Sampling of the North Sea trawl fishery for lesser sandeel (Ammodytes marinus) showed that 96% of the catch weight consisted of the target species, and experimental sea trials demonstrated that the ...observed small bycatch percentages of haddock (Melanogrammus aeglefinus), mackerel (Scomber scombrus) and grey gurnard (Eutrigla gurnardus) could be significantly lowered by inserting a netting-based sorting device, an Excluder, in front of the codend. The sandeel fishery is conducted with small meshes in the codend, due to the small size and elongated body shape of this species. It is not mandatory for sandeel trawls to have any other selection devices than the small-meshed codend, and this can potentially cause problems with bycatch of unwanted species, if these are abundant on the fishing grounds. Therefore, we sampled the catch composition in this fishery and further, we compared the capture efficiency and species composition of a standard trawl, and one fitted with an additional sorting device called the Excluder. Overall, results showed small percentages of bycatch in the trips sampled and during the trials, the excluder significantly reduced the bycatches of mackerel, grey gurnard, and haddock above certain sizes. For other bycatch species results were inconclusive due to wide confidence limits affected by low bycatch numbers during the trials. The overall capture efficiency for the target species was not affected by adding the excluder in the trawl except for a significant reduction for a few semi-centimetre groups of the largest sizes of the species. These results highlight the potential of the Excluder as a bycatch reduction tool in the sandeel fishery for situations where bycatch can constitute a problem.
Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved ...survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m2 per day) or prednisone (60 mg/m2 per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response PGR) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).
•Dexamethasone vs prednisone in induction of pediatric ALL led to significant relapse reduction and increased treatment-related mortality.•No overall survival benefit was achieved with dexamethasone except in the subset of patients with T-cell ALL and good early treatment response.
Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients ...of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1-positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.
There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we ...conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10
), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10
) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10
), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10
). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.
•An effective Salmonella infection model was demonstrated in goats.•Salmonella was consistently found in all lymph nodes of every goat.•Carcass vascular rinsing successfully delivered bacteriophages ...to the lymph nodes.•Vascular rinsing without or with bacteriophages did not cause Salmonella reduction.
An animal infection model was evaluated on sheep and goats to confirm which species infected with Salmonella enterica serovar Enteritidis C StR (SE13) would provide a consistent and high frequency of Salmonella colonization in lymph nodes (LNs) without causing undue animal morbidity. Sheep and goats (n = 5) were intradermally inoculated with Salmonella, postincubated for 7 days, and euthanized. Superficial cervical, medial iliac, subiliac, mammary, and popliteal LNs were excised from each carcass. Goat LNs had approximately 53% greater Salmonella level compared to sheep. Also, Salmonella was inconsistently recovered from the sheep LNs. Thus, goats were selected to determine the ability of carcass vascular rinsing (with and without bacteriophages) to reduce Salmonella in infected LNs. Goats with similar characteristics were grouped together before being randomly assigned to 3 postharvest treatments; control (CN, not vascularly rinsed; n = 10), vascularly rinsed with a standard Rinse & Chill® solution (RC; 98.5% water and a blend of saccharides and phosphates; n = 10), or vascularly rinsed with a standard Rinse & Chill® solution plus the addition of bacteriophages (BP; n = 10). Rinse & Chill® system was able to successfully deliver a mean 7.0 log PFU/g to the S. Enteritidis-infected LNs (mean 3.5 log CFU/g). However, neither Rinse & Chill® without bacteriophages nor with bacteriophages caused Salmonella reduction (P > 0.05) compared to the nonrinsed goat carcasses.
Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor ...(BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1
. The IKZF1
group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1
definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1
. The IKZF1
prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1
patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1
patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1
describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1
patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.
A new bycatch reduction device, termed "Excluder", is presented as an alternative to a traditional rigid sorting grid, mandatory in the small-meshed Norway Pout (Trisopterus esmarkii) trawl fishery ...in the North Sea. The fishery is a high-volume fishery with large vessels, large demersal trawls and catches up to 100 tons per haul of this small forage fish. The Excluder is a 30 m long netting-based sorting system, developed to reduce bycatch (70 mm square meshes) and improving on board gear-handling and safety. The Excluder was tested against a 5.8 m2 standard sorting grid (35 mm bar spacing) in a twin-trawl experiment from the commercial 70 m trawler "S364 Rockall". Catch data were analysed by species and length using the catch comparison method. For all bycatch species analysed, the Excluder had significantly lower catches relative to the grid: herring (21%), whiting (6%), mackerel (5%), American plaice (70%), witch flounder (15%), and lesser silver smelt (71%). For Norway Pout there was a significant increase in the overall catch efficiency of 32%. These results are explained by a 10 cm smaller L50 (the length of fish with 50% probability of being rejected by the sorting system) of the Excluder and a 15 times larger sorting area, which reduces the risk of clogging and loss of function. With these documented effects of improved sorting and target species catch efficiency, implementation of the Excluder would improve sustainability and address two main barriers of the current Norway pout fishery that limit quota capitalization; a tendency for Norway pout to mix with herring and whiting and lowered catch rates from grid-clogging. Additionally, gear-handling and safety on board would be improved.
There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing ...for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
•A new solver for the GRP without an exact Riemann solver.•Turn any HLL-type Riemann solver into a GRP solver of any higher order.•No need to compute eigenvectors or higher order derivatives of the ...system.
The generalized Riemann problem (GRP) is the initial value problem for a conservation law with piecewise smooth, but discontinuous initial data. We provide a new method for solving the GRP approximately, that can be used as a building block for high order finite volume or discontinuous Galerkin methods. Our new GRP solvers use the approximate states and wave speeds obtained through a HLL-type Riemann solver and use this information to build an approximation of the state in the GRP of any order. What is new about this approach compared to most previous solvers is that we no longer need to solve a classical Riemann problem exactly. We give a detailed explanation of this strategy for HLL and HLLC solvers for the Euler equations, as well as for the HLLD solver for MHD equations. We demonstrate the performance of the solvers from this new family of GRP solvers for a broad range of test problems.
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