Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Immunohistochemical localization of TNF-α and IL-4 in granulomas of immunocompetent and immunosuppressed New Zealand white rabbits infected with Encephalitozoon cuniculi.

Encephalitozoon cuniculi is a fungi-related, obligate, zoonotic, spore-forming intracellular eukaryotic microorganism. This emerging pathogen causes granulomas to form in the brain and kidneys of infected individuals. The objective of the current study was to detect the distribution of TNF-α- and IL-4-positive cells using immunohistochemistry within these granulomas in both infected immunocompetent (group A) and immunosuppressed (group B) New Zealand white rabbits. In the brain, labeled TNF-α immune cells were mainly located in the granuloma peripheries in group B. Granulomas examined in the kidneys of groups A and B were TNF-α positive, but were significantly different (p < 0.001) when compared with the brain. IL-4-producing immune cells in the brain and kidneys were disseminated within granulomas in groups A and B; however, no significant difference (p > 0.05), was observed. IL-4 positive cells were more numerous in brain sections of group B and differed significantly (p < 0.05) when compared with kidneys. Granulomas were not observed in control animals (groups C and D). In conclusion, we identified TNF-α positive cells in both the brain and kidneys of immunocompetent and immunosuppressed animals; IL-4 positive cells were numerous in the brains of immunosuppressed rabbits; however, in terms of percentage were numerous in the brains of immunocompetent rabbits. Immunosuppression appeared to stimulate a change in the cellular phenotype of Th1- to Th2-like granulomas in the brain and kidneys via an unknown mechanism. Expression of pro- and pre-inflammatory cytokines in microsporidian granulomas suggests a mechanism by which E. cuniculi evades the immune response, causing more severe disease. These results increase our understanding of TNF-α and IL-4-positive cells within the E. cuniculi granuloma microenvironment.

Estimation of the real burden of invasive meningococcal disease in Argentina.

Among the different existing types of bacterial meningitis, the one caused by Neisseria meningitidis is the main presentation of invasive meningococcal disease (IMD). IMD is a significant public health concern and has a reported incidence rate in Argentina of 0.44 cases per 100 000 inhabitants in 2015. However, the actual incidence is thought to be higher as passive surveillance systems neither report nor identify 100% of all cases. The aim of this study is to develop an estimation of the burden of IMD in Argentina closer to reality by adjusting/correcting several limitations observed in the surveillance data available. A retrospective observational study has been performed using four Argentinean national databases recording the number of IMD cases and deaths, serogroups of N. meningitidis and ages, between 2007 to 2016. The reported data were adjusted to account for underreporting and to also integrate the cases missed due to well-known limitations associated with the diagnosis of N. meningitidis detection methods. Data were further analysed by serogroups of N. meningitidis and by age groups. After these adjustments, the potential numbers of IMD cases and IMD-related deaths are estimated to be 3.1 and 1.9 higher than reported, respectively. The study corrects the previous underestimation of the disease burden and provides expectedly more robust estimates aligned with international evidence and highlights the importance of active surveillance, with high-quality methods, for a better definition of preventive strategies against IMD in Argentina.

Spacetime Symmetries and Conformal Data in the Continuous Multiscale Entanglement Renormalization Ansatz.

The generalization of the multiscale entanglement renormalization ansatz (MERA) to continuous systems, or cMERA [Haegeman et al., Phys. Rev. Lett. 110, 100402 (2013)PRLTAO0031-900710.1103/PhysRevLett.110.100402], is expected to become a powerful variational ansatz for the ground state of strongly interacting quantum field theories. In this Letter, we investigate, in the simpler context of Gaussian cMERA for free theories, the extent to which the cMERA state |Ψ^{Λ}⟩ with finite UV cutoff Λ can capture the spacetime symmetries of the ground state |Ψ⟩. For a free boson conformal field theory (CFT) in 1+1 dimensions, as a concrete example, we build a quasilocal unitary transformation V that maps |Ψ⟩ into |Ψ^{Λ}⟩ and show two main results. (i) Any spacetime symmetry of the ground state |Ψ⟩ is also mapped by V into a spacetime symmetry of the cMERA |Ψ^{Λ}⟩. However, while in the CFT, the stress-energy tensor T_{µν}(x) (in terms of which all the spacetime symmetry generators are expressed) is local, and the corresponding cMERA stress-energy tensor T_{µν}^{Λ}(x)=VT_{µν}(x)V^{†} is quasilocal. (ii) From the cMERA, we can extract quasilocal scaling operators O_{α}^{Λ}(x) characterized by the exact same scaling dimensions Δ_{α}, conformal spins s_{α}, operator product expansion coefficients C_{αßγ}, and central charge c as the original CFT. Finally, we argue that these results should also apply to interacting theories.

Local Scale Transformations on the Lattice with Tensor Network Renormalization.

Consider the partition function of a classical system in two spatial dimensions, or the Euclidean path integral of a quantum system in two space-time dimensions, both on a lattice. We show that the tensor network renormalization algorithm [G. Evenbly and G. Vidal Phys. Rev. Lett. 115, 180405 (2015)] can be used to implement local scale transformations on these objects, namely, a lattice version of conformal maps. Specifically, we explain how to implement the lattice equivalent of the logarithmic conformal map that transforms the Euclidean plane into a cylinder. As an application, and with the 2D critical Ising model as a concrete example, we use this map to build a lattice version of the scaling operators of the underlying conformal field theory, from which one can extract their scaling dimensions and operator product expansion coefficients.

Factors affecting milking speed in Murciano-Granadina breed goats.

Milk flow during the first minute of milking was analyzed using data from 1,132 Murciano-Granadina breed goats belonging to 17 herds. During the individual lactations, 2 test days were scheduled for recording several milk flow traits, total milk, milk composition (fat and protein percentages), and somatic cell count. Average lag time from teatcup attachment to arrival of milk at the milk claw (T0) was 4.9 s and at the milk meter (T1) was 15.8 s. Average milk flow after 30 s (MF0.5) was 0.29kg/30 s (0 to 1.1kg/30 s) and milk flow at 60 s or milking speed (MF1) was 0.67kg/min (0.1 to 2.1kg/min). Repeatabilities of T0, T1, MF0.5, and MF1 were 0.45, 0.58, 0.62, and 0.68, respectively. The MF1 showed high phenotypic correlation withT1(-0.63) and MF0.5 (0.90), medium values withT0(-0.42) and total milk (0.22), and very low values (-0.04 to -0.12) with fat, protein, and somatic cell count. We found no differences between flows during the first 3 lactations, with a reduction as the lactation number increased. Months in milk since parturition affected MF1, being highest in the first 3mo (0.67-0.71kg/min) and decreasing until the end of lactation (0.58kg/min). The effect of herd-test day was significant for all traits. Inclusion of all these effects for the analysis of milk flow traits is considered necessary.

Tensor Network Renormalization.

We introduce a coarse-graining transformation for tensor networks that can be applied to study both the partition function of a classical statistical system and the Euclidean path integral of a quantum many-body system. The scheme is based upon the insertion of optimized unitary and isometric tensors (disentanglers and isometries) into the tensor network and has, as its key feature, the ability to remove short-range entanglement or correlations at each coarse-graining step. Removal of short-range entanglement results in scale invariance being explicitly recovered at criticality. In this way we obtain a proper renormalization group flow (in the space of tensors), one that in particular (i) is computationally sustainable, even for critical systems, and (ii) has the correct structure of fixed points, both at criticality and away from it. We demonstrate the proposed approach in the context of the 2D classical Ising model.

Tensor Network Renormalization Yields the Multiscale Entanglement Renormalization Ansatz.

We show how to build a multiscale entanglement renormalization ansatz (MERA) representation of the ground state of a many-body Hamiltonian H by applying the recently proposed tensor network renormalization [G. Evenbly and G. Vidal, Phys. Rev. Lett. 115, 180405 (2015)] to the Euclidean time evolution operator e(-ßH) for infinite ß. This approach bypasses the costly energy minimization of previous MERA algorithms and, when applied to finite inverse temperature ß, produces a MERA representation of a thermal Gibbs state. Our construction endows tensor network renormalization with a renormalization group flow in the space of wave functions and Hamiltonians (and not merely in the more abstract space of tensors) and extends the MERA formalism to classical statistical systems.

[Use of inflammatory markers for monitoring paediatric asthma]. / Utilidad de los marcadores inflamatorios en el control del asma pediátrica.

The assessment of asthma control takes into account the symptoms, quality of life, lung function, and inflammatory markers. In the last few years, there has been a large increase in the number of publications related to the study of biomarkers in the management of paediatric asthma. Despite the large variety of inflammatory markers described in research studies, only a small group has shown to be useful in monitoring the disease. Induced sputum eosinophils offer the most solid evidence in assessing asthma control. Exhaled breath condensate and urinary leucotrienes could be useful in the future if there is standardisation in their procedures and interpretation of the results. Nitric oxide, basic eosinophil cationic protein, and bronchial biopsy with bronchoalveolar lavage, only appeared to be useful in a reduced group of patients.

Class of highly entangled many-body states that can be efficiently simulated.

We describe a quantum circuit that produces a highly entangled state of N qubits from which one can efficiently compute expectation values of local observables. This construction yields a variational ansatz for quantum many-body states that can be regarded as a generalization of the multiscale entanglement renormalization ansatz (MERA), which we refer to as the branching MERA. In a lattice system in D dimensions, the scaling of entanglement of a region of size L(D) in the branching MERA is not subject to restrictions such as a boundary law L(D-1), but can be proportional to the size of the region, as we demonstrate numerically.

Real-space decoupling transformation for quantum many-body systems.

We propose a real-space renormalization group method to explicitly decouple into independent components a many-body system that, as in the phenomenon of spin-charge separation, exhibits separation of degrees of freedom at low energies. Our approach produces a branching holographic description of such systems that opens the path to the efficient simulation of the most entangled phases of quantum matter, such as those whose ground state violates a boundary law for entanglement entropy. As in the coarse-graining transformation of Vidal [Phys. Rev. Lett. 99, 220405 (2007).

Enhanced phosphorus removal from sewage in mesocosm-scale constructed wetland using zeolite as medium and artificial aeration.

Phosphorus (P) contained in sewage maybe removed by mesocosm-scale constructed wetlands (MCW), although removal efficiency is only between 20% and 60%. P removal can be enhanced by increasing wetland adsorption capacity using special media, like natural zeolite, operating under aerobic conditions (oxidation-reduction potential (ORP) above +300 mV). The objective of this study was to evaluate P removal in sewage treated by MCW with artificial aeration and natural zeolite as support medium for the plants. The study compared two parallel lines of MCW: gravel and zeolite. Each line consisted in two MCW in series, where the first MCW of each line has artificial aeration. Additionally, four aeration strategies were evaluated. During the operation, the following parameters were measured in each MCW: pH, temperature, dissolved oxygen and ORP. Phosphate (PO4(-3) - P) and chemical oxygen demand (COD), five-day biological oxygen demand (BOD5), total suspended solids (TSS) and ammonium. (NH4(+) - N) were evaluated in influents and effluents. Plant growth (biomass) and proximate analysis for P content into Schoenoplectus californicus were also performed. The results showed that PO4(-3) - P removal efficiency was 70% in the zeolite medium, presenting significant differences (p < .05) with the results obtained by the gravel medium. Additionally, aeration was found to have a significant effect (p < .05) only in the gravel medium with an increase in up to 30% for PO43 - P removal. Thus, S. californicus contributed to 10-20% of P removal efficiency.

[Pediatric asthma control and quality of life questionnaires]. / Cuestionarios de control de asma pediátrica y calidad de vida.

The assessment of symptoms and quality of life are important aspects in the control of childhood asthma. Questionnaires regarding symptoms control and quality of life give valuable information about the disease from the perspective of the child and his family. The aim of this study is to discuss the most important characteristics of this type of questionnaire such as age range, language of validation, number of questions, administration mode, the evaluated period and fields, and the minimum clinically relevant difference. The ACT questionnaires, for children older than 11 years of age, and CAN questionnaires, for children between 2 and 14 years of age in their Spanish versions, are suitable for measuring asthma control in our country. Regarding quality of life, PAQLQ for children between 7 and 17 years of age and PACQLQ for their care givers are the most popular oversees; Spanish versions have been adapted for Chile.

Identification of Cryptosporidium parvum and Blastocystis hominis subtype ST3 in Cholga mussel and treated sewage: Preliminary evidence of fecal contamination in harvesting area.

Cryptosporidium parvum and Blastocystis hominis are foodborne parasites known for causing diarrhea. They accumulate in mussels grown on contaminated water bodies, due to the discharge of treated sewage from sewage treatment plants (STP). Despite this, some countries like Chile do not include these parasites in the control or monitoring of sewage water. The objective of this research was to evaluate the contamination of C. parvum. and B. hominis from treated sewage (disinfected by chlorination) and Cholga mussels in a touristic rural cove from the bay of Concepción. Cholga mussels from commercial stores and a treated sewage sample were analyzed. Cryptosporidium spp. was identified by Ziehl-Neelsen-Staining (ZNS) and C. parvum by direct-immunofluorescence assay (IFA) from ZNS-positive samples. Blastocystis hominis was identified by PCR using locus SSU rDNA. C. parvum and B. hominis subtype ST3 were found in 40% and 45% of Cholga mussel samples, respectively, and both parasites were identified in the treated sewage. Blastocystis hominis SSU rDNA gene alignment from Cholga mussels and treated sewage showed 89% of similarity, indicating that could be the same parasite in both samples. We describe the first evidence of possible contamination with these parasites from treated sewage to Cholga mussel suggesting an environmental contamination with high human risk. Based on these results, further studies will consider all the rural coves and STP from the bay to prevent possible contamination of these parasites.

Characterizing topological order by studying the ground States on an infinite cylinder.

Given a microscopic lattice Hamiltonian for a topologically ordered phase, we propose a numerical approach to characterize its emergent anyon model and, in a chiral phase, also its gapless edge theory. First, a tensor network representation of a complete, orthonormal set of ground states on a cylinder of infinite length and finite width is obtained through numerical optimization. Each of these ground states is argued to have a different anyonic flux threading through the cylinder. Then a quasiorthogonal basis on the torus is produced by chopping off and reconnecting the tensor network representation on the cylinder. From these two bases, and by using a number of previous results, most notably the recent proposal of Y. Zhang et al. [Phys. Rev. B 85, 235151 (2012)] to extract the modular U and S matrices, we obtain (i) a complete list of anyon types i, together with (ii) their quantum dimensions d(i) and total quantum dimension D, (iii) their fusion rules N(ij)(k), (iv) their mutual statistics, as encoded in the off-diagonal entries S(ij) of S, (v) their self-statistics or topological spins θ(i), (vi) the topological central charge c of the anyon model, and, in a chiral phase (vii) the low energy spectrum of each sector of the boundary conformal field theory. As a concrete application, we study the hard-core boson Haldane model by using the two-dimensional density matrix renormalization group. A thorough characterization of its universal bulk and edge properties unambiguously shows that it realizes a ν=1/2 bosonic fractional quantum Hall state.

Effect of estrus synchronization on daily somatic cell count variation in goats according to lactation number and udder health status.

Two repeated experiments were carried out in 2 different years to study the effect of estrus on somatic cell count (SCC) in dairy goats. In the first year, 36 Murciano-Granadina goats were used [12 primiparous and 24 multiparous; 22 healthy and 14 with an intramammary infection (IMI)] and, after a 6-d pre-experimental period, were divided into 2 groups according to lactation number, udder health status, SCC, and milk production. One group was kept as a control, whereas the other received an estrus synchronization hormonal treatment lasting 11d. At 24, 48, and 72h after cessation of the hormone treatment, goats were placed in contact with a buck to confirm that they were in estrus. For 32 consecutive days (6 pre-experimental, 11 in hormone treatment, and 15 post-treatment) the SCC per gland and udder were monitored in all animals. In the second year, we repeated the same experimental design using a total of 38 Murciano-Granadina breed goats (12 primiparous and 26 multiparous; 26 healthy and 12 with IMI). Throughout this experiment, milk yield and composition were also recorded daily for each goat. Upon termination of the hormonal treatment, the SCC in udder milk increased significantly in the treatment group compared with the control group over 3 consecutive days. This increase was observed for year (1 and 2), parity (primiparous and multiparous), and udder health status (healthy and IMI). The log10 SCC (cells/mL) increased from 5.5±0.09 before estrus to 6.04±0.09 during treatment; therefore, the geometric mean of the SCC increased 3.5 times during treatment. The maximum values obtained in healthy glands of primiparous goats (geometric mean=0.37 million cells/mL) were lower than in healthy glands (1.1 million cells/mL) or infected glands (1.7 million cells/mL) of multiparous goats. The increase in SCC observed during estrus (200% increase in geometric means) could not be explained by the changes in milk production, which only fell by 13%. During estrus, the percentage of protein and dry matter in the milk also increased significantly. We concluded that it is necessary to consider the presence of estrus to correctly interpret milk SCC, as an indirect method for detecting IMI or as a commercial milk quality parameter.

Performance of 14 full-scale sewage treatment plants: comparison between four aerobic technologies regarding effluent quality, sludge production and energy consumption.

The performance of 14 Full-Scale Sewage Treatment Plants (STPs) was evaluated. STPs were divided into four aerobic technologies: a) Aerated Lagoon (AL), and three configurations of activated sludge technologies, b) conventional (CAS), c) Extended Aeration (EA), d) Sequencing Batch Reactor (SBR). Comparison between these configurations were made regarding: a) control parameters, organic loading rate (OLR), Mixed Liquor Volatile Suspended Solids (MLVSS) concentrations, Food to Microorganism ratio (F/M), sludge age (theta(c)), Hydraulic Retention Time (HRT) and return sludge ratio (R); b) effluent quality, through 5-day Biological Oxygen Demand (BOD5), Chemical Oxygen Demand (COD), Total Suspended Solids (TSS), Total Kjeldahl Nitrogen (TKN), Total Phosphorus (TP); and c) indicators related to sludge production (on a dry basis) and electrical energy consumption. Also, complementary costs analyses were made. The results show that in terms of effluent quality, for all configurations organic matter (BOD5 and COD) and TKN removal efficiency were up to 90%, while TSS and TP were up to 90% and 50%, respectively. However, CAS, EA, SBR, and AL had stability problems with effluent concentrations. The results of the electrical energy consumption and sludge production analyses show that SBRs reduce these indicators by 40%. Cost analysis showed that CAS, EA, SBR and AL had similar cost structures, with more than 50% of total operating and maintenance cost being related to electrical energy and sludge management. Therefore, SBR could be defined as the configuration with a more stable performance.

Effect of organic load and nutrient ratio on the operation stability of the moving bed bioreactor for kraft mill wastewater treatment and the incidence of polyhydroxyalkanoate biosynthesis.

This paper studies the effect of organic load rate (OLR) and nutrient ratio on operation stability of the moving bed bioreactor (MBBR) for kraft mill wastewater treatment, analyzing the incidence of polyhydroxyalkanoate (PHA) production. The MBBR operating strategy was to increase OLR from 0.25 ± 0.05 to 2.41 ± 0.19 kg COD m(-3) d(-1) between phases I and IV. The BOD(5):N:P ratio (100:5:1 and 100:1:0.2) was evaluated as an operation strategy for phases IV to V. A stable MBBR operation was found when the OLR was increased during 225 days in five phases. The maximum absolute fluorescence against the proportion of cells accumulating PHA was obtained for an OLR of 2.41 ± 0.19 kg COD m(-3)d(-1) and a BOD(5):N:P relationship of 100:1:0.2. The increase of PHA biosynthesis is due to the increased OLR and is not attributable to the increased cell concentration, which is maintained constant in stationary status during bioreactor biosynthesis.

Automated assays for trace elements and ferritin measurement in saliva of pigs: Analytical validation and a pilot application to evaluate different iron status.

The aim of this study was to validate automated methods to measure iron (Fe), zinc (Zn), copper (Cu) and ferritin in pig saliva samples. A complete analytical validation was performed of all assays. In addition, these methods were applied to saliva of Fe supplemented (n = 22) and non-supplemented (n = 20) piglets. All assays were able to measure these biomarkers in pig saliva with adequate precision, accuracy and high sensitivity and, in case of trace elements without needing a deproteinization pre-process. The group of piglets supplemented with Fe presented significantly higher levels of ferritin and Zn in saliva. In conclusion, the automated assays evaluated were able to measure Fe, Zn, Cu and ferritin in saliva of pigs, and in case of trace elements, they have the advantage of not needing a deproteinization pre-treatment and thus these analytes can be measured in a simple and fast manner.