Model Predictive Robustness of Signal Temporal Logic Predicates

The robustness of signal temporal logic not only assesses whether a signal adheres to a specification but also provides a measure of how much a formula is fulfilled or violated. The calculation of robustness is based on evaluating the robustness of underlying predicates. However, the robustness of predicates is usually defined in a model-free way, i.e., without including the system dynamics. Moreover, it is often nontrivial to define the robustness of complicated predicates precisely. To address these issues, we propose a notion of model predictive robustness, which provides a more systematic way of evaluating robustness compared to previous approaches by considering model-based predictions. In particular, we use Gaussian process regression to learn the robustness based on precomputed predictions so that robustness values can be efficiently computed online. We evaluate our approach for the use case of autonomous driving with predicates used in formalized traffic rules on a recorded dataset, which highlights the advantage of our approach compared to traditional approaches in terms of expressiveness. By incorporating our robustness definitions into a trajectory planner, autonomous vehicles obey traffic rules more robustly than human drivers in the dataset.Comment: 7 pages, 6 figures, conference paper in submissio

Persistent Occurrence of Cryptosporidium hominis and Giardia duodenalis Subtypes in a Welfare Institute

Few data are available on the transmission dynamics of intestinal protozoa in children in welfare institutes. In this study, fecal specimens were collected from 396 children in a welfare institute in Shanghai, China during December 2011 (207 specimens), June 2012 (78 specimens), and September 2013 (111 specimens), and examined for Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi by PCR analysis of the small subunit rRNA, triosephosphate isomerase, and internal transcribed spacer genes, respectively. The Cryptosporidium hominis and G. duodenalis assemblage A identified were further subtyped by multilocus sequence typing. Altogether, Cryptosporidium was detected in 39 (9.8%) children, with infection rates of 11.6% (24/207), 9.0% (7/78), and 7.2% (8/111) in December 2011, June 2012, and September 2013, respectively. Infection rates were higher in children of 0–12 months (20.4% compared to 0–7.3% in other age groups, P = 0.0001) and those with diarrhea (17.9% compared to 7.7% in those with no diarrhea, P = 0.006). In contrast, G. duodenalis was detected in 161/396 (40.7%), with infection rates of 48.3% (100/207), 35.9% (28/78), and 29.7% (33/111) in December 2011, June 2012, and September 2013, respectively. There were no significant gender- or diarrhea-associated differences, but the G. duodenalis infection rate in children of 13–24 months (50%) was significantly higher than in the age groups of 0–12 months and > 48 months (29.8–36.5%, P = 0.021). Co-infection of Cryptosporidium and G. duodenalis was seen in 19 (4.8%) children, but no E. bieneusi infection was detected in this study. All Cryptosporidium-positive specimens belonged to the subtype IaA14R4 of C. hominis, while all G. duodenalis-positive specimens belonged to sub-assemblage AII. Both were the same subtypes in a previous outbreak of cryptosporidiosis and giardiasis in a hospital ward hosting children from the welfare institute. Results of the study indicate that there was a persistent occurrence of limited C. hominis and G. duodenalis subtypes in the small enclosed community, with differences in age distribution and association with diarrhea occurrence between cryptosporidiosis and giardiasis

Psychometric properties of the Chinese version of the preoperative assessment of readiness tool among surgical patients

BackgroundThe evaluation of the surgical readiness of patients plays an important role in clinical care. Preoperative readiness assessment is needed to identify the inadequacy among surgical patients, which provides guide for interventions to improve patients’ preoperative readiness. However, there is a paucity of high-level, quality tool that evaluate surgical readiness of patients in China. The purpose of this study is to translate the Preoperative Assessment of Readiness Tool (PART) into Chinese and determine the reliability and validity of the Chinese version in the population of surgical patients.MethodsUsing a standard translation-backward method, the original English version of PART was translated into Chinese. A convenient sampling of 210 surgical patients was recruited from 6 hospitals in Zhejiang Province to test the psychometric properties of this scale including internal consistency, split-half reliability, content validity, structure validity, and floor/ceiling effect.ResultsA total of 194 patients (92%) completed questionnaires. The Chinese version of PART achieved Cronbach’s alphas 0.948 and McDonald’s omega coefficient 0.947, respectively, for the full scale. The estimated odd-even split-half reliability was 0.959. The scale-level content validity index was 0.867, and the items content validity index ranged from 0.83 to 1.0.The output of confirmatory factor analysis (CFA) revealed a two-factor model (χ2 = 510.96; df = 86; p < 0.001; root mean square error approximation = 0.08) with no floor/ceiling effect.ConclusionThe Chinese version of PART demonstrated acceptable reliability and validity among surgical patients. It can be used to evaluate patients’ preoperative preparation and help health professionals provide proper preoperative support

Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair.

While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that the combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL interaction inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to robust apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not non-homologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-κB) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL interaction inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia

Prediction of protein assemblies, the next frontier: The CASP14-CAPRI experiment

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70–75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70–80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands.Cancer Research UK, Grant/Award Number: FC001003; Changzhou Science and Technology Bureau, Grant/Award Number: CE20200503; Department of Energy and Climate Change, Grant/Award Numbers: DE-AR001213, DE-SC0020400, DE-SC0021303; H2020 European Institute of Innovation and Technology, Grant/Award Numbers: 675728, 777536, 823830; Institut national de recherche en informatique et en automatique (INRIA), Grant/Award Number: Cordi-S; Lietuvos Mokslo Taryba, Grant/Award Numbers: S-MIP-17-60, S-MIP-21-35; Medical Research Council, Grant/Award Number: FC001003; Japan Society for the Promotion of Science KAKENHI, Grant/Award Number: JP19J00950; Ministerio de Ciencia e Innovación, Grant/Award Number: PID2019-110167RB-I00; Narodowe Centrum Nauki, Grant/Award Numbers: UMO-2017/25/B/ST4/01026, UMO-2017/26/M/ST4/00044, UMO-2017/27/B/ST4/00926; National Institute of General Medical Sciences, Grant/Award Numbers: R21GM127952, R35GM118078, RM1135136, T32GM132024; National Institutes of Health, Grant/Award Numbers: R01GM074255, R01GM078221, R01GM093123, R01GM109980, R01GM133840, R01GN123055, R01HL142301, R35GM124952, R35GM136409; National Natural Science Foundation of China, Grant/Award Number: 81603152; National Science Foundation, Grant/Award Numbers: AF1645512, CCF1943008, CMMI1825941, DBI1759277, DBI1759934, DBI1917263, DBI20036350, IIS1763246, MCB1925643; NWO, Grant/Award Number: TOP-PUNT 718.015.001; Wellcome Trust, Grant/Award Number: FC00100

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial

Background: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. Methods: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. Results: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups. Conclusions: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. Trial registration: ISRCTN, ISRCTN12233792. Registered November 20th, 2017

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BackgroundPrevious cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes.MethodsWe conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment.ResultsForty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups.ConclusionsIn this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness.Trial registrationISRCTN, ISRCTN12233792 . Registered November 20th, 2017