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Background: First responders, when arriving at a disaster, need a rapid analysis of the environment in which they are going to operate, as they have to assess the conditions surrounding potential victims and neutralize any risks that may exist.The EU-funded INTREPID develops a new technology platform to assist first responders when arriving on the scene of a disaster. The project INTREPID aims to support safer operations in the form of more efficient, fast, and safe disaster site assessments. The objective of the study is to implement new technologies into rescue operations to facilitate and improve situational awareness and operation management capabilities to save lives. The focus of the study is relevant to the field of mass casualty incident management and disaster, as proper communication is extremely relevant in the management of catastrophes., Method: The first phase of the project started with a qualitative methodology SCRUM, for catching the end user's feedback and requirements to design the interface platform. It was developed a platform to support first responders in disasters areas improving the 3D scanning and analysis of disaster areas. This platform is based on the concepts of intelligence amplification and eXtended Reality, with hololens, drones and robots. The project continued with a β phase in which the platform with all tools integrated were tested in simulated mass casualty disasters., Results: These technologies are tested in different disaster scenarios: A flooded subway stop in Stockholm, an accident in the chemical industry in Marseille, and a man-made explosion in a hospital in Madrid. Through this platform, first responders can immediately initiate operations without exposing personnel to potential harmful risks without specialized equipment, with all important information shared and coordinated, among all responders, whether they are security, firefighters, or emergency health professionals., Conclusions: The performance pilots and the questionnaire results validated the effectiveness and usability of the final version of the INTREPID platform and tools., (© 2024. The Author(s).)

Introduction: Mass casualty incidents (MCI) are unforeseeable and complex events that occur worldwide, therefore enhancing the training that medical first responders (MFRs) receive is fundamental to strengthening disaster preparedness and response. In recent years, extended reality (XR) technology has been introduced as a new approach and promising teaching technique for disaster medicine education., Objective: To assess the effectiveness of XR simulation as a tool to train MFRs in MCIs, and to explore the perception and experience of participants to these new forms of training., Design: Systematic review., Methods: This systematic review was conducted in accordance with the "Preferred reporting items for systematic reviews and meta-analyses" (PRISMA) statement. Four databases were searched (MEDLINE, EMBASE, CINAHL and LILACs) using a comprehensive search strategy to identify relevant articles, and MetaQAT was used as a study quality assessment tool. Data from included studies was not pooled for meta-analysis due to heterogeneity. Extracted data was synthesised in a narrative, semi-quantitative manner., Results: A total of 18 studies were included from 8 different countries. Studies encompassed a variety of participants (e.g., nurses, paramedics, physicians), interventions (virtual, mixed and augmented reality), comparators (comparison between two groups and single groups with pre-post evaluation), and outcomes (effectiveness and MFR perception). The synthesis of data indicated that XR was an effective tool for prehospital MCI training by means of improved triage accuracy, triage time, treatment accuracy, performance correctness and/or knowledge acquired. These XR systems were well perceived by MFRs, who expressed their interest and satisfaction towards this learning experience and emphasized its usefulness and relevance., Conclusion: This research supports the usefulness and significance of XR technology that allows users to enhance their skills and confidence when facing forthcoming disasters. The findings summarize recommendations and suggestions for the implementation, upgrade and/or assessment of this novel and valuable teaching method., (© 2024. The Author(s).)

Introduction: Medical First Responders (MFRs) in the emergency department SUMMA 112 are tasked with handling the initial management of Mass Casualty Incidents (MCI) and building response capabilities. Training plays a crucial role in preparing these responders for effective disaster management. Yet, evaluating the impact of such training poses challenges since true competency can only be proven amid a major event. As a substitute gauge for training effectiveness, self-efficacy has been suggested., Objective: The purpose of this study is to employ a pre- and post-test assessment of changes in perceived self-efficacy among MFRs following an intervention focused on the initial management of MCI. It also aimed to evaluate a self-efficacy instrument for its validity and reliability in this type of training., Method: In this study, we used a pretest (time 1 = T1) - post-test (time 2 = T2) design to evaluate how self-efficacy changed after a training intervention with 201 MFRs in initial MCI management. ANOVA within-subjects and between subjects analyses were used., Results: The findings reveal a noteworthy change in self-efficacy before and after training among the 201 participants. This suggests that the training intervention positively affected participants' perceived capabilities to handle complex situations like MCI., Conclusion: The results allow us to recommend a training program with theory components together with practical workshops and live, large-scale simulation exercises for the training of medical first responders in MCI, as it significantly increases their perception of the level of self-efficacy for developing competencies associated with disaster response., (© 2024. The Author(s).)

Objective: Cartilaginous tumors of the larynx are rare, representing less than 1% of all laryngeal tumors. Chondromas are benign mesenchymal tumors characterized by a slow-paced growth, primarily originated in the cricoid cartilage, followed by the thyroid, arytenoid, and epiglottic cartilages. This scoping review aims to understand the extent of evidence on the epidemiology, clinical characteristics, morbidity, and recurrence of the laryngeal chondroma (LC)., Data Sources: MEDLINE (Ovid), Embase (Elsevier), Web of Science (Clarivate), Cochrane Central Register of Controlled Trials and Systematic Reviews, Lilacs, Scopus, and Google Scholar databases., Review Methods: The scoping review was conducted from 1816 to 2023, for observational studies describing LC. Titles and abstracts were screened for relevance, followed by an evaluation of the full text for eligibility. The data were collected from the qualifying articles, and a narrative summary of the outcomes was prepared., Results: One hundred and nineteen studies met the inclusion criteria. Ninety-four case reports, 22 case series, and 3 cohorts. Two hundred and four participants with a diagnosis of LC were described. Male:female ratio was 2.8:1. The most common localization was the cricoid (113; 47.08%), followed by the thyroid (45; 18.75%), and the arytenoid cartilage (27; 11.25%). Dyspnea (78.85%) and hoarseness (74.28%) were the most reported symptoms. The recurrence rate was 11.25%, and complications were uncommon following the resection., Conclusion: This scoping review found a low-frequency rate over all the cartilaginous laryngeal tumors. Most patients were treated with resection, with a low rate of malignancy conversion. This population has low attributable mortality, morbidity, and recurrence according to the current literature., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Introduction: Bronchiolitis poses a considerable challenge during its seasonal peak, overwhelming the material and human resources available to care for affected patients. As a result, interhospital transfers increase exponentially. We did not find any studies analysing the characteristics of patients with bronchiolitis managed in out-of-hospital urgent care (OHUC) services and the impact of the COVID-19 pandemic on the epidemiology of bronchiolitis., Objective: To establish the characteristics of paediatric and neonatal patients with acute bronchiolitis (AB) managed in OHUC services in the Community of Madrid and to analyse the impact of the COVID-19 pandemic on the epidemiology of bronchiolitis., Methods: Retrospective cross-sectional observational and descriptive study carried out in OHUC settings in the Community of Madrid between 2016 and 2023. We included patients with a diagnosis of acute bronchiolitis based on the ICD-10 codes documented in the electronic records of urgent care visits and interhospital transports. We collected data on sociodemographic, clinical and treatment (ventilation and medication) variables., Results: The sample included 630 patients with AB: 343 managed in non-neonatal OHUC (non-neo) services and 287 by the mobile neonatal intensive care unit transport team (NTT). The median age was 3.7 months (IQR, 2.8-4.7) in patients in the non-neo OHUC group and 19 days (IQR, 14.2-23.7) in the NTT group. There was a statistically significant increase in age in the 2020/2021 season in the non-neo OHUC group. The severity score was significantly higher in the NTT group. There was an unusual peak in bronchiolitis cases in June 2021, coinciding with the end of the 4th wave of the COVID-19 pandemic. The incidence of bronchiolitis was highest after the 6th wave of the pandemic (13.5 cases per 10 000 children aged < 2 years)., Conclusions: The median age of paediatric patients with AB managed in OHUC services increased following the end of the lockdown imposed due to the COVID-19 pandemic, which was probably associated with the lack of exposure to the viruses that cause it. This also may explain why the incidence of bronchiolitis was highest in the season following the 6th wave of the pandemic. The severity score was higher in neonatal patients. Epidemiological surveillance, the introduction of protocols and the implementation of an ongoing training programme for non-specialized health care staff involved in the transport of these patients could improve their management., (Copyright © 2023 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasures that avoid enhancement of infection associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following repeated DENV infections. We identified several new bnAbs with comparable or superior breadth and potency to known bnAbs, and with distinct recognition determinants. Unlike all known flavivirus bnAbs, which are IgG1, one newly identified cross-flavivirus bnAb (F25.S02) was derived from IgA1. Both IgG1 and IgA1 versions of F25.S02 and known bnAbs displayed neutralizing activity, but only IgG1 enhanced infection in monocytes expressing IgG and IgA Fc receptors. Moreover, IgG-mediated enhancement of infection was inhibited by IgA1 versions of bnAbs. We demonstrate a role for IgA in flavivirus infection and immunity with implications for vaccine and therapeutic strategies., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: LG, JL, FAM, DKR, LML are inventors on a patent application filed by Fred Hutchinson Cancer Center relating to newly discovered antibodies described in this paper. SK, ED, BJD are employees of Integral Molecular, Inc.; BJD is also a shareholder of the company., (Copyright: © 2023 Lubow et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Approximately 5 million dengue virus-infected patients progress to a potentially life-threatening severe dengue (SD) infection annually. To identify the immune features and temporal dynamics underlying SD progression, we performed deep immune profiling by mass cytometry of PBMCs collected longitudinally from SD progressors (SDp) and uncomplicated dengue (D) patients. While D is characterized by early activation of innate immune responses, in SDp there is rapid expansion and activation of IgG-secreting plasma cells and memory and regulatory T cells. Concurrently, SDp, particularly children, demonstrate increased proinflammatory NK cells, inadequate expansion of CD16 + monocytes, and high expression of the FcγR CD64 on myeloid cells, yet a signature of diminished antigen presentation. Syndrome-specific determinants include suppressed dendritic cell abundance in shock/hemorrhage versus enriched plasma cell expansion in organ impairment. This study reveals uncoordinated immune responses in SDp and provides insights into SD pathogenesis in humans with potential implications for prediction and treatment.

The fundamental principles that govern antiferroelectric (AFE)-ferroelectric (FE) transitions are not well understood for many solid solutions of perovskite compounds. For example, crystal chemical considerations based on the average Goldschmidt tolerance factor or ionic polarizability do not precisely predict the boundary between the AFE and FE phases in dilute solid solutions of alkali niobates, such as K x Na 1- x NbO 3 ( x ≤ 0.02). Here, based on detailed structural analysis from neutron total scattering experiments, we provide insights about how the relative local distortions around the A- and B-sites of the ABO 3 perovskite structure affect the AFE/FE order of the average crystallographic phases in K x Na 1- x NbO 3 . We show that a higher (lower) ratio of B-site-centered distortions over A-site-centered distortions drives transition toward a long-range FE (AFE) phase, which is based on a competition between the long-range polarizing field of the Nb-O dipoles and the disordering effect of local distortions around the A-site. Our study provides a predictive tool for designing complex solid-solution perovskites with tunable (anti)ferroelectric polarization properties, which can be of interest for various energy-related applications such as high-density energy storage and solid-state cooling.

The stereochemical activity of lone pair electrons plays a central role in determining the structural and electronic properties of both chemically simple materials such as H 2 O, as well as more complex condensed phases such as photocatalysts or thermoelectrics. TlReO 4 is a rare example of a non-magnetic material exhibiting a re-entrant phase transition and emphanitic behavior in the long-range structure. Here, we describe the role of the Tl + 6s 2 lone pair electrons in these unusual phase transitions and illustrate its tunability by chemical doping, which has broad implications for functional materials containing lone pair bearing cations. First-principles density functional calculations clearly show the contribution of the Tl + 6s 2 in the valence band region. Local structure analysis, via neutron total scattering, revealed that changes in the long-range structure of TlReO 4 occur due to changes in the correlation length of the Tl + lone pairs. This has a significant effect on the anion interactions, with long-range ordered lone pairs creating a more densely packed structure. This resulted in a trade-off between anionic repulsions and lone pair correlations that lead to symmetry lowering upon heating in the long-range structure, whereby lattice expansion was necessary for the Tl + lone pairs to become highly correlated. Similarly, introducing lattice expansion through chemical pressure allowed long-range lone pair correlations to occur over a wider temperature range, demonstrating a method for tuning the energy landscape of lone pair containing functional materials.

Pseudomonas viridiflava was originally reported as a bean pathogen, and subsequently as a wide-host range pathogen affecting numerous plants species. In addition, several authors have reported the epiphytic presence of this bacterium in "non-host plants", which may act as reservoir of P. viridiflava and source of inoculum for crops. A new biotype of this bacterium, showing an atypical LOPAT profile, was found in Asturias, a Northern region of Spain, causing significant damage in beans, kiwifruit, lettuce, and Hebe . In order to investigate the involvement of weeds in bean disease, samples were collected from beans and weeds growing in the same fields. A total of 48 isolates of P. viridiflava were obtained, 39 from weeds and 9 from beans. 48% and 52% of them showed typical (L- O- P+ A- T+) and atypical (L+ O- P v A- T+) LOPAT profiles, and they displayed high biochemical diversity. Regarding virulence factors, the T-PAI and S-PAI pathogenicity islands were found in 29% and 70.8% of the isolates, 81.2% displayed pectinolytic activity on potato slices, and 59% of the weed isolates produced symptoms after inoculation on bean pods. A phylogenetic tree based on concatenated rpoD , gyrB , and gltA sequences separated the strains carrying S-PAI and T-PAI into different clusters, both containing isolates from beans and weeds, and pathogenic as well as non-pathogenic strains. Closely related strains were found in the two hosts, and more than half of the weed isolates proved to be pathogenic in beans. This is consistent with the role of weeds as a reservoir and source of inoculum for bean infection. Detection of P. viridiflava in weeds throughout the year further supports these roles.

Background: Immune-mediated inflammatory diseases (IMID) predispose to a higher infection risk by modifying the host's immune response, which acts as a key factor in SARS-CoV-2 infection resolution. Recent publications show that IMID patients and its treatments do not worsen the outcome of SARS-CoV-2 infection., Objectives: To describe the clinical characteristics and outcomes of patients with IMID who required hospital admission due to SARS-CoV-2 infection. Secondly, to compare clinical characteristics and outcomes between patients who required hospital admission due to SARS-CoV-2 infection with IMID and those who were not affected., Methods: We performed an observational retrospective cohort study, including admitted patients with suspected SARS-CoV-2 infection, treated according to medical criteria and local protocols based on the best available scientific evidence. Clinical data were collected from their electronical clinical history. Statistical analysis determined the differences in the characteristics and clinical outcome of the infection in IMID patients., Results: Of a total number of 612 revised patients, 23 had an IMID and 9 of them were positive for the SARS-CoV-2 infection. We did not observe a correlation between these two disorders. There was a higher frequency of obesity and cardiovascular disease among IMID patients, but without statistical significance. The clinical outcomes were no different between hospitalized IMID and non IMID patients., Conclusion: IMID and its treatments do not determine the outcome of patients admitted with SARS-CoV-2 infection., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Background: Acute respiratory failure (ARF) has become one of the most prevalent serious pathologies encountered in the emergency medical service (EMS). In hospital settings, noninvasive ventilation (NIV) therapy prevents complications from more aggressive treatments for that condition. However, the scarce evidence on the benefits of NIV in prehospital EMS (i.e., during transport to the hospital) is inconclusive., Objectives: To determine whether the administration of NIV during prehospital EMS in cases of ARF reduces in-hospital mortality compared with starting NIV on arrival to in-patient EMS., Methods: This is a multicentre, observational, prospective cohort study. We recruited a total of 317 patients from the Madrid region (Spain) who were prescribed NIV for their ARF using a nonprobabilistic consecutive sampling method. Analyses of the main outcome (in-hospital mortality) and secondary outcomes (length of hospital stay, readmissions, percentage of intensive care unit admissions, and cost-effectiveness) will include descriptive analyses of patients' characteristics, as well as bivariate and multivariate analyses and cost-effectiveness analysis., Discussion: This study will provide data on NIV management in prehospital and in-patient EMS in patients with ARF. Results will contribute to the existing evidence on the benefits of NIV in the context of prehospital EMS while underlining the importance of a standardized formal training for physicians and nurses working in prehospital and in-patient EMSs., Conclusion: The VentilaMadrid study will provide valuable data on the clinical factors of patients receiving NIV in prehospital EMS. Further, were our hypothesis to be confirmed, our results would strongly suggest that the administration of NIV in prehospital EMS by medical and nursing profesionals formally trained in the technique reduces mortality and improves prognoses., (Copyright © 2021 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Each year 3-6 million people develop life-threatening severe dengue (SD). Clinical warning signs for SD manifest late in the disease course and are nonspecific, leading to missed cases and excess hospital burden. Better SD prognostics are urgently needed., Methods: We integrated 11 public datasets profiling the blood transcriptome of 365 dengue patients of all ages and from seven countries, encompassing biological, clinical, and technical heterogeneity. We performed an iterative multi-cohort analysis to identify differentially expressed genes (DEGs) between non-severe patients and SD progressors. Using only these DEGs, we trained an XGBoost machine learning model on public data to predict progression to SD. All model parameters were "locked" prior to validation in an independent, prospectively enrolled cohort of 377 dengue patients in Colombia. We measured expression of the DEGs in whole blood samples collected upon presentation, prior to SD progression. We then compared the accuracy of the locked XGBoost model and clinical warning signs in predicting SD., Results: We identified eight SD-associated DEGs in the public datasets and built an 8-gene XGBoost model that accurately predicted SD progression in the independent validation cohort with 86.4% (95% CI 68.2-100) sensitivity and 79.7% (95% CI 75.5-83.9) specificity. Given the 5.8% proportion of SD cases in this cohort, the 8-gene model had a positive and negative predictive value (PPV and NPV) of 20.9% (95% CI 16.7-25.6) and 99.0% (95% CI 97.7-100.0), respectively. Compared to clinical warning signs at presentation, which had 77.3% (95% CI 58.3-94.1) sensitivity and 39.7% (95% CI 34.7-44.9) specificity, the 8-gene model led to an 80% reduction in the number needed to predict (NNP) from 25.4 to 5.0. Importantly, the 8-gene model accurately predicted subsequent SD in the first three days post-fever onset and up to three days prior to SD progression., Conclusions: The 8-gene XGBoost model, trained on heterogeneous public datasets, accurately predicted progression to SD in a large, independent, prospective cohort, including during the early febrile stage when SD prediction remains clinically difficult. The model has potential to be translated to a point-of-care prognostic assay to reduce dengue morbidity and mortality without overwhelming limited healthcare resources., (© 2022. The Author(s).)

Leishmaniasis and Chagas diseases are two of the most important parasitic diseases in the world. Both belong to the category of Neglected Tropical Diseases, and they cannot be prevented by vaccination. Their treatments are founded in outdated drugs that possess many pernicious side-effects and they're not easy to administer. With the aim of discovering new compounds that could serve as anti-trypanosomal drugs, an antiparasitic study of a synthetic compound family has been conducted. A series of new 1,4-bis(alkylamino)- and 1-alkylamino-4-chloroazine and benzoazine derivatives 1-4 containing imidazole rings have been synthesized and identified. Their structures showed a possible interest based on previous work. Their in vitro anti-Leishmania infantum, anti-L. braziliensis, anti-L. donovani and anti-T. cruzi activity were tested, as well as the inhibition of Fe-SOD enzymes. It was found that some of them exhibited quite relevant values indicative of being worthy of future more detailed studies, as most of them showed activity to more than only one parasite species, especially compound 3 c was active for the three studied Leishmania species and also for T. cruzi, which is a very interesting trait as it covers a wide spectrum., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Introduction: Flaviviridae family belongs to the Spondweni serocomplex, which is mainly transmitted by vectors from the Aedes genus. Zika virus (ZIKV) is part of this genus. It was initially reported in Brazil in December 2014 as an unknown acute generalized exanthematous disease and was subsequently identified as ZIKV infection. ZIKV became widespread all over Brazil and was linked with potential cases of microcephaly., Case Report: We report a case of a 28-year-old Colombian woman, who came to the Obstetric Department with an assumed conglomerate of fetal abnormalities detected via ultrasonography, which was performed at 29.5 weeks of gestation. The patient presented with multiple abnormalities, which range from a suggested Arnold-Chiari malformation, compromising the lateral and third ventricles, liver calcifications, bilateral pyelocalic dilatations, other brain anomalies, and microcephaly. At 12 weeks of gestation, the vertical transmission of ZIKV was suspected. At 38.6 weeks of gestation, the newborn was delivered, with the weight in the 10th percentile (3,180 g), height in the 10th percentile (48 cm), and cephalic circumference under the 2nd percentile (31 cm). Due to the physical findings, brain magnetic resonance imaging (MRI) was performed, revealing a small and deviated brain stem, narrowing of the posterior fossa, a giant posterior fossa cyst with ventricular dilatation, a severe cortical and white matter thinning, cerebellar vermis with hypoplasia, and superior and lateral displacement of the cerebellum. In addition, hydrocephalus was displayed by the axial sequence, and the cerebral cortex was also compromised with lissencephaly. Schizencephaly was found with left frontal open-lip, and no intracranial calcifications were found. Two novel heterozygous nonsense mutations were identified using whole-exome sequencing, and both are located in exon 8 under the affection of ZIKV congenital syndrome (CZS) that produced a premature stop codon resulting in the truncation of the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) protein., Conclusion: We used molecular and microbiological assessments to report the initial case of vertically transmitted ZIKV infection with congenital syndrome associated with a neurological syndrome, where a mutation in the CDK5RAP2 gene was also identified. The CDK5RAP2 gene encodes a pericentriolar protein that intervenes in microtubule nucleation and centriole attachment. Diallelic mutation has previously been associated with primary microcephaly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Candelo, Sanz, Ramirez-Montaño, Diaz-Ordoñez, Granados, Rosso, Nevado, Lapunzina and Pachajoa.)

Background: Several descriptive cohort studies of patients affected by COVID-19 have been published., Objective: To describe the characteristics of patients with SARS-CoV-2 infection who were admitted to Hospital Universitario la Plana, Castellón, Spain., Methods: Retrospective, observational cohort study that included 18-year-old or older patients who were consecutively admitted with SARS-CoV2 confirmed infection. Demographic characteristics, comorbidities, clinical symptoms, laboratory results and radiological tests are described., Results: The study included 255 patients with a mean age of 70 years; 54.9 % were males. Most common comorbidities were high blood pressure (58 %), dyslipidemia (42.4 %), diabetes (25.5 %) and obesity (24.3 %). Median number of days from the onset of clinical symptoms prior to hospital admission was seven. Most common manifestations prior to admission were fever (74.5 %), dry cough (61.2 %), malaise (51.8 %) and dyspnea (51.0 %); 19 patients (7.4 %) were admitted to the intensive care unit, where mortality was 50 %; overall mortality was 16.9 %., Conclusions: Our cohort reflects similar characteristics to those of other European series. Mortality was lower than that in similar studies., (Copyright: © 2020 Permanyer.)

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) >95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene ( LDLR, APOB, PCSK9 , or ApoE ), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Nevertheless, an important proportion of serious HC cases, denominated polygenic hypercholesterolemia (PH), may be attributed to the small additive effect of a number of single nucleotide variants (SNVs), located along the whole genome. The diagnosis, prevalence, and cardiovascular risk associated with PH has not been fully established at the moment. Cascade screening to detect a specific genetic defect is advised in all first- and second-degree relatives of subjects with FH. Conversely, in the rest of cases of HC, it is only advised to screen high values of LDL-C in first-degree relatives since there is not a consensus for the genetic diagnosis of PH. FH is associated with the highest cardiovascular risk, followed by PH and other forms of HC. Early detection and initiation of high-intensity lipid-lowering treatment is proposed in all subjects with severe HC for the primary prevention of ASCVD, with an objective of LDL-C <100 mg/dl or a decrease of at least 50%. A more aggressive reduction in LDL-C is necessary in HC subjects who associate personal history of ASCVD or other cardiovascular risk factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Jarauta, Bea-Sanz, Marco-Benedi and Lamiquiz-Moneo.)

Background: Vector-borne diseases are a public health problem in Colombia, where dengue virus infection is hyperendemic. The introduction of other arboviruses, such as chikungunya and Zika in the last three years, has aggravated the situation. Mobile health (mHealth) offers new strategies for strengthening health care and surveillance systems promoting the collection, delivery, and access of health information to professionals, researchers, and patients. Assessing mobile application performance has been a challenge in low- and middle-income countries due to the difficulty of implementing these technologies in different clinical settings. In this study, we evaluate the usability and acceptability of a mobile application, FeverDX, as a support tool in the management of patients with febrile syndrome and suspected arboviruses infection by general practitioners from Colombia., Methods: A pilot implementation study was conducted to evaluate the usability and acceptability of FeverDX using the modified version of the Mobile Application Rating Scale (uMARS). The evaluation form included 25 questions regarding quantity and quality of information, engagement, functionality, aesthetics, impact, and acceptability by healthcare workers. Each item uses a 5-point scale (1-Inadequate, 2-Poor, 3-Acceptable, 4-Good, 5-Excellent). A global score was obtained for the evaluation form test by determining the median scores of each subsection. A descriptive statistical analysis of the data obtained was performed., Results: Between December 2016 and January 2017, a total of 20 general practitioners from the Emergency room and hospitalization areas evaluated FeverDX. Less than half (9/20) of the evaluators had a comprehensive knowledge of the Colombian Ministry of Health's guidelines for the diagnosis and management of arboviruses, and evaluators partially (4/9) or completely (5/9) agreed that the content of the application follows the management guidelines. On uMARS scale, FeverDX excelled regarding impact (median 5; IQR = 5-5), functionality (median 5; IQR = 4.8-5), and information and scientific basis (median 4; IQR = 4-4). FeverDX scored well regarding user feedback (median 4; IQR = 4-4.5), design and aesthetics (median 4; IQR = 4-4.3), and subjective assessment of quality (median 4.5; IQR = 4.3-4.8)., Conclusions: FeverDX, a mobile application, is a novel mHealth strategy to strengthen care processes and facilitate the detection and reporting of notifiable surveillance diseases. It could improve adherence to clinical practice guidelines for the management and prevention of prevalent diseases as arboviruses in healthcare settings. Although this pilot study used a small sample size, FeverDx performed adequately in a simulated emergency consultation. Further implementation studies are needed to increase the reliability of mHealth technologies in different scenarios., Competing Interests: The authors have declared that no competing interests exist.

Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design., Competing Interests: ND, AA, OS, EC, JP, MR, AS, LA, FR No competing interests declared, EW, DC, FZ, SE, SQ, KM, LG Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019, MF, ED Employee of Integral Molecular, BD Employee and shareholder of Integral Molecular, (© 2019, Durham et al.)

Dengue fever is the most prevalent arbovirus infection among humans, and tropical regions are hyperendemic for this infection. The number of solid organ transplant recipients is continuously increasing, and there are few data regarding the clinical course and outcomes of dengue infection among this population. We report on a retrospective case series of solid organ transplant recipients with dengue virus infection from 2001 to 2018 at Fundación Valle del Lili in Cali, Colombia. A total of 20 patients were included. The median age was 50.5 years (interquartile range [IQR] = 31-63.5 years) and 65% were female. Regarding the clinical course, 75% of patients had at least one warning sign, 45% were managed in the intensive care unit, and 30% had severe dengue. The median of time from transplant and dengue infection was 27.6 months (IQR = 3.82-59.12 months), and three patients had the disease in the first month after the transplant. All patients were discharged, and none of them had graft rejection. Dengue is an endemic disease in our region and represents a threat among solid organ transplantation recipients. All patients had a full recovery after the infection, suggesting that timely and effective management of patients and the access to high-complexity services could prevent fatal cases.

Introduction: Aeromonas species are renowned enteric pathogens with virulence determinants linked to human diseases, such as gastroenteritis, skin, soft-tissue and muscle infections, and septicemia. A recent concern of resistance in this organism has emerged, especially the presence carbapenemases. Herein we describe a case series of emerging carbapenem-resistant Aeromonas species infection in our hospital in Cali, Colombia., Materials and Methods: Cases from 2012 to 2018 are reported. Clinical data was abstracted from the clinical charts and laboratory information. Phenotypic detection of resistance was identified using the VITEK®2 system (BioMérieux) and broth microdilution MicroScan WalkAway plus System (Beckman Coulter). CARBA NP-test and multiplex qPCR assay was performed in 11 isolates to identify genes encoding carbapenemases (bla KPC, bla VIM, bla IMP and bla NDM )., Results: 21 cases of Aeromonas infection in hospitalized patients with phenotypic resistance to carbapenems were studied. The median age was 50 years, 55% (12/21) were male, and 67% (14/21) were healthcare-associated infections (HAI). Aeromonas hydrophila was the most common species (19/21). Forty-three percent (9/21) of the patients were immunocompromised. The mortality was 33% (7/21), and in patients with bacteremia was 100%. Most patients received empirical treatment with meropenem and failed to this treatment. PCR amplification tests showed negative results for the carbapenemases analyzed., Conclusion: Emerging phenotypic carbapenem-resistant infection has been seen in our hospital, most as HAI. High mortality was found, especially in immunocompromised patients and in those who failled empirical treatment with carbapenems. As the main carbapenemases tested were negative, carbapenem-resistant could be attributed to an intrinsic metallo-β-lactamase, CphA encoded by the cphA gene, possible hyperproduction of ampC β-lactamase and/or porins expression., (Copyright © 2019 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

There is a need to identify biomarkers predictive of severe dengue. Single-cohort transcriptomics has not yielded generalizable results or parsimonious, predictive gene sets. We analyzed blood samples of dengue patients from seven gene expression datasets (446 samples, five countries) using an integrated multi-cohort analysis framework and identified a 20-gene set that predicts progression to severe dengue. We validated the predictive power of this 20-gene set in three retrospective dengue datasets (84 samples, three countries) and a prospective Colombia cohort (34 patients), with an area under the receiver operating characteristic curve of 0.89, 100% sensitivity, and 76% specificity. The 20-gene dengue severity scores declined during the disease course, suggesting an infection-triggered host response. This 20-gene set is strongly associated with the progression to severe dengue and represents a predictive signature, generalizable across ages, host genetic factors, and virus strains, with potential implications for the development of a host response-based dengue prognostic assay., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The Autonomous Community of Madrid procures the largest number of organs from uncontrolled non-heart-beating donors (NHBD) after circulatory death in Spain. The aim of this study was to analyze the yield of these donations in terms of viable organs procured (category IIa) according to information extracted from the CORE registry of the Spanish National Transplant Organization (ONT) for the Madrid area., Methods: Retrospective observational study of NHBD data registered between 2007 and 2017, including age, height, weight, body mass index (BMI), emergency care times, method of chest compressions applied (mechanical cardiopump vs manual compressions), and viable organs extracted., Results: A total of 679 circulatory death donors were registered; 458 (67.6%) of them were utilized donors. The median BMI correlated negatively (-0.161) with the number of viable organs extracted (P<.001). The method of applying chest compressions significantly influenced liver viability: only those extracted after mechanical cardiopump compressions were viable for transplantation. Type of compressions did not effect kidney or lung viability., Conclusion: Variables to bear in mind as predictors of success in NHBD donation are BMI and type of chest compressions applied.

Dengue virus (DENV) infection can result in severe complications. However, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that contain DENV RNA in vivo. Accordingly, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here, we applied virus-inclusive single-cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls and to characterize distinct leukocyte subtypes that harbor viral RNA (vRNA). Multiple IFN response genes, particularly MX2 in naive B cells and CD163 in CD14 + CD16 + monocytes, were up-regulated in a cell-specific manner before progression to SD. The majority of vRNA-containing cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and various antiviral genes, followed by monocytes. Bystander, non-vRNA-containing B cells also demonstrated immune activation, and IgG1 plasmablasts from two patients exhibited clonal expansions. Lastly, assembly of the DENV genome sequence revealed diversity at unexpected sites. This study presents a multifaceted molecular elucidation of natural dengue infection in humans with implications for any tissue and viral infection and proposes candidate biomarkers for prediction of SD., Competing Interests: Conflict of interest statement: F.Z., M.L.R., D.C., L.G., S.R.Q., and S.E. have filed US Provisional Application No. 62/715,628 related to this manuscript. S.R.Q. and A.K.S. are coauthors on a 2017 review article., (Copyright © 2018 the Author(s). Published by PNAS.)

Dengue fever is a vector-transmitted viral infection. Non-vectorial forms of transmission can occur through organ transplantation. We reviewed medical records of donors and recipients with suspected dengue in the first post-transplant week. We used serologic and molecular analysis to confirm the infection. Herein, we describe four cases of dengue virus transmission through solid organ transplantation. The recipients had positive serology and RT-PCR. Infection in donors was detected through serology. All cases presented with fever within the first week after transplantation. There were no fatal cases. After these cases, we implemented dengue screening with NS1 antigen detection in donors during dengue outbreaks, and no new cases were detected. In the literature review, additional cases had been published through August 2017. Transmission of Dengue virus can occur through organ donation. In endemic regions, it is important to suspect and screen for dengue in febrile and thrombocytopenic recipients in the postoperative period., (Copyright © 2018 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.)

Unlabelled: Pseudomonas syringae pv. phaseolicola, the causative agent of halo blight in common bean (Phaseolus vulgaris L.), was isolated from weeds associated with bean crops in Spain. The bacterium was recovered from Fumaria sp, Mercurialis annua, Solanum nigrum and Sonchus oleraceus. Ps. s. pv. phaseolicola had previously been isolated from leguminous plants and S. nigrum, but to our knowledge, this is the first time it was recovered from the other three species. The isolates were phenotypically and genetically characterized, and they were compared with isolates recovered from common beans. Five different genotypic profiles were detected by PmeI-PFGE, two of them being of new description. Weed isolates were as pathogenic on bean plants as bean isolates, but they were not pathogenic on S. nigrum. Regarding the survival of the pathogen in weeds, Ps. s. pv. phaseolicola was isolated from So. oleraceus 11 weeks after the end of the bean crop. These results strongly support the idea of weeds as a potential source of inoculum for halo blight in bean., Significance and Impact of the Study: It has traditionally been considered that the main source of inoculum of Pseudomonas syringae pv. phaseolicola causing halo blight disease in Phaseolus vulgaris are the bean seeds, and that the host range of the bacterium is almost restricted to leguminous plants. In this study, the bacterium was recovered from four nonleguminous weed species collected in bean fields, and its permanence in weeds for at least 11 weeks after the harvesting of the beans was demonstrated. We have also proved that the strains isolated from weeds were pathogenic on bean plants. Accordingly, the host range of Ps. s. pv. phaseolicola could be broader than previously thought and weeds appear to be acting as a reservoir of the pathogen until the next crop., (© 2016 The Society for Applied Microbiology.)

Background: The Godelieve Denys-Struyf method (GDS) is a motor learning intervention that may be applied in group or individualized sessions., Objective: The study objective was to compare the effectiveness of routine physical therapy, group GDS (GDS-G) sessions, and group and individualized GDS (GDS-I) sessions., Design: This was a cluster randomized controlled trial., Setting: The study took place in 21 primary care physical therapy units ("clusters") of the Spanish National Health Service (SNHS)., Participants: The participants were 461 people with subacute and chronic low back pain (LBP)., Intervention: Clusters were randomized into 3 groups. All participants received medical treatment and a 15-minute group education session on active management. Additional interventions were as follows: control (fifteen 40-minute sessions of transcutaneous electrical nerve stimulation, microwave treatment, and standardized exercises), GDS-G (eleven 50-minute group GDS sessions), and GDS-I (the same 11 sessions plus four 50-minute individualized GDS sessions)., Measurements: Primary outcomes at baseline and 2, 6, and 12 months later were LBP and pain referred down the leg (separate pain intensity numeric rating scales) and disability (Roland-Morris Questionnaire [RMQ]). Secondary outcomes were use of medication and self-reported health (mental and physical component summaries of the 12-Item Short-Form Health Survey [SF-12]). Separate linear mixed models for LBP, pain referred down the leg, and disability were developed to adjust for potential confounders. Randomization, outcome assessment, and data analyses were masked., Results: At 12 months, disability improved 0.7 (95% confidence interval [CI]=-0.4, 1.8) RMQ point in the control group, 1.5 (95% CI=0.4, 2.7) RMQ points in the GDS-I group, and 2.2 (95% CI=1.2, 3.2) RMQ points in the GDS-G group. There were no differences in pain., Limitations: The amount of exercise was smaller in the control group, and GDS-I sessions were provided by junior physical therapists., Conclusions: The improvement in disability was slightly higher with group GDS sessions than with the program routinely used in clusters within the SNHS. Adding individualized GDS sessions eliminated this advantage. Further studies should compare the GDS with other types of exercise., (© 2015 American Physical Therapy Association.)

Five strains of gram negative bacteria, isolated from soybean (LPPA 221(T), 222 and 223) and weeds (LPPA 816 and 1442), were analyzed by a polyphasic approach. The isolates showed variation in their phenotypic traits and were placed in the Pseudomonas fluorescens lineage, based on 16S rRNA gene sequence phylogeny, as a single but well separated cluster. MLSA analysis based on gyrB and rpoD sequences clustered the strains in a single branch in the Pseudomonas syringae group, and revealed P. viridiflava as closest relative. DNA-DNA hybridizations showed medium levels of DNA-DNA relatedness with the type strain of P. viridiflava (50%) and lower levels (<32%) with other type strains of the P. syringae group, supporting classification within a novel species of the genus Pseudomonas. The strains can be distinguished from species of the P. syringae group by the fatty acid C17:0 cyclo that is present in a low amount (2.5%) and from P. viridiflava by their inability to assimilate d-tartrate and d-sorbitol, and by the formation of red colonies on TTC medium. For this new species, the name Pseudomonas asturiensis sp. nov. is proposed. The type strain is LPPA 221(T) (=LMG 26898(T)=CECT 8095(T))., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Although the reduction and prevalence of dental caries in many countries has been largely associated with the use of fluorine and improving dental hygiene, eating habits also play a role in the development of caries. Fermentable carbohydrates characteristics of the food, rate of consumption, food protectors, the quality and quantity of saliva indices that determine the remineralization of teeth are factors to be considered. All these elements are analyzed through the sociodemographic, behavioral, physical and biological environment directly or indirectly with diet and caries., (Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.)

A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.

The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.

The synthesis and trypanosomatic behavior of a new series of 1,4-bis(alkylamino)benzo[g]phthalazines 1- 4 containing the biologically significant imidazole ring are reported. In vitro antiparasitic activity against Trypanosoma cruzi epimastigotes is remarkable, especially for compound 2, whereas toxicity against Vero cells is very low. Conversion of epimastigotes to metacyclic forms in the presence of the tested compounds causes significant decreases in the amastigote and trypomastigote numbers. Fe-SOD inhibition is noteworthy, whereas effect on human Cu/Zn-SOD is negligible.

Twelve different Ty1-copia and Ty3-gypsy group LTR retrotransposons were compared for their usefulness in SSAP marker development in two agriculturally important Vicia species. Three of the retrotransposons, PDR1, Tps19 and Tvf4, yielded useful SSAP marker systems in V. faba, and V. narbonensis. Another, Tvf1 was a good source of SSAP markers in V. narbonensis alone. The optimized SSAP marker systems were applied to the analysis of two diverse Vicia germplasm sets. Two hundred and two polymorphic Tvf1 SSAP markers were scored in 56 V. narbonensis samples and 196 polymorphic markers derived from the other three most useful retrotransposons were scored in a collection of 20 V. faba samples. The marker data were then used to construct phylogenetic trees. The trees for both species tend to show long-branch lengths, with rather little fine structure. Some V. narbonensis accessions cluster by geographical origin but many do not and a given geographical region is often represented by multiple diverse groups in the tree, suggesting a deep and ancient structure for the diversity of V. narbonensis that spans its current geographic range. The tree for the V. faba accessions also shows very limited clustering with geographical origin and no obvious correlation between diversity and morphology-based taxonomic groupings for the species.

The synthesis of a new series of 1,4-bis(alkylamino)benzo[g]phthalazines 1-3 is reported, and their ability to form dinuclear complexes with Cu(II) assayed. The geometry of the complexes is dependent on the nature of the electron-donor sites at the sidechains. Compounds 1 and 2, that contain sp3 or sp2 nitrogens at the end of the alkylamino groups, originate monopodal dinuclear complexes which seem to include endogenous OH bridges, and the sidechains seem to actively participate in complexation. However, the substitution of nitrogen by oxygen in 3 leads to a tripodal dinuclear complex in which the sidechains are not involved. The in vitro antiparasitic activity on Trypanosoma cruzi epimastigotes and amastigotes and the SOD activity inhibition have been evaluated for compounds 1-3, and, as expected, 1 and 2 show in all cases relevant results, whereas 3 is always the less active among the three substrates tested.

The synthesis of a new series of mono- and dinuclear 1-alkylamino-4-chlorobenzo[g]phthalazine derivatives 7-10 containing flexible polyaminic chains is reported. It has been achieved by the reaction of 1,4-dichlorobenzo[g]phthalazine with the corresponding polyamines. In vitro antitumoral activity against HT-29 human colon carcinoma cells was evaluated and showed best results for compound 10, in which two heteroaromatic units are linked by a N-methylsubstituted polyaminic chain. Molecular modelling of the complexes of 9 and 10 with DNA strongly suggests the possibility of bisintercalation, and also that the N-methyl group of 10 plays an important role in the formation of a specially stable DNA complex.

In the present paper, we report the synthesis and the binding profile on 5-HT1A, alpha1 and D2 receptors of a new series of 1-[omega-(4-arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene)- 2, 5-pyrrolidinediones (III) (1-4) and -3-(9H-fluoren-9-ylidene)-2, 5-pyrrolidinediones (IV) (1-4), in which the alkyl linker contains 1-4 methylenes and the aryl group is variously substituted. The results obtained are compared to those previously reported for bicyclohydantoin (I) and the related bicyclic amine (II) series. A considerable part of the tested compounds 1-4 demonstrated moderate to high affinity for 5-HT1A and alpha1 receptor binding sites but had no affinity for D2 receptors. The study of the length of the alkyl chain and the imide substructure has allowed us to suggest some differences between the 5-HT1A and the alpha1-adrenergic receptors: (i) for III and IV, affinity for the 5-HT1A receptor as a function of the length of the methylene linker decreases in the order 4 > 1 >> 3 approximately 2, while for the alpha1 receptor affinity decreases in the order 3 approximately 4 > 1 approximately 2; (ii) the no-pharmacophoric steric pocket (receptor zone which does not hold the pharmacophore of the ligand but holds a nonessential fragment of the molecule) in the 5-HT1A receptor has less restriction than the corresponding pocket in the alpha1 receptor. Compounds 3a,e, which are highly selective for alpha1-adrenergic receptors, displayed antagonist activity. On the other hand, the best compromise between affinity and selectivity for 5-HT1A receptors is reached in these new series with n = 1, which is in agreement with our previous results for the bicyclohydantoin derivatives I. Two selected compounds (1d and 4e) retain agonist properties at postsynaptic 5-HT1A receptors. The same 5-HT1A agonist profile found in these compounds suggests the existence of two different no-pharmacophoric steric pockets in this receptor and a different interaction of compounds with n = 1 and n = 4. The information obtained from the interpretation of the energy minimization and 2D-NOESY experiments of compounds 1-4 together with the synthesis and binding data of new conformationally restrained analogues 4k-m is in good agreement with this working hypothesis.

In the present paper, we report the synthesis and the binding profile on 5-HT1A, alpha 1 and D2 receptors of a new series of imide-arylpiperazines 3. The study of the length of the alkyl chain and the imide substructure allows us to suggest some important differences between the no-pharmacophoric sites of both 5-HT1A and alpha 1-adrenergic receptors, which could be of great importance in order to design new selective ligands.

A series of new arylpiperazine derivatives 2, which are devoid of the terminal amide fragment present in related 5-HT1A ligands, was prepared and evaluated for affinity at 5-HT1A and alpha 1 receptors. All the compounds 2 demonstrated high affinity for the 5-HT1A receptor and moderate affinity for alpha 1 receptor binding sites. Structure-activity relationship (SAR) studies suggest that there is influence of electronic factors on the no-pharmacophoric part of the alpha 1 receptor site. However there is no influence of electronic interactions on the stabilization of the 5-HT1A receptor-ligand complex.

A series of new bicyclohydantoin-arylpiperazines was prepared and evaluated for affinity at 5-HT1A, alpha 1, and D2 receptors. Most of the compounds showed very low affinity for D2 receptors, and most of them demonstrated moderate to high affinity for 5-HT1A and alpha 1 receptor binding sites. SAR observations indicated that the length of the alkyl chain between the arylpiperazine and the hydantoin moiety is of great importance for 5-HT1A/alpha 1 affinity and selectivity, n = 1 being the optimal value. Compound 1h, 2-[[4-(o-methoxyphenyl)piperazin-1-yl] methyl]-1,3-dioxoperhydroimidazo [1,5-alpha]pyridine, bound at 5-HT1A sites with nanomolar affinity (Ki = 31.7 nM) and high selectivity over alpha 1, D2, and 5-HT2A receptors (Ki > 1000, > 10 000, and > 1000 nM, respectively). Preliminary studies showed that this agent is probably functioning as a partial to full 5-HT1A agonist, and it displayed anxiolytic activity on the social interaction test in mice.

Female rats weighing about 180 g were separated into two groups. One group (A) received phenylhydrazine (PHZ) every other day during three weeks (for induction of an uncompensated hemolytic state), while the control group (C) received saline. The evidence for the establishment of the uncompensated hemolytic state was obtained by hematocrit value, reticulocyte count, and red-cell-volume-59Fe uptake. Body-weight gain (which is a measure of overall body growth rate), body-length gain (which is a measure of longitudinal skeletal growth rate), food intake, and maxillary incisor eruption rate (ER) were significantly depressed in rats of group A during the PHZ-injection period, in relation to rats of group C. These results indicate that anemia and/or associated factors depress ER, along with body growth and skeletal growth.