Outpatient glucocorticoid use and COVID-19 outcomes: a population-based study.

INTRODUCTION: Owing to controversy information surrounds effect of glucocorticoids on the evolution of COVID-19, we evaluate the effects of outpatient glucocorticoid use on the severity and progression of COVID-19 and risk of infection and analyse the effect of window of exposure and dose. METHODS: We conducted a population-based case - control study, involving 4 substudies: (i) Hospitalisation; (ii) Mortality, using subjects hospitalised with a PCR + as cases and subjects without a PCR + as controls; (iii) Progression, including subjects with a PCR + (hospitalised versus non-hospitalised); and (iv) Susceptibility, with all subjects with a PCR + and subjects without a PCR + . Adjusted odds ratios (ORa) and their 95% confidence intervals (95% CI) were calculated. RESULTS: The outpatient glucocorticoid use was associated with an increased risk of hospitalisation (aOR 1.79; 95% CI 1.56-2.05), mortality (aOR 2.30; 95% CI 1.68-3.15), progression (aOR 1.69; 95% CI 1.43-2.00) and susceptibility (aOR 1.29, 95% CI 1.19-1.41). Furthermore, the effects was observed to be greater at higher doses and the closer that drug use approached the outcome date, with an almost fourfold increase in mortality among users in the previous month (aOR 3.85; 95% CI 2.63-5.62). CONCLUSIONS: According to the results of this real-world data study, outpatient glucocorticoid use should be considered in making decisions about intrahospital treatment.

Effectiveness of fosfomycin trometamol as oral step-down therapy for bacteraemic urinary tract infections due to MDR Escherichia coli: a post hoc analysis of the FOREST randomized trial.

BACKGROUND: Fosfomycin is a potentially attractive option as step-down therapy for bacteraemic urinary tract infections (BUTI), but available data are scarce. Our objective was to compare the effectiveness and safety of fosfomycin trometamol and other oral drugs as step-down therapy in patients with BUTI due to MDR Escherichia coli (MDR-Ec). METHODS: Participants in the FOREST trial (comparing IV fosfomycin with ceftriaxone or meropenem for BUTI caused by MDR-Ec in 22 Spanish hospitals from June 2014 to December 2018) who were stepped-down to oral fosfomycin (3 g q48h) or other drugs were included. The primary endpoint was clinical and microbiological cure (CMC) 5-7 days after finalization of treatment. A multivariate analysis was performed using logistic regression to estimate the association of oral step-down with fosfomycin with CMC adjusted for confounders. RESULTS: Overall, 61 patients switched to oral fosfomycin trometamol and 47 to other drugs (cefuroxime axetil, 28; amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, 7 each; ciprofloxacin, 5) were included. CMC was reached by 48/61 patients (78.7%) treated with fosfomycin trometamol and 38/47 (80.9%) with other drugs (difference, -2.2; 95% CI: -17.5 to 13.1; P = 0.38). Subgroup analyses provided similar results. Relapses occurred in 9/61 (15.0%) and 2/47 (4.3%) of patients, respectively (P = 0.03). The adjusted OR for CMC was 1.11 (95% CI: 0.42-3.29, P = 0.75). No relevant differences in adverse events were seen. CONCLUSIONS: Fosfomycin trometamol might be a reasonable option as step-down therapy in patients with BUTI due to MDR-Ec but the higher rate of relapses would need further assessment.

The impact of nutritional risk factors and sarcopenia on survival in patients treated with pelvic exenteration for recurrent gynaecological malignancy: a retrospective cohort study.

PURPOSE: The aim of the present study is to investigate the prognostic significance of nutritional risk factors and sarcopenia on the outcome of patients with recurrent gynaecological malignancies treated by pelvic exenteration. METHODS: We retrospectively evaluated muscle body composite measurements based on pre-operative CT scans, nutritional risk factors as assessed by a validated pre-operative questionnaire, and clinical-pathological parameters in 65 consecutive patients with recurrent gynaecological malignancies, excluding ovarian cancer, treated by pelvic exenteration at the Royal Marsden Hospital London. Predictive value for postoperative morbidity was investigated by logistic regression analyses. Relevant parameters were included in uni- and multivariate survival analyses. RESULTS: We found only (1) low muscle attenuation (MA)-an established factor for muscle depletion-and (2) moderate risk for malnutrition to be independently associated with shorter overall survival (p = 0.006 and p = 0.008, respectively). MA was significantly lower in overweight and obese patients (p = 0.04). Muscle body composite measurements were not predictive for post-operative morbidity. CONCLUSION: The study suggests that pre-operative low MA and moderate risk for malnutrition are associated with shorter survival in patients with recurrent gynaecological malignancies treated with pelvic exenteration. Further studies are needed to validate these findings in larger cohorts.

A decade of changes in management of immune thrombocytopenia, with special focus on elderly patients.

BACKGROUND: Ten years after their availability, thrombopoietin receptor agonists (TPO-RA) have heralded a paradigm shift in the treatment of immune thrombocytopenia (ITP). This study was aimed to analyze the implementation of current recommendations in the standard practice of adult ITP patients, and how age may influence those changes. METHODS: We included 121 adult patients (> 65 years, n = 54; younger individuals, n = 67) who initiated treatment with TPO-RA between January 2012 and December 2014. RESULTS: Patients older than 65 years treated with TPO-RA presented at diagnosis with significantly higher platelet counts, less bleeding, and a more prothrombotic profile than younger ones. The high efficacy rates of TPO-RA, preferentially used during the last decade in non-chronic phases, precluded from further therapies in the majority of ITP patients. Their administration was associated with a sharp decline in the last decade in the use of splenectomy and intravenous immunoglobulin, especially in younger ITP individuals. CONCLUSION: These results confirm (1) that there is a preferential use of TPO-RAs in elderly ITP patients with fewer bleeding complications but more unfavorable prothrombotic conditions than in younger individuals, and (2) that early use of these agents has been established as an effective therapeutic alternative to other second line therapies.

Recommendations on the pharmacological treatment of epithelial ovarian cancer in Mexico.

Ovarian cancer is the third most frequent gynaecological malignancy worldwide and in Mexico, with a high mortality rate, due to that in many cases its diagnosis is made in advanced stages. Prognosis is important for determining the subtype and the degree of evolution. During lasts years, the management of ovarian cancer has undergone an important evolution with the incorporation of new therapeutic options, which in turn represent an increase in the survival of these patients. We present recommendations for the management of ovarian cancer developed by an expert panel Mexican based on available evidence so far and the characteristics of health care in the country.

El cáncer de ovario es la tercera neoplasia maligna ginecológica más frecuente globalmente y también en México, con una elevada tasa de mortalidad debido a que en muchos casos su diagnóstico se realiza en etapas avanzadas. Para establecer su pronóstico es importante la determinación del subtipo y del grado de evolución. En los últimos años, el manejo del cáncer de ovario ha sufrido una importante evolución con la incorporación de nuevas opciones terapéuticas, que a su vez representan un incremento en la supervivencia de estas pacientes. Se presentan las recomendaciones para el manejo del cáncer de ovario elaboradas por un panel de expertos mexicanos basadas en la evidencia disponible hasta el momento y en las características de la atención sanitaria del país.

The allosteric modulation of thyroxine-binding globulin affinity is entropy driven.

BACKGROUND: Thyroxine-binding globulin (TBG) is a non-inhibitory member of the serpin family of proteins whose main structural element is the reactive center loop (RCL), that, upon cleavage by proteases, is inserted into the protein core adopting a ß-strand conformation (stressed to relaxed transition, S-to-R). After S-to-R transition thyroxine (T4) affinity decreases. However, crystallographic studies in the presence or absence of the hormone in different states are unable to show significant differences in the structure and interactions of the binding site. Experimental results also suggest the existence of several S states (differing in the number of inserted RCL residues), associated with a differential affinity. METHODS: To shed light into the molecular basis that regulates T4 affinity according to the degree of RCL insertion in TBG, we performed extended molecular dynamics simulations combined with several thermodynamic analysis of the T4 binding to TBG in three different S states, and in the R state. RESULTS: Our results show that, despite T4 binding in the protein by similar interactions in all states, a good correlation between the degree of RCL insertion and the binding affinity, driven by a change in TBG conformational entropy, was observed. CONCLUSION: TBG allosteric regulation is entropy driven. The presence of multiple S states may allow more efficient T4 release due to protease activity. GENERAL SIGNIFICANCE: The presented results are clear examples of how computer simulation methods can reveal the thermodynamic basis of allosteric effects, and provide a general framework for understanding serpin allosteric affinity regulation.

Mechanisms of Oryza sativa (Poaceae) resistance to Tagosodes orizicolus (Homoptera: Delphacidae) under greenhouse condition in Venezuela.

Tagosodes orizicolus is one of the main plagues of rice in tropical America causing two types of damages, the direct one, feeding and oviposition effect, and an indirect one, by the transmission of the "Rice hoja blanca virus". During 2006-2007 we carried out research under greenhouse conditions at Fundaci6n Danac, Venezuela, in order to determine the mechanisms of antixenosis, antibiosis and tolerance to T. orizicolus, which could be acting in commercial varieties and advanced lines of the rice genetic breeding programs of INIA and Fundaci6n Danac. The method of free feeding was used for the antixenosis evaluation, whereas the method of forced feeding was used for antibiosis evaluation (effect on survival and oviposition). Additionally, we used the indirect method based on biomass depression to estimate the tolerance. Some of the evaluated traits included: grade of damage, number of insects settling on rice plants, percentage of sogata mortality at the mature state, number of eggs in the leaf midrib and an index of tolerance. The results showed that rice genotypes possess different combinations of resistance mechanisms, as well as different grades of reactions. The susceptible control 'Bluebonnet 50' was consistently susceptible across experiments and the resistant control 'Makalioka' had high antixenosis and high antibiosis based on survival and oviposition. The rest of the genotypes presented lower or higher degrees of antixenosis and antibiosis for survival and oviposition. The genotype 'FD0241-M-17-6-1-1-1-1' was identified with possible tolerance to the direct damage of sogata.

A Methodological Framework for Assessing the Sustainability of Solid Biofuels Systems.

This paper introduces a methodological framework for assessing the sustainability of solid biofuels in Mexico. The designed framework comprises 13 normalized indicators and two diagnostic studies, covering the economic, social, environmental, and institutional sustainability dimensions, and their intersections. Indicators are normalized using the concept of load capacity of a system, similarly to the planetary boundaries. Thus, the graphical representation of results facilitates their multidimensional analysis. The framework was applied to three case studies: traditional fuelwood in rural households, charcoal for restaurant grilling, and electricity cogeneration from sugarcane bagasse. This was part of an iterative process of testing and refining the framework and simultaneously demonstrating its application in the Mexican bioenergy context. This led to the conclusion that the resulting framework (a) provides a useful, quantitative, and comprehensive overview of both broad and specific sustainability aspects of the assessed system; (b) requires a balance of accessible but also scattered or sensitive data, similarly to most existing frameworks; (c) is highly flexible and applicable to both modern and traditional solid biofuels; and (d) is simple to communicate and interpret for a wide audience. Key directions for improvement of the framework are also discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s12155-021-10365-2.

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections: A Randomized Clinical Trial.

Importance: The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. Objective: To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. Design, Setting, and Participants: This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. Interventions: Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or parenteral ertapenem for the comparator group after 4 days. Main Outcomes and Measures: The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. Results: Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to ∞ percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI, -∞ to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). Conclusions and Relevance: This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections. Trial Registration: ClinicalTrials.gov Identifier: NCT02142751.

Glucanases and chitinases as causal agents in the protection of Acacia extrafloral nectar from infestation by phytopathogens.

Nectars are rich in primary metabolites and attract mutualistic animals, which serve as pollinators or as an indirect defense against herbivores. Their chemical composition makes nectars prone to microbial infestation. As protective strategy, floral nectar of ornamental tobacco (Nicotiana langsdorffii x Nicotiana sanderae) contains "nectarins," proteins producing reactive oxygen species such as hydrogen peroxide. By contrast, pathogenesis-related (PR) proteins were detected in Acacia extrafloral nectar (EFN), which is secreted in the context of defensive ant-plant mutualisms. We investigated whether these PR proteins protect EFN from phytopathogens. Five sympatric species (Acacia cornigera, A. hindsii, A. collinsii, A. farnesiana, and Prosopis juliflora) were compared that differ in their ant-plant mutualism. EFN of myrmecophytes, which are obligate ant-plants that secrete EFN constitutively to nourish specialized ant inhabitants, significantly inhibited the growth of four out of six tested phytopathogenic microorganisms. By contrast, EFN of nonmyrmecophytes, which is secreted only transiently in response to herbivory, did not exhibit a detectable inhibitory activity. Combining two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis with nanoflow liquid chromatography-tandem mass spectrometry analysis confirmed that PR proteins represented over 90% of all proteins in myrmecophyte EFN. The inhibition of microbial growth was exerted by the protein fraction, but not the small metabolites of this EFN, and disappeared when nectar was heated. In-gel assays demonstrated the activity of acidic and basic chitinases in all EFNs, whereas glucanases were detected only in EFN of myrmecophytes. Our results demonstrate that PR proteins causally underlie the protection of Acacia EFN from microorganisms and that acidic and basic glucanases likely represent the most important prerequisite in this defensive function.

Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors.

Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells. Compounds targeting this pathway are under active development as anticancer therapeutics and some of them have reached advanced clinical trials or been approved by the FDA. Dual PI3K/mTOR inhibitors combine multiple therapeutic efficacies in a single molecule by inhibiting the pathway both upstream and downstream of AKT. Herein, we report our efforts on the exploration of novel small molecule macrocycles (MCXs) as dual PI3K/mTOR inhibitors. Macrocyclization is an attractive approach used in drug discovery, as the semi-rigid character of these structures could provide improved potency, selectivity and favorable pharmacokinetic properties. Importantly, this strategy allows access to new chemical space thus obtaining a better intellectual property position. A series of MCXs based on GSK-2126458, a known clinical PI3K/mTOR inhibitor is described. These molecules showed potent biochemical and cellular dual PI3K/mTOR inhibition, demonstrated strong antitumoral effects in human cancer cell lines, and displayed good drug-like properties. Among them, MCX 83 presented remarkable selectivity against a panel of 468 kinases, high in vitro metabolic stability, and favorable pharmacokinetic parameters without significant CYP450 and h-ERG binding inhibition. This profile qualified this compound as a suitable candidate for future in vivo PK-PD and efficacy studies in mouse cancer models.

Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors.

The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2-d]pyrimidine MCXs, which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35-37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity.

Airborne induction and priming of plant defenses against a bacterial pathogen.

Herbivore-induced plant volatiles affect the systemic response of plants to local damage and hence represent potential plant hormones. These signals can also lead to "plant-plant communication," a defense induction in yet undamaged plants growing close to damaged neighbors. We observed this phenomenon in the context of disease resistance. Lima bean (Phaseolus lunatus) plants in a natural population became more resistant against a bacterial pathogen, Pseudomonas syringae pv syringae, when located close to conspecific neighbors in which systemic acquired resistance to pathogens had been chemically induced with benzothiadiazole (BTH). Airborne disease resistance induction could also be triggered biologically by infection with avirulent P. syringae. Challenge inoculation after exposure to induced and noninduced plants revealed that the air coming from induced plants mainly primed resistance, since expression of PATHOGENESIS-RELATED PROTEIN2 (PR-2) was significantly stronger in exposed than in nonexposed individuals when the plants were subsequently challenged by P. syringae. Among others, the plant-derived volatile nonanal was present in the headspace of BTH-treated plants and significantly enhanced PR-2 expression in the exposed plants, resulting in reduced symptom appearance. Negative effects on growth of BTH-treated plants, which usually occur as a consequence of the high costs of direct resistance induction, were not observed in volatile organic compound-exposed plants. Volatile-mediated priming appears to be a highly attractive means for the tailoring of systemic acquired resistance against plant pathogens.

Short signalling distances make plant communication a soliloquy.

Plants respond to attack by herbivores or pathogens with the release of volatile organic compounds. Neighbouring plants can receive these volatiles and consecutively induce their own defence arsenal. This 'plant communication', however, appears counterintuitive when it benefits independent and genetically unrelated receivers, which may compete with the emitter. As a solution to this problem, a role for volatile compounds in within-plant signalling has been predicted. We used wild-type lima bean (Phaseolus lunatus) to quantify under field conditions the distances over which volatile signals move, and thereby determine whether these cues will mainly trigger resistance in other parts of the same plant or in independent plants. Independent receiver plants exhibited airborne resistance to herbivores or pathogens at maximum distances of 50 cm from a resistance-expressing emitter. In undisturbed clusters of lima bean, over 80 per cent of all leaves that were located around a single leaf at this distance were other leaves of the same plant, whereas this percentage dropped below 50 per cent at larger distances. Under natural conditions, resistance-inducing volatiles of lima bean move over distances at which most leaves that can receive the signal still belong to the same plant.

Accelerated Preclinical Paths to Support Rapid Development of COVID-19 Therapeutics.

When SARS-CoV-2 emerged at the end of 2019, no approved therapeutics or vaccines were available. An urgent need for countermeasures during this crisis challenges the current paradigm of traditional drug discovery and development, which usually takes years from start to finish. Approaches that accelerate this process need to be considered. Here we propose the minimum data package required to move a compound into clinical development safely. We further define the additional data that should be collected in parallel without impacting the rapid path to clinical development. Accelerated paths for antivirals, immunomodulators, anticoagulants, and other agents have been developed and can serve as "roadmaps" to support prioritization of compounds for clinical testing. These accelerated paths are fueled by a skewed risk-benefit ratio and are necessary to advance therapeutic agents into human trials rapidly and safely for COVID-19. Such paths are adaptable to other potential future pandemics.

Penicillin-susceptible Staphylococcus aureus bacteremia: Epidemiological and clinical relevance. Possible therapeutic implications. / Bacteriemia por Staphylococcus aureus sensible a penicilina. Importancia epidemiológica, clínica y posibles implicaciones terapéuticas.

INTRODUCTION: The increase in penicillin susceptibility among Staphylococcus aureus (SA-PenS) might have therapeutic relevance. We aimed to study the current situation in our environment. MATERIAL AND METHODS: Over a 2.5 years period, all SA isolates from bacteraemia in one hospital were analysed. For all isolates, antimicrobial susceptibility profile, beta-lactam resistance genes (blaZ, mecA) and Panton-Valentine leucocidine encoding-genes were studied. For SA-PenS-blaZnegative isolates, spa-type, MLST and the presence of other resistance genes were studied. RESULTS: Among 84 patients with SA bacteraemia (35.7% MRSA and 64.3% MSSA), 77 were analysed; 22.2% of MSSA isolates were PenS and blaZnegative (Pen-MIC≤0.03µg/ml) corresponding to 14.3% of the total SA. In MSSA-PenS-blaZnegative isolates, eight spa-types and 7 clonal-complexes were detected. CONCLUSION: A high prevalence of MRSA/SA and MSSA-PenS-blaZnegative/MSSA was detected in blood cultures. Pen-MIC≤0,3µg/ml corresponded to MSSA-PenS-blaZnegative. This situation raises therapeutic options which should be further evaluated in larger studies and clinical trials.

Objective and subjective quality of life in adults with autism spectrum disorders in southern Spain.

Subjective and objective measures of quality of life (QoL) were obtained for adults with autism spectrum disorders (ASDs) living in Andalusia (Spain). Seventy-four families responded to questionnaires about objective QoL indicators such as employment, health, adaptive behaviour and social network, and were asked to act as proxies for subjective QoL measures. Outcome on objective QoL was extremely poor. Social networks were most frequently composed of family members. Community-oriented resources were absent in most cases. For two-thirds of the families, the ability to act as proxies for subjective QoL was seriously limited by the participants' poor social and communicative abilities. The results are indicative of the need for additional support to families of adults with ASD and increased community-based resources. Further conceptualization of indicators and measurement of subjective QoL in individuals with severe disabilities and ASD is also needed in order to include their own perspective in the evaluation of service provision.

Interaction of the antibiotic peptide nisin with anionic membranes in different phase-states: a vibrational study.

Interactions between the antibiotic peptide nisin and multilamellar vesicles of phosphoglycerol lipids in different phase-states were studied using vibrational spectroscopy. The infrared amide I' band of nisin, both in solution and in the membrane-bound state, was analyzed in the temperature range comprised between 20 and 60 °C in order to study its conformational behavior. Nisin presented mainly unordered and ß-turns conformations. Their relative populations varied according to the environment and as the temperature increased: ß turns were more favored in the membrane-bound state than in solution, but at higher temperatures the disordered conformation was dominant in both states. Spectral changes of specific infrared bands belonging to the hydrocarbon and polar moieties of lipids were also analyzed to evaluate the perturbation of the lipid membrane order. Nisin interactions with the membrane polar region induced a high restriction to water incorporation, promoting a small increase in the temperature of the lipid phase transition. Raman spectra of nisin/phosphoglycerol systems at ambient temperature were also analyzed. They revealed that the peptide incorporation to a membrane in the fluid phase caused drastic structural modifications in the hydrophobic region of the bilayer. Although nisin may be able to disrupt the hydrophobic portion of the bilayer in the gel phase, the most of the peptide molecule remained at the membrane surface interacting with the polar headgroups. This work provides evidence of a differential effect of nisin on anionic membranes, depending on the phase-state of the lipid.

Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia.

Very few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 109/l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs. eltrombopag (P = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs. 2.2%, P < 0.001), and to previous splenectomy in younger patients (100% vs. 33%, P = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA.

Melatonin reduces body weight in goldfish (Carassius auratus): effects on metabolic resources and some feeding regulators.

The objective of the present study was to analyze the effects of chronic melatonin (10 microg/g body weight) on body weight and the main energetic reserves, particularly hepatic and muscle content of proteins, lipids and glycogen in goldfish. In addition, we studied plasma leptin and ghrelin, and hypothalamic content of neuropeptide Y (NPY) and monoamines after chronic melatonin treatment in order to elucidate a possible interplay between melatonin and these feeding regulators on the body weight regulation in this species. Body weight gain and specific growth rate were reduced (74% and 76%, respectively) after chronic (10 days) intraperitoneal (i.p.) treatment with melatonin. The carbohydrate and lipid metabolism was regulated by melatonin in goldfish, because this indoleamine reduced muscle glycogen stores and increased lipid mobilization. A suppressive trend, but not statistically significant, in circulating ghrelin was observed after chronic treatment with melatonin. Chronic melatonin administration significantly reduced noradrenergic metabolism and increased dihydroxiphenylacetic acid content in the hypothalamus, without significant modifications in the serotoninergic system. Thus, it could be suggested that melatonin may mediate its action on energy balance in fish, at least in part, via interactions with hypothalamic catecholaminergic system. Plasma leptin and hypothalamic NPY remained unaltered after melatonin treatment, suggesting that these feeding regulators may not be involved in the effects of melatonin on energy homeostasis in fish.