Comparison of characteristics of patients with lung cancer in U.K. primary care databases: Clinical Practice Research Datalink Aurum and GOLD.

INTRODUCTION: In recent years, the number of general practices contributing to the Clinical Practice Research Datalink (CPRD) database GOLD is decreasing. Therefore, for research questions addressing for instance novel treatments requiring up-to-date data, sample size will become an important consideration in study feasibility. In recent years, CPRD Aurum, containing information of practices that use EMIS software, has become an additional data source that is being used for CPRD studies. In order to establish whether Aurum is suited to act as data source for future studies in the field of lung cancer research, we aimed to compare characteristics between patients with lung cancer in Aurum and GOLD. METHODS: A retrospective study was performed comparing characteristics and overall survival (OS) of patients with lung cancer in Aurum and GOLD. To further evaluate similarity, hypothetical eligibility of these patients in Aurum and GOLD was compared for 11 randomized clinical trials (RCTs). RESULTS: Baseline characteristics registered in Aurum and GOLD were largely similar, with some clinically irrelevant differences for previous malignancies, deviant laboratory values and drug use. Median OS was 9.8 and 9.0 months for patients in Aurum and GOLD, respectively. Potential RCT eligibility varied between 49.4% and 79.5% and 49.1% and 78.1% for patients in Aurum and GOLD, respectively. Mortality rates and the comparison of the obtained HRs per hypothetical eligibility cohort per RCT were similar in Aurum and GOLD. CONCLUSION: This study showed that data of patients with lung cancer in Aurum and GOLD are largely comparable, suggesting that Aurum is suitable for future epidemiological lung cancer research.

Quantifying citrate-enhanced phosphate root uptake using microdialysis.

AIMS: Organic acid exudation by plant roots is thought to promote phosphate (P) solubilisation and bioavailability in soils with poorly available nutrients. Here we describe a new combined experimental (microdialysis) and modelling approach to quantify citrate-enhanced P desorption and its importance for root P uptake. METHODS: To mimic the rhizosphere, microdialysis probes were placed in soil and perfused with citrate solutions (0.1, 1.0 and 10 mM) and the amount of P recovered from soil used to quantify rhizosphere P availability. Parameters in a mathematical model describing probe P uptake, citrate exudation, P movement and citrate-enhanced desorption were fit to the experimental data. These parameters were used in a model of a root which exuded citrate and absorbed P. The importance of soil citrate-P mobilisation for root P uptake was then quantified using this model. RESULTS: A plant needs to exude citrate at a rate of 0.73 µmol cm-1 of root h-1 to see a significant increase in P absorption. Microdialysis probes with citrate in the perfusate were shown to absorb similar quantities of P to an exuding root. CONCLUSION: A single root exuding citrate at a typical rate (4.3 × 10-5 µmol m-1 of root h-1) did not contribute significantly to P uptake. Microdialysis probes show promise for measuring rhizosphere processes when calibration experiments and mathematical modelling are used to decouple microdialysis and rhizosphere mechanisms.

Incidence and outcomes of chronic total occlusion percutaneous coronary intervention in the Netherlands: data from a nationwide registry.

BACKGROUND: Patients with chronic total coronary occlusions (CTO) are at increased risk for poor clinical outcomes. We aimed to determine the incidence of CTO percutaneous coronary intervention (PCI) and to identify CTO patients at risk for cardiac events in the nationwide Netherlands Heart Registration (NHR). METHODS: We included all PCI procedures with ≥1 CTO registered in the NHR from January 2015 to December 2018, excluding acute interventions. We used multivariable logistic regression of baseline characteristics to calculate the risk for events as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Of the PCIs performed during the study period, 6.3% (8,343/133,042) were for CTOs, with the percentage increasing significantly over time from 5.9% in 2015 to 6.6% in 2018 (p < 0.001). Coronary artery bypass grafting <24 h was carried out in 0.3%, and the only significant predictor was diabetes mellitus (OR 2.97, 95% CI 1.04-8.49, p = 0.042). Myocardial infarction (MI) <30 days occurred in 0.5%, and renal insufficiency (i.e. estimated glomerular filtration rate <30 ml/min per 1.73 m2) was identified as an independent predictor (OR 4.70, 95% CI 1.07-20.61, p = 0.040). Among patients undergoing CTO-PCI, 1­year mortality was 3.7%, and independent predictors included renal insufficiency (OR 5.59, 95% CI 3.25-9.59, p < 0.001), left ventricular ejection fraction <30% (OR 3.43, 95% CI 2.00-5.90, p < 0.001), previous MI (OR 1.62, 95% CI 1.14-2.31, p = 0.007) and age (OR 1.06 per year increment, 95% CI 1.04-1.07, p < 0.001). Target-vessel revascularisation <1 year occurred in 11.3%. CONCLUSION: CTO-PCI is still infrequently performed in the Netherlands. The most important predictor of mortality after CTO-PCI was renal insufficiency. Identification of patients at risk may help improve the prognosis of CTO patients in the future.

Percutaneous coronary intervention versus medical therapy for chronic total coronary occlusions: a systematic review and meta-analysis of randomised trials.

BACKGROUND: The results of chronic total occlusion percutaneous coronary intervention (CTO-PCI) trials are inconclusive. Therefore, we studied whether CTO-PCI leads to improvement of clinical endpoints and patient symptoms when combining all available randomised data. METHODS AND RESULTS: This meta-analysis was registered in PROSPERO prior to starting. We performed a literature search and identified all randomised trials comparing CTO-PCI to optimal medical therapy alone (OMT). A total of five trials were included, comprising 1790 CTO patients, of whom 964 were randomised to PCI and 826 to OMT. The all-cause mortality was comparable between groups at 1­year [risk ratio (RR) 1.70, 95% confidence interval (CI) 0.50-5.80, p = 0.40] and at 4­year follow-up (RR 1.14, 95% CI 0.38-3.40, p = 0.81). There was no difference in the incidence of major adverse cardiac events (MACE) between groups at 1 year (RR 0.69, 95% CI 0.36-1.33, p = 0.27) and at 4 years (RR 0.85, 95% CI 0.60-1.22, p = 0.38). Left ventricular function and volumes at follow-up were comparable between groups. However, the PCI group had fewer target lesion revascularisations (RR 0.28, 95% CI 0.15-0.52, p < 0.001) and was more frequently free of angina at 1­year follow-up (RR 0.65, 95% CI 0.50-0.84, p = 0.001), although the scores on the subscales of the Seattle Angina Questionnaire were comparable. CONCLUSION: In conclusion, in this meta-analysis of 1790 CTO patients, CTO-PCI did not lead to an improvement in survival or in MACE as reported at long-term follow-up of up to 4 years, or to improvement of left ventricular function. However, CTO-PCI resulted in less angina and fewer target lesion revascularisations compared to OMT.

Mineral reaction kinetics constrain the length scale of rock matrix diffusion.

Mass transport by aqueous fluids is a dynamic process in shallow crustal systems, redistributing nutrients as well as contaminants. Rock matrix diffusion into fractures (void space) within crystalline rock has been postulated to play an important role in the transient storage of solutes. The reacted volume of host rock involved, however, will be controlled by fluid-rock reactions. Here we present the results of a study which focusses on defining the length scale over which rock matrix diffusion operates within crystalline rock over timescales that are relevant to safety assessment of radioactive and other long-lived wastes. Through detailed chemical and structural analysis of natural specimens sampled at depth from an active system (Toki Granite, Japan), we show that, contrary to commonly proposed models, the length scale of rock matrix diffusion may be extremely small, on the order of centimetres, even over timescales of millions of years. This implies that in many cases the importance of rock matrix diffusion will be minimal. Additional analyses of a contrasting crystalline rock system (Carnmenellis Granite, UK) corroborate these results.

Implementing managed entry agreements in practice: The Dutch reality check.

BACKGROUND: Conditional financing (CF) of expensive hospital drugs was applied in the Netherlands between 2006 and 2012; a 4-year coverage with evidence development (CED) framework for expensive hospital drugs. This study aims to evaluate the CF framework, focusing on Health Technology Assessment (HTA) procedures. METHODS: Using a standardised data extraction form, researchers independently extracted information on procedural, methodological and decision-making aspects from HTA reports of drugs selected for CF. RESULTS: Forty-nine drugs were chosen for CF, of which 12 underwent the full procedure. The procedure extended beyond the envisioned 4 years period for 11/12 drugs. Outcomes research studies conducted as part of CF provided insufficient scientific data to reach conclusions on appropriate use and cost-effectiveness of 5/12 drugs. After re-assessment, continuation of reimbursement was advised for 10/12 drugs, with 6 necessitating yet additional conditions for evidence generation. Notably, advice to discontinue reimbursement for 2/12 drugs has not yet been implemented in Dutch healthcare practice. CONCLUSIONS: Theoretically, CF provided an option for quick but conditional access to drugs. However, numerous aspects related to the design and implementation of CF negatively affected its value in practice. Future CED schemes should aim to incorporate learnings from the CF example to increase their impact in healthcare practice.

Measurement of micro-scale soil deformation around roots using four-dimensional synchrotron tomography and image correlation.

This study applied time lapse (four-dimensional) synchrotron X-ray computed tomography to observe micro-scale interactions between plant roots and soil. Functionally contrasting maize root tips were repeatedly imaged during ingress into soil columns of varying water content and compaction. This yielded sequences of three-dimensional densiometric data, representing time-resolved geometric soil and root configurations at the micronmetre scale. These data were used as inputs for two full-field kinematic quantification methods, which enabled the analysis of three-dimensional soil deformation around elongating roots. Discrete object tracking was used to track rigid mineral grains, while continuum digital volume correlation was used to track grey-level patterns within local sub-volumes. These techniques both allowed full-field soil displacements to be quantified at an intra-rhizosphere spatial sampling scale of less than 300 µm. Significant differences in deformation mechanisms were identified around different phenotypes under different soil conditions. A uniquely strong contrast was observed between intact and de-capped roots grown in dry, compacted soil. This provides evidence that functional traits of the root cap significantly reduce the amount of soil disturbance per unit of root elongation, with this effect being particularly significant in drier soil.

Leaf metallome preserved over 50 million years.

Large-scale Synchrotron Rapid Scanning X-ray Fluorescence (SRS-XRF) elemental mapping and X-ray absorption spectroscopy are applied here to fossil leaf material from the 50 Mya Green River Formation (USA) in order to improve our understanding of the chemistry of fossilized plant remains. SRS-XRF of fossilized animals has previously shown that bioaccumulated trace metals and sulfur compounds may be preserved in their original distributions and these elements can also act as biomarkers for specific biosynthetic pathways. Similar spatially resolved chemical data for fossilized plants is sparsely represented in the literature despite the multitude of other chemical studies performed. Here, synchrotron data from multiple specimens consistently show that fossil leaves possess chemical inventories consisting of organometallic and organosulfur compounds that: (1) map discretely within the fossils, (2) resolve fine scale biological structures, and (3) are distinct from embedding sedimentary matrices. Additionally, the chemical distributions in fossil leaves are directly comparable to those of extant leaves. This evidence strongly suggests that a significant fraction of the chemical inventory of the examined fossil leaf material is derived from the living organisms and that original bioaccumulated elements have been preserved in situ for 50 million years. Chemical information of this kind has so far been unknown for fossilized plants and could for the first time allow the metallome of extinct flora to be studied.

Effect of external cephalic version in late pregnancy on presentation at delivery: a randomized controlled trial.

The effect of repeated external cephalic version, performed at between 33 and 40 weeks gestation, on presentation at delivery was studied in a randomized controlled trial comprising 180 pregnant women with breech presentation. No tocolysis, analgesia or anaesthesia was used. Approximately 25% of all attempts in the study group of 90 women were successful; repeated external version resulted in cephalic presentation at delivery in 48% of patients. Spontaneous version to cephalic presentation occurred in 23 (26%) of the 90 women in the control group in whom version was not attempted, indicating a therapeutic gain from the procedure of 22%, with a 95% confidence interval of 8 to 35%. No severe complications of external cephalic version were noted. We conclude that external cephalic version reduces the frequency of breech presentation at delivery. This mainly benefits the mother because of the decrease in the number of caesarean sections and their inherent maternal morbidity.

Correlation between cataract and glutathione metabolism.

Riboflavin status was studied in 156 older healthy people living at home in The Netherlands by assaying erythrocyte glutathione reductase (with and without FAD). The average activation coefficient of glutathione reductase was found to be 1.42 +/- 0.19. 7% of the population studied showed cataract (based on the eye examination). It seems that no correlation exists between cataract and riboflavin deficiency.

Opacities of the lens indicating carrier status in the oculo-cerebro-renal (Lowe) syndrome.

Three families with a total of five patients with Lowe's syndrome are described. We tried to trace female heterozygotes by ophthalmological abnormalities in order to realize prevention of this serious X-chromosomal recessive disease. Of the fourteen female relatives examined, eight showed pathological opacities of the lens, two of these being proven heterozygotes. In our opinion, in Lowe's syndrome, examination of the eyes can play an important role in the detection of heterozygotes.