Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

<p><b>Background:</b> The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.</p> <p><b>Methods:</b> The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.</p> <p><b>Results:</b> Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.</p> <p><b>Conclusion:</b> With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.</p&gt

Thoracic Electrical Impedance Tomography—The 2022 Veterinary Consensus Statement

Electrical impedance tomography (EIT) is a non-invasive real-time non-ionising imaging modality that has many applications. Since the first recorded use in 1978, the technology has become more widely used especially in human adult and neonatal critical care monitoring. Recently, there has been an increase in research on thoracic EIT in veterinary medicine. Real-time imaging of the thorax allows evaluation of ventilation distribution in anesthetised and conscious animals. As the technology becomes recognised in the veterinary community there is a need to standardize approaches to data collection, analysis, interpretation and nomenclature, ensuring comparison and repeatability between researchers and studies. A group of nineteen veterinarians and two biomedical engineers experienced in veterinary EIT were consulted and contributed to the preparation of this statement. The aim of this consensus is to provide an introduction to this imaging modality, to highlight clinical relevance and to include recommendations on how to effectively use thoracic EIT in veterinary species. Based on this, the consensus statement aims to address the need for a streamlined approach to veterinary thoracic EIT and includes: an introduction to the use of EIT in veterinary species, the technical background to creation of the functional images, a consensus from all contributing authors on the practical application and use of the technology, descriptions and interpretation of current available variables including appropriate statistical analysis, nomenclature recommended for consistency and future developments in thoracic EIT. The information provided in this consensus statement may benefit researchers and clinicians working within the field of veterinary thoracic EIT. We endeavor to inform future users of the benefits of this imaging modality and provide opportunities to further explore applications of this technology with regards to perfusion imaging and pathology diagnosis

Facile control of silica nanoparticles using a novel solvent varying method for the fabrication of artificial opal photonic crystals

In this work, the Stöber process was applied to produce uniform silica nanoparticles (SNPs) in the meso-scale size range. The novel aspect of this work was to control the produced silica particle size by only varying the volume of the solvent ethanol used, whilst fixing the other reaction conditions. Using this one-step Stöber-based solvent varying (SV) method, seven batches of SNPs with target diameters ranging from 70 to 400 nm were repeatedly reproduced, and the size distribution in terms of the polydispersity index (PDI) was well maintained (within 0.1). An exponential equation was used to fit the relationship between the particle diameter and ethanol volume. This equation allows the prediction of the amount of ethanol required in order to produce particles of any target diameter within this size range. In addition, it was found that the reaction was completed in approximately 2 h for all batches regardless of the volume of ethanol. Structurally coloured artificial opal photonic crystals (PCs) were fabricated from the prepared SNPs by self-assembly under gravity sedimentation

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Randomised clinical comparison of sedation, cardiopulmonary function and recovery of dexmedetomidine versus medetomidine isoflurane balanced anaesthesia in horses

The aim of this prospective, blinded, randomised study was to compare the effects of two balanced anaesthetic protocols on sedation, cardiopulmonary function and recovery in horses. Sixty healthy horses presented for elective surgery were sedated with either dexmedetomidine 3.5 μg kg-1 (group Dex) or medetomidine 7 μg kg-1 (group Med) intravenously (IV). After scoring and topping up sedation if necessary, anaesthesia was induced with ketamine 2.2 mg kg-1 mixed with diazepam 0.02 mg kg-1 IV and maintained with isoflurane in O2 and air complemented by dexmedetomidine 1.75 μg kg-1 hour-1 or medetomidine 3.5 μg kg-1 hour-1, Ringer’s Lactate and dobutamine. All horses were mechanically ventilated. Heart rate, invasive blood pressure, in- and expired gas composition, blood gases including electrolytes, total haemoglobin and lactate were measured. Either dexmedetomidine 1 μg kg-1 or medetomidine 2 μg kg-1 IV were administered before the scored recovery phase. The significantly different sedation doses were (median, with range given in brackets) dexmedetomidine 4 μg kg-1 (3.5–9) and medetomidine 7 μg kg-1 (7–9). Recovery scores in group Dex were significantly better compared to group Med. Neither of the other parameters differed significantly. Das Ziel dieser prospektiven, randomisierten, verblindeten Studie war es, die Effekte zweier balancierter Anästhesieprotokolle auf Sedation, cardiopulmonäre Funktion und postanästhetische Aufwachphase bei Pferden zu vergleichen. Insgesamt 60 gesunde Pferde, vorgestellt für elektive Chirurgie, wurden entweder mit 3.5 μg kg-1 Dexmedetomidin (Gruppe Dex) oder mit 7 μg kg-1 Medetomidin (Gruppe Med) intravenös (IV) sediert. Nach der Bewertung und einer allfälligen Vertiefung der Sedation wenn nötig, wurde die Allgemeinanästhesie mit 2.2 mg kg-1 Ketamin und 0.02 mg kg-1 Diazepam IV eingeleitet. Isofluran in O2 und Luft diente zur Aufrechterhaltung der Anästhesie, ergänzt durch Dauertropfinfusionen von 1.75 μg kg-1 h-1 Dexmedetomidin (Gruppe Dex) oder 3.5 μg kg-1 h-1 Medetomidin (Gruppe Med), Ringer-Laktat-Lösung und Dobutamin. Alle Pferde wurden künstlich beatmet. Gemessen wurden Herzfrequenz, invasiver Blutdruck, ein- und ausgeatmete Gaszusammensetzungen, Blutgase einschliesslich Elektrolyte sowie Hämoglobin und Laktat. Für die bewertete Aufwachphase wurde den Pferden jeweils 1 μg kg-1 Dexmedetomidin oder 2 μg kg-1 Medetomidin IV appliziert. Die signifikant unterschiedliche Sedationsdosierung (Median, Range in Klammern) betrug 4 μg kg-1 (3.5–9) für Dexmedetomidin und 7 μg kg-1 (7–9) für Medetomidin. Die qualitative Bewertung der Aufwachphase zeigte signifikant bessere Werte in Gruppe Dex als in Gruppe Med. Alle anderen Werte waren statistisch nicht signifikant unterschiedlich

Evaluation der Messgenauigkeit von Atemvolumina des Anästhesiegerätes Tafonius® in vitro und in vivo

The anaesthesiologic risk is higher in horses than in other domesticated animal species and thereby ventilation is a vital problem. The aimof this study was to evaluate the accuracy of the anaesthesia device Tafonius® tidal volume measurements in vitro as well as in vivo. In an in vitro study the whole system was flushed by air to reduce the air moisture to a minimum. The preparation of the anaesthesia device was exactly the same, as if there was a surgery on a patient. But instead of a horse, a seven liter calibration syringe was connected to the Y-piece of the anaesthesia device and the whole system was flooded by pure oxygen. By touch screen on the monitor of the anaesthesia device, a CPAP (Continuous Positive Airway Pressure), a tidal volume of 20 liters and an airway pressure of 20cmH2O were adjusted. The leakage test was repeated and the connections tightened until the leak was 168mL gas per minute. All the measurements were made randomly, without breaks or changes of the adjustments. For tidal volume measurements a seven liter calibration syringe was used. A connecting piece was specially manufactured, to attach the syringe to the Tafonius® without gas leakage.14 different tidal volumes were evaluated in a random order, covering the range from 500mL to 7000mL using 500mL steps. To imitate respiration during anaesthesia, three respiratory rates were simulated: 30, 15 and 6 times per minute. All the measurements were performed in duplicate, once with NICO® interconnected and once without it. The respiratory rates and tidal volumes were chosen in random order, as well as whether the flow meter was interconnected or not. In a in vivo study twenty-one patients with a mean weight of 516 kilograms submitted for elective surgery were included. All of them received a balanced anaesthesia regime (inhalation anaesthesia with isoflurane and constant rate infusion with medetomidine (3.5mcg/kg/h) and controlled mechanical ventilation. 16 horses were positioned in dorsal and five in lateral recumbency. The flow meter NICO® was connected ones a steady state in the plane of anaesthesia was reached. The flow meter was left during 38 to 190 breaths. A total of 2368 breaths were measured. Mean tidal volumes reached from 4107mL to 8964 mL. In vitro data were analysed by descriptive statistics to determine measurement accuracy. Bland-Altman plots with limits of agreement (loa) were used to analyze in vivo data. The mean difference between the volume given by the calibration syringe and the volume shown on the Tafonius® screen was -19.45% (standard deviation 11%). The data stored on the computer showed an average difference of -20.5% (standard deviation 15.57%). Whether NICO® was interconnected or not resulted in a change in accuracy of 0.36% in the volume measurement of the Tafonius®. The mean difference of the volume produced with the calibration syringe and the measured volume of the NICO® was 0.73% (standard deviation 4.3%). The Bland-Altman analysis from NICO® to Tafonius® gave a lower limit of agreement of -2427mL and an upper limit of agreement of 1436mL and a bias of -496mL. From 500mL to seven liter the Tafonius® measures tidal volumes 20% lower than a reference volume provided by a calibration syringe. Inadequate ventilation of the lung might be a consequence of this in horses under controlled mechanical ventilation. In vivo gained tidal volume data automatically stored by Tafonius® were very variable and probably a result of outliers. In vivo analyses of accuracy of tidal volume measurement should be repeated at the bedside, using data displayed on the screen of the device instead of automatically stored data