Enabling trade-offs between accuracy and computational cost: Adaptive algorithms to reduce time to clinical insight

The efficacy of drug treatments depends on how tightly small molecules bind to their target proteins. Quantifying the strength of these interactions (the so called 'binding affinity') is a grand challenge of computational chemistry, surmounting which could revolutionize drug design and provide the platform for patient specific medicine. Recently, evidence from blind challenge predictions and retrospective validation studies has suggested that molecular dynamics (MD) can now achieve useful predictive accuracy (1 kcal/mol) This accuracy is sufficient to greatly accelerate hit to lead and lead optimization. To translate these advances in predictive accuracy so as to impact clinical and/or industrial decision making requires that binding free energy results must be turned around on reduced timescales without loss of accuracy. This demands advances in algorithms, scalable software systems, and intelligent and efficient utilization of supercomputing resources. This work is motivated by the real world problem of providing insight from drug candidate data on a time scale that is as short as possible. Specifically, we reproduce results from a collaborative project between UCL and GlaxoSmithKline to study a congeneric series of drug candidates binding to the BRD4 protein-inhibitors of which have shown promising preclinical efficacy in pathologies ranging from cancer to inflammation. We demonstrate the use of a framework called HTBAC, designed to support the aforementioned requirements of accurate and rapid drug binding affinity calculations. HTBAC facilitates the execution of the numbers of simulations while supporting the adaptive execution of algorithms. Furthermore, HTBAC enables the selection of simulation parameters during runtime which can, in principle, optimize the use of computational resources whilst producing results within a target uncertainty

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

Impact of continuity on quality of primary care - from the perspective of citizens' preferences and multimorbidity: Position Paper of the European Forum for Primary Care

Background Continuity of care is one of the cornerstones of primary care. Initially, the concept of continuity largely corresponded to one care provider and continuity between doctor and patient, but today, healthcare processes and organisations have grown and become more complex. A survey of patients with complex care needs found that in all of 11 countries studied care was often poorly coordinated. Multidimensional models of continuity have to be developed. Aim To study existing evidence concerning significance of continuity in primary care with special consideration given to the preferences of citizens and to patients with complex care needs. Methods Contemporary literature was studied from the aspects of primary care, patients’ point of view, multimorbidity and organisational models. Examples from country systems were collected. The topic and drafts were presented and discussed at two EFPC conference workshops. Results Evidence shows that both patients and caregivers identify and value continuity in the form of regular sources of care, and that provider continuity is related to lower total healthcare costs on a macro level. Continuity is a considerable component of quality in primary care. Methods to measure and compare between primary care centres, organisations and countries to stimulate improvements in continuity is lacking. The complexity of operationalising continuity in the context of multidisciplinary team-based primary care today and in the future remains a challenge. Conclusions Continuity is, and will be, an important component of quality in primary care, especially from the perspective of citizens and growing multimorbidity. Methods to develop continuity should be promoted

Effects of metabolic syndrome on arterial function in different age groups: The Advanced Approach to Arterial Stiffness study

Objective: The aim of the Advanced Approach to Arterial Stiffness study was to compare arterial stiffness measured simultaneously with two different methods in different age groups of middle-aged and older adults with or without metabolic syndrome (MetS). The specific effects of the different MetS components on arterial stiffness were also studied. Methods: This prospective, multicentre, international study included 2224 patients aged 40 years and older, 1664 with and 560 without MetS. Patients were enrolled in 32 centres from 18 European countries affiliated to the International Society of Vascular Health &amp;amp; Aging. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) and the carotid-femoral pulse wave velocity (CF-PWV) in four prespecified age groups: 40-49, 50-59, 60-74, 75-90 years. In this report, we present the baseline data of this study. Results: Both CF-PWV and CAVI increased with age, with a higher correlation coefficient for CAVI (comparison of coefficients P&amp;lt;0.001). Age-adjusted and sex-adjusted values of CF-PWV and CAVI were weakly intercorrelated (r2=0.06, P&amp;lt;0.001). Age-adjusted and sex-adjusted values for CF-PWV but not CAVI were higher in presence of MetS (CF-PWV: 9.57±0.06 vs. 8.65±0.10, P&amp;lt;0.001; CAVI: 8.34±0.03 vs. 8.29±0.04, P=0.40; mean±SEM; MetS vs. no MetS). The absence of an overall effect of MetS on CAVI was related to the heterogeneous effects of the components of MetS on this parameter: CAVI was positively associated with the high glycaemia and high blood pressure components, whereas lacked significant associations with the HDL and triglycerides components while exhibiting a negative association with the overweight component. In contrast, all five MetS components showed positive associations with CF-PWV. Conclusion: This large European multicentre study reveals a differential impact of MetS and age on CAVI and CF PWV and suggests that age may have a more pronounced effect on CAVI, whereas MetS increases CF-PWV but not CAVI. This important finding may be due to heterogeneous effects of MetS components on CAVI. The clinical significance of these original results will be assessed during the longitudinal phase of the study. Copyright © 2018 The Author(s)

Effects of metabolic syndrome on arterial function in different age groups: The Advanced Approach to Arterial Stiffness study

Objective: The aim of the Advanced Approach to Arterial Stiffness study was to compare arterial stiffness measured simultaneously with two different methods in different age groups of middle-aged and older adults with or without metabolic syndrome (MetS). The specific effects of the different MetS components on arterial stiffness were also studied. Methods: This prospective, multicentre, international study included 2224 patients aged 40 years and older, 1664 with and 560 without MetS. Patients were enrolled in 32 centres from 18 European countries affiliated to the International Society of Vascular Health &amp; Aging. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) and the carotid-femoral pulse wave velocity (CF-PWV) in four prespecified age groups: 40-49, 50-59, 60-74, 75-90 years. In this report, we present the baseline data of this study. Results: Both CF-PWV and CAVI increased with age, with a higher correlation coefficient for CAVI (comparison of coefficients P&lt;0.001). Age-adjusted and sex-adjusted values of CF-PWV and CAVI were weakly intercorrelated (r2=0.06, P&lt;0.001). Age-adjusted and sex-adjusted values for CF-PWV but not CAVI were higher in presence of MetS (CF-PWV: 9.57±0.06 vs. 8.65±0.10, P&lt;0.001; CAVI: 8.34±0.03 vs. 8.29±0.04, P=0.40; mean±SEM; MetS vs. no MetS). The absence of an overall effect of MetS on CAVI was related to the heterogeneous effects of the components of MetS on this parameter: CAVI was positively associated with the high glycaemia and high blood pressure components, whereas lacked significant associations with the HDL and triglycerides components while exhibiting a negative association with the overweight component. In contrast, all five MetS components showed positive associations with CF-PWV. Conclusion: This large European multicentre study reveals a differential impact of MetS and age on CAVI and CF PWV and suggests that age may have a more pronounced effect on CAVI, whereas MetS increases CF-PWV but not CAVI. This important finding may be due to heterogeneous effects of MetS components on CAVI. The clinical significance of these original results will be assessed during the longitudinal phase of the study. Copyright © 2018 The Author(s)

Effects of metabolic syndrome on arterial function in different age groups: The Advanced Approach to Arterial Stiffness study

Objective: The aim of the Advanced Approach to Arterial Stiffness study was to compare arterial stiffness measured simultaneously with two different methods in different age groups of middle-aged and older adults with or without metabolic syndrome (MetS). The specific effects of the different MetS components on arterial stiffness were also studied. Methods: This prospective, multicentre, international study included 2224 patients aged 40 years and older, 1664 with and 560 without MetS. Patients were enrolled in 32 centres from 18 European countries affiliated to the International Society of Vascular Health &amp; Aging. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) and the carotid-femoral pulse wave velocity (CF-PWV) in four prespecified age groups: 40-49, 50-59, 60-74, 75-90 years. In this report, we present the baseline data of this study. Results: Both CF-PWV and CAVI increased with age, with a higher correlation coefficient for CAVI (comparison of coefficients P&lt;0.001). Age-adjusted and sex-adjusted values of CF-PWV and CAVI were weakly intercorrelated (r2=0.06, P&lt;0.001). Age-adjusted and sex-adjusted values for CF-PWV but not CAVI were higher in presence of MetS (CF-PWV: 9.57±0.06 vs. 8.65±0.10, P&lt;0.001; CAVI: 8.34±0.03 vs. 8.29±0.04, P=0.40; mean±SEM; MetS vs. no MetS). The absence of an overall effect of MetS on CAVI was related to the heterogeneous effects of the components of MetS on this parameter: CAVI was positively associated with the high glycaemia and high blood pressure components, whereas lacked significant associations with the HDL and triglycerides components while exhibiting a negative association with the overweight component. In contrast, all five MetS components showed positive associations with CF-PWV. Conclusion: This large European multicentre study reveals a differential impact of MetS and age on CAVI and CF PWV and suggests that age may have a more pronounced effect on CAVI, whereas MetS increases CF-PWV but not CAVI. This important finding may be due to heterogeneous effects of MetS components on CAVI. The clinical significance of these original results will be assessed during the longitudinal phase of the study. Copyright © 2018 The Author(s)