Oil spill preparedness planning: filling critical species data gaps using habitat suitability modelling

Under the World Class Tanker Safety System Initiative (WCTSS) a national framework was developed to identify marine biological organisms most vulnerable to ship-source oil spills. The Pacific regional application of this framework identified 27 highly vulnerable biological groups, with sea grasses, salt marsh grasses/succulents, sea otters, and baleen whales at the top of the list. A gap analysis during the Pacific regional application identified critical species data gaps that must now be filled to ensure effective response in marine oil spill emergencies. In the absence of robust species distribution and abundance data, habitat suitability models can be used to predict this information using environmental spatial data layers and limited species distribution data. The Oceans Protection Plan (OPP) Habitat Suitability Modelling team is developing a workbook of standardized habitat suitability modelling approaches to illustrate how critical species data gaps may be filled. This workbook will include recommendations for data requirements, models to use, and how to deal with modelling challenges. Models will be developed and tested using data from Canada’s North Central Coast study area and then applied in the Salish Sea to the Strait of Georgia study area in support of the south coast Area Response Plan. In addition to the modelling workbook and model predictions, another major output of this project is the extension of bottom type classification layers from 50-200 m depth, which will be useful for other marine spatial planning analyses. The habitat suitability modelling workbook, model predictions, and extended bottom type classification layers will serve as valuable pieces in the larger puzzle of international transboundary ecosystem protection and recovery

Population screening for colorectal cancer means getting FIT:the past, present, and future of colorectal cancer screening using the fecal immunochemical test for hemoglobin (FIT)

Fecal immunochemical tests for hemoglobin (FIT) are changing the manner in which colorectal cancer (CRC) is screened. Although these tests are being performed worldwide, why is this test different from its predecessors? What evidence supports its adoption? How can this evidence best be used? This review addresses these questions and provides an understanding of FIT theory and practices to expedite international efforts to implement the use of FIT in CRC screening

Quantifying precision and accuracy of measurements of dissolved inorganic carbon stable isotopic composition using continuous-flow isotope-ratio mass spectrometry

RATIONALE: We describe an analytical procedure that allows sample collection and measurement of carbon isotopic composition (δ13CV-PDB value) and dissolved inorganic carbon concentration, [DIC], in aqueous samples without further manipulation post field collection. By comparing outputs from two different mass spectrometers, we quantify with the statistical rigour uncertainty associated with the estimation of an unknown measurement. This is rarely undertaken, but it is needed to understand the significance of field data and to interpret quality assurance exercises.<p></p> METHODS: Immediate acidification of field samples during collection in evacuated, pre-acidified vials removed the need for toxic chemicals to inhibit continued bacterial activity that might compromise isotopic and concentration measurements. Aqueous standards mimicked the sample matrix and avoided headspace fractionation corrections. Samples were analysed using continuous-flow isotope-ratio mass spectrometry, but for low DIC concentration the mass spectrometer response could be non-linear. This had to be corrected for.<p></p> RESULTS: Mass spectrometer non-linearity exists. Rather than estimating precision as the repeat analysis of an internal standard, we have adopted inverse linear calibrations to quantify the precision and 95% confidence intervals (CI) of the δ13CDIC values. The response for [DIC] estimation was always linear. For 0.05–0.5 mM DIC internal standards, however, changes in mass spectrometer linearity resulted in estimations of the precision in the δ13CVPDB value of an unknown ranging from ± 0.44‰ to ± 1.33‰ (mean values) and a mean 95% CI half-width of ±1.1–3.1‰.<p></p> CONCLUSIONS: Mass spectrometer non-linearity should be considered in estimating uncertainty in measurement. Similarly, statistically robust estimates of precision and accuracy should also be adopted. Such estimations do not inhibit research advances: our consideration of small-scale spatial variability at two points on a small order river system demonstrates field data ranges larger than the precision and uncertainties. However, without such statistical quantification, exercises such as inter-lab calibrations are less meaningful.<p></p&gt

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs

Evaluation of a Participatory Ergonomics Intervention in Small Commercial Construction Firms

BACKGROUND: Work-related musculoskeletal disorders (WMSD) among construction workers remain high. Participatory ergonomics (PE) interventions that engage workers and employers in reducing work injury risks have shown mixed results. METHODS: Eight-six workers from seven contractors participated in a PE program. A logic model guided the process evaluation and summative evaluation of short term and intermediate impacts and long term outcomes from surveys and field records. RESULTS: Process measures showed good delivery of training, high worker engagement, and low contractor participation. Workers’ knowledge improved and workers reported changes to work practices and tools used; contractor provision of appropriate equipment was low (33%). No changes were seen in symptoms or reported physical effort. CONCLUSIONS: The PE program produced many worker-identified ergonomic solutions, but lacked needed support from contractors. Future interventions should engage higher levels of the construction organizational system to improve contractor involvement for reducing WMSD

CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza virus pathogenicity in vivo

Human infections with influenza viruses exhibit mild to severe clinical outcomes as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin domain family 5 member A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of proinflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes. Infection of bone marrow-derived macrophages from CLEC5A-deficient mice showed reduced levels of tumor necrosis factor alpha (TNF-α) and IP-10 but elevated alpha interferon (IFN-α) compared to those of wild-type mice. The heightened type I IFN response in the macrophages of CLEC5A-deficient mice was associated with upregulated TLR3 mRNA after treatment with double-stranded RNA. Upon lethal challenges with a recombinant H5N1 virus, CLEC5A-deficient mice showed reduced levels of proinflammatory cytokines, decreased immune cell infiltration in the lungs, and improved survival compared to the wild-type mice, despite comparable viral loads noted throughout the course of infection. The survival difference was more prominent at a lower dose of inoculum. Our results suggest that CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo and may be considered a therapeutic target in combination with effective antivirals. Well-orchestrated host responses together with effective viral clearance are critical for optimal clinical outcome after influenza infections.published_or_final_versio

Mycobacterium leprae genomes from a British medieval leprosy hospital: towards understanding an ancient epidemic.

BACKGROUND: Leprosy has afflicted humankind throughout history leaving evidence in both early texts and the archaeological record. In Britain, leprosy was widespread throughout the Middle Ages until its gradual and unexplained decline between the 14th and 16th centuries. The nature of this ancient endemic leprosy and its relationship to modern strains is only partly understood. Modern leprosy strains are currently divided into 5 phylogenetic groups, types 0 to 4, each with strong geographical links. Until recently, European strains, both ancient and modern, were thought to be exclusively type 3 strains. However, evidence for type 2 strains, a group normally associated with Central Asia and the Middle East, has recently been found in archaeological samples in Scandinavia and from two skeletons from the medieval leprosy hospital (or leprosarium) of St Mary Magdalen, near Winchester, England. RESULTS: Here we report the genotypic analysis and whole genome sequencing of two further ancient M. leprae genomes extracted from the remains of two individuals, Sk14 and Sk27, that were excavated from 10th-12th century burials at the leprosarium of St Mary Magdalen. DNA was extracted from the surfaces of bones showing osteological signs of leprosy. Known M. leprae polymorphisms were PCR amplified and Sanger sequenced, while draft genomes were generated by enriching for M. leprae DNA, and Illumina sequencing. SNP-typing and phylogenetic analysis of the draft genomes placed both of these ancient strains in the conserved type 2 group, with very few novel SNPs compared to other ancient or modern strains. CONCLUSIONS: The genomes of the two newly sequenced M. leprae strains group firmly with other type 2F strains. Moreover, the M. leprae strain most closely related to one of the strains, Sk14, in the worldwide phylogeny is a contemporaneous ancient St Magdalen skeleton, vividly illustrating the epidemic and clonal nature of leprosy at this site. The prevalence of these type 2 strains indicates that type 2F strains, in contrast to later European and associated North American type 3 isolates, may have been the co-dominant or even the predominant genotype at this location during the 11th century

Effect of hyperglycaemia in combination with moxifloxacin on cardiac repolarization in male and female patients with type I diabetes.

BACKGROUND: Patients with Type 1 diabetes mellitus have been shown to be at a two to ten-fold higher risk of sudden cardiac death (SCD) (Svane et al., Curr Cardiol 2020; 22:112) than the general population, but the underlying mechanism is unclear. Hyperglycaemia is a recognised cause of QTc prolongation; a state patients with type 1 diabetes are more prone to, potentially increasing their risk of ventricular arrhythmia. Understanding the QTc prolongation effect of both hyperglycaemia and the concomitant additive risk of commonly prescribed QTc-prolonging drugs such as Moxifloxacin may help to elucidate the mechanism of sudden cardiac death in this cohort. This single-blinded, placebo-controlled study investigated the extent to which hyperglycaemia prolongs the QTc in controlled conditions, and the potential additive risk of QTc-prolonging medications. METHODS: 21 patients with type 1 diabetes mellitus were enrolled to a placebo-controlled crossover study at a single clinical trials unit. Patients underwent thorough QTc assessment throughout the study. A 'hyperglycaemic clamp' of oral and intravenous glucose was administered with a target blood glucose of > 25 mM and maintained for 2 h on day 1 and day 3, alongside placebo on day 1 and moxifloxacin on day 3. Day 2 served as a control day between the two active treatment days. Thorough QTc assessment was conducted at matched time points over 3 days, and regular blood sampling was undertaken at matched time intervals for glucose levels and moxifloxacin exposure. RESULTS: Concentration-effect modelling showed that acute hyperglycaemia prolonged the QTc interval in female and male volunteers with type 1 diabetes by a peak mean increase of 13 ms at 2 h. Peak mean QTc intervals after the administration of intravenous Moxifloxacin during the hyperglycaemic state were increased by a further 9 ms at 2 h, to 22 ms across the entire study population. Regression analysis suggested this additional increase was additive, not exponential. Hyperglycaemia was associated with a significantly greater mean QTc-prolonging effect in females, but the mean peak increase with the addition of moxifloxacin was the same for males and females. This apparent sex difference was likely due to the exclusive use of basal insulin in the male patients, which provided a low level of exogenous insulin during the study assessments thereby mitigating the effects of hyperglycaemia on QTc. This effect was partially overcome by Moxifloxacin administration, suggesting both hyperglycaemia and moxifloxacin prolong QTc by different mechanisms, based on subinterval analysis. CONCLUSIONS: Hyperglycaemia was found to be a significant cause of QTc prolongation and the additional effect of a QTc-prolonging positive control (moxifloxacin) was found to be additive. Given the high risk of sudden cardiac death in type 1 diabetes mellitus, extra caution should be exercised when prescribing any medication in this cohort for QTc effects, and further research needs to be undertaken to elucidate the exact mechanism underlying this finding and explore the potential prescribing risk in diabetes. TRIAL REGISTRATION: NCT number: NCT01984827

Use of Short Tandem Repeat Sequences to Study Mycobacterium leprae in Leprosy Patients in Malawi and India

Molecular typing has provided an important tool for studies of many pathogens. Such methods could be particularly useful in studies of leprosy, given the many outstanding questions about the pathogenesis and epidemiology of this disease. The approach is particularly difficult with leprosy, however, because of the genetic homogeneity of M. leprae and our inability to culture it. This paper describes molecular epidemiological studies carried out on leprosy patients in Malawi and in India, using short tandem repeat sequences (STRS) as markers of M. leprae strains. It reveals evidence for continuous changes in these markers within individual patients over time, and for selection of different STRS-defined strains between different tissues (skin and nerve) in the same patient. Comparisons between patients collected under different circumstances reveal the uses and limitations of the approach—STRS analysis may in some circumstances provide a means to trace short transmission chains, but it does not provide a robust tool for distinguishing between relapse and reinfection. This encourages further work to identify genetic markers with different stability characteristics for incorporation into epidemiological studies of leprosy

Accurate detection of Neisseria gonorrhoeae ciprofloxacin susceptibility directly from genital and extragenital clinical samples: towards genotype-guided antimicrobial therapy.

INTRODUCTION: Increasing use of nucleic acid amplification tests (NAATs) as the primary means of diagnosing gonococcal infection has resulted in diminished availability of Neisseria gonorrhoeae antimicrobial susceptibility data. We conducted a prospective diagnostic assessment of a real-time PCR assay (NGSNP) enabling direct detection of gonococcal ciprofloxacin susceptibility from a range of clinical sample types. METHODS: NGSNP, designed to discriminate an SNP associated with ciprofloxacin resistance within the N. gonorrhoeae genome, was validated using a characterized panel of geographically diverse isolates (n = 90) and evaluated to predict ciprofloxacin susceptibility directly on N. gonorrhoeae-positive NAAT lysates derived from genital (n = 174) and non-genital (n = 116) samples (n = 290), from 222 culture-confirmed clinical episodes of gonococcal infection. RESULTS: NGSNP correctly genotyped all phenotypically susceptible (n = 49) and resistant (n = 41) panel isolates. Ciprofloxacin-resistant N. gonorrhoeae was responsible for infection in 29.7% (n = 66) of clinical episodes evaluated. Compared with phenotypic susceptibility testing, NGSNP demonstrated sensitivity and specificity of 95.8% (95% CI 91.5%-98.3%) and 100% (95% CI 94.7%-100%), respectively, for detecting ciprofloxacin-susceptible N. gonorrhoeae, with a positive predictive value of 100% (95% CI 97.7%-100%). Applied to urogenital (n = 164), rectal (n = 40) and pharyngeal samples alone (n = 30), positive predictive values were 100% (95% CI 96.8%-100%), 100% (95% CI 87.2%-100%) and 100% (95% CI 82.4%-100%), respectively. CONCLUSIONS: Genotypic prediction of N. gonorrhoeae ciprofloxacin susceptibility directly from clinical samples was highly accurate and, in the absence of culture, will facilitate use of tailored therapy for gonococcal infection, sparing use of current empirical treatment regimens and enhancing acquisition of susceptibility data for surveillance