Effective Soft-Core Potentials and Mesoscopic Simulations of Binary Polymer Mixtures

Mesoscopic molecular dynamics simulations are used to determine the large scale structure of several binary polymer mixtures of various chemical architecture, concentration, and thermodynamic conditions. By implementing an analytical formalism, which is based on the solution to the Ornstein-Zernike equation, each polymer chain is mapped onto the level of a single soft colloid. From the appropriate closure relation, the effective, soft-core potential between coarse-grained units is obtained and used as input to our mesoscale simulations. The potential derived in this manner is analytical and explicitly parameter dependent, making it general and transferable to numerous systems of interest. From computer simulations performed under various thermodynamic conditions the structure of the polymer mixture, through pair correlation functions, is determined over the entire miscible region of the phase diagram. In the athermal regime mesoscale simulations exhibit quantitative agreement with united atom simulations. Furthermore, they also provide information at larger scales than can be attained by united atom simulations and in the thermal regime approaching the phase transition.Comment: 19 pages, 11 figures, 3 table

Estrategia para conservar las poblaciones de buitres del viejo mundo utilizando el enfoque de una salud

One Health brings the powerful interrelationship between human and wildlife health together with ecosystem health. The initial concept of One Health was formulated decades ago and focused on disease transfer from wildlife to human populations. More recently, the concept has been used to associate resilience to disease with the health of the ecosystem and resilience to environmental stressors. The need for a One Health approach is particularly evident in the plight of Old World vultures, which are facing a conservation crisis due to drastic reductions in populations across their entire range. Moreover, vulture conservation exemplifies many contemporary tenets of One Health; vultures are critical to a sustainable and resilient ecosystem, which in turn is essential for the socio-ecological health of human communities. In this review, we examine the complex factors contributing to the demise of Old World vulture populations, using the lens of One Health to conceptualize the primary drivers impacting the health and sustainability of these populations. The One Health concept provides the basis for the development of a framework that incorporates a multidimensional approach and includes human health, wildlife health, environmental and disease-related stressors, disease incidences, societal pressures, and environmental contaminants. Integrating societal needs with management aimed at maintaining healthy vulture populations is key for successfully using a One Health framework to optimize the health of human and wildlife populations and ensure ecosystem health.El enfoque ‘‘Una Salud’’ promueve una poderosa interrelacio´n entre la salud de los humanos y de la fauna salvaje asociados a la salud de los ecosistemas. El concepto inicial de Una Salud fue formulado de´cadas atra´s y se enfocaba en la transferencia de enfermedades de la fauna salvaje a las poblaciones humanas. Ma´s recientemente, el concepto ha sido usado para asociar la resiliencia a las enfermedades con la salud de los ecosistemas y la resiliencia a factores de estre´s ambiental. La necesidad de utilizar el enfoque de Una Salud es particularmente evidente ante la dif´ıcil situacio´n de los buitres del Viejo Mundo, los cuales se enfrentan a una situacio´n de crisis de conservacio´n debido a la reduccio´n dra´stica en sus poblaciones a lo largo de toda su a´rea de distribucio´n. Adema´s, la conservacio´n de los buitres ejemplifica mucho de los principios contempora´neos de Una Salud; los buitres son cr´ıticos para un ecosistema sostenible y resiliente, lo que a su vez es esencial para la salud socio-ecolo´gica de las comunidades humanas. En esta revisio´n, examinamos los factores complejos que contribuyen al descenso de las poblaciones de buitres del Viejo Mundo, usando el enfoque de Una Salud para conceptualizar los factores principales que impactan en la salud y la sostenibilidad de estas poblaciones. El concepto de Una Salud proporciona las bases para el desarrollo de un marco de referencia que incorpora un enfoque multidimensional, incluyendo la salud humana y de la vida silvestre, factores estresantes ambientales y de enfermedades, incidencia de enfermedades, presiones sociales y qu´ımicos ambientales. Integrar las necesidades de la sociedad con la gestio´n destinada a mantener poblaciones saludables de buitres es clave para usar exitosamente el marco de referencia de Una Salud y as´ı optimizar la salud de las poblaciones humanas y de la fauna salvaje asegurando la salud del ecosistema.The National Science Foundationhttps://bioone.org/journals/journal-of-raptor-researcham2022Zoology and Entomolog

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Reference state for the generalized Yvon–Born–Green theory: Application for coarse-grained model of hydrophobic hydration

Coarse-grained (CG) models provide a computationally efficient means for investigating phenomena that remain beyond the scope of atomically detailed models. Although CG models are often parametrized to reproduce the results of atomistic simulations, it is highly desirable to determine accurate CG models from experimental data. Recently, we have introduced a generalized Yvon–Born–Green (g-YBG) theory for directly (i.e., noniteratively) determining variationally optimized CG potentials from structural correlation functions. In principle, these correlation functions can be determined from experiment. In the present work, we introduce a reference state potential into the g-YBG framework. The reference state defines a fixed contribution to the CG potential. The remaining terms in the potential are then determined, such that the combined potential provides an optimal approximation to the many-body potential of mean force. By specifying a fixed contribution to the potential, the reference state significantly reduces the computational complexity and structural information necessary for determining the remaining potentials. We also validate the quantitative accuracy of the proposed method and numerically demonstrate that the reference state provides a convenient framework for transferring CG potentials from neat liquids to more complex systems. The resulting CG model provides a surprisingly accurate description of the two- and three-particle solvation structures of a hydrophobic solute in methanol. This work represents a significant step in developing the g-YBG theory as a useful computational framework for determining accurate CG models from limited experimental data