The proton nuclear magnetic resonance spectrum of plasma is divided into 110 integration regions, representing the metabolic phenotype. These integration regions reflect the relative metabolite concentrations and were used to train a classification model in discriminating between 233 patients with lung cancer and 226 controls. The validity of the model was examined by classifying an independent cohort of 98 patients with lung cancer and 89 controls. RESULTS: The model makes it possible to correctly classify 78% of patients with lung cancer and 92% of controls, with an area under the curve of 0.88. Important moreover is the fact that the model is convincing, which is demonstrated by validation in the independent cohort with a sensitivity of 71%, a specificity of 81%, and an area under the curve of 0.84. Patients with lung cancer have increased glucose and decreased lactate and phospholipid levels. The limited number of patients in the subgroups and their heterogeneous nature do not (yet) enable differentiation between histological subtypes and tumor stages. CONCLUSIONS: Metabolic phenotyping of plasma allows detection of lung cancer, even in an early stage. Increased glucose and decreased lactate levels are pointing to an increased gluconeogenesis and are in accordance with recently published findings. Furthermore, decreased phospholipid levels confirm the enhanced membrane synthesis.