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Objectives: The aims of this research are to explore the diet, mobility, social organization, and environmental exploitation patterns of early Mediterranean farmers, particularly the role of marine and plant resources in these foodways. In addition, this work strives to document possible gendered patterns of behavior linked to the neolithization of this ecologically rich area. To achieve this, a set of multiproxy analyses (isotopic analyses, dental calculus, microremains analysis, ancient DNA) were performed on an exceptional deposit (n = 61) of human remains from the Les Bréguières site (France), dating to the transition of the sixth to the fifth millennium BCE. Materials and Methods: The samples used in this study were excavated from the Les Bréguières site (Mougins, Alpes‐Maritimes, France), located along the southeastern Mediterranean coastline of France. Stable isotope analyses (C, N) on bone collagen (17 coxal bones, 35 craniofacial elements) were performed as a means to infer protein intake during tissue development. Sulfur isotope ratios were used as indicators of geographical and environmental points of origin. The study of ancient dental calculus helped document the consumption of plants. Strontium isotope analysis on tooth enamel (n = 56) was conducted to infer human provenance and territorial mobility. Finally, ancient DNA analysis was performed to study maternal versus paternal diversity within this Neolithic group (n = 30). Results: Stable isotope ratios for human bones range from −20.3 to −18.1‰ for C, from 8.9 to 11.1‰ for N and from 6.4 to 15‰ for S. Domestic animal data range from −22.0 to −20.2‰ for C, from 4.1 to 6.9‰ for N, and from 10.2 to 12.5‰ for S. Human enamel 87Sr/86Sr range from 0.7081 to 0.7102, slightly wider than the animal range (between 0.7087 and 0.7096). Starch and phytolith microremains were recovered as well as other types of remains (e.g., hairs, diatoms, fungal spores). Starch grains include Triticeae type and phytolith includes dicotyledons and monocot types as panicoid grasses. Mitochondrial DNA characterized eight different maternal lineages: H1, H3, HV (5.26%), J (10.53%), J1, K, T (5.2%), and U5 (10.53%) but no sample yielded reproducible Y chromosome SNPs, preventing paternal lineage characterization. Discussion: Carbon and nitrogen stable isotope ratios indicate a consumption of protein by humans mainly focused on terrestrial animals and possible exploitation of marine resources for one male and one undetermined adult. Sulfur stable isotope ratios allowed distinguishing groups with different geographical origins, including two females possibly more exposed to the sea spray effect. While strontium isotope data do not indicate different origins for the individuals, mitochondrial lineage diversity from petrous bone DNA suggests the burial includes genetically differentiated groups or a group practicing patrilocality. Moreover, the diversity of plant microremains recorded in dental calculus provide the first evidence that the groups of Les Bréguières consumed a wide breadth of plant foods (as cereals and wild taxa) that required access to diverse environments. This transdisciplinary research paves the way for new perspectives and highlights the relevance for novel research of contexts (whether recently discovered or in museum collections) excavated near shorelines, due to the richness of the biodiversity and the wide range of edible resources available. [ABSTRACT FROM AUTHOR]

Objectives: Dental calculus is among the richest known sources of ancient DNA in the archaeological record. Although most DNA within calculus is microbial, it has been shown to contain sufficient human DNA for the targeted retrieval of whole mitochondrial genomes. Here, we explore whether calculus is also a viable substrate for whole human genome recovery using targeted enrichment techniques. Materials and methods: Total DNA extracted from 24 paired archaeological human dentin and calculus samples was subjected to whole human genome enrichment using in‐solution hybridization capture and high‐throughput sequencing. Results: Total DNA from calculus exceeded that of dentin in all cases, and although the proportion of human DNA was generally lower in calculus, the absolute human DNA content of calculus and dentin was not significantly different. Whole genome enrichment resulted in up to four‐fold enrichment of the human endogenous DNA content for both dentin and dental calculus libraries, albeit with some loss in complexity. Recovering more on‐target reads for the same sequencing effort generally improved the quality of downstream analyses, such as sex and ancestry estimation. For nonhuman DNA, comparison of phylum‐level microbial community structure revealed few differences between precapture and postcapture libraries, indicating that off‐target sequences in human genome‐enriched calculus libraries may still be useful for oral microbiome reconstruction. Discussion: While ancient human dental calculus does contain endogenous human DNA sequences, their relative proportion is low when compared with other skeletal tissues. Whole genome enrichment can help increase the proportion of recovered human reads, but in this instance enrichment efficiency was relatively low when compared with other forms of capture. We conclude that further optimization is necessary before the method can be routinely applied to archaeological samples. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The Early Neolithic involved an important social and economic shift that can be tested not only with the material culture, but also through biomolecular approaches. The Iberian Peninsula presents few Early Neolithic sites where fauna and humans can be analyzed together from an isotopic perspective. Here we present an isotopic study on the site of Cueva de Chaves as an example for understanding the dietary and economical changes that took place during Early Neolithic in Iberia. Material and methods: Here we apply carbon and nitrogen stable isotope analysis to bone collagen from 4 humans and 64 faunal samples from 14 different species. The large dataset belongs to the same unique chrono‐cultural context secured by 20 radiocarbon dates. Three direct new radiocarbon dates were carried out on the human remains analyzed. Results: Faunal isotope values show no significant differences between wild and domestic herbivores, although the latter have more homogeneous values. Domestic pigs, potentially considered omnivorous, also show signatures of a herbivore diet. Human isotopic results show a diet mainly based on terrestrial C3 resources and possibly high meat consumption. The only individual found buried with a special funerary treatment presents a slightly different protein intake, when taking into account the long contemporaneous baseline analyzed. Discussion: Similar values between wild and domestic species could be the result of common feeding resources and/or grazing on the same parts of the landscape. The herbivore diet seen amongst domestic pigs rules out feeding on household leftovers. High meat consumption by humans would support the hypothesis of the existence of a specialized animal husbandry management community in which agriculture was not intensively developed. Our results suggest that the development of agricultural practices and animal husbandry were not necessarily associated together in the early stages of the Western Mediterranean Neolithic. [ABSTRACT FROM AUTHOR]

This paper examines the identification of kinship relations in archaeological multiple burials and advocates the application of different methods and lines of research to clarify such issues in relation to funerary practices. Recognizing family relationships - an important task in research on prehistoric societies - is especially complicated and interpretations have often been made without an adequate empirical basis. Bioarchaeological, isotopic and DNA analyses applied to the triple burial of Los Tolmos (Cogotas I archaeological culture, Iberian Bronze Age) have provided direct information on this issue. In this respect, the new results also imply the need to consider gender constructs in greater depth and to be more open-minded towards other forms of relationship in the past beyond the traditional heteronormative nuclear family. [ABSTRACT FROM AUTHOR]

Piroxicam is a non-steroidal anti-inflammatory drug actually used with limitations because of serious side effects. It is poorly soluble in pure water and exhibit a minimum of four conformers according to the pH conditions of the solution, but not all of them are medically active. In this study, we present, firstly, the Raman characterization of piroxicam in different organic solvents (dimethyl sulfoxide, 1,4-dioxane, ethanol, 1-propanol). These results have permitted us to analyze surface-enhance Raman scattering spectra of piroxicam adsorbed on gold or silver nanoparticles surface at several pHs (1, 2, 4, and 7), imitating the environment of the drug in the body, either in the gastrointestinal tract or in healthy and disease tissues. Results indicate that, below pH = 7, piroxicam is mainly in the zwitterionic conformer, and molecules are oriented parallel to the noble metal surface; however at pH ≥ 7, the main specie detected is the anionic one, differently oriented with respect to the nanoparticle surface. The metal-piroxicam systems here characterized by surface-enhance Raman scattering spectroscopy could constitute nanocarriers in future projects of transporting and releasing of the drug in the body. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: The evaluation of peripheral dose has become a relevant issue recently, in particular, the contribution of secondary neutrons. However, after the revision of the Recommendations of the International Commission on Radiological Protection, there has been a lack of experimental procedure for its evaluation. Specifically, the problem comes from the replacement of organ dose equivalent by the organ-equivalent dose, being the latter "immeasurable" by definition. Therefore, dose equivalent has to be still used although it needs the calculation of the radiation quality factor Q, which depends on the unrestricted linear energy transfer, for the specific neutron irradiation conditions. On the other hand, equivalent dose is computed through the radiation weighting factor wR, which can be easily calculated using the continuous function provided by the recommendations. The aim of the paper is to compare the dose equivalent evaluated following the definition, that is, using Q, with the values obtained by replacing the quality factor with wR. Methods: Dose equivalents were estimated in selected points inside a phantom. Two types of medical environments were chosen for the irradiations: a photon- and a proton-therapy facility. For the estimation of dose equivalent, a poly-allyl-diglicol-carbonate-based neutron dosimeter was used for neutron fluence measurements and, additionally, Monte Carlo simulations were performed to obtain the energy spectrum of the fluence in each point. Results: The main contribution to dose equivalent comes from neutrons with energy higher than 0.1 MeV, even when they represent the smallest contribution in fluence. For this range of energy, the radiation quality factor and the radiation weighting factor are approximately equal. Then, dose equivalents evaluated using both factors are compatible, with differences below 12%. Conclusions: Quality factor can be replaced by the radiation weighting factor in the evaluation of dose equivalent in radiotherapy environments simplifying the practical procedure. [ABSTRACT FROM AUTHOR]

Purpose: To characterize stray radiation around the target volume in scanning proton therapy and study the performance of active neutron monitors. Methods:Working Group 9 of the European Radiation Dosimetry Group (EURADOS WG9--Radiation protection in medicine) carried out a large measurement campaign at the Trento Centro di Protonterapia (Trento, Italy) in order to determine the neutron spectra near the patient using two extended-range Bonner sphere spectrometry (BSS) systems. In addition, the work focused on acknowledging the performance of different commercial active dosimetry systems when measuring neutron ambient dose equivalents, H *(10), at several positions inside (8 positions) and outside (3 positions) the treatment room. Detectors included three TEPCs--tissue equivalent proportional counters (Hawk type from Far West Technology, Inc.) and six rem-counters (WENDI-II, LB 6411, RadEye™ NL, a regular and an extended-range NM2B). Meanwhile, the photon component of stray radiation was deduced from the low-lineal energy transfer part of TEPC spectra or measured using a Thermo Scientific™ FH-40G survey meter. Experiments involved a water tank phantom (60 × 30 × 30 cm³) representing the patient that was uniformly irradiated using a 3 mm spot diameter proton pencil beam with 10 cm modulation width, 19.95 cm distal beam range, and 10 × 10 cm² field size. Results:Neutron spectrometry around the target volume showed two main components at the thermal and fast energy ranges. The study also revealed the large dependence of the energy distribution of neutrons, and consequently of out-of-field doses, on the primary beam direction (directional emission of intranuclear cascade neutrons) and energy (spectral composition of secondary neutrons). In addition, neutron mapping within the facility was conducted and showed the highest H *(10) value of -51 µSv Gy-1; this was measured at 1.15 m along the beam axis. H *(10) values significantly decreased with distance and angular position with respect to beam axis falling below 2 nSv Gy-1 at the entrance of the maze, at the door outside the room and below detection limit in the gantry control room, and at an adjacent room (<0.1 nSv Gy-1). Finally, the agreement on H *(10) values between all detectors showed a direct dependence on neutron spectra at the measurement position. While conventional rem-counters (LB 6411, RadEye™ NL, NM2-458) underestimated the H *(10) by up to a factor of 4, Hawk TEPCs and the WENDI-II range-extended detector were found to have good performance (within 20%) even at the highest neutron fluence and energy range. Meanwhile, secondary photon dose equivalents were found to be up to five times lower than neutrons; remaining nonetheless of concern to the patient. Conclusions:Extended-range BSS, TEPCs, and the WENDI-II enable accurate measurements of stray neutrons while other rem-counters are not appropriate considering the high-energy range of neutrons involved in proton therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Neanderthals have been commonly depicted as top predators who met their nutritional needs by focusing entirely on meat. This information mostly derives from faunal assemblage analyses and stable isotope studies: methods that tend to underestimate plant consumption and overestimate the intake of animal proteins. Several studies in fact demonstrate that there is a physiological limit to the amount of animal proteins that can be consumed: exceeding these values causes protein toxicity that can be particularly dangerous to pregnant women and newborns. Consequently, to avoid food poisoning from meat-based diets, Neanderthals must have incorporated alternative food sources in their daily diets, including plant materials as well. Yrbk Phys Anthropol 156:43-71, 2015. © 2014 American Association of Physical Anthropologists [ABSTRACT FROM AUTHOR]

Purpose: Knowing the contribution of neutron to collateral effects in treatments is both a complex and a mandatory task. This work aims to present an operative procedure for neutron estimates in any facility using a neutron digital detector. Methods: The authors' previous work established a linear relationship between the total second cancer risk due to neutrons (TRn) and the number of MU of the treatment. Given that the digital detector also presents linearity with MU, its response can be used to determine the TRn per unit MU, denoted as m, normally associated to a generic Linac model and radiotherapy facility. Thus, from the number of MU of each patient treatment, the associated risk can be estimated. The feasibility of the procedure was tested by applying it in eight facilities; patients were evaluated as well. Results: From the reading of the detector under selected irradiation conditions, m values were obtained for different machines, ranging from 0.25 x 10-4% per MU for an Elekta Axesse at 10 MV to 6.5 x 10-4% per MU for a Varian Clinac at 18 MV. Using these values, TRn of patients was estimated in each facility and compared to that from the individual evaluation. Differences were within the range of uncertainty of the authors' methodology of equivalent dose and risk estimations. Conclusions: The procedure presented here allows an easy estimation of the second cancer risk due to neutrons for any patient, given the number of MU of the treatment. It will enable the consideration of this information when selecting the optimal treatment for a patient by its implementation in the treatment planning system. [ABSTRACT FROM AUTHOR]

L7665 --> 942.2 --> Glioblastomas (GBMs) are primary brain malignancies with poor overall survival; however, disease sequelae following primary treatment is highly variable in nature—leading to variation in therapy response and overall survival. Recent discoveries characterizing the underlying GBM microenvironment evidence dynamic responses in both residential and recruited immune cell populations which may in fact drive these clinical observations. To validate these finding and evaluate the potential role of immune cells in differential survival, we analyzed recurrent GBM RNAseq data from the Chinese Glioma Genome Atlas and subsequently performed unsupervised clustering through k‐means to define 3 sub‐clusters of recurrent GBM with differential overall survival (p = 0.019). Subsequently, to evaluate the role of immune cells in this paradigm, we applied Weighted Gene Correlation Network analysis to our findings which indicate modulation of immune response as a key driver of this differential clinical pattern. Translating these findings to actionable clinical utilization in neuropathology is however challenged by poor signal‐to‐noise ratios during immuno‐staining and complex arborization of microglial processes. We thus present a convolutional neural network workflow using a UNET framework in python which can mitigate these challenges and successfully annotate diagnostic pathology slides from real glioblastoma patients treated at Ohio State with 80% accuracy—with attribution of lowered accuracy due to annotation error. Using this approach, we plan to subsequently annotate additional histology slides and utilize the morphologic variation within our segmented microglial population to discern post‐surgical response patterns in glioblastoma patients. [ABSTRACT FROM AUTHOR]

Raman and surface-enhanced Raman scattering spectroscopy were used to follow the chemical modification of quercetin (QUC) on silver nanoparticles. Different metallic systems were fabricated to check the influence of the interface, in terms of electric charge or total available surface, on the catalytic change undergone by QUC. The effect of QUC surface coverage was crucial to reveal information about the different orientation and the interaction mechanism with the metal at different concentrations of this flavonoid. Surface-enhanced Raman scattering spectra of good quality of QUC were observed at concentrations down to 10-8 M. Chemical modifications in the presence of nanostructure metal surfaces include oxidation followed by a subsequent polymerization via a condensation of rings whereas different chemical species have been recognized under different experimental conditions. The assignment of the new species formed on the metal surface was conducted. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article discusses the research on prediction of properties of the porous materials. As motioned, several application are based on this issue including the use of supercritical fluids to modify porous materials, physical adsorption of trace components from gaseous effluents and gas storage using micro porous materials. It says that prediction of chemical and materials engineering has continuing interest in this field of research.

ABSTRACT This study examines the role of satisfaction strength on the correspondence between reported satisfaction and intention to purchase a new product. The market testing underlying this study analyzes the market opportunities for a novel prototype. The research was conducted at a central location with 239 randomly selected consumers. Results indicate that (un)certainty, ambivalence, and importance cognitions and feelings significantly moderate the relationship between reported satisfaction and individuals' intention to purchase. For example, the association between consumers' reported satisfaction level and purchasing intention of the new product is weaker as uncertainty increases. Significant moderated-mediation and mediated-moderation effects were also found with Structural Equation Modelling. Judgments of ambivalence moderate the satisfaction-purchasing intention relationship through the mediating effect of importance. (Un)certainty fully mediates the moderating effect of importance on the satisfaction-purchasing intention link. The research validates the usefulness of assessing the satisfaction strength concept and illustrates its potential as a better predictor of intentions than satisfaction level alone. The study argues on the nomological validity of the satisfaction construct and reveals that assessment of satisfaction strength should support the management goal of identifying truly satisfied customers. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Asthma is a major problem worldwide, which is estimated to affect 300 million individuals. The global prevalence ranges from 1% to 18% of the population. The incidence, morbidity and mortality of the condition have increased over the last 50 years despite the development of new anti-asthmatic drugs. Fewer than 1% of the asthmatic population are steroid-dependent, but these patients consume most of the resources and time at asthma units. The consensus documents published by professional societies all support a stepwise therapeutic approach for asthma. However, patients who require frequent or continuous oral corticosteroid administration have received little attention. Due to the severe side-effects of oral corticosteroids when administered over long periods or at high doses, many drugs have been assessed in the search for a possible corticosteroid-sparing agent. Recently, the update of the Global Initiative for Asthma (GINA) introduced a new drug - omalizumab - as an alternative to oral corticosteroids in patients included in step V. Other alternatives include immunosuppressive drugs, among which methotrexate has been found to offer the best benefit/risk ratio. This paper will review, comment and criticize the evidence of the effectiveness of immunomodulatory drugs, as an alternative to oral glucocorticosteroid treatment in GINA step V asthma patients. The experience of the authors combined with the information of the literature will lead to the conclusion that methotrexate and omalizumab are the only advisable drugs and will clarify when and how these drugs should be used. [ABSTRACT FROM AUTHOR]

Objective Differential diagnosis of infections that cause similar diseases and may be active simultaneously in the same geographical areas is greatly needed. Dengue and yellow fever viruses (DENV and YFV) are transmitted by the same species of mosquito and both can cause haemorrhagic fever symptoms. These viruses are active mainly in regions where expensive and sophisticated technologies are not available. Our objective was to develop a simple, reliable and easy-to-perform method to detect and identify these viruses. Methods We slightly modified a generic RT-PCR able to detect the mentioned viruses and other members of this genus: specific primers for each one of these viruses were designed and included in the nested reaction instead of one of the generic ones. The reaction was optimized and viruses are amplified giving rise to bands of different sizes distinguishable in agarose gels. Results This test is able to detect and identify the four DENVs and YFV to a high level of sensitivity and specificity and can be used with clinical samples. This simple, reliable and easy-to-perform method able to detect and identify dengue 1–4 and YFV can be used in poor endemic countries. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disease commonly driven by allergic and/or eosinophilic inflammation, both of which may be present in severe disease. Most approved biologics for severe asthma are indicated for specific phenotypes and target individual downstream type 2 components of the inflammatory cascade. Tezepelumab, a human monoclonal antibody (immunoglobulin G2λ), binds specifically to thymic stromal lymphopoietin (TSLP), an epithelial cytokine that initiates and sustains allergic and eosinophilic inflammation in asthma. By blocking TSLP, tezepelumab has demonstrated efficacy across known asthma phenotypes and acts upstream of all current clinically used biomarkers. In a pooled analysis of the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies, compared with placebo, tezepelumab reduced the annualized asthma exacerbation rate over 52 weeks by 62% (95% confidence interval [CI]: 53, 70) in patients with perennial aeroallergen sensitization (allergic asthma); by 71% (95% CI: 62, 78) in patients with a baseline blood eosinophil count ≥300 cells/μL; and by 71% (95% CI: 59, 79) in patients with allergic asthma and a baseline blood eosinophil count ≥300 cells/μL. This review examines the efficacy and mode of action of tezepelumab in patients with allergic asthma, eosinophilic asthma and coexisting allergic and eosinophilic phenotypes., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins-4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long-term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL)., Methods: Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV 1 ), 5-item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO., Results: Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high-dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313-0.494). Improvements in pre-BD FEV 1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups., Conclusions: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS., (© 2023 Sanofi and The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L)., Methods: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV 1 ), percent-predicted pre-BD FEV 1 (ppFEV 1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period., Results: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV 1 , pre-bronchodilator FEV 1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV 1 and asthma control were observed by Week 52., Conclusion: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without., (© 2023 Sanofi and The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Severe asthma exacerbations increase the risk of accelerated lung function decline. This analysis examined the effect of dupilumab on forced expiratory volume in 1 s (FEV 1 ) in patients with moderate-to-severe asthma and elevated type 2 biomarkers from phase 3 LIBERTY ASTHMA QUEST (NCT02414854)., Methods: Changes from baseline in pre- and post-bronchodilator (BD) FEV 1 and 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed in patients with elevated type 2 biomarkers at baseline (type 2-150/25: eosinophils ≥150 cells/μl and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb; type 2-300/25: eosinophils ≥300 cells/μl and/or FeNO ≥25 ppb), stratified as exacerbators (≥1 severe exacerbation during the study) or non-exacerbators., Results: In exacerbators and non-exacerbators, dupilumab increased pre-BD FEV 1 by Week 2 vs placebo; differences were maintained to Week 52 (type 2-150/25: LS mean difference (LSMD) vs placebo: 0.17 L (95% CI: 0.10-0.24) and 0.17 L (0.12-0.23); type 2-300/25: 0.22 L (0.13-0.30) and 0.21 L (0.15-0.28)), in exacerbators and non-exacerbators, respectively (p < .0001). Similar trends were seen for post-BD FEV 1 . Dupilumab vs placebo also showed significantly greater improvements in post-BD FEV 1 0-42 days after first severe exacerbation in type 2-150/25 (LSMD vs placebo: 0.13 L [0.06-0.20]; p = .006) and type 2-300/25 (0.14 L [0.06-0.22]; p = .001) patients. ACQ-5 improvements were greater with dupilumab vs placebo in both groups., Conclusion: Dupilumab treatment led to improvements in lung function independent of exacerbations and appeared to reduce the impact of exacerbations on lung function in patients who experienced a severe exacerbation during the study., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2-like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti-tumor, M1-like, tumor-associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific human GS inhibitor. Glufosinate was tested in both cultured macrophages and on mice bearing metastatic lung, skin and breast cancer. We found that glufosinate rewires macrophages toward an M1-like phenotype both at the primary tumor and metastatic site, countering immunosuppression and promoting vessel sprouting. This was also accompanied to a reduction in cancer cell intravasation and extravasation, leading to synchronous and metachronous metastasis growth inhibition, but no effects on primary tumor growth. Glufosinate treatment was well-tolerated, without liver and brain toxicity, nor hematopoietic defects. These results identify GS as a druggable enzyme to rewire macrophage functions and highlight the potential of targeting metabolic checkpoints in macrophages to treat cancer metastasis., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Aims: There are no specific criteria for a step-down or withdrawal dose of omalizumab (OMA). Our purpose was to evaluate the viability of a protocol for OMAlizumab DOse REduction (the OMADORE study) in severe allergic asthma (SAA)., Methods: The study population included 35 SAA patients treated during a minimum period of 1 year with oral corticosteroids (OC) equivalent to a mean daily dose of 4 mg of methyl-prednisolone. To qualify for the protocol, the patients had to have received treatment with OMA for at least one and a half years, OC dose had to have reached the lowest tolerated dose and spirometry had to be greater than or equal to that at entry. The interventions were (a) OMA dose was reduced by half; (b) if patients were clinically stable after 6 months, the dose was halved again; (c) if repeated OC boosters were needed and/or spirometry worsened by more than 10%, OMA dose was raised to the previous figure until stabilization., Results: Mean age was 52.5 (17) years, median monthly OC dose was 120 (IQR: 225) mg. Pulmonary function: FVC: 79.7 (20.2)%; FEV 1 : 64.8 (21.7)%; FEV 1 / FVC: 61.7(13.8)%. OMA could be withdrawn in 34.3% of the patients; 22.9% tolerated a reduction, and in 42.9% the dose could not be modified. Follow-up time after reduction or withdrawal ranged from 12 to 30 months. There were no severe exacerbations requiring emergency assistance or admission., Conclusions: The OMADORE study found that in more than 50% of SAA patients on OC, OMA dose can be safely reduced or withdrawn based on a progressive dose reduction protocol., (© 2017 The British Pharmacological Society.)

Background and Objectives: Tobacco use is a significant public health issue on a global scale. Prevalence of daily tobacco smoking for men in China is much higher than in the United States. Although prevailing literature suggests a negative relationship between smoking and quality of life, this pilot study sought to evaluate whether smoking reduction/cessation impacted on the perception of quality of life in an in-patient population in China., Methods: Twenty Chinese patients meeting DSM-IV criteria for schizophrenia were recruited from Beijing Hui-Long-Guan Hospital, an in-patient facility in Beijing, China, for participation in this 4-week study. Seventeen participants with schizophrenia completed the study and were included in the final analysis. Cigarette consumption was recorded daily and the World Health Organization Quality of Life-BREF (WHOQOL-BREF) was completed at baseline and at week 4. The relationships between smoking and perceived quality of life were evaluated using correlations between changes in WHOQOL-BREF and changes in cigarettes consumed as measured from baseline to week 4., Results: We found an increase in perceived quality of life in the social relationships domain with increased cigarette consumption in contrast to a decrease in this domain with decreased consumption. However, decreased cigarette consumption was associated with an increase in the psychological domain compared to the social domain., Conclusions and Scientific Significance: These associations suggest a need for interventions to improve the social relationship perceptions with any successful reduction in cigarette consumption among Chinese schizophrenics in order to match their perceived psychological improvement., (© American Academy of Addiction Psychiatry.)

While the worldwide prevalence of cocaine use remains significant, medications, or small molecule approaches, to treat drug addictions have met with limited success. Anti-addiction vaccines, on the other hand, have demonstrated great potential for treating drug abuse using a distinctly different mechanism of eliciting an antibody response that blocks the pharmacological effects of drugs. We provide a review of vaccine-based approaches to treating stimulant addictions; specifically and cocaine addictions. This selective review article focuses on the one cocaine vaccine that has been into clinical trials and presents new data related to pre-clinical development of a methamphetamine (MA) vaccine. We also review the mechanism of action for vaccine induced antibodies to abused drugs, which involves kinetic slowing of brain entry as well as simple blocking properties. We present pre-clinical innovations for MA vaccines including hapten design, linkage to carrier proteins and new adjuvants beyond alum. We provide some new information on hapten structures and linkers and variations in protein carriers. We consider a carrier, outer membrance polysaccharide coat protein (OMPC), that provides some self-adjuvant through lipopolysaccharide components and provide new results with a monophosopholipid adjuvant for the more standard carrier proteins with cocaine and MA. The review then covers the clinical trials with the cocaine vaccine TA-CD. The clinical prospects for advances in this field over the next few years include a multi-site cocaine vaccine clinical trial to be reported in 2013 and phase 1 clinical trials of a MA vaccine in 2014., (© 2013 The British Pharmacological Society.)

Background: Unattended home sleep studies have been implemented to minimize the cost and delay in establishing obstructive sleep apnoea syndrome (OSAS) diagnosis and therapy. However, their accuracy and validity remain disputed. The purpose of our study is to assess their effectiveness (i.e. their technical reliability in real life conditions)., Setting: Private sleep unit attending to private and social security patients., Population: Consecutively admitted patients, aged over 18 years, referred to our clinic for confirmation or treatment of OSAS without co-morbidities., Methods: A clinical history was obtained for each patient with special attention to sleep, smoking habit, educational level and type of insurance. Chest X-ray and forced spirometry were performed. For the portable respiratory recording device an eight-channel polygraph was used and for continuous positive airway pressure (CPAP) titration an automatic positive airway pressure device was applied; both instruments were previously validated. Patients were instructed how to use the devices at the clinic and then applied them at home by themselves., Results: For diagnostic sleep studies, 145 out of 150 (96.7%: CI: 92.4-98.9) and for CPAP titration 42 out of the 61 patients (69%: CI: 56.4-81.3) performed the sleep study correctly according to the pre-established criteria. No statistically significant differences were found between correct performance and educational level, sex, smoking habit or type of health insurance., Conclusions: (1) Unattended home sleep studies appear as effective as in-hospital studies for diagnosis of OSAS without co-morbidities; (2) for CPAP titration, the effectiveness was slightly lower; and (3) factors such as patients' educational level or type of health insurance do not appear to influence outcome., (© 2010 Blackwell Publishing Ltd.)

Objective: Familial Mediterranean fever (FMF) is a genetically recessive inflammatory disease caused by mutations in the MEFV gene. Most patients of non-Ashkenazi Jewish ancestry or those who are homozygous for M694V manifest a severe disease course, but some express a mild form of the disease. We therefore searched for other genes which could possibly be implicated in the disease phenotype. We tested MICA (major histocompatibility complex class I chain-related gene A) because it has been associated with a number of other inflammatory disorders., Methods: One hundred fifty FMF probands and their family members were evaluated. The MEFV gene was screened by a combination of denaturing gradient-gel electrophoresis, restriction fragment length polymorphism, and amplification refractory mutation system. The MICA transmembrane polymorphism in exon 5 was analyzed after biotin-labeled polymerase chain reaction products were loaded onto sequencing gels and subjected to autoradiography., Results: The contribution of MICA to the FMF phenotype was confirmed after adjustment for the patient's ancestry and for the MEFV genotype. MEFV was individually the most important prognostic factor for the disease. However, the impact of M694V homozygosity on the age at disease onset (OR 2.3) was aggravated if patients also inherited MICA-A9 (OR 6.3). In contrast, the frequency of attacks was found to be dramatically reduced (OR 0.16) in patients with MICA-A4., Conclusion: We have identified the first FMF modifier locus, MICA. FMF is the first model of a Mendelian disease associated with MICA. These results clarify, at least partly, the inconsistent phenotype-MEFV correlation in FMF.