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A series of stilbene analogues, in which a phenyl ring was replaced by the pyridazin-3(2H)-one nucleus, was designed and synthesized to be explored as platelet aggregation inhibitors. The proposed stilbene-pyridazinone hybrids were successfully obtained from simple starting materials and by Wittig's reaction. Most of the target compounds displayed improved in vitro activity in comparison with the standard drug, resveratrol, highlighting as the most potent the analogues 10d and 10e, with inhibition percentages of 94.15 % at 100 µM and 100 % at 50 µM, respectively. The pharmacokinetic and toxicity (ADME/T) properties of the novel hybrids were also estimated with the SwissADME and ProTox-II web servers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Integrated long-term, in-situ observations are needed to document ongoing environmental change, to "ground-truth" remote sensing and model outputs and to predict future Earth system behaviour. The scientific and societal value of in-situ observations increases with site representativeness, temporal duration, number of parameters measured and comparability within and across sites. Research Infrastructures (RIs) can support harmonised, cross-site data collection, curation and publication. Integrating RI networks through site co-location and standardised observation methods can help answers three questions about the terrestrial carbon sink: (i) What are present and future carbon sequestration rates in northern European forests? (ii) How are these rates controlled? (iii) Why do the observed patterns exist? Here, we present a conceptual model for RI co-location and highlight potential insights into the terrestrial carbon sink achievable when long-term in-situ Earth observation sites participate in multiple RI networks (e.g., ICOS and eLTER). Finally, we offer recommendations to promote RI co-location., (© 2023. The Author(s).)

Background: Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30-64 years participating in the ESTAMPA study., Methods: Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated., Findings: 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0-53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3-96.7). Specificity was 96.5% (95% CI: 96.3-96.7) using cytology and 88.7% (95% CI: 88.3-89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%-100% and 83.6-90.8%, respectively)., Interpretation: The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America., Funding: IARC/WHO, UNDP, HRP/WHO, NCI and local funders., Competing Interests: All other authors declare no competing interests., (© 2023 Published by Elsevier Ltd.)

Eucalyptus snout beetles are a complex of at least eight cryptic species (Curculionidae: Gonipterus scutellatus complex), native to mainland Australia and Tasmania, that defoliate Eucalyptus trees and are considered important pests. Since the 19th century, three species of the complex have been introduced to other continents. Here, we document the presence of Eucalyptus snout beetles in Ecuador. We used DNA data for species identification and unambiguously demonstrated that the Ecuadorian specimens belong to the species Gonipterus platensis , which has low genetic diversity compared with other species in the complex. We analyzed G. platensis ' potential distribution in South America with ecological niche models and found several areas of high to intermediate climatic suitability, even in countries where the pest has not been registered, like Peru and Bolivia. Accurate identification of species in the G. scutellatus complex and understanding of their potential distribution are essential tools for improved management and prevention tactics., Competing Interests: The authors have declared that no competing interests exist., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

VIA is recommended for triage of HPV-positive women attending cervical screening. In the multicentric ESTAMPA study, VIA performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV-positive women was evaluated. Women aged 30-64 years were screened with HPV testing and cytology and referred to colposcopy if either test was positive. At colposcopy visit, study-trained midwives/nurses/GPs performed VIA ahead of colposcopy. VIA was considered positive if acetowhite lesions were observed in or close to the transformation zone. Ablative treatment eligibility was assessed for VIA positives. Performance indicators were estimated. Three thousand one hundred and forty-two HPV-positive women were included. Sensitivity for CIN3+ was 85.9% (95% CI 81.2-89.5) among women <50 years and, although not significant, slightly lower in women 50+ (78.0%, 95% CI 65.9-86.6). Overall specificity was 58.6% (95% CI 56.7-60.5) and was significantly higher among women 50+ (70.3%, 95% CI 66.8-73.5) compared to women <50 (54.3%, 95% CI 52.1-56.5). VIA positivity was lower among women 50+ (35.2%, 95% CI 31.9-38.6) compared to women <50 (53.2, 95% CI 51.1-55.2). Overall eligibility for ablative treatment was 74.5% and did not differ by age. VIA sensitivity, specificity, and positivity, and ablative treatment eligibility varied highly by provider (ranges: 25%-95.4%, 44.9%-94.4%, 8.2%-65.3%, 0%-98.7%, respectively). VIA sensitivity for cervical precancer detection among HPV-positive women performed by trained providers was high with an important reduction in referral rates. However, scaling-up HPV screening triaged by VIA will be challenging due to the high variability of VIA performance and providers' need for training and supervision., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Dental anterior fractures are common injuries, especially in those who practice extreme sports. This report describes a 25-year-old Bolivian patient who attended our private dental clinic in La Paz, Bolivia after experiencing an accident during downhill mountain biking. An intraoral examination revealed a fracture line on the buccal side in the middle third of the coronal portion of the right central maxillary incisor which extended towards the proximal and lingual sides. Multidisciplinary treatment, including crown lengthening, osteotomy, root canal treatment, fiberglass post insertion, and reattachment of the fracture segment was performed. A follow-up examination at 10 months later revealed that the tooth was completely reestablished both functionally and esthetically and that there was no periapical pathosis or discomfort. This outcome suggests that if a patient seeks a dental consultation soon after a complex crown-root fracture has occurred, and if the broken tooth segment is available, then reattachment offers an economical and simple treatment option which will allow immediate restoration of functionality and esthetic standards. Continued follow-up should form part of such a treatment plan to allow long-term pulp vitality and periodontal health status to be monitored.

Background: Colposcopy, currently included in WHO recommendations as an option to triage human papillomavirus (HPV)-positive women, remains as the reference standard to guide both biopsy for confirmation of cervical precancer and cancer and treatment approaches. We aim to evaluate the performance of colposcopy to detect cervical precancer and cancer for triage in HPV-positive women., Methods: This cross-sectional, multicentric screening study was conducted at 12 centres (including primary and secondary care centres, hospitals, laboratories, and universities) in Latin America (Argentina, Bolivia, Colombia, Costa Rica, Honduras, Mexico, Paraguay, Peru, and Uruguay). Eligible women were aged 30-64 years, sexually active, did not have a history of cervical cancer or treatment for cervical precancer or a hysterectomy, and were not planning to move outside of the study area. Women were screened with HPV DNA testing and cytology. HPV-positive women were referred to colposcopy using a standardised protocol, including biopsy collection of observed lesions, endocervical sampling for transformation zone (TZ) type 3, and treatment as needed. Women with initial normal colposcopy or no high-grade cervical lesions on histology (less than cervical intraepithelial neoplasia [CIN] grade 2) were recalled after 18 months for another HPV test to complete disease ascertainment; HPV-positive women were referred for a second colposcopy with biopsy and treatment as needed. Diagnostic accuracy of colposcopy was assessed by considering a positive test result when the colposcopic impression at the initial colposcopy was positive minor, positive major, or suspected cancer, and was considered negative otherwise. The main study outcome was histologically confirmed CIN3+ (defined as grade 3 or worse) detected at the initial visit or 18-month visit., Findings: Between Dec 12, 2012, and Dec 3, 2021, 42 502 women were recruited, and 5985 (14·1%) tested positive for HPV. 4499 participants with complete disease ascertainment and follow-up were included in the analysis, with a median age of 40·6 years (IQR 34·7-49·9). CIN3+ was detected in 669 (14·9%) of 4499 women at the initial visit or 18-month visit (3530 [78·5%] negative or CIN1, 300 [6·7%] CIN2, 616 [13·7%] CIN3, and 53 [1·2%] cancers). Sensitivity was 91·2% (95% CI 88·9-93·2) for CIN3+, whereas specificity was 50·1% (48·5-51·8) for less than CIN2 and 47·1% (45·5-48·7) for less than CIN3. Sensitivity for CIN3+ significantly decreased in older women (93·5% [95% CI 91·3-95·3] in those aged 30-49 years vs 77·6% [68·6-85·0] in those aged 50-65 years; p<0·0001), whereas specificity for less than CIN2 significantly increased (45·7% [43·8-47·6] vs 61·8% [58·7-64·8]; p<0·0001). Sensitivity for CIN3+ was also significantly lower in women with negative cytology than in those with abnormal cytology (p<0·0001)., Interpretation: Colposcopy is accurate for CIN3+ detection in HPV-positive women. These results reflect ESTAMPA efforts in an 18-month follow-up strategy to maximise disease detection with an internationally validated clinical management protocol and regular training, including quality improvement practices. We showed that colposcopy can be optimised with proper standardisation to be used as triage in HPV-positive women., Funding: WHO; Pan American Health Organization; Union for International Cancer Control; National Cancer Institute (NCI); NCI Center for Global Health; National Agency for the Promotion of Research, Technological Development, and Innovation; NCI of Argentina and Colombia; Caja Costarricense de Seguro Social; National Council for Science and Technology of Paraguay; International Agency for Research on Cancer; and all local collaborative institutions., Competing Interests: Declaration of interests GV reports conference fees from Roche. GIS reports provision of reagents from Roche. CP reports royalties and conferences fees from Roche, MSD, Seegene, Abbot, and Exeltis. TMD reports grants from the US National Cancer Institute, consulting fees from Antiva, and participation on an advisory board for Roche. All other authors declare no competing interests., (© 2023 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Objectives: To assess the effect of hydroxychloroquine (HCQ) and Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis on COVID-19 risk., Methods: EPICOS is a double-blind, placebo-controlled randomized trial conducted in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to the following: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo, and TDF/FTC placebo plus HCQ placebo. Randomization was performed in groups of four. Primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19. We compared group-specific 14-week risks via differences and ratios with 95% CIs., Results: Of 1002 individuals screened, 926 (92.4%) were eligible and there were 14 cases of symptomatic COVID-19: 220 were assigned to the TDF/FTC plus HCQ group (3 cases), 231 to the TDF/FTC placebo plus HCQ group (3 cases), 233 to the TDF/FTC plus HCQ placebo group (3 cases), and 223 to the double placebo group (5 cases). Compared with the double placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00-1.98) for TDF + HCQ, 0.34 (0.00-2.06) for TDF, and 0.49 (0.00-2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21-1.00) for TDF + HCQ, 0.81 (0.44-1.49) for TDF, and 0.73 (0.41-1.38) for HCQ. Adverse events were generally mild., Discussion: The target sample size was not met. Our findings are compatible with both benefit and harm of pre-exposure prophylaxis with TDF/FTC and HCQ, alone or in combination, compared with placebo., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Many patients with major depressive disorder (MDD) remain untreated or do not respond to cognitive behavioral therapy (CBT). Physical exercise shows antidepressive effects and may serve as an effective augmentation treatment. However, research on combining exercise with CBT is sparse in MDD and underlying mechanisms of exercise are not well understood to date., Methods: 120 outpatients with MDD were randomized to either a high intensity exercise group (HEX), a low intensity exercise group (LEX), or a waiting list control group (WL). After 12 weeks of exercise training or waiting period, all patients received a manualized CBT., Results: Seventy-five patients with MDD completed both the exercise program/ waiting period and the CBT. While physical fitness improved in HEX after the exercise program, it did not change in LEX and WL. Depressive symptoms improved in all three groups from baseline to post-CBT and the group by time interaction was not significant. Regression analyses revealed that the amount of fitness improvement during exercise predicted the subsequent CBT response., Limitations: The dropout rate was relatively high, preparatory CBT sessions during exercise / waiting period may have influenced depressive symptoms, and no patients with severe MDD were included., Conclusions: High intense physical exercise did not lead to a general enhancement of CBT outcome, but higher increases in physical fitness seem to improve symptom change during CBT. Our results suggest that the implementation of more individually tailored exercise programs could be a promising approach for future research and clinical practice., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6 - 8 , which display the dithiocarbamate scaffold at N2, and compounds 9 , in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H 3 PO 4 , and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6 - 8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e , 8e , 6g , 9a - b , 9d , and 9g with IC 50 values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.

Background: Replacement of cytology screening with HPV testing is recommended and essential for cervical cancer elimination. HPV testing for primary screening was implemented in 12 laboratories within 9 Latin American countries, as part of the ESTAMPA cervical cancer screening study. Our observations provide information on critical operational aspects for HPV testing implementation in diverse resource settings., Methods: We describe the implementation process of HPV testing in ESTAMPA, focusing on laboratory aspects. We assess the readiness of 12 laboratories to start HPV testing and their continuity capacity to maintain good quality HPV testing until end of recruitment or up to December 2021. Readiness was based on a checklist. Information from the study database; regular meetings and monitoring visits; and a questionnaire on laboratory operational aspects sent in May 2020 were used to assess continuity capacity . Compliance with seven basic requirements (readiness) and eight continuity requirements (continuity capacity) was scored (1 = compliant, 0 = not compliant) and totaled to classify readiness and continuity capacity as very limited, limited, moderate or high. Experiences, challenges, and enablers of the implementation process are also described., Results: Seven of 12 laboratories had high readiness , three moderate readiness , and of two laboratories new to HPV testing, one had limited readiness and the other very limited readiness . Two of seven laboratories with high readiness also showed high continuity capacity , one moderate continuity capacity , and the other four showed limited continuity capacity since they could not maintain good quality HPV testing over time. Among three laboratories with moderate readiness , one kept moderate continuity capacity and two reached high continuity capacity. The two laboratories new to HPV testing achieved high continuity capacity . Based on gained expertise, five laboratories have become part of national screening programs., Conclusion: High readiness of laboratories is an essential part of effective implementation of HPV testing. However, high readiness is insufficient to guarantee HPV testing high continuity capacity , for which a "culture of quality" should be established with regular training, robust monitoring and quality assurance systems tailored to local context. All efforts to strengthen HPV laboratories are valuable and crucial to guarantee effective implementation of HPV-based cervical screening., Competing Interests: Author MH was employed by SMS-Oncology, Amsterdam, Netherlands. Author FD was employed by Laboratorio de Patología Oncológica, SAC, Peru. The remaining 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 © 2022 Rol, Picconi, Ferrera, Sánchez, Hernández, Lineros, Peraza, Brizuela, Mendoza, Mongelós, Cabrera, Rodríguez de la Peña, Correa, Terán, Colque Reynaga, García, Ramírez, Hernández-Nevarez, Doimi, Ramón, Arias-Stella, Zúñiga, Villagra, Bobadilla, Cardinal, Valls, Lucas, Baena, Fleider, Venegas, Cruz-Valdez, Rodríguez, Calderón, Wiesner, Luciani, Broutet, Herrero and Almonte.)

Novel aryl guanidinium analogues containing the pyridazin-3(2 H )-one core were proposed as minor groove binders (MGBs) with the support of molecular docking studies. The target dicationic or monocationic compounds, which show the guanidium group at different positions of the pyridazinone moiety, were synthesized using the corresponding silyl-protected pyridazinones as key intermediates. Pyridazinone scaffolds were converted into the adequate bromoalkyl derivatives, which by reaction with N , N '-di-Boc-protected guanidine followed by acid hydrolysis provided the hydrochloride salts 1 - 14 in good yields. The ability of new pyridazin-3(2 H )-one-based guanidines as DNA binders was studied by means of DNA UV-thermal denaturation experiments. Their antiproliferative activity was also explored in three cancer cell lines (NCI-H460, A2780, and MCF-7). Compounds 1 - 4 with a bis-guanidinium structure display a weak DNA binding affinity and exhibit a reasonable cellular viability inhibition percentage in the three cancer cell lines studied., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.

Wildlife animals have been affected by human activities and the diminution of the areas needed to develop wildlife. In Colombia, artisanal and industrial mining focuses on gold extraction, which uses mercury and causes contamination in water sources. Bats may be susceptible to chemical contamination and primarily to bioaccumulated heavy metal contaminants in the food chain. The primary source of exposure is contaminated food and water ingest, followed by dermic exposition and inhalation. The objective was to evaluategenotoxic damage and mercury concentration in bats. Forty-five samples of blood and organs of bats captured in Ayapel and Majagual were collected. Erythrocytes were searched for micronuclei by peripheral blood smear. Mercury concentration in 45 liver and spleen samples was determined by atomic absorption spectroscopy (DMA80 TRICELL, Milestone Inc, Italy). Bats from four families were studied: Phyllostomidae (6 species), Molossidae (3 species), Vespertilionidae (1 species), and Emballonuridae (1 species). Mercury was found in all bat species from the different dietary guilds. Insectivores had the highest concentration of mercury in the liver (0,23 µg/g) and spleen (0,25 µg/g) and the highest number of micronuclei (260 micronuclei/10,000). The specimens captured in Majagual had the highest frequency of micronuclei (677 micronuclei/10,000), and those captured in Ayapel had the highest mercury concentration (0,833 µg/g). This is the first study in Colombia to report that bats could act as sentinels to the environment's genotoxic chemical agents. Mercury and a high frequency of micronuclei were found in the tissues of captured bats. In addition to mercury contamination, there could also be other contaminants affecting Chiroptera., (Copyright © 2021. Published by Elsevier B.V.)

Tetrapod taxa with broad geographic distributions across the Neotropics are often composed of multiple evolutionary lineages. In this paper, we present the most complete phylogeny of Leptophis to date and assess morphology-based species limits within the broadly distributed green parrot snake Leptophis ahaetulla sensu lato, which occurs from Mexico to Argentina. Although L. ahaetulla sensu stricto, L. nigromarginatus and L. occidentalis were recovered as paraphyletic, tree topology tests failed to reject their monophyly. Monophyly of L. bocourti, L. coeruleodorsus, L. cupreus, L. depressirostris, L. marginatus, L. riveti and L. sp. nov. was strongly supported. Our phylogenetic trees support recognition of multiple species within Leptophis ahaetulla sensu lato and suggest that color evolution and the uplift of the Andes played an important role in the diversification of parrot snakes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A novel class of potential MAO-B inhibitors was designed and synthesized in good yield by combining the pyridazinone moiety with the dithiocarbamate framework, two relevant pharmacophores for drug discovery. The biological results obtained for the different pyridazinone/dithiocarbamate hybrids (compounds 8-14) indicated that most of them reversibly and selectively inhibit the hMAO-B in vitro with IC 50 values in the µM range and exhibit not significant cellular toxicity. The analogues 9a 1 , 11a 1 , 12a 2 , 12b 1 and 12b 2 , which present the dithiocarbamate fragment derivatized with a piperidin-1-yl or pyrrolidin-1-yl group and placed at C3 or C4 of the diazine ring, were the most attractive compounds of these series. Molecular modeling studies were performed to analyze the binding mode to the enzyme and the structure activity relationships of the titled compounds, as well as to predict their drug-like properties., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Robotic surgery is a technological advance that is used in multiple surgical specialties in the world. Its acceptance in various areas has been supported by comparative studies with laparoscopic surgery and open surgery., Objective: To document the robotic surgery program initial experience in a private hospital of Mexico City by analyzing its results and complications., Material and Method: The first 500 robotic surgeries practiced at ABC Medical Center were included, covering a three-year period (January 2017 to December 2019). The following was documented: specialties involved, surgeries broken down by specialty and type of surgery, surgical times, complications and number of doctors involved in the initial experience., Results: Out of 500 patients, 367 (73.4 %) were males and 133 (26.4 %) were females. The three most common surgeries were radical prostatectomy (269), hysterectomy (64) and inguinal repair (33). Average age was 58 years (range: 18 to 90 years). A total of 40 certified surgeons from five specialties performed all the procedures., Conclusions: Starting a program in a private medical center has several implications. The creation of a robotic surgery committee made up of certified robotic surgery specialists from each specialty and hospital authorities for the accreditation of guidelines for both certification and recertification of their doctors can benefit programs like ours by creating a center of excellence in robotic surgery and thus reduce complications and improve results., (Copyright: © 2021 Permanyer.)

A new phylogeny for the Pristimantis lacrimosus species group is presented, its species content reviewed, and three new species described from the eastern slopes of the Ecuadorian Andes. Our phylogeny includes, for the first time, samples of P. aureolineatus , P. bromeliaceus , and P. lacrimosus . The morphology of hyperdistal subarticular tubercles is also assessed among 21 species of Pristimantis . The P. lacrimosus species group is composed of 36 species distributed in the Chocó, Guiana, and Amazon regions of tropical South America with a single species reaching Central America. Ancestral area reconstruction indicates that, despite its high diversity in the Amazon region, the P. lacrimosus group originated in the Pacific basin, Chocó region of Ecuador and Colombia. Pristimantis amaguanae sp. nov. is most closely related to P. bromeliaceus . It differs from P. bromeliaceus by being smaller, having transversal dark bands in the hindlimbs (absent or faint in P. bromeliaceus ) and the absence of discoidal fold (present in P. bromeliaceus ). Pristimantis nankints sp. nov. and P. romeroae sp. nov. are part of a clade of predominantly light-green frogs that includes P. acuminatus , P. enigmaticus , P. limoncochensis , and P. omeviridis . Pristimantis nankints sp. nov. and P. romeroae sp. nov. can be distinguished from all of them by the presence of a dark dorsolateral stripe that borders a light green band on a green background. Hyperdistal tubercles are present in all examined species of the P. lacrimosus species group and its sister clade. Species with hyperdistal tubercles are characterized by having relatively long terminal phalanges and narrow T-shaped expansion at the end of the terminal phalange. We discuss the phylogenetic distribution of these characters and their potential diagnostic significance., (Santiago R. Ron, Julio Carrión, Marcel A. Caminer, Yerka Sagredo, María J. Navarrete, Jhael A. Ortega, Andrea Varela-Jaramillo, Gabriela A. Maldonado-Castro, Claudia Terán.)

The 3-pyridazinylcoumarin scaffold was previously reported as an efficient core for the discovery of reversible and selective inhibitors of MAO-B, a validated drug target for PD therapy which also plays an important role in the AD progress. Looking for its structural optimization, novel compounds of hybrid structure coumarin-pyridazine, differing in polarizability and lipophilicity properties, were synthesized and tested against the two MAO isoforms, MAO-A and MAO-B (compounds 17a-f and 18a-f). All the designed compounds selectively inhibited the MAO-B isoenzyme, exhibiting many of them IC 50 values ranging from sub-micromolar to nanomolar grade and lacking neuronal toxicity. The 7-bromo-3-(6-bromopyridazin-3-yl)coumarin (18c), the most potent compound of these series (IC 50  = 60 nM), was subjected to further in vivo studies in a reserpine-induced mouse PD model. The obtained results suggest a promising potential for 18c as antiparkinsonian agent. Molecular modeling studies also provided valuable information about the enzyme-drug interactions and the potential pharmacokinetic profile of the novel compounds., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Chagas disease (CD) is highly endemic in the Bolivian Chaco. The municipality of Monteagudo has been targeted by national interventions as well as by Médecins Sans Frontières to reduce infection rates, and to decentralize early diagnosis and treatment. This study seeks to determine the knowledge and attitudes of a population with increased awareness and to identify remaining factors and barriers for sustained vector control, health care seeking behaviour, and access, in order to improve future interventions., Methodology/principal Findings: A cross-sectional survey was conducted among approximately 10% (n = 669) of the municipality of Monteagudo's households that were randomly selected. Additionally, a total of 14 in-depth interviews and 2 focus group discussions were conducted with patients and key informants. Several attitudes and practices were identified that could undermine effective control against (re-)infection. Knowledge of clinical symptoms and secondary prevention was limited, and revealed specific misconceptions. Although 76% of the participants had been tested for CD, only 18% of those who tested positive concluded treatment with benznidazole (BNZ). Sustained positive serologies after treatment led to perceived ineffectiveness of BNZ. Moreover, access barriers such as direct as well as indirect costs, BNZ stock-outs and a fear of adverse reactions triggered by other community members made patients opt for alternative treatments against CD such as veterinary ivermectin, used by 28% of infected participants in our study. The lack of accessible care for chronic complications as well as socioeconomic consequences, such as the exclusion from both job opportunities and bank loans contributed to the ongoing burden of CD., Conclusions/significance: Large scale interventions should be accompanied by operational research in order to identify misconceptions and unintended consequences early on, to generate accessible data for future interventions, and for rigorous evaluation. An integrated, community-based approach tackling social determinants and including both traditional and animal health sectors might help to overcome current barriers and advocate for patients' rights., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Human papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC., Methods and Analysis: Women aged 30-64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre., Ethics and Dissemination: The study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings., Trial Registration Number: NCT01881659., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

The equine encephalitis viruses, Venezuelan (VEEV), East (EEEV) and West (WEEV), belong to the genus alphavirus, family Togaviridae and still represent a threat for human and animal public health in the Americas. In both, these infections are characterized by high viremia, rash, fever, encephalitis and death. VEEV encephalitis is similar, clinically, to other arboviral diseases, such as dengue, Zika or chikungunya. Most of the alphaviruses are transmitted between vertebrates and mosquitoes. They are able to replicate in a wide number of hosts, including mammals, birds, reptiles, amphibian and arthropods. The VEEV has enzootic and epizootic transmission cycles. At the enzootic one, enzootic strains (subtype I, serotypes D-F and serotypes II-VI) are continuously circulating between mosquitoes and wild rodents in tropical forests and mangroves of the Americas. The main reseroivrs are wild rodent species of the subfamily Sigmodontinae. However, bats can be also accidental reservoirs of VEEV. In this article, we reviewed the main features, epidemiology, clinical aspects and the current perspectives of the VEEV.

Background: Causes of non-resuming peritoneal dialysis (PD) after complicated peritonitis requiring peritoneal catheter (PC) removal remain poorly studied., Methods: We reviewed all peritonitis episodes in our center between 1997 and 2017. Patients who restarted PD after PC removal (Group 1) were compared to those who did not (Group 2), identifying the causes., Results: Of 284 peritonitis episodes, PC was removed in 48 patients (16.9%). In 18 (37.5%) patients PC was reinserted, and PD successfully resumed in all, with a median duration of PD afterwards of 14.1 months. In other 30 (62.5%) reinsertion of PC was not attempted. Causes of non-reinsertion were: transfer to hemodialysis 76.6% (n = 23), death 16.7% (n = 5) and transplantation 6.7% (n = 2). Hemodialysis switch was due to non-medical reasons in 47.8% (n = 11) including fear of peritonitis, family decision and social dependence. Group 1 was younger (p = 0.041), with lower Charlson index (p = 0.045) and higher men proportion (p = 0.049). Group 1 had a better patient survival than group 2 (survival at 24 months: 67% and 53%, respectively; log-rank test p: 0.01). There were no differences in survival between groups when adjusted for significant basal characteristics., Conclusions: Resuming PD after severe peritonitis requiring PC removal is feasible but a high proportion of patients do not restart PD for non-medical reasons, usually older patients with higher Charlson index. A properly structured interview would be a useful tool that could improve return to technique in these patients.

Background: The use of antimicrobials and myeloablative chemotherapy regimens has promoted multiresistant microorganisms to emerge as nosocomial pathogens, such as vancomycin-resistant Enterococcus faecium (VREfm). We described a polyclonal outbreak of bloodstream infection caused by Efm in a hemato-oncological ward in Mexico. Our aim was to describe the clonal complex (CC) of the Efm strains isolated in the outbreak in comparison with commensal and environmental isolates. Methodology: Sixty Efm clinical, environmental, and commensal strains were included. We constructed a cladogram and a phylogenetic tree using Vitek and Multilocus sequence typing data, respectively. Results: We reported 20 new sequence types (ST), among which 17/43 clinical isolates belonged to CC17. The predominant ST in the clinical strains were ST757, ST1304, ST412, and ST770. Neither environmental nor commensal isolates belonged to CC17. The phylogeny of our collection shows that the majority of the clinical isolates were different from the environmental and commensal isolates, and only a small group of clinical isolates was closely related with environmental and commensal isolates. The cladogram revealed a similar segregation to that of the phylogeny. Conclusions: We found a high diversity among clinical, environmental, and commensal strains in a group of samples in a single hospital. Highest diversity was found between commensal and environmental isolates.

Aim: The current limitations of antiplatelet therapy promote the search for new antithrombotic agents. Here we describe novel platelet aggregation inhibitors that combine pyridazinone and coumarin scaffolds in their structure. Results: The target compounds were synthesized in good yield from maleic anhydride, following a multistep strategy. The in vitro studies demonstrated significant antiplatelet activity in many of these compounds, with IC 50 values in the low micromolar range, revealing that the activity was affected by the substitution pattern of the two selected cores. Additional studies point out their effect as inhibitors of glycoprotein (Gp) IIb/IIIa activation.  Conclusion: This novel hybrid structure can be considered a good prototype for the development of potent platelet aggregation inhibitors.

Physiological mechanisms of an anti-depressive effect of physical exercise in major depressive disorder (MDD) seem to involve alterations in brain-derived neurotrophic factor (BDNF) level. However, previous studies which investigated this effect in a single bout of exercise, did not control for confounding peripheral factors that contribute to BDNF-alterations. Therefore, the underlying cause of exercise-induced BDNF-changes remains unclear. The current study aims to investigate serum BDNF (sBDNF)-changes due to a single-bout of graded aerobic exercise in a group of 30 outpatients with MDD, suggesting a more precise analysis method by taking plasma volume shift and number of platelets into account. Results show that exercise-induced increases in sBDNF remain significant (p < .001) when adjusting for plasma volume shift and controlling for number of platelets. The interaction of sBDNF change and number of platelets was also significant (p = .001) indicating larger sBDNF-increase in participants with smaller number of platelets. Thus, findings of this study suggest an involvement of peripheral as well as additional - possibly brain-derived - mechanisms explaining exercise-related BDNF release in MDD. For future studies in the field of exercise-related BDNF research, the importance of controlling for peripheral parameters is emphasized., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Phthalazin-1(2H)-one is a diazaheterobicycle found in a wide variety of synthetic molecules relevant to several branches of chemistry, including medicinal chemistry. The versatility of phthalazinone core in drug discovery has promoted the search for new synthetic methods to get access to differently substituted and functionalized derivatives. This review highlights the latest advances in synthesis of phthalazinone derivatives that have relevance to drug discovery processes, analyzing modifications of classical methodologies based on [4 + 2] two-component cyclocondensations as well as novel multicomponent approaches, mostly based on a [3 + 2+1] three-component strategy and very attractive not only because of its synthetic efficiency but also in the matter of environmental compatibility., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background/aims: Even though cognitive behavioral therapy has become a relatively effective treatment for major depressive disorder and cognitive behavioral therapy-related changes of dysfunctional neural activations were shown in recent studies, remission rates still remain at an insufficient level. Therefore, the implementation of effective augmentation strategies is needed. In recent meta-analyses, exercise therapy (especially endurance exercise) was reported to be an effective intervention in major depressive disorder. Despite these findings, underlying mechanisms of the antidepressant effect of exercise especially in combination with cognitive behavioral therapy have rarely been studied to date and an investigation of its neural underpinnings is lacking. A better understanding of the psychological and neural mechanisms of exercise and cognitive behavioral therapy would be important for developing optimal treatment strategies in depression. The SPeED study (Sport/Exercise Therapy and Psychotherapy-evaluating treatment Effects in Depressive patients) is a randomized controlled trial to investigate underlying physiological, neurobiological, and psychological mechanisms of the augmentation of cognitive behavioral therapy with endurance exercise. It is investigated if a preceding endurance exercise program will enhance the effect of a subsequent cognitive behavioral therapy., Methods: This study will include 105 patients diagnosed with a mild or moderate depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). The participants are randomized into one of three groups: a high-intensive or a low-intensive endurance exercise group or a waiting list control group. After the exercise program/waiting period, all patients receive an outpatient cognitive behavioral therapy treatment according to a standardized therapy manual. At four measurement points, major depressive disorder symptoms (Beck Depression Inventory, Hamilton Rating Scale for Depression), (neuro)biological measures (neural activations during working memory, monetary incentive delay task, and emotion regulation, as well as cortisol levels and brain-derived neurotrophic factor), neuropsychological test performance, and questionnaires (psychological needs, self-efficacy, and quality of life) are assessed., Results: In this article, we report the design of the SPeED study and refer to important methodological issues such as including both high- and low-intensity endurance exercise groups to allow the investigation of dose-response effects and physiological components of the therapy effects., Conclusion: The main aims of this research project are to study effects of endurance exercise and cognitive behavioral therapy on depressive symptoms and to investigate underlying physiological and neurobiological mechanisms of these effects. Results may provide important implications for the development of effective treatment strategies in major depressive disorder, specifically concerning the augmentation of cognitive behavioral therapy by endurance exercise.

Background: Nonsteroidal anti-inflammatory drugs (NSAID)-induced hypersensitivity reactions can be clinically apparent with asthma, rhinosinusitis, anaphylaxis or rash. Although natural anti-inflammatory products can have similar components, they are not subjected to rigorous quality control standards., Case Report: The case is presented of a 22-year-old female with NSAID allergy who attended with facial and laryngeal angioedema associated with pruritus in eyelids and pharynx. She developed these symptoms fifteen minutes after taking an over-the-counter (OTC) natural anti-inflammatory product. She received treatment with epinephrine, antihistamines and corticosteroids., Conclusion: Different natural anti-inflammatory products are freely available both OTC and online. Some contain dangerous substances that can cause important, and even lethal. side effects. Allergologists, dermatologists and general practitioners should be able to recognize that the consumption of these products, which is widely spread, can cause angioedema.

Compounds of hybrid structure pyridazine-coumarin were discovered as potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B). These compounds were synthesized in good yield following a multistep approach based on Knoevenagel reaction and using as key intermediate pyridazinone 16, which was obtained from maleic anhydride and furan. Compounds 9b and 9d are the most active compounds of these series, with IC 50 values in the sub-micromolar range, and lack of cytotoxic effects. Theoretical calculation of ADME properties also suggested a good pharmacokinetic profile for both compounds. Docking simulations provided insights into enzyme inhibitor interactions and allowed us to rationalize the observed structure-activity relationships (SARs)., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Introduction: Physical activity (PA) can play an important role in improving the mental and physical health in patients with mental disorders but is not well studied in this population. The aim of this study was to assess the status of PA in outpatients with mental disorders, compare the convergence of self-rating and accelerometer measurement and examine the influence of social cognitive variables from the Motivation-Volition (MoVo) model and clinical measures on PA., Methods: Eighty-four patients were recruited from three psychiatric outpatient clinics and local psychiatrists (Distribution of ICD-10-Diagnoses: F3.x = 59.5%, F4.x = 20.2%, F2.x = 17.9%, F1.x = 2.4%). PA, Self-efficacy, Outcome-expectancies, Intention, Self-concordance, Action- and Coping-planning, Health-related Quality of Life (SF-12) and Psychiatric Symptoms (SCL-27) were assessed through questionnaires. PA was assessed objectively by accelerometers., Results: Most of the participants did not reach PA recommendations. Subjective and objective measurement of PA showed good accordance for total PA on group level but lower accordance on individual level. Motivational and volitional determinants of health behavior change showed a similar pattern of correlations with PA as in populations without mental disorders., Conclusion: Outpatients with mental disorders have the ability and are willing to perform PA but a large proportion of our sample did not meet PA recommendations. To assess group levels of PA, subjective and objective measurement seem equally apt, for individual diagnostics, a combination of both should be considered. Social cognitive determinants of health behavior change seem to be as helpful for the design of PA interventions for patients with mental disorders as they are in other populations.

Chagas disease is caused by the parasite Trypanosoma cruzi. It affects several million people, mainly in Latin America, and severe cardiac and/or digestive complications occur in ~30% of the chronically infected patients. Disease acute stage is mostly asymptomatic and infection goes undiagnosed. In the chronic phase direct parasite detection is hampered due to its concealed presence and diagnosis is achieved by serological methods, like ELISA or indirect hemagglutination assays. Agreement in at least two tests must be obtained due to parasite wide antigenic variability. These techniques require equipped labs and trained personnel and are not available in distant regions. As a result, many infected people often remain undiagnosed until it is too late, as the two available chemotherapies show diminished efficacy in the advanced chronic stage. Easy-to-use rapid diagnostic tests have been developed to be implemented in remote areas as an alternative to conventional tests. They do not need electricity, nor cold chain, they can return results within an hour and some even work with whole blood as sample, like Chagas Stat-Pak (ChemBio Inc.) and Chagas Detect Plus (InBIOS Inc.). Nonetheless, in order to qualify a rapidly diagnosed positive patient for treatment, conventional serological confirmation is obligatory, which might risk its start. In this study two rapid tests based on distinct antigen sets were used in parallel as a way to obtain a fast and conclusive Chagas disease diagnosis using whole blood samples. Chagas Stat-Pak and Chagas Detect Plus were validated by comparison with three conventional tests yielding 100% sensitivity and 99.3% specificity over 342 patients seeking Chagas disease diagnosis in a reference centre in Sucre (Bolivia). Combined used of RDTs in distant regions could substitute laborious conventional serology, allowing immediate treatment and favouring better adhesion to it.

Background: Enterococcus faecium causes bloodstream infection (BSI) in patients with hematologic malignancies (HMs). We studied the clinical features and outcomes of patients with HM with vancomycin-sensitive E faecium (VSE) and vancomycin-resistant E faecium (VRE) BSI and determined the genetic relatedness of isolates and circumstances associated with the upsurge of E faecium BSI., Methods: Case-control study of patients with HM and E faecium-positive blood culture from January 2008-December 2012; cases were patients with VRE and controls were VSE isolates. The strains were tested for Van genes by polymerase chain reaction amplification and we performed pulsed-field gel electrophoresis to determine genetic relatedness., Results: Fifty-eight episodes of E faecium BSI occurred: 35 sensitive and 23 resistant to vancomycin. Mortality was 46% and 57%, attributable 17% and 40%, respectively. Early stage HM was associated with VSE (P = .044), whereas an episode of BSI within the 3 months before the event (P = .039), prophylactic antibiotics (P = .013), and vancomycin therapy during the previous 3 months (P = .001) was associated with VRE. The VanA gene was identified in 97% of isolates studied. E faecium isolates were not clonal., Conclusions: E faecium BSI was associated with high mortality. This outbreak of VRE was not clonal; it was associated with antibiotic-use pressure and highly myelosuppressive chemotherapy., (Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Phthalazinones are an important kind of nitrogen atom containing heterocyclic compounds due to their synthetic and pharmacological versatility. This fused heterocycle system represents a common structural feature for many bioactive compounds showing a variety of pharmacological activities such as anticancer, anti-diabetic, anti-asthmatic, antihistaminic, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant or antimicrobial agents, which makes it an attractive scaffold for the design and development of new drugs. This review summarizes detailed and updated information, described in recent non-patent literature, about the most relevant pharmacological properties of phthalazinone derivatives, highlighting the application of this potent pharmacophore in drug discovery., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable β(α)-substituted γ-hydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low μM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U-46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Worldwide, acute gastroenteritis causes substantial morbidity and mortality in children less than five years of age. In Bolivia, which has one of the lower GDPs in South America, 16% of child deaths can be attributed to diarrhea, and the costs associated with diarrhea can weigh heavily on patient families. To address this need, the study goal was to identify predictors of cost burden (diarrhea-related costs incurred as a percentage of annual income) and catastrophic cost (cost burden ≥ 1% of annual household income)., Methods: From 2007 to 2009, researchers interviewed caregivers (n = 1,107) of pediatric patients (<5 years old) seeking treatment for diarrhea in six Bolivian hospitals. Caregivers were surveyed on demographics, clinical symptoms, direct (e.g. medication, consult fees), and indirect (e.g. lost wages) costs. Multivariate regression models (n = 551) were used to assess relationships of covariates to the outcomes of cost burden (linear model) and catastrophic cost (logistic model)., Results: We determined that cost burden and catastrophic cost shared the same significant (p < 0.05) predictors. In the logistic model that also controlled for child sex, child age, household size, rural residence, transportations taken to the current visit, whether the child presented with complications, and whether this was the child's first episode of diarrhea, significant predictors of catastrophic cost included outpatient status (OR 0.16, 95% CI [0.07, 0.37]); seeking care at a private hospital (OR 4.12, 95% CI [2.30, 7.41]); having previously sought treatment for this diarrheal episode (OR 3.92, 95% CI [1.64, 9.35]); and the number of days the child had diarrhea prior to the current visit (OR 1.14, 95% CI [1.05, 1.24])., Conclusions: Our analysis highlights the economic impact of pediatric diarrhea from the familial perspective and provides insight into potential areas of intervention to reduce associated economic burden.

In the title compound, C21H24N2O2Si, a new pyridazin-3(2H)-one derivative, the carbonyl group of the heterocyclic ring and the O atom of the silyl ether are located on the same side of the pyridazinone ring and the C-C-O-Si torsion angle is -140.69 (17)°. In the crystal, mol-ecules are linked by pairs of strong N-H⋯O hydrogen bonds into centrosymmetric dimers with graph-set notation R 2 (2)(8). Weak C-H⋯π inter-actions are also observed.

The title N-benzyl-phthalimide derivative, C16H13NO3, consists of two planar moieties, viz. the phthalimide system (r.m.s. deviation = 0.007 Å) and the phenyl ring, which make a dihedral angle of 84.7 (6)°. The meth-oxy group is almost coplanar with the phathalimide ring, as shown by the C-C-O-C torsion angle of -171.5 (2)°. In the crystal, the mol-ecules are self-assembled via non-classical C-H⋯O hydrogen bonds, forming a tape motif along [110].

Objective: To determine prognostic role of NT-proBNP as predictor of 30 day-mortality and readmission in the elderly with acute heart failure (AHF) treated in Spanish Emergency Departments (EDs), and to analyse the confounding factors when the NT-proBNP value is interpreted., Material and Methods: A multicentre and multi-purpose cohort study with prospective follow-up was conducted on all patients aged 65 years or older with AHF treated in Spanish EDs. The variables recorded include demographic characteristics, comorbidity, details of episode, and NT-proBNP value. The outcome variables were 30 day-mortality and readmission. An NT-proBNP ≥ 5,180 pg/ml was adopted as the cut-off limit. The statistical package SPSS 18.0 was used to analyse the data., Results: A total of 585 patients were included, with a mean age of 80.4 (SD: 6.9) years old. The cut-off NT-proBNP ≥ 5,180 pg/ml was independently associated with a severely impaired glomerular filtration (<30 ml/h) (P < .001) and severe episode (NYHA II-IV) (P = .012). The NT-proBNP area under curve (AUC) for 30 day-mortality was 0.71 (CI 95%: 0.63-0.77; P < .001) and for 30 day-readmission, was 0.50 (CI 95%: 0.45-0.56; P = .846). A multivariable analysis showed that the cut-off NT-proBNP ≥ 5,180 pg/ml was an independent factor associated with 30 day-mortality in the elderly with AHF attended in Spanish EDs., Conclusions: The NT-proBNP value is associated with short-term mortality in the elderly with AHF attended in the EDs independently of the presence of confounding factors, such as the severity of the episode and glomerular filtration reduction, but not with 30 day-readmission., (Copyright © 2012 SEGG. Published by Elsevier Espana. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent diseases and a major cause of morbidity and mortality in Spain. Currently, COPD is considered a treatable disease with an inflammatory origin that is frequently associated with other diseases. The prevalence of comorbidity is clearly increased in patients with COPD, irrespective of other confounding variables such as smoking. Current treatments have been proven to slow the loss of lung function, decrease the number of exacerbations and improve health-related quality of life and survival. New advances regarding the classics and more recent phenotypes such as patients with frequent exacerbations or COPD with associated comorbidity should allow for more individualized treatment while advances in genetic research and inflammatory mechanisms of the disease will help us to increase our knowledge of the disease and the development of new treatments., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Background and Objective: Hospitalizations for chronic obstructive pulmonary disease (COPD) occur mostly in elderly patients. We describe the characteristics and treatment of elderly patients hospitalized for COPD in Internal Medicine Services, compared with the younger age group., Patients and Methods: Observational, prospective, multicenter study. We compared the differences between patients older than 80 years and the rest regarding comorbidity, severity of COPD, previous admissions, length of stay and treatment prescribed. Comorbidity was assessed by the Charlson index and a questionnaire was designed for this purpose., Results: We included 398 subjects, 353 men (89%) with a mean age of 73.7 years (SD 8.8), of whom about 107 (26.9%) were older than 80 years. These patients had less severe COPD according to the GOLD classification (P<.02). Although the overall morbidity was similar in both groups, elderly patients had greater presence of arrhythmias (P<.01), left ventricular hypertrophy (P<.01) and received more diuretics (P<.05). Dyspnoea, length of stay and mortality were similar between both populations. Home oxygen therapy prior to and use of inhaled corticosteroids and oxygen therapy was lower in older patients, even when they were clinically indicated., Conclusions: A quarter of patients hospitalized for COPD in Internal Medicine Services are over 80 years. Although they present less obstruction, they have a similar degree of dyspnea, increased cardiac morbidity and their treatment is less consistent with the recommendations of the guidelines., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Purpose: To study the prevalence of vertebral fractures (VF), the associated risk factors and the degree of diagnosis and prescription upon discharge in a series of hospitalized medical patients ≥50 years of age., Methods: A cross-sectional, multicentre and observational study in which a prevalence cut-off was carried out concerning patients admitted to six Internal Medicine departments in Malaga (Spain). The main variables were the existence of a fracture in the spine lateral x-ray, the inclusion of the diagnosis of a fracture in the discharge report, and the establishment of anti-osteoporotic treatment at discharge., Results: 254 patients were included (mean age 66.4±14.9 years). The prevalence of VF was of 14.2% (36 cases). Patients with VF presented with a higher mean age, compared to those without VF (70.14 vs. 65.7 years) (p=0.035). The means contrast for the FRAX index variable (major osteoporotic and hip fracture), grouping according to the presence of VF, did not show any statistical significance (p=0.369 and p=0.788, respectively). Only in 8.3% of the discharge reports of patients with VF had the diagnosis of VF and/or osteoporosis been recorded and the prescription of anti-osteoporotic drugs been included., Conclusions: A high prevalence of asymptomatic VF is verified in medical inpatients ≥50 years of age. The FRAX index did not turn out to be predictive of the presence of VF in this population. There is an underdiagnosis of osteoporotic VF in the coding at hospital discharge. Action protocols are necessary to avoid clinical inactivity regarding this entity., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

New series of 6-substituted-3-arylcoumarins displaying several alkyl, hydroxyl, halogen, and alkoxy groups in the two benzene rings have been designed, synthesized, and evaluated in vitro as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Most of the studied compounds showed a high affinity and selectivity to the hMAO-B isoenzyme, with IC(50) values on nanomolar and picomolar range. Ten of the 22 described compounds displayed higher MAO-B inhibitory activity and selectivity than selegiline. Coumarin 7 is the most active compound of this series, being 64 times more active than selegiline and also showing the highest hMAO-B specificity. In addition, docking experiments were carried out on hMAO-A and h-MAO-B structures. This study provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of this 3-arylcoumarin scaffold.

Several pyridazin-3(2H)-one derivatives were synthesized starting from alkyl furans using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of the synthetic strategy followed. For all pyridazinones reported, a complete assignment of the (1)H and (13)C NMR spectra using one- and two-dimensional NMR spectroscopic methods, which included NOE, DEPT, COSY, HSQC and HMBC experiments, was accomplished. Correlations between the chemical shifts of the heterocyclic ring atoms and substituents at N-2 and C-6 were analyzed., (Copyright © 2011 John Wiley & Sons, Ltd.)

Several new purine nucleosides derivatives of allofuranose were prepared according to Vorbrüggen method, starting from 1,2,5,6-di-O-isopropylidene-α-D-allofuranose and using 1,2,3,5,6-pentaacetoxy-β-D-allofuranose as key intermediate. The synthesized allofuranosyl nucleosides, as well as some acetyl derivatives, were evaluated for their cytotoxicity in vitro in three human cancer cell lines (MCF-7, Hela-229 and HL-60). Among the studied compounds the 9-(2,3,5,6-tetra-O-acetyl-β-D-allofuranosyl)-2,6-dichloropurine (9) was the most potent one on the three cell lines evaluated, being its activity against HL-60 cells similar to cisplatin., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

New 6-substituted and 2,6-disubstituted pyridazinone derivatives were obtained starting from easily accessible alkyl furans by using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of this synthetic strategy. The new pyridazinone derivatives have been studied as vasorelaxant and antiplatelet agents. Analysis of biological data revealed the silyl ethers (4a-i) and N,O-dibenzyl derivatives (6g-i) as the most active compounds., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

(1)H and (13)C NMR chemical shifts of cis and trans isonucleoside analogues of purine in which the furanose moiety is substituted by a tetrahydropyran ring were completely assigned using one- and two-dimensional NMR experiments that include NOE, DEPT, COSY and HSQC. The significant (1)H and (13)C NMR signals differentiating between the cis and trans stereoisomers were compared., (Copyright (c) 2010 John Wiley & Sons, Ltd.)

Sacral neuromodulation is a new treatment for urinary and fecal incontinence that has demonstrated good therapeutic results. This treatment modality has shown not only to reduce urinary dysfunction symptoms and urinary and fecal incontinence but improve quality of life scores as well. We present a 73 years old female patient with severe fecal and urinary incontinence with major quality of life impact. She was referred after failure of different surgical and conservative therapeutic approaches. Her evaluation met inclusion criteria for sacral neuromodulation treatment. Acute sacral nerve evaluation (PNE) proved to be therapeutic in the patient as measured by at least a 50 percent improvement in her symptoms so a permanent implant (Medtronic InterStim System) was placed. After the implant there was a significant improvement in urinary and fecal functional scores. Fecal Incontinence Severity Index improved from 34 to 8 and Urinary Sandvik's Severity Index from very severe urinary incontinence to minor urinary incontinence after the placement of the implant. Using standard quality of life questionnaires, she improved in the areas of lifestyle,coping and behavior and her experience with depression and self-perception.

Aims: To describe the epidemiology of hospital admissions for heart failure in 32 hospitals. To define the profile of those attended by Internal Medicine (IM)., Methods and Results: Analysis of the Minimum-Basic-Data-Set registry of 32 public Spanish hospitals, during 1998-2002, identifying those cases whose main or secondary diagnosis was heart failure, with attention to age, sex, length of stay, season, outcome, number of diagnoses, Diagnostic Related Groups (DRG), and coded procedures. There were 2,787,008 discharges, 27,248 with heart failure (15,737 IM, 7,735 Cardiology and 3,776 other services). Discharges for heart failure increase from 1998 to 2002 (r(2) = 0.7232). Of the total, 44% were men (average age 70.98 years; 95% CI 70.08-70.47) and 56% were women (74.77 years; 95% CI 74.61-74.93; p < 0.0001). The global in-hospital mortality rate was 11.1% and we found differences between Cardiology and MI. MI patients were older (74 years compared to 69, p < 0.0001), had greater comorbidity, a similar length of stay (11.1 days), and a lower number of coded diagnostic procedures. Associated pathologies were different. Seasonal variation is clear., Conclusion: The incidence of discharges for heart failure is high and steadily increasing, although this is more evident in IM. The populations attended by the two services are different, which makes it difficult to ascertain differences in handling. The results are slightly different from those reported in other countries.

In view of the large libraries of nucleoside analogues that are now being handled in organic synthesis, the identification of drug biological activity is advisable prior to synthesis and this can be achieved by employing predictive biological property methods. In this sense, Quantitative Structure-Activity Relationships (QSAR) or docking approaches have emerged as promising tools. Although a large number of in silico approaches have been described in the literature for the prediction of different biological activities, the use of QSAR applications to develop adenosine receptor (AR) antagonists is not common as for the case of the antibiotics and anticancer compounds for instance. The intention of this review is to summarize the present knowledge concerning computational predictions of new molecules as adenosine receptor antagonists., (Copyright (c) 2007 Wiley-Periodicals, Inc.)