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.

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.

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.

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.

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.