Coronary artery disease-associated genetic variants and biomarkers of inflammation

Introduction: Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers. Methods: We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers. Results: The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score. Conclusions: In stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers

Integration of decision support systems to improve decision support performance

Decision support system (DSS) is a well-established research and development area. Traditional isolated, stand-alone DSS has been recently facing new challenges. In order to improve the performance of DSS to meet the challenges, research has been actively carried out to develop integrated decision support systems (IDSS). This paper reviews the current research efforts with regard to the development of IDSS. The focus of the paper is on the integration aspect for IDSS through multiple perspectives, and the technologies that support this integration. More than 100 papers and software systems are discussed. Current research efforts and the development status of IDSS are explained, compared and classified. In addition, future trends and challenges in integration are outlined. The paper concludes that by addressing integration, better support will be provided to decision makers, with the expectation of both better decisions and improved decision making processes

Anatomy of terminal moraine segments and implied lake stability on Ngozumpa Glacier, Nepal, from electrical resistivity tomography (ERT)

This research was supported financially by the European Commission FP7-MC-IEF (PIEF-GA-2012-330805), the University Centre in Svalbard (UNIS), National Geographic Society GRANT #W135-10.Moraine-dammed lakes at debris-covered glaciers are becoming increasingly common and pose significant outburst flood hazards if the dam is breached. While moraine subsurface structure and internal processes are likely to influence dam stability, only few sites have so far been investigated. We conducted electrical resistivity tomography (ERT) surveys at two sites on the terminal moraine complex of the Ngozumpa Glacier, Nepal, to aid assessment of future terminus stability. The resistivity signature of glacier ice at the site (100-15 kΩ m) is more consistent with values measured from cold glacier ice and while this may be feasible, uncertainties in the data inversion introduce ambiguity to this thermal interpretation. However, the ERT data does provide a significant improvement to our knowledge of the subsurface characteristics at these sites, clearly showing the presence (or absence) of glacier ice. Our interpretation is that of a highly complex latero-terminal moraine, resulting from interaction between previous glacier advance, recession and outburst flooding. If the base-level Spillway Lake continues to expand to a fully formed moraine-dammed glacial lake, the degradation of the ice core could have implications for glacial lake outburst risk.Publisher PDFPeer reviewe

Vaccines as alternatives to antibiotics for food producing animals. Part 1:challenges and needs

Vaccines and other alternative products can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations, and are central to the future success of animal agriculture. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, part of a two-part series, synthesizes and expands on the expert panel discussions regarding opportunities, challenges and needs for the development of vaccines that may reduce the need for use of antibiotics in animals; new approaches and potential solutions will be discussed in part 2 of this series. Vaccines are widely used to prevent infections in food animals. Various studies have demonstrated that their animal agricultural use can lead to significant reductions in antibiotic consumption, making them promising alternatives to antibiotics. To be widely used in food producing animals, vaccines have to be safe, effective, easy to use, and cost-effective. Many current vaccines fall short in one or more of these respects. Scientific advancements may allow many of these limitations to be overcome, but progress is funding-dependent. Research will have to be prioritized to ensure scarce public resources are dedicated to areas of potentially greatest impact first, and private investments into vaccine development constantly compete with other investment opportunities. Although vaccines have the potential to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks, targeted research and development investments and concerted efforts by all affected are needed to realize that potential

Preoperative Red Cell Distribution Width and 30-day mortality in older patients undergoing non-cardiac surgery: a retrospective cohort observational study

Increased red cell distribution width (RDW) is associated with poorer outcomes in various patient populations. We investigated the association between preoperative RDW and anaemia on 30-day postoperative mortality among elderly patients undergoing non-cardiac surgery. Medical records of 24,579 patients aged 65 and older who underwent surgery under anaesthesia between 1 January 2012 and 31 October 2016 were retrospectively analysed. Patients who died within 30 days had higher median RDW (15.0%) than those who were alive (13.4%). Based on multivariate logistic regression, in our cohort of elderly patients undergoing non-cardiac surgery, moderate/severe preoperative anaemia (aOR 1.61, p = 0.04) and high preoperative RDW levels in the 3rd quartile (>13.4% and ≤14.3%) and 4th quartile (>14.3%) were significantly associated with increased odds of 30-day mortality - (aOR 2.12, p = 0.02) and (aOR 2.85, p = 0.001) respectively, after adjusting for the effects of transfusion, surgical severity, priority of surgery, and comorbidities. Patients with high RDW, defined as >15.7% (90th centile), and preoperative anaemia have higher odds of 30-day mortality compared to patients with anaemia and normal RDW. Thus, preoperative RDW independently increases risk of 30-day postoperative mortality, and future risk stratification strategies should include RDW as a factor

Pharmacokinetic analysis of two different docetaxel dose levels in patients with non-small cell lung cancer treated with docetaxel as monotherapy or with concurrent radiotherapy

<p>Abstract</p> <p>Background</p> <p>Previous pharmacokinetic studies with docetaxel have mostly used 3-weekly (75 mg/m²and 100 mg/m²) or weekly regimens (35–40 mg/m²). The pharmacokinetics and radiosensitizing efficacy of weekly 20 mg/m²docetaxel, has however not been well characterized. We examined the pharmacokinetics of weekly docetaxel when administered with concurrent radiotherapy and compared the results with a 3-weekly 100 mg/m²regimen.</p> <p>Methods</p> <p>Thirty-four patients with non small cell lung cancer (NSCLC) were included in this study, 19 receiving 100 mg/m²docetaxel 3-weekly as single therapy, and 15 receiving 20 mg/m²docetaxel weekly with concurrent radiotherapy. A newly developed HPLC method was used for measuring docetaxel levels, capable of quantifying docetaxel in plasma down to the nanomolar level.</p> <p>Results</p> <p>The HPLC method showed detectable concentrations of docetaxel in plasma even after 72 hours. In the present study we have demonstrated that median docetaxel plasma levels of 3 nM can be obtained 72 hours after a dose of 20 mg/m².</p> <p>Conclusion</p> <p>The pharmacokinetics of docetaxel is characterized by great inter-individual variability and at some time points plasma concentrations for 20 mg/m²and 100 mg/m²docetaxel were overlapping. Extrapolation of these results indicates that radio sensitizing docetaxel concentrations may be present for as long as 1 week, thus supporting the use of 20 mg/m²weekly docetaxel.</p

Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study

<p>Abstract</p> <p>Background</p> <p>To assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs).</p> <p>Methods</p> <p>A total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A→G polymorphism at bp 304 in <it>GSTP1</it>, and deletions in <it>GST-M1 </it>and <it>GST-T1</it>. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment.</p> <p>Results</p> <p>All six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either <it>GSTP1-AG </it>or <it>GSTP1</it>-<it>AA</it>, the 37 TCSs with the genotype <it>GSTP1-GG</it>, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22–0.96] and p = 0.023, OR 0.42 [0.20–0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14–0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08–3.03]).</p> <p>Conclusion</p> <p>In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in <it>GSTP1 </it>and <it>GSTM1</it>. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.</p

High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection

BACKGROUND: The taxanes paclitaxel and docetaxel have traditionally been used in high doses every third week in the treatment of cancer. Lately there has been a trend towards giving weekly low doses to improve the therapeutic index. This article describes the development of high performance liquid chromatographic (HPLC) methods suitable for monitoring taxane levels in patients, focusing on patients receiving low-dose therapy. METHODS: Paclitaxel and docetaxel were extracted from human plasma by solid phase extraction, and detected by absorbance at 227 nm after separation by reversed phase high performance liquid chromatography. The methods were validated and their performance were tested using samples from patients receiving paclitaxel or docetaxel. RESULTS: The limits of quantitation were 1 nM for docetaxel and 1.2 nM for paclitaxel. For both compounds linearity was confirmed from the limit of quantitation up to 1000 nM in plasma. The recoveries ranged between 92% and 118% for docetaxel and between 76% and 104% for paclitaxel. Accuracy and precision were within international acceptance criteria, that is within ± 15%, except at the limit of quantitation where values within ± 20% are acceptable. Low-dose patients included in an on going clinical trial had a median docetaxel concentration of 2.8 nM at 72 hours post infusion. Patients receiving 100 mg/m(2 )of paclitaxel had a mean paclitaxel concentration of 21 nM 48 hours after the end of infusion. CONCLUSION: We have developed an HPLC method using UV detection capable of quantifying 1 nM of docetaxel in plasma samples. The method should be useful for pharmacokinetic determinations at all relevant doses of docetaxel. Using a similar methodology paclitaxel can be quantified down to a concentration of 1.2 nM in plasma with acceptable accuracy and precision. We further demonstrate that the previously reported negative influence of Cremophor EL on assay performance may be overcome by degradation of the detergent by incubation with lipase

Association of metabolic equivalent of task (MET) score in length of stay in hospital following radical cystectomy with urinary diversion:a multi-institutional study

PURPOSE: The Metabolic equivalent of task (MET) score is used in patients’ preoperative functional capacity assessment. It is commonly thought that patients with a higher MET score will have better postoperative outcomes than patients with a lower MET score. However, such a link remains the subject of debate and is yet unvalidated in major urological surgery. This study aimed to explore the association of patients’ MET score with their postoperative outcomes following radical cystectomy. METHODS: We used records-linkage methodology with unique identifiers (Community Health Index/hospital number) and electronic databases to assess postoperative outcomes of patients who had underwent radical cystectomies between 2015 and 2020. The outcome measure was patients’ length of hospital stay. This was compared with multiple basic characteristics such as age, sex, MET score and comorbid conditions. A MET score of less than four (< 4) is taken as the threshold for a poor functional capacity. We conducted unadjusted and adjusted Cox regression analyses for time to discharge against MET score. RESULTS: A total of 126 patients were included in the analysis. Mean age on date of operation was 66.2 (SD 12.2) years and 49 (38.9%) were female. A lower MET score was associated with a statistically significant lower time-dependent risk of hospital discharge (i.e. longer hospital stay) when adjusted for covariates (HR 0.224; 95% CI 0.077–0.652; p = 0.006). Older age (adjusted HR 0.531; 95% CI 0.332–0.848; p = 0.008) and postoperative complications (adjusted HR 0.503; 95% CI 0.323–0.848; p = 0.002) were also found to be associated with longer hospital stay. Other comorbid conditions, BMI, disease staging and 30-day all-cause mortality were statistically insignificant. CONCLUSION: A lower MET score in this cohort of patients was associated with a longer hospital stay length following radical cystectomy with urinary diversion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11255-021-02813-x