Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer

Background Selective cyclooxygenase inhibitors may retard the progression of cancer, but they have enhanced thrombotic potential. We report on cardiovascular adverse events in patients receiving rofecoxib to reduce rates of recurrence of colorectal cancer. Methods All serious adverse events that were cardiovascular thrombotic events were reviewed in 2434 patients with stage II or III colorectal cancer participating in a randomized, placebo-controlled trial of rofecoxib, 25 mg daily, started after potentially curative tumor resection and chemotherapy or radiotherapy as indicated. The trial was terminated prematurely owing to worldwide withdrawal of rofecoxib. To examine possible persistent risks, we examined cardiovascular thrombotic events reported up to 24 months after the trial was closed. Results The median duration of active treatment was 7.4 months. The 1167 patients receiving rofecoxib and the 1160 patients receiving placebo were well matched, with a median follow-up period of 33.0 months (interquartile range, 27.6 to 40.1) and 33.4 months (27.7 to 40.4), respectively. Of the 23 confirmed cardiovascular thrombotic events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards model; 95% confidence interval [CI], 1.03 to 6.86; P = 0.04). Analysis of the Antiplatelet Trialists’ Collaboration end point (the combined incidence of death from cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction; and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative risk of 1.60 (95% CI, 0.57 to 4.51; P = 0.37). Fourteen more cardiovascular thrombotic events, six in the rofecoxib group, were reported within the 2 years after trial closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94; P = 0.24). Four patients in the rofecoxib group and two in the placebo group died from thrombotic causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes. Conclusions Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular events among patients with a median study treatment of 7.4 months’ duration. (Current Controlled Trials number, ISRCTN98278138.

Neuronal pentraxins mediate synaptic refinement in the developing visual system

Peer reviewedPublisher PD

Recovery and evolutionary analysis of complete integron gene cassette arrays from Vibrio

BACKGROUND: Integrons are genetic elements capable of the acquisition, rearrangement and expression of genes contained in gene cassettes. Gene cassettes generally consist of a promoterless gene associated with a recombination site known as a 59-base element (59-be). Multiple insertion events can lead to the assembly of large integron-associated cassette arrays. The most striking examples are found in Vibrio, where such cassette arrays are widespread and can range from 30 kb to 150 kb. Besides those found in completely sequenced genomes, no such array has yet been recovered in its entirety. We describe an approach to systematically isolate, sequence and annotate large integron gene cassette arrays from bacterial strains. RESULTS: The complete Vibrio sp. DAT722 integron cassette array was determined through the streamlined approach described here. To place it in an evolutionary context, we compare the DAT722 array to known vibrio arrays and performed phylogenetic analyses for all of its components (integrase, 59-be sites, gene cassette encoded genes). It differs extensively in terms of genomic context as well as gene cassette content and organization. The phylogenetic tree of the 59-be sites collectively found in the Vibrio gene cassette pool suggests frequent transfer of cassettes within and between Vibrio species, with slower transfer rates between more phylogenetically distant relatives. We also identify multiple cases where non-integron chromosomal genes seem to have been assembled into gene cassettes and others where cassettes have been inserted into chromosomal locations outside integrons. CONCLUSION: Our systematic approach greatly facilitates the isolation and annotation of large integrons gene cassette arrays. Comparative analysis of the Vibrio sp. DAT722 integron obtained through this approach to those found in other vibrios confirms the role of this genetic element in promoting lateral gene transfer and suggests a high rate of gene gain/loss relative to most other loci on vibrio chromosomes. We identify a relationship between the phylogenetic distance separating two species and the rate at which they exchange gene cassettes, interactions between the non-mobile portion of bacterial genomes and the vibrio gene cassette pool as well as intragenomic translocation events of integrons in vibrios

The long-term evolution of the Douro River as evidenced by strath terrace staircases located at NE Portugal (western Iberia)

In western Iberia, mechanisms that explain the transition from endorheic to exorheic continental-scale drainage reorganisation are foreland basin overspill, headwards erosion and capture by an Atlantic river, or a combination of both. To explore these controls we have investigated the Portuguese sector of the Douro River, the site of drainage re-organsation. The Douro River routes downstream through weak sedimentary infill of the Douro Cenozoic Basin (Spain), after which the river cuts down through granitic and metamorphic rocks cut by active fault zones (NE Portugal), before reaching the Atlantic coast. We investigated the drainage reorganisation using an integrated remote sensing, field survey and geochronological approach applied to Pliocene-Quaternary fluvial sediments and landforms. The older drainage record is documented by a series of high and intermediate landform levels comprising 1) a high level (1000-600 m) faulted regional fluvial erosion surface, the North Iberian Meseta Planation Surface (NIMPS); 2) an inset level (650-600 m altitude) comprising a broad fluvial surface formed onto a large ENE-WSW depression that overlies resistant ProterozoicandPaleozoic bedrock and 3) an inset (500450m) fluvial surface. The younger drainage record comprises an entrenched fluvial strath terrace sequence of up to 9 levels (T9 = oldest positioned at 246-242 m above the modern river base (a.r.b); T1 = youngest positioned at 17-13 m a.r.b.). Levels T1 and T3 display fault offsets where the cross active NNE-SSW fault zones. The three lowest terrace levels (T1-T3) were dated using optically stimulated luminescence (OSL) techniques using Quartz-OSL and post infra-red stimulated luminescence (pIRIR). Results ranged from 39-12ka (T1), 57ka (T2) and >360ka (minimum) (T3). Fluvial incision rates of the younger (terrace) drainage record were quantified and temporally exptrapolated to model the ages of the high to intermediate elevation levels of the early drainage record. Integration of incision data with fault zone derived crustal uplift values informs on the timing of the endorheic to exhoreic drainage reorganization. We interpret the NIMPS to be part of the endorehic Douro Cenozoic Basin drainage divide erosion. The inset wide fluvial surface at 650-600 m altitude represents the overspill level in the area of the Mesão Frio ridges (drainage divide with the Atlantic drainage). Development of the exhoreic ancestral Douro valley is documented in the 500-450 m fluvial surface with our age and uplift modelling suggesting this became established during the upper Pleistocene (3.6 Ma) through to the Early Pleistocene (1.8 Ma). The entrenched river terrace sequence spans the Pleistocene, developing via spatial and temporal variations in rock strength, uplift and cyclic cool climate variability as the river adjusts to the Atlantic base level

Non-maximally entangled states: production, characterization and utilization

Using a spontaneous-downconversion photon source, we produce true non-maximally entangled states, i.e., without the need for post-selection. The degree and phase of entanglement are readily tunable, and are characterized both by a standard analysis using coincidence minima, and by quantum state tomography of the two-photon state. Using the latter, we experimentally reconstruct the reduced density matrix for the polarization. Finally, we use these states to measure the Hardy fraction, obtaining a result that is $122 \sigma$ from any local-realistic result.Comment: 4 pages, 4 figures. To appear in Phys. Rev. Let

Techniques to increase lumbar puncture success in newborn babies: the NeoCLEAR RCT

Background Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50–60%). Standard technique includes lying infants on their side and removing the stylet ‘late’, that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet ‘early’, that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives The aim of the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of ‘early’ rather than ‘late’ stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations This trial predominantly recruited term-born infants who were 2.5 kg. The impact of practitioners’ seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators’ previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information

Altered Peripheral Sensitivity to Glucocorticoids in Primary Open-Angle Glaucoma

PURPOSE. Increased levels of glucocorticoids are associated with raised intraocular pressure (IOP). The activity of glucocorticoids is regulated at a prereceptor level by 11␤-hydroxysteroid dehydrogenases (11␤-HSD). This study was an investigation of the central and peripheral sensitivity to glucocorticoids in patients with POAG or ocular hypertension (OHT) and the differential metabolism of glucocorticoids by 11␤-HSDs. METHODS. Patients with POAG or OHT and normal control subjects were studied. Peripheral sensitivity to glucocorticoids was assessed as dermal blanching and central sensitivity by dexamethasone suppression testing. Daily production rates of glucocorticoids were determined by quantifying metabolites in 24-hour urine. Plasma cortisol levels were determined at baseline (9 AM) and after an overnight low-dose dexamethasone suppression test. In a separate study, plasma and aqueous humor cortisol levels were determined in patients with POAG and normal subjects. RESULTS. Patients with POAG exhibited a greater cutaneous vasoconstrictor response to glucocorticoids than patients with OHT and normal subjects (20.7 Ϯ 3.1 vs. 8.5 Ϯ 4.4 and 8.6 Ϯ 4.5 arbitrary units, respectively; P Ͻ 0.05 in each case). Total glucocorticoid production rates were not different between groups, nor were total circulating cortisol levels before or after suppression of the hypothalamic-pituitary-adrenal axis by dexamethasone or concentrations in aqueous humor. The ratio of urinary cortisol to cortisone metabolites was elevated in POAG versus normal control and OHT (1.74 Ϯ 0.13 vs. 1.34 Ϯ 0.11 and 1.32 Ϯ 0.14; P Ͻ 0.05 in each case), indicating a change in the balance of 11␤-HSDs, without a change in other metabolic pathways. CONCLUSIONS. Patients with POAG exhibit increased peripheral vascular sensitivity to glucocorticoids. Increased sensitivity of glucocorticoid receptors, may enhance local glucocorticoid action in the eye and exacerbate the adverse effects of glucocorticoids in this condition (Invest Ophthalmol Vis Sci

Oscillations of a solid sphere falling through a wormlike micellar fluid

We present an experimental study of the motion of a solid sphere falling through a wormlike micellar fluid. While smaller or lighter spheres quickly reach a terminal velocity, larger or heavier spheres are found to oscillate in the direction of their falling motion. The onset of this instability correlates with a critical value of the velocity gradient scale $\Gamma_{c}\sim 1$ s$^{-1}$. We relate this condition to the known complex rheology of wormlike micellar fluids, and suggest that the unsteady motion of the sphere is caused by the formation and breaking of flow-induced structures.Comment: 4 pages, 4 figure

Health systems performance for hypertension control using a cascade of care approach in South Africa, 2011–2017

Hypertension is a major contributor to global morbidity and mortality. In South Africa, the government has employed a whole systems approach to address the growing burden of non-communicable diseases. We used a novel incident care cascade approach to measure changes in the South African health system's ability to manage hypertension between 2011 and 2017. We used data from Waves 1-5 of the National Income Dynamics Study (NIDS) to estimate trends in the hypertension care cascade and unmet treatment need across four successive cohorts with incident hypertension. We used a negative binomial regression to identify factors that may predict higher rates of hypertension control, controlling for socio-demographic and healthcare factors. In 2011, 19.6% (95%CI 14.2, 26.2) of individuals with incident hypertension were diagnosed, 15.4% (95%CI 10.8, 21.4) were on treatment and 7.1% had controlled blood pressure. By 2017, the proportion of individuals with diagnosed incident hypertension had increased to 24.4% (95%CI 15.9, 35.4). Increases in treatment (23.3%, 95%CI 15.0, 34.3) and control (22.1%, 95%CI 14.1, 33.0) were also observed, translating to a decrease in unmet need for hypertension care from 92.9% in 2011 to 77.9% in 2017. Multivariable regression showed that participants with incident hypertension in 2017 were 3.01 (95%CI 1.77, 5.13) times more likely to have a controlled blood pressure compared to those in 2011. Our data show that while substantial improvements in the hypertension care cascade occurred between 2011 and 2017, a large burden of unmet need remains. The greatest losses in the incident hypertension care cascades came before diagnosis. Nevertheless, whole system programming will be needed to sufficiently address significant morbidity and mortality related to having an elevated blood pressure

Respiratory syncytial virus infection activates IL-13–producing group 2 innate lymphoid cells through thymic stromal lymphopoietin

BACKGROUND: Respiratory syncytial virus (RSV) is a major health care burden with a particularly high worldwide morbidity and mortality rate among infants. Data suggest that severe RSV-associated illness is in part caused by immunopathology associated with a robust type 2 response. OBJECTIVE: We sought to determine the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model. METHODS: Wild-type (WT) BALB/c, thymic stromal lymphopoietin receptor (TSLPR) knockout (KO), or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4 to 6 days of infection, lungs were collected for evaluation of viral load, protein concentration, airway mucus, airway reactivity, or ILC2 numbers. Results were confirmed with 2 additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential. RESULTS: RSV induced a 3-fold increase in the number of IL-13-producing ILC2s at day 4 after infection, with a concurrent increase in total lung IL-13 levels. Both thymic stromal lymphopoietin (TSLP) and IL-33 levels were increased 12 hours after infection. TSLPR KO mice did not mount an IL-13-producing ILC2 response to RSV infection. Additionally, neutralization of TSLP significantly attenuated the RSV-induced IL-13-producing ILC2 response. TSLPR KO mice displayed reduced lung IL-13 protein levels, decreased airway mucus and reactivity, attenuated weight loss, and similar viral loads as WT mice. Both 12/11-19 and 12/12-6 similarly induced IL-13-producing ILC2s through a TSLP-dependent mechanism. CONCLUSION: These data demonstrate that multiple pathogenic strains of RSV induce IL-13-producing ILC2 proliferation and activation through a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection