Exchange Rules for Diradical π-Conjugated Hydrocarbons

A variety of planar π-conjugated hydrocarbons such as heptauthrene, Clar’s goblet and, recently synthesized, triangulene have two electrons occupying two degenerate molecular orbitals. The resulting spin of the interacting ground state is often correctly anticipated as S = 1, extending the application of Hund’s rules to these systems, but this is not correct in some instances. Here we provide a set of rules to correctly predict the existence of zero mode states as well as the spin multiplicity of both the ground state and the low-lying excited states, together with their open- or closed-shell nature. This is accomplished using a combination of analytical arguments and configuration interaction calculations with a Hubbard model, both backed by quantum chemistry methods with a larger Gaussian basis set. Our results go beyond the well established Lieb’s theorem and Ovchinnikov’s rule, as we address the multiplicity and the open-/closed-shell nature of both ground and excited states.J.F.-R. and R.O. acknowledge financial support from MINECO-Spain (grant no. MAT2016-78625-C2) and from the Portuguese “Fundação para a Ciência e a Tecnologia” (FCT) for the project P2020-PTDC/FIS-NAN/4662/2014. J.F.-R., M.M.-F. and N.G.-M. acknowledge support from the P2020-PTDC/FISNAN/3668/2014. J.F.-R. acknowledges support from UTAPEXPL/NTec/0046/2017 projects as well as Generalitat Valenciana funding (Prometeo2017/139). R.O. and J.C.S.-G. acknowledge ACIF/2018/175 (Generalitat Valenciana and Fondo Social Europeo). M.M.-F. and R.B. acknowledge the Portuguese “Fundação para a Ciência e a Tecnologia” (FCT) for the project IF/00894/2015 and FCT ref. UID/CTM/50011/2019 for CICECO - Aveiro Institute of Materials. This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 664878

Use of Biomarkers to Improve 28-Day Mortality Stratification in Patients with Sepsis and SOFA ≤ 6

Molecular diagnosis; Mortality; Sepsis biomarkersDiagnóstico molecular; Mortalidad; Biomarcadores de sepsisDiagnòstic molecular; Mortalitat; Biomarcadors de sèpsiaEarly diagnosis and appropriate treatments are crucial to reducing mortality risk in septic patients. Low SOFA scores and current biomarkers may not adequately discern patients that could develop severe organ dysfunction or have an elevated mortality risk. The aim of this prospective observational study was to evaluate the predictive value of the biomarkers mid-regional pro-adrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and lactate for 28-day mortality in patients with sepsis, and patients with a SOFA score ≤6. 284 were included, with a 28-day all-cause mortality of 8.45% (n = 24). Non-survivors were older (p = 0.003), required mechanical ventilation (p = 0.04), were ventilated for longer (p = 0.02), and had higher APACHE II (p = 0.015) and SOFA (p = 0.027) scores. Lactate showed the highest predictive ability for all-cause 28-day mortality, with an area under the receiver-operating characteristic curve (AUROC) of 0.67 (0.55–0.79). The AUROC for all-cause 28-day mortality in patients with community-acquired infection was 0.69 (0.57–0.84) for SOFA and 0.70 (0.58–0.82) for MR-proADM. A 2.1 nmol/L cut-off point for this biomarker in this subgroup of patients discerned, with 100% sensibility, survivors from non-survivors at 28 days. In patients with community-acquired sepsis and initial SOFA score ≤ 6, MR-proADM could help identify patients at risk of 28-day mortality.This research was funded by a restricted grant from Thermo Fisher (Hennigsdorf, Germany), consisting of free-of-charge kits. However, the funding organization had no role in the collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication

Body Composition Changes in Hemodialysis Patients: Implications for Prognosis

Background: Overhydration, inflammation and protein-energy wasting have been related to all-cause mortality in dialysis patients, being lean mass loss, a poor prognostic factor. Objective: to monitor body composition changes (BCC) in hemodialysis (HD) patients and to relate BCC to mortality. Methods: Prospective follow up study: Bioimpedance spectroscopy (BIS) and nutritional parameters were performed every 6 months during three years. Results : Overall data show a significant loss of weight at 12m, 24m, and 36m, with decrease of lean tissue index and phase angle (PA) in each period measured. Fat tissue index (FTI) diminished in the third year’s measurements. End of first year, 41 % of patients gain weight, them at baseline had lower age, higher serum albumin, lower Extracelular/intracellular water index (ECW/ICW) and higher PA, showing a significant FTI increase. Higher baseline PA was gain weight predictor by binary logistic regression. Cox regression analyses: Age, diabetes, HD technique, albumin, ECW/ICW, and PA were mortality predictors in univariate analysis; being PA the main mortality predictor in multivariate analysis. BCC were not associated with mortality. ROC curve: PA higher than 4.85° is protective for mortality. Conclusions: Lean mass loss was the most important change during follow up; we have not observed association between BCC with mortality. PA was the main mortality predictor.S

Setae from the pine processionary moth (Thaumetopoea pityocampa) contain several relevant allergens

BACKGROUND: Pine processionary larvae produce urticating hairs (setae) that serve for protection against predators. Setae induce cutaneous reactions in animals and humans. The presence of toxic or allergic mechanisms is a matter of debate. OBJECTIVES: To detect the presence of allergens in setae and to characterize them. MATERIALS AND METHODS: Setae extracts were characterized by gel staining and immunoblot, with sera from patients with immediate reactions and positive prick test reactions, as well as a rabbit antiserum raised against setae. Setae proteins were fractionated by high-performance liquid chromatography. The most relevant allergen was analysed by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS), and its sequence was deduced from an expressed sequence tag bank. Results. Setae contained at least seven different allergens. The most intense detection corresponded to a protein of MW ~ 14,000 that was similar to thaumetopoein, a previously described protein with mast cell-degranulating properties. MALDI-MS-based de novo sequencing provided a partial amino acid sequence different from that of the previously described allergen Tha p 1, and it was named Tha p 2. This allergen was detected in 61% of patients, and it is therefore a new major caterpillar allergen. CONCLUSIONS: Penetration of the setae from the pine processionary caterpillar delivers their allergenic content in addition to causing mechanical or toxic injury.This work was supported by URTICLIM, a French project funded by the ‘Agence Nationale de la Recherche’ (ANR 07BDIV 013). Ana I. Rodriguez-Mahillo is a beneficiary of contract CA07/00046 from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion, Spain.S

From cyclic nanorings to single-walled carbon nanotubes: disclosing the evolution of their electronic structure with the help of theoretical methods

We systematically investigate the relationships between structural and electronic effects of finite size zigzag or armchair carbon nanotubes of various diameters and lengths, starting from a molecular template of varying shape and diameter, i.e. cyclic oligoacene or oligophenacene molecules, and disclosing how adding layers and/or end-caps (i.e. hemifullerenes) can modify their (poly)radicaloid nature. We mostly used tight-binding and finite-temperature density-based methods, the former providing a simple but intuitive picture about their electronic structure, and the latter dealing effectively with strong correlation effects by relying on a fractional occupation number weighted electron density (ρFOD), with additional RAS-SF calculations backing up the latter results. We also explore how minor structural modifications of nanotube end-caps might influence the results, showing that topology, together with the chemical nature of the systems, is pivotal for the understanding of the electronic properties of these and other related systems.A. J. P. J. and J. C. S. G acknowledge the project CTQ2014-55073-P from the Spanish Government (MINECO/FEDER) and the project AICO/2018/175 from the Regional Government (GVA/FSE). J. F. R. acknowledges the projects MAT2016-78625 from the Spanish Government (MINECO/FEDER) and projects No. PTDC/FIS-NAN/4662/2014 and No. PTDC/FIS-NAN/3668/2014 from the Portuguese Government (Fundaçao para a Ciencia e Tecnologia). D. C. is thankful to projects IT588-13 (Eusko Jaurlaritza) and CTQ2016-80955 from the Spanish Government (MINECO/FEDER). M. E. S.-S. acknowledges CONACyT-México for a PhD fellowship (ref. 591700). R. O. C. acknowledges “Generalitat Valenciana” and “Fondo Social Europeo” for a PhD fellowship (ACIF/2018/198)

TcVac1 vaccine delivery by intradermal electroporation enhances vaccine induced immune protection against Trypanosoma cruzi infection in mice

Trabajo de investigación doctoral de Wael Hegazy Hassan Moustafa bajo la dirección de Juan Carlos Vázquez ChagoyánThe efforts for the development and testing of vaccines against Trypanosoma cruzi infection have increased during the past years. We have designed a TcVac series of vaccines composed of T. cruzi derived, GPI-anchored membrane antigens. The TcVac vaccines have been shown to elicit humoral and cellular mediated immune responses and provide significant (but not complete) control of experimental infection in mice and dogs. Herein, we aimed to test two immunization protocols for the delivery of DNA-prime/ DNA-boost vaccine (TcVac1) composed of TcG2 and TcG4 antigens in a BALB/c mouse model. Mice were immunized with TcVac1 through intradermal/electroporation (IDE) or intramuscular (IM) routes, challenged with T. cruzi, and evaluated during acute phase of infection. The humoral immune response was evaluated through the assessment of anti-TcG2 and anti-TcG4 IgG subtypes by using an ELISA. Cellular immune response was assessed through a lymphocyte proliferation assay. Finally, clinical and morphopathological aspects were evaluated for all experimental animals. Our results demonstrated that when comparing TcVac1 IDE delivery vs IM delivery, the former induced significantly higher level of antigen-specific antibody response (IgG2a + IgG2b > IgG1) and lymphocyte proliferation, which expanded in response to challenge infection. Histological evaluation after challenge infection showed infiltration of inflammatory cells (macrophages and lymphocytes) in the heart and skeletal tissue of all infected mice. However, the largest increase in inflammatory infiltrate was observed in TcVac1_IDE/Tc mice when compared with TcVac1_IM/Tc or non-vaccinated/infected mice. The extent of tissue inflammatory infiltrate was directly associated with the control of tissue amastigote nests in vaccinated/ infected (vs. non-vaccinated/infected) mice. Our results suggest that IDE delivery improves the protective efficacy of TcVac1 vaccine against T. cruzi infection in mice when compared with IM delivery of the vaccine.Universidad Autónoma de Estado de México (proyecto No. 3326/2012C), Consejo Nacional de Ciencia y Tecnología (Proyecto No. 156701) . Beca CONACyT a M.Sc. Wael Hegazy Hassan Moustafa (Beca numero No. 518232/291117)

New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial

Background: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. Methods: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18–50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. Findings: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73–99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73–99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64–95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65–95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67–97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64–95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths. Interpretation: Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results. Funding: Drugs for Neglected Diseases initiative (DNDi). Translation: For the Spanish translation of the abstract see Supplementary Materials section.Fil: Torrico, Faustino. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; Bolivia. Universidad Mayor de San Simón; BoliviaFil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; España. Universidad de Barcelona; EspañaFil: Barreira, Fabiana. DNDi Latin America; BrasilFil: Blum, Bethania. DNDi Latin America; BrasilFil: Almeida, Igor C. University of Texas at El Paso; Estados UnidosFil: Alonso Vega, Cristina. DNDi Latin America; Brasil. Instituto de Salud Global de Barcelona; EspañaFil: Barboza, Tayná. DNDi Latin America; BrasilFil: Bilbe, Graeme. Drugs For Neglected Diseases Initiative; SuizaFil: Correia, Erika. DNDi Latin America; BrasilFil: Garcia, Wilson. Universidad Mayor de San Simón; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente ; BoliviaFil: Ortiz, Lourdes. Universidad Autónoma Juan Misael Saracho; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; BoliviaFil: Parrado, Rudy. Universidad Mayor de San Simón; BoliviaFil: Ramirez Gomez, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; ArgentinaFil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; SuizaFil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; SuizaFil: Vaillant, Michel. Luxembourg Institute Of Health; LuxemburgoFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. DNDi Latin America; Brasi