Background: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and ...mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment. Methods: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided. Results: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval CI = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P<.001), and axillary operative time was reduced (P = .055). Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P≤.003). These benefits were seen with no increase in anxiety levels in the sentinel lymph node biopsy group (P>.05). Conclusion: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.
Adhesion of conidia of the insect pathogenic fungus, Metarhizium anisopliae, to the arthropod host cuticle initially involves hydrophobic forces followed by consolidation facilitated by the action of ...extracellular enzymes and secretion of mucilage. Gene expression analysis and atomic force microscopy were used to directly quantify recognition and adhesion between single conidia of M. anisopliae and the cuticle of the aquatic larval stage of Aedes aegypti and a representative terrestrial host, Tenebrio molitor. Gene expression data indicated recognition by the pathogen of both hosts; however, the forces for adhesion to the mosquito were approximately five times lower than those observed for Tenebrio. Although weak forces were recorded in response to Aedes, Metarhizium was unable to consolidate firm attachment. An analysis of the cuticular composition revealed an absence of long-chain hydrocarbons in Aedes larvae which are thought to be required for fungal development on host cuticle. This study provides, to our knowledge, the first evidence that Metarhizium does not form firm attachment to Ae. aegypti larvae in situ, therefore preventing the normal route of invasion and pathogenesis from occuring.
Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug ...targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.
We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.
We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).
Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.
US National Institutes of Health.
The National Institute for Health and Care Excellence (NICE) has recently updated the guideline for Acute kidney injury: prevention, detection and management (NG148), providing new recommendations on ...preventing acute kidney injury (AKI) in adults receiving intravenous iodine-based contrast media. The association between intravenous iodinated contrast media and AKI is controversial, particularly with widespread use of iso-osmolar agents. Associations between contrast media administration and AKI are largely based on observational studies, with inherent heterogeneity in patient populations, definitions applied, and timing of laboratory investigations. In an attempt to mitigate risk, kidney protection has typically been employed using intravenous volume expansion and/or oral acetylcysteine. Such interventions are in widespread use, despite lacking high-quality evidence of benefit. In the non-emergency setting, glomerular filtration rate (GFR) measurements should be obtained within the preceding 3 months before offering intravenous iodine-based contrast media. In the acute setting, adults should also have their risk of AKI assessed before offering intravenous iodine-based contrast media; however, this should not delay emergency imaging. Based on the evidence available from randomised controlled trials, the NICE committee recommends that oral hydration should be encouraged in adults at increased risk of AKI and that volume expansion with intravenous V fluids should only be considered for inpatients at particularly high risk.
Aliment Pharmacol Ther
31
, 834–845
Summary
Background
There is little information on the effects of vaptans in patients with cirrhosis.
Aim
To investigate the short‐term effects of satavaptan, a ...selective vasopressin V
2
receptor antagonist on ascites in cirrhosis without hyponatraemia.
Methods
A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double‐blind, randomized, controlled study of 14 days comparing three fixed doses of satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20–25 mg/day.
Results
Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was −0.36 kg (±3.03) for placebo vs. −2.46 kg (±3.11), −2.08 kg (±4.17) and −2.28 kg (±3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively;
P
= 0.036,
P
= 0.041 and
P
= 0.036 for satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with satavaptan compared with placebo, while other adverse events were similar.
Conclusions
The administration satavaptan for a 14‐day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.
•Two novel methods used to determine renewable energy content and yield from mixed waste materials.•Biogenic content of waste components measured, along with proximate and ultimate ...analysis.•Determined values accurate to within 5% of actual values.•Key applications include renewable energy yield prior to combustion and classification of SRF.
Two novel techniques are presented in this study which together aim to provide a system able to determine the renewable energy potential of mixed waste materials. An image analysis tool was applied to two waste samples prepared using known quantities of source-segregated recyclable materials. The technique was used to determine the composition of the wastes, where through the use of waste component properties the biogenic content of the samples was calculated. The percentage renewable energy determined by image analysis for each sample was accurate to within 5% of the actual values calculated. Microwave-based multiple-point imaging (AutoHarvest) was used to demonstrate the ability of such a technique to determine the moisture content of mixed samples. This proof-of-concept experiment was shown to produce moisture measurement accurate to within 10%. Overall, the image analysis tool was able to determine the renewable energy potential of the mixed samples, and the AutoHarvest should enable the net calorific value calculations through the provision of moisture content measurements. The proposed system is suitable for combustion facilities, and enables the operator to understand the renewable energy potential of the waste prior to combustion.
To assess the role of the DNA-PKcs nonhomologous DNA end-joining (NHEJ) protein in Ig heavy chain class switch recombination (CSR), we assayed CSR ability of DNA-PKcs-deficient (DP-T) B cells ...generated via complementation of DP-T mice with Ig heavy chain and light chain knockin transgenes (DP-T/HC/LC mice). DP-T/HC/LC mice were severely deficient for all serum IgH isotypes except IgM and, unexpectedly, IgG1. Upon appropriate stimulation, DP-T/HC/LC B cells showed normal proliferation, germline C
H gene transcription, and AID induction, indicating that DNA-PKcs deficiency did not affect cellular events upstream to CSR. Yet, in vitro activated DP-T/HC/LC B cells again underwent switching only to IgG1 and, like wild-type cells, frequently underwent CSR to γ1 on both chromosomes. We conclude that DNA-PKcs is required for CSR to most C
H genes but that CSR to γ1 occurs via a DNA-PKcs-independent mechanism.
The observed patterns and variations in the ecology, epidemiology, distribution and prevalence of the West Nile Virus (WNV) in different areas of the Western Hemisphere make this pathogen of ...particular importance as a model for understanding the potential risk factors associated with emerging pathogens worldwide, particularly those involving zoonotic pathogens whose epidemiology involves the potential for vertical transmission in arthropod vector species, and horizontal and vertical transmission within and among vertebrate host species. Record numbers of human WNV cases were recorded in Canada during 2007, with >50% more cases than documented in any previous year. Although overall numbers of human infections recorded in the United States were not exceptionally high during 2007 relative to epidemic levels reported in 2002 and 2003, the state of Oklahoma reported that the highest-ever number of human WNV cases and the numbers of human cases recorded in Canada were 50% higher than previous record levels recorded in 2003. The record and near-record numbers of human WNV infections recorded in several regions of North America during 2007 have important implications for the future management and surveillance of WNV vectors and reservoirs in North America. The spatiotemporal distribution of WNV infections in humans and animals recorded during 2007 in North America and South America have important implications for the surveillance and management of public health threats from WNV in the Western Hemisphere. Serological surveys conducted in areas of intense WNV transmission in the United States have reported low prevalence of antibodies to WNV in human s populations, indicating that additional epidemic outbreaks of human disease from WNV can be expected in the future.
We use measurements from the South Pole Telescope (SPT) Sunyaev-Zel'dovich (SZ) cluster survey in combination with X-ray measurements to constrain cosmological parameters. We present a statistical ...method that fits for the scaling relations of the SZ and X-ray cluster observables with mass while jointly fitting for cosmology. The method is generalizable to multiple cluster observables, and self-consistently accounts for the effects of the cluster selection and uncertainties in cluster mass calibration on the derived cosmological constraints. We apply this method to a data set consisting of an SZ-selected catalog of 18 galaxy clusters at z > 0.3 from the first 178 deg{sup 2} of the 2500 deg{sup 2} SPT-SZ survey, with 14 clusters having X-ray observations from either Chandra or XMM-Newton. Assuming a spatially flat {Lambda}CDM cosmological model, we find the SPT cluster sample constrains {sigma}{sub 8}({Omega} {sub m}/0.25){sup 0.30} = 0.785 {+-} 0.037. In combination with measurements of the cosmic microwave background (CMB) power spectrum from the SPT and the seven-year Wilkinson Microwave Anisotropy Probe data, the SPT cluster sample constrains {sigma}{sub 8} = 0.795 {+-} 0.016 and {Omega} {sub m} = 0.255 {+-} 0.016, a factor of 1.5 improvement on each parameter over the CMB data alone. We consider several extensions beyond the {Lambda}CDM model by including the following as free parameters: the dark energy equation of state (w), the sum of the neutrino masses ({Sigma}m {sub {nu}}), the effective number of relativistic species (N {sub eff}), and a primordial non-Gaussianity (f {sub NL}). We find that adding the SPT cluster data significantly improves the constraints on w and {Sigma}m {sub {nu}} beyond those found when using measurements of the CMB, supernovae, baryon acoustic oscillations, and the Hubble constant. Considering each extension independently, we best constrain w = -0.973 {+-} 0.063 and the sum of neutrino masses {Sigma}m {sub {nu}} < 0.28 eV at 95% confidence, a factor of 1.25 and 1.4 improvement, respectively, over the constraints without clusters. Assuming a {Lambda}CDM model with a free N {sub eff} and {Sigma}m {sub {nu}}, we measure N {sub eff} = 3.91 {+-} 0.42 and constrain {Sigma}m {sub {nu}} < 0.63 eV at 95% confidence. We also use the SPT cluster sample to constrain f {sub NL} = -220 {+-} 317, consistent with zero primordial non-Gaussianity. Finally, we discuss the current systematic limitations due to the cluster mass calibration, and future improvements for the recently completed 2500 deg{sup 2} SPT-SZ survey. The survey has detected {approx}500 clusters with a median redshift of {approx}0.5 and a median mass of {approx}2.3 Multiplication-Sign 10{sup 14} M {sub Sun} h {sup -1} and, when combined with an improved cluster mass calibration and existing external cosmological data sets will significantly improve constraints on w.
The lack of persistence of transferred autologous mature lymphocytes in humans has been a major limitation to the application of effective cell transfer therapies. The results of a pilot clinical ...trial in 13 patients with metastatic melanoma suggested that conditioning with nonmyeloablative chemotherapy before adoptive transfer of activated tumor-reactive T cells enhances tumor regression and increases the overall rates of objective clinical responses. The present report examines the relationship between T cell persistence and tumor regression through analysis of the TCR beta-chain V region gene products expressed in samples obtained from 25 patients treated with this protocol. Sequence analysis demonstrated that there was a significant correlation between tumor regression and the degree of persistence in peripheral blood of adoptively transferred T cell clones, suggesting that inadequate T cell persistence may represent a major factor limiting responses to adoptive immunotherapy.
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