Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.

SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein- and ß-arrestin (ßarr)-dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR1a conformations toward Gαq activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR1a-related brain disorders involving the pathological dysregulation of dopamine.

Biomarkers predicting the controller dose of omalizumab in patients with chronic spontaneous urticaria.

BACKGROUND: Clinical trials showed the efficacy of 300 mg/4 weeks of omalizumab (OMA) during 6 months in patients with severe chronic spontaneous urticaria (CSU). Nevertheless, in real life, many patients require higher doses and/or longer treatment. This study assesses the real-life performance of OMA in severe CSU and identifies factors associated with the response. METHODS: CSU patients eligible for OMA were recruited prospectively. Clinical data and a blood test were collected before OMA initiation. Urticaria Activity Score 7 (UAS7) was calculated at baseline and every 3 months during OMA treatment. CSU control was defined as UAS7 <7 points. This work was partially sponsored by OMA manufacturer. RESULTS: Eighty-nine adults (19.1% males) with severe CSU were recruited. Median duration of CSU prior to OMA initiation was 2 years, and median severity by UAS7 at baseline was 24 points (range 10-42 points). OMA controlled 94.4% of patients, but 17.9% of responders required doses >300 mg/4 weeks. A blood basophil count >20 cells/µL (OR 13.33; 95% CI 3.32-52.63; p < .001) and the absence of hypothyroidism (OR 3.65; 95% CI 0.78-16.95; p = .099) were identified as predictive factors to achieve control with 300 mg/4 weeks. Twelve patients were able to stop OMA during the study (responders in remission, RR). RR had received OMA for a median of 29 months (12-53 months). Conversely, 32 patients had been on OMA for >29 months at the end of the study (active responders, AR). AR had received OMA for a median of 45 months (30-100 months). There were no significant differences in clinical or analytical factors between RR and AR patients. CONCLUSIONS: Low blood basophil count and the presence of hypothyroidism might serve as biomarkers for the controller dose of OMA in severe CSU patients.

Patient-reported outcomes before treatment for localized prostate cancer: are there differences among countries? Data from the True North Global Registry.

INTRODUCTION: Similar Patient-Reported Outcomes (PROs) at diagnosis for localized prostate cancer among countries may indicate that different treatments are recommended to the same profile of patients, regardless the context characteristics (health systems, medical schools, culture, preferences…). The aim of this study was to assess such comparison. METHODS: We analyzed the EPIC-26 results before the primary treatment of men diagnosed of localized prostate cancer from January 2017 onwards (revised data available up to September 2019), from a multicenter prospective international cohort including seven regions: Australia/New Zealand, Canada, Central Europe (Austria / Czech Republic / Germany), United Kingdom, Italy, Spain, and the United States. The EPIC-26 domain scores and pattern of three selected items were compared across regions (with Central Europe as reference). All comparisons were made stratifying by treatment: radical prostatectomy, external radiotherapy, brachytherapy, and active surveillance. RESULTS: The sample included a total of 13,483 men with clinically localized or locally advanced prostate cancer. PROs showed different domain patterns before treatment across countries. The sexual domain was the most impaired, and the one with the highest dispersion within countries and with the greatest medians' differences across countries. The urinary incontinence domain, together with the bowel and hormonal domains, presented the highest scores (better outcomes) for all treatment groups, and homogeneity across regions. CONCLUSIONS: Patients with localized or locally advanced prostate cancer undergoing radical prostatectomy, EBRT, brachytherapy, or active surveillance presented mainly negligible or small differences in the EPIC-26 domains before treatment across countries. The results on urinary incontinence or bowel domains, in which almost all patients presented the best possible score, may downplay the baseline data role for evaluating treatments' effects. However, the heterogeneity within countries and the magnitude of the differences found across countries in other domains, especially sexual, support the need of implementing the PRO measurement from diagnosis.

Long non-coding RNA H19 as a biomarker for hepatocellular carcinoma.

BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer. METHODS: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+ CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort. RESULTS: EpCAM+ CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025). CONCLUSION: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.

Consensus on the Definition of Control and Remission in Chronic Urticaria.

The terms control and remission and other key terms used in chronic urticaria (CU) such as flare-up, relapse, exacerbation, and recurrence have not been fully defined in the literature. Disease monitoring and treatment goals in clinical practice are not well established. After a qualitative appraisal of available evidence, we aimed to find a consensus definition of control and remission, clarify key terminology, provide guidance on how to monitor the disease, and establish treatment goals in clinical practice. A modified Delphi consensus approach was used. Based on a literature review, a scientific committee provided 137 statements addressing controversial definitions and terms, available patient-reported outcomes (PROs), and recommendations on how to measure therapeutic objectives in CU. The questionnaire was evaluated by 138 expert allergists and dermatologists. A consensus was reached on 105 out of the 137 proposed items (76.6%). The experts agreed that complete control and remission of CU could be defined as the absence of signs or symptoms while on treatment and in the absence of treatment, respectively. Consensus was not reached on the definition of other key terms such as flare-up, exacerbation, and recurrence. The panel agreed that the objective of therapy in CU should be to achieve complete control. PROs that define the degree of control (complete, good, partial, or absence) were established. An algorithm for disease assessment is provided. In conclusion, this work offers consensus definitions and tools that may be useful in the management of patients with CU.

A Specialized Therapeutic Approach to Chronic Urticaria Refractory to H1-Antihistamines Improves Disease Burden: The Spanish AWARE Experience.

OBJECTIVE: During its first year, the AWARE study assessed disease activity, patient quality of life (QOL), and treatment patterns in chronic urticaria (CU) refractory to H1-antihistamines (H1-AH) in clinical practice. METHODS: We performed an observational, prospective (24 months), international, multicenter study. The inclusion criteria were age ≥18 years and H1-AH-refractory CU (>2 months). At each visit, patients completed questionnaires to assess disease burden (Urticaria Control Test [UCT]), disease activity (7 day-Urticaria Activity Score [UAS7]), and QOL (Dermatology Life Quality index [DLQI], Chronic Urticaria Quality of Life Questionnaire [CU-Q2oL], and Angioedema Quality of Life Questionnaire [AE-QoL]). We present data for Spain. RESULTS: The study population comprised 270 evaluable patients (73.3% female, mean [SD] age, 48.9 [14.7] years). At baseline, 89.3% were prescribed a CU treatment. After 1 year, first- and second-line treatments became less frequent and third-line treatments became more frequent. At baseline, 47.0% of patients experienced angioedema; at 1 year, this percentage had fallen to 11.8%. The mean (SD) AE-QoL score decreased from 45.2 (28.7) to 24.0 (25.8). The mean (SD) UCT score decreased from 7.0 (4.5) to 12.1 (4.1). According to UAS7, 38.2% of patients reported absence of wheals and itch in the previous 7 days at 1 year compared with 8.3% at baseline. The mean (SD) DLQI score decreased from 8.0 (7.4) to 2.8 (4.6). At the 1-year visit, the percentage of patients reporting a high or very high impact on QOL fell from 29.9% to 9.6%. CONCLUSION: H1-AH-refractory CU in Spain is characterized by absence of control of symptoms and a considerable impact on QOL. Continuous follow-up of CU patients and third-line therapies reduce disease burden and improve patients' QOL.

Unraveling the Diagnosis of Kiwifruit Allergy: Usefulness of Current Diagnostic Tests.

OBJECTIVES: To determine the usefulness of the in vitro and in vivo methods used in the diagnosis of kiwifruit allergy and to specifically assess the impact of seed proteins on sensitivity. METHODS: We performed skin prick tests (SPTs) using various commercial extracts, homemade pulp, and seed extracts and prick-prick tests with kiwifruit on 36 allergic patients. The presence of specific IgE (sIgE) was assessed using the ImmunoCAP (kiwifruit extract), ELISA (Act d 1, Act d 2), ISAC, and FABER assays. Immunoblotting of seed extract was carried out, and a single-blind oral food challenge was performed with whole seeds in seed-sensitized individuals. RESULTS: The prick prick test with kiwifruit demonstrated the highest diagnostic capacity (81.8% sensitivity and 94.1% specificity) among the in vivo tests. The sIgE levels measured using ImmunoCAP (kiwifruit extract) showed a similar sensitivity to that of global ISAC and FABER (63.9%, 59.5%, and 58.3%, respectively). Act d 1 was the major allergen. Sensitization to Act d 1 was associated with positive sIgE results to whole kiwifruit extract detected by ImmunoCAP (P<.000). A positive SPT result to kiwifruit seeds was associated with severe symptoms induced by kiwifruit (P=.019) as a marker of advanced disease, but not with clinically relevant sensitization. Challenge testing with kiwifruit seeds performed on 8 seed-sensitized patients yielded negative results. CONCLUSION: Sensitization to Act d 1 is associated with a positive result in conventional diagnostic techniques, whereas kiwifruit seed sensitization does not increase the sensitivity of the diagnostic techniques evaluated.

Real-world corticosteroid use in severe pneumonia: a propensity-score-matched study.

BACKGROUND: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide despite correct antibiotic use. Corticosteroids have long been evaluated as a treatment option, but heterogeneous effects on survival have precluded their widespread implementation. We aimed to evaluate whether corticosteroids might improve clinical outcomes in patients with severe CAP and high inflammatory responses. STUDY DESIGN AND METHODS: We analyzed two prospective observational cohorts of patients with CAP in Barcelona and Rome who were admitted to intensive care with a high inflammatory response. Propensity score (PS) matching was used to obtain balance among the baseline variables in both groups, and we excluded patients with viral pneumonia or who received hydrocortisone. RESULTS: Of the 610 patients admitted with severe CAP, 198 (32%) received corticosteroids and 387 had major criteria for severe CAP. All patients had a baseline serum C-reactive protein above 15 mg/dL. Patients who received corticosteroids were more commonly male, had more comorbidities (e.g., cancer or chronic obstructive pulmonary disease), and presented with significantly higher sequential organ failure assessment scores. Eighty-nine patients met major severity criteria (invasive mechanical ventilation and/or septic shock) and were matched per group. Twenty-eight-day mortality was lower among patients receiving corticosteroids (16 patients, 18%) than among those not receiving them (28 patients, 31%; p = 0.037). After PS matching, corticosteroid therapy reduced the 28-day mortality risk in patients who met major severity criteria (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.29-0.98) (p = 0.043). In patients who did not meet major severity criteria, no benefits were observed with corticosteroid use (HR 0.88 (95%CI 0.32-2.36). CONCLUSIONS: Corticosteroid treatment may be of benefit for patients with CAP who have septic shock and/or a high inflammatory response and requirement for invasive mechanical ventilation. Corticosteroids appear to have no impact on mortality when these features are not present.

Smartphone App for monitoring Asthma in children and adolescents.

PURPOSE: The asthma stepwise treatment approach recommended is based on monitoring patients' symptoms. The Asthma Research in Children and Adolescents (ARCA) cohort was created to provide evidence about the evolution of persistent asthma. This manuscript describes the development of an electronic health tool, comprising a mobile health application for patients with asthma and its associated online platform for pediatricians to monitor them. METHODS: The development process followed 7 phases: the first 5 (Conceptualization, Preparation, Assessment scheduling, Image and user interface, and Technical development) defined and designed the tool, followed by a testing phase (functionality assessment and pilot test with ARCA patients), and a last phase which evaluated usability. Since the target population was aged 6-16 years, three versions were designed within the same smartphone application: parents/proxy, children, and adolescents. The online platform for pediatricians provides real-time information from the application: patients' responses over time with color-coded charts (red/amber/green, as in traffic lights). RESULTS: The pilot test through semi-structured phone interviews of the first 50 participants included in the ARCA study (n = 53) detected their misunderstandings. Pediatricians were trained to emphasize that the application is free of charge and requires monthly answers. Median of the System Usability Scale scores (n = 85), ranging 0 (negative)-100 (positive), was > 93 in the three age versions of the application. CONCLUSIONS: Technology has the capability of transforming the use of patient-reported outcomes. Describing all the development phases of a mobile health application for monitoring children and adolescents with asthma may increase the knowledge on how to design applications for young patients.

Should deep eutectic solvents be treated as a mixture of two components or as a pseudo-component?

Deep eutectic solvents (DESs) and dilutions thereof (mainly in H2O but also in many other non-aqueous solvents and co-solvent mixtures) have recently attracted great attention. It is well known that DES dilutions exhibit deviations from ideality. Interestingly, the treatment of DES as a mixture of two components or a pseudo-component is by no means trivial when determining deviations in density and, mainly, in viscosity. Herein, we studied aqueous dilutions of one of the most widely studied DES, this is, that composed of choline chloride and urea in a 1:2 molar ratio (e.g., ChCl2U). Using density and viscosity data reported in previous works, we calculated the excess molar volumes (VE) and excess viscosities (ln ηE) considering ChCl2U as either a mixture of two components or a pseudo-component, that is, taking the DES molecular weight as MChCl2U = fChClMChCl + fUMU = 86.58 g mol-1 (with fChCl = 1/3 and fU = 2/3) or as M* ChCl2U = MChCl + 2 MU = 259.74 g mol-1. We found that neither the sign of VE and VE* nor their evolution with temperature was influenced by the use of either MChCl2U or M* ChCl2U, and only the absolute magnitude of the deviation and the DES content (in wt. %) at which the minimum appears exhibited some differences. However, ln ηE and ln ηE* exhibited opposite signs, negative and positive, respectively. The odd achievement of negative ln ηE in aqueous dilutions of ChCl2U characterized by the formation of HB networks suggest the treatment of ChCl2U as a pseudo-component as more appropriate. Moreover, the role played by the presence of U in the evolution of ln ηE* with temperature was also discussed.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases.

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy.

Encoding Metal-Cation Arrangements in Metal-Organic Frameworks for Programming the Composition of Electrocatalytically Active Multimetal Oxides.

In the present contribution, we report how through the use of metal-organic frameworks (MOFs) composed of addressable combinations of up to four different metal elements it is possible to program the composition of multimetal oxides, which are not attainable by other synthetic methodologies. Thus, due to the ability to distribute multiple metal cations at specific locations in the MOF secondary building units it is possible to code and transfer selected metal ratios to multimetal oxides with novel, desired compositions through a simple calcination process. The demonstration of an enhancement in the electrocatalytic activity of new oxides by preadjusting the metal ratios is here reported for the oxygen reduction reaction, for which activity values comparable to commercial Pt/C catalysts are reached, while showing long stability and methanol tolerance.

Health-related quality of life in men with prostate cancer undergoing active surveillance versus radical prostatectomy, external-beam radiotherapy, prostate brachytherapy and reference population: a cross-sectional study.

BACKGROUND: The purpose of this study is to describe Health-Related Quality of Life (HRQoL) of localized prostate cancer patients in an Active Surveillance (AS) program, and to compare them with those undergoing radical prostatectomy (RP), external-beam radiotherapy (XRT) and brachytherapy (BT). METHODS: Multi-institutional pooled cross-sectional analysis on patients in an AS protocol: < 75 years old; pathologically confirmed LPC (maximum of three positive cylinders); Gleason score < 3 + 4; clinical stage T1a-T2b; and PSA < 15 ng/ml. Exclusion criteria for this study were: less than 6 months in AS, termination of AS protocol, or incomplete data. Patients in AS were matched with those treated with RP, XRT or BT from the 'Spanish Multicentric Study of Clinically Localized Prostate Cancer' cohort according to risk group, time from treatment selection to HRQoL survey, and age. Prostate-specific (EPIC) and generic (SF-36) HRQoL instruments were completed. Analysis was stratified by HRQoL survey moment (>or < 2.5 years from treatment selection), and age (>or < 70 years old). RESULTS: Median of time from treatment selection to HRQoL survey in the total 396 patients (99 per treatment group) was 2.4 years (range 0.5-8.3). Patients in AS presented higher (better) urinary incontinence scores than RP ones in both stratus of time from treatment selection to HRQoL survey (92.6 vs 67.0 and 81.4 vs 64.4, p <  0.01). Patients in AS for < 2.5 years presented greater sexual scores than any active treatment (p <  0.01), but only statistically higher than RP for those in AS for longer than 2.5 years. The magnitude of the differences between AS and RP groups in both EPIC domains ranged from moderate (0.7 SD) to large (1.0 SD). Regardless of treatment applied, patients presented similar and slightly increased SF-36 scores than US general population reference norms. Nonetheless, patients in AS for < 2.5 years reported worse outcomes than other treatment groups on physical health domains, especially in bodily pain (0.5-0.6 SD), and vitality (0.6-0.8 SD). CONCLUSIONS: Considering patients' well-being, AS can be a good therapeutic option due to the low impact caused on urinary continence and sexual function. However, longitudinal studies are required to take into account HRQoL evolution over time.

Adjuvants in Allergen-Specific Immunotherapy: Modulating and Enhancing the Immune Response.

Allergen-specific immunotherapy (AIT) is the only treatment that can affect the natural course of allergic diseases such as allergic asthma, allergic rhinitis, and IgE-mediated food allergy. Adjuvants are used to induce a quicker, more potent, and longer-lasting immune response. Only 4 compounds are used as adjuvants in currently marketed AIT products: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine (MCT), and monophosphoryl lipid A (MPL). The first 3 adjuvants are delivery systems with a depot effect, although they may also have immunomodulatory properties. These first-generation adjuvants are still widely used, especially aluminum hydroxide. However, aluminum is subject to limitations. MCT is the depot formulation of L-tyrosine; it enhances IgG production without inducing a significant increase in IgE, is biodegradable, and has good local and systemic tolerability. In turn, MPL is an immunostimulatory agent that is the only second-generation adjuvant currently used for AIT. In addition, multiple adjuvants are currently being studied, including immunostimulatory sequences (ISSs), nanoparticles (liposomes, virus-like particles, and biodegradable polymers), and phosphatidylserine derivatives. In a murine model of allergic bronchial inflammation by sensitization to olive pollen, the specific IgE level was significantly higher in sensitized mice treated with olive pollen and aluminum hydroxide. However, specific IgE levels were significantly reduced and bronchial hyperreactivity significantly improved in sensitized mice treated with olive pollen and bacterial derivatives (MPL or ISSs).

3D Engineering of Ocular Tissues for Disease Modeling and Drug Testing.

The success rate from investigational new drug filing to drug approval has remained low for decades despite major scientific and technological advances, and a steady increase of funding and investment. The failure to demonstrate drug efficacy has been the major reason that drug development does not progress beyond phase II and III clinical trials. The combination of two-dimensional (2D) cellular in vitro and animal models has been the gold standard for basic science research and preclinical drug development studies. However, most findings from these systems fail to translate into human trials because these models only partly recapitulate human physiology and pathology. The lack of a dynamic three-dimensional microenvironment in 2D cellular models reduces the physiological relevance, and for these reasons, 3D and microfluidic model systems are now being developed as more native-like biological assay platforms. 3D cellular in vitro systems, microfluidics, self-organized organoids, and 3D biofabrication are the most promising technologies to mimic human physiology because they provide mechanical cues and a 3D microenvironment to the multicellular components. With the advent of human-induced pluripotent stem cell (iPSC) technology, the 3D dynamic in vitro systems further enable extensive access to human-like tissue models. As increasingly complex 3D cellular systems are produced, the use of current visualization technologies is limited due to the thickness and opaqueness of 3D tissues. Tissue-clearing techniques improve light penetration deep into tissues by matching refractive indices among the 3D components. 3D segmentation enables quantitative measurements based on 3D tissue images. Using these state-of-the-art technologies, high-throughput screening (HTS) of thousands of drug compounds in 3D tissue models is slowly becoming a reality. In order to screen thousands of compounds, machine learning will need to be applied to help maximize outcomes from the use of cheminformatics and phenotypic approaches to drug screening. In this chapter, we discuss the current 3D ocular models recapitulating physiology and pathology of the back of the eye and further discuss visualization and quantification techniques that can be implemented for drug screening in ocular diseases.

First-time-in-human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification.

AIMS: SNF472 is a calcification inhibitor being developed for the treatment of cardiovascular calcification in haemodialysis (HD) and in calciphylaxis patients. This study investigated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) SNF472 in healthy volunteers (HV) and HD patients. METHODS: This is a first-time-in-human, double-blind, randomized, placebo-controlled Phase I study to assess the safety, tolerability and PK of SNF472 after ascending single IV doses in HV and a single IV dose in HD patients. A pharmacodynamic analysis was performed to assess the capability of IV SNF472 to inhibit hydroxyapatite formation. RESULTS: Twenty HV and eight HD patients were enrolled. The starting dose in HV was 0.5 mg kg-1 and the dose ascended to 12.5 mg kg-1 . The dose selected for HD patients was 9 mg kg-1 . Safety analyses support the safety and tolerability of IV SNF472 in HD patients and HV. Most treatment-emergent adverse events were mild in intensity. No clinically significant effects were observed on vital signs or laboratory tests. PK results were similar in HD patients and HV and indicate a lack of significant dialysability. Pharmacodynamic analyses demonstrated that SNF472 administration reduced hydroxyapatite crystallization potential in HD patients who received IV SNF472 9 mg kg-1 by 80.0 ± 2.4% (mean ± standard error of the mean, 95% CI, 75.3-84.8) compared to placebo (8.7 ± 21.0%, P < 0.001, 95% CI, -32.4 to 49.7). CONCLUSION: The results from this study showed acceptable safety and tolerability, and lack of significant dialysability of IV SNF472. It is a potential novel treatment for cardiovascular calcification in end-stage renal disease and calciphylaxis warranting further human studies.

Reline aqueous solutions behaving as liquid mixtures of H-bonded co-solvents: microphase segregation and formation of co-continuous structures as indicated by Brillouin and 1H NMR spectroscopies.

Deep eutectic solvents (DESs) offer a suitable alternative to conventional solvents in terms of both performance and cost-effectiveness. Some DESs also offer certain green features, the greenness of which is notoriously enhanced when combined with water. Aqueous DES dilutions are therefore attracting great attention as a novel green medium for biotechnological processes, with the aqueous dilutions of reline - a DES composed of urea and choline chloride - being one of the most studied systems. Despite their macroscopic homogeneous appearance, both 1H NMR spectroscopic studies and molecular dynamics simulations have revealed the occurrence of certain dynamic heterogeneity at a microscopic molecular level. Ultrasonic measurements were also used with the aim of getting further insights but nonconclusive results were obtained. Herein, we have studied aqueous reline dilutions by Brillouin spectroscopy given its proved suitability for detecting local structure rearrangements in liquid mixtures of H-bonded co-solvents. Brillouin spectroscopy revealed the formation of a co-continuous structure resulting from local structure rearrangements and micro-segregation into aqueous and DES phases. Interestingly, there is agreement between 1H NMR and Brillouin spectroscopy when pointing to the DES content where microphase segregation and formation of co-continuous structures occurred.

Effect of antibiotics on biofilm inhibition and induction measured by real-time cell analysis.

AIMS: The purpose of the current work was to study the pattern and dynamics of biofilm formation in clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis in the presence of 10 antibiotics with different action mechanisms. METHODS AND RESULTS: By using impedance measurements in microtitre plates with gold electrodes we have assessed the antibiotic effect on bacterial biofilm growth in real time. The impedance measurements appear to combine both cellular growth and matrix production, representing a measurement of total biofilm mass. Several clinical and reference strains were tested, showing different slopes and cell index values which correlated with their capacity to form biofilms as assessed by attachment to standard microtitre well plates and safranin staining. Biofilms were heavily reduced in biofilm mutants or by protease treatment in protein-based biofilm matrixes. Antibiotic resistance patterns of biofilms, which were very different to those obtained by traditional methods like epsilon-tests on solid media, revealed features that would pass unnoticed by end-point methods. CONCLUSIONS: Once the biofilm is formed, antibiotic efficacy dramatically reduced and sub-inhibitory concentrations of some antibiotics, such as linezolid and clarithromycin, stimulated biofilm growth, stressing the importance of studying antibiotic resistance under biofilm growth conditions in real time. SIGNIFICANCE AND IMPACT OF THE STUDY: Real-time biofilm analysis provides a promising tool to evaluate antibiotic therapy in clinical biofilm-mediated infections.

Ten important articles on noninvasive ventilation in critically ill patients and insights for the future: A report of expert opinions.

BACKGROUND: Noninvasive ventilation is used worldwide in many settings. Its effectiveness has been proven for common clinical conditions in critical care such as cardiogenic pulmonary edema and chronic obstructive pulmonary disease exacerbations. Since the first pioneering studies of noninvasive ventilation in critical care in the late 1980s, thousands of studies and articles have been published on this topic. Interestingly, some aspects remain controversial (e.g. its use in de-novo hypoxemic respiratory failure, role of sedation, self-induced lung injury). Moreover, the role of NIV has recently been questioned and reconsidered in light of the recent reports of new techniques such as high-flow oxygen nasal therapy. METHODS: We conducted a survey among leading experts on NIV aiming to 1) identify a selection of 10 important articles on NIV in the critical care setting 2) summarize the reasons for the selection of each study 3) offer insights on the future for both clinical application and research on NIV. RESULTS: The experts selected articles over a span of 26 years, more clustered in the last 15 years. The most voted article studied the role of NIV in acute exacerbation chronic pulmonary disease. Concerning the future of clinical applications for and research on NIV, most of the experts forecast the development of innovative new interfaces more adaptable to patients characteristics, the need for good well-designed large randomized controlled trials of NIV in acute "de novo" hypoxemic respiratory failure (including its comparison with high-flow oxygen nasal therapy) and the development of software-based NIV settings to enhance patient-ventilator synchrony. CONCLUSIONS: The selection made by the experts suggests that some applications of NIV in critical care are supported by solid data (e.g. COPD exacerbation) while others are still waiting for confirmation. Moreover, the identified insights for the future would lead to improved clinical effectiveness, new comparisons and evaluation of its role in still "lack of full evidence" clinical settings.

Management of chronic spontaneous urticaria in routine clinical practice: A Delphi-method questionnaire among specialists to test agreement with current European guidelines statements.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a frequent clinical entity that often presents a diagnostic and therapeutic challenge. OBJECTIVE: To explore the degree of agreement that exists among the experts caring for patients with CSU diagnosis, evaluation, and management. METHODS: An online survey was conducted to explore the opinions of experts in CSU, address controversial issues, and provide recommendations regarding its definition, natural history, diagnosis, and treatment. A modified Delphi method was used for the consensus. RESULTS: The questionnaire was answered by 68 experts (dermatologists, allergologists, and primary care physicians). A consensus was reached on 54 of the 65 items posed (96.4%). The experts concluded that CSU is a difficult-to-control disease of unpredictable evolution. Diagnostic tests should be limited and based on clinical history and should not be indiscriminate. Autoinflammatory syndromes and urticarial vasculitis must be ruled out in the differential diagnosis. A cutaneous biopsy is only recommended when wheals last more than 24h, to rule out urticarial vasculitis. The use of specific scales to assess the severity of the disease and the quality of life is recommended. In patients with severe and resistant CSU, second-generation H1-antihistamines could be used at doses up to four times the standard dose before giving second-line treatments. Omalizumab is a safe and effective treatment for CSU that is refractory to H1-antihistamines treatment. In general, diagnosis and treatment recommendations given for adults could be extrapolated to children. CONCLUSIONS: This work offers consensus recommendations that may be useful in the management of CSU.