An interpretable machine learning model for real-time sepsis prediction based on basic physiological indicators.

OBJECTIVE: In view of the important role of risk prediction models in the clinical diagnosis and treatment of sepsis, and the limitations of existing models in terms of timeliness and interpretability, we intend to develop a real-time prediction model of sepsis with high timeliness and clinical interpretability. PATIENTS AND METHODS: We used eight real-time basic physiological monitoring indicators of patients, including heart rate, respiratory rate, oxygen saturation, mean arterial pressure, systolic blood pressure, diastolic blood pressure, temperature and blood glucose, extracted three-hour dynamic feature sequences, and calculated 3 linear parameters (mean, standard deviation, and endpoint value), a 24-dimensional feature vector was constructed, and finally a real-time sepsis prediction model was constructed based on the Local Interpretable Model-Agnostic Explanation (LIME) interpretability method. RESULTS: The area under the receiver operating characteristic curve (AUROC), Accuracy and F1 scores of Extremely Randomized Trees we built were higher than those of other models, with AUROC above 0.76, showing the best performance. The Imbalance XGBoost has a high specificity (0.86) in predicting sepsis. The LIME local interpretable model we built can display a large amount of valid model prediction details for clinical workers' reference, including the prediction probability and the influence of each feature on the prediction result, thus effectively assisting the work of clinical workers and improving diagnostic efficiency. CONCLUSIONS: This model can provide real-time dynamic early warning of sepsis for critically ill patients under supervision and provide a reference for clinical decision support. At the same time, interpretive analysis of sepsis prediction models can improve the credibility of the models.

[Effect of progesterone receptor status on efficacy of aromatase inhibitors and survival time in patients with advanced breast cancer].

To investigate the effect of progesterone receptor (PR) on the efficacy of first-line aromatase inhibitor (AI) endocrine therapy and progression-free survival (PFS) in patients with estrogen receptor (ER) positive HER-2 negative advanced breast cancer. The clinical data of 198 patients with advanced breast cancer treated in Henan Cancer Hospital from January 2014 to October 2019 were collected. The Chi-square test was used to compare the difference between the two groups, and the Cox regression model was used to analyze the related prognostic factors. The median progression-free survival time ((PFS)) of PR+and PR- patients were 12.5 months and 9.0 months, respectively, and the difference was statistically significant (P=0.004). The clinical benefit rate (CBR) was 81.1% and 63.1%, respectively, and the difference was not statistically significant (P<0.001). PR is an independent prognostic factor of first-line AI endocrine therapy in ER-positive HER-2-negative patients. PR+type breast cancer has a better response to first-line AI endocrine therapy and longer PFS time than PR- type advanced breast cancer.

[Clinical observation of palbociclib combined with endocrine therapy in hormone receptor positive and HER2 negative advanced breast cancer].

Objective: To analyze the application, efficacy, and safety of palbociclib in hormone receptor positive (HR+) and HER2 negative (HER2-) advanced breast cancer in the real world. Methods: The information of patients who received palbociclib treatment from September 2018 to September 2020 was collected, and the general medical history data and disease characteristics were summarized. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and safety were analyzed. Results: A total of 55 patients with HR+/HER2-advanced breast cancer who received a treatment regimen containing palbociclib were enrolled. The ORR was 48.8%, and DCR was 88.4%. The median PFS was 12.0 months (95%CI, 11.1-13.0 months), and the median TTF was 8.50 months (95%CI, 2.5-14.5 months). Among them, palbociclib was superior to multi-line therapy in the first line (P=0.000 1). The prognosis of patients with non-liver metastases was better (P=0.01). Hematological toxicity was the focus of observation of adverse events, including leukopenia, neutropenia, and thrombocytopenia. The incidence rates of them were 78.2%, 85.5%, and 34.5%, respectively. No other grade 3-4 nonhematological toxicity was found. Conclusions: Palbociclib combined with endocrine therapy in patients with HR+/HER2-advanced breast cancer has good efficacy and controllable adverse reactions. It can be used as a first-line or multi-line treatment option for HR+/HER2-advanced breast cancer.

[Clinical observation of apatinib mesylate for the treatment of multi-drug resistant advanced breast cancer].

Objective: To assess the clinical efficacy and adverse outcomes of apatinib mesylate for the treatment of multi-drug resistant advanced breast cancer. Methods: A total of 24 patients with multi-drug-resistant advanced breast cancer who underwent apatinib mesylate treatment were retrospectively analyzed at the Diagnosis and Treatment Center for Breast Cancer of Henan Cancer Hospital. Patients were reviewed every 4 weeks after initial treatment and then every 8 weeks after stable disease. Objective response rate (ORR), progression free survival (PFS), overall survival (OS) , toxicity and adverse outcomes of apatinib mesylate treatment were evaluated by imaging examinations. Results: Totally, 24 patients received apatinib mesylate at a dose of 500 mg QD. Out of the 24 patients treated, complete remission (CR) occurred in none of the patients, partial remission (PR) in 10 cases, stable disease (SD) in 10 cases, progressive disease (PD) in 4 cases, and drug with drawal in 2 cases due to adverse outcomes. Treatment with apatinib mesylate resulted in an ORR of 41.7% (10/24), disease control rate (DCR) of 83.3%, PFS of 4.7 months, and OS of 8.0 months. Adverse outcomes included proteinuria, high blood pressure, fatigue, hand-foot skin reaction (HFSR), hyperbilirubinemia, leukopenia, hair/skin pigmentation decreased. Most of the adverse events were tolerable and can be controlled after symptomatic management. Conclusions: Single-agent apatinib mesylate demonstrated the good short-term efficacy for multi-drug resistant advanced breast cancer in patients who previously underwent multiple line treatment failures. Adverse effects were controllable after symptomatic management. Treatment with apatinib mesylate maybe a viable option when other treatment modalities failed.

[Synergistic lethal effect of combined treatment of arsenic trioxide and aclacinomycin on human acute myeloid leukemia cell line KG-1a].

Objective: To investigate the synergistic lethal effect and mechanism of arsenic trioxide (ATO) and aclacinomycin (ACM) on human acute myeloid leukemia cell line KG-1a. Methods: Colony-forming assay was used to detect the proliferation of KG-1a cells treated with different concentration of ATO and ACM. Compusyn software was used to analyze the synergistic effect of ATO and ACM. Flow cytometry and Wright's staining were used to analyze the apoptotic rate of KG-1a cells induced by combined treatment of ATO and ACM. Western blot was used to determine the expression of proteins associated with apoptosis. Results: The cytotoxicity of arsenic trioxide or aclacinomycin alone was in a dose-dependent manner. Flow cytometry analysis showed that the apoptotic rate of KG-1a cells treated with both 0.4 µmol/L ATO and 10 nmol/L ACM was (34.5±3.1)%, significantly higher than (7.6±1.1)% of 0.4 µmol/L ATO treatment or (18.7±2.3) % of 10 nmol/L ACM treatment alone (P<0.05). The apoptotic rate of KG-1a cells treated with both 1.5 µmol/L ATO and 37.5 nmol/L ACM was (52.5±4.7)%, significantly higher than (19.1±3.2)% of 1.5 µmol/L ATO treatment or (27.7±2.2)% of 37.5 nmol/L ACM treatment alone (P<0.05). The apoptotic rate of KG-1a cells treated with both 3.0 µmol/L ATO and 75 nmol/L ACM was (61.3±4.5)%, significantly higher than (29.5±2.5)% of 3.0 µmol/L ATO treatment or (28.6±3.4) % of 75 nmol/L ACM treatment alone (P<0.05). In addition, the result of Wright's staining showed that combined treatment of ATO and ACM induced a more apparent phenotype of apoptosis when compared with single agent treatment. Compusyn software analysis showed that the combination index (CI) value of combined treatment group was less than 1, which indicated the synergistic effect of these two agents. Conclusions: Combined treatment of ATO and ACM shows a synergistic lethal effect on human acute myeloid leukemia cell line KG-1a via activating the apoptotic pathway, which inhibits cell growth and induces apoptosis.

Ten novel MHC-DPB1 alleles identified in Tibetan macaque (Macaca thibetana).

Ten novel MHC-DPB1 alleles of Tibetan macaque, were identified by cloning and sequencing.

Procalcitonin and C-reactive protein in early diagnosis of sepsis caused by either Gram-negative or Gram-positive bacteria.

BACKGROUND: Sepsis is the most frequent cause of systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT) and C-reactive protein (CRP) are well-known predictors of sepsis. Serum PCT levels are associated with blood culture positivity in patients with sepsis, but the magnitude of elevation of PCT and CRP levels at the onset of sepsis is unknown in Gram-negative (GN) bacteremia and in Gram-positive (GP) bacteremia. AIMS: To evaluate the PCT and CRP levels in 72 h at the onset of sepsis in GN and GP bacteremia. METHODS: We retrospectively analyzed the data from 648 blood-positive specimens from three integrated teaching hospitals in Xiamen, China. One hundred and forty-seven adult patients with sepsis within 72 h enrolled in the study. Serum PCT and CRP level were assessed according GN or GP bacteremia. RESULTS: A total of 147 (22.68 %) patients were eligible for inclusion in the study, including 56 GP sepsis and 91 GN sepsis. PCT, but not CRP levels, was significantly higher in patients in the GP group than in the GN group (23.64 vs 6.18 ng/mL, p < 0.001). The area under the receiver-operating characteristic (ROC) curve of PCT was 0.73 (95 % confidence interval 0.65-0.81) and that under the ROC curve of CRP was 0.52 (95 % confidence interval 0.43-0.62). A positive predictive value of 72.5 % and a negative predictive value of 67.9 % were achieved with a PCT cutoff value of 2.1 ng/ml. CONCLUSION: Serum PCT levels are higher in GN sepsis than GP sepsis in 72 h. There are not differences in CRP. The separation of PCT and CRP phenomenon is helpful for early diagnosis of GP sepsis.

Sequence characterization and phylogenetic analysis of Toll-like receptor (TLR) 4 gene in the Tibetan macaque (Macaca thibetana).

In this study, the complete coding region sequence of an innate immune-related TLR4 gene was obtained from the Tibetan macaque (Macaca thibetana) genome via PCR and direct sequencing. The sequence had a total length of 2481 bp, contained 3 complete exons, and encoded 826 amino acids (AAs); its isoelectric point was 5.703, and the molecular weight was 94.72 kDa. The high structure prediction showed that the protein was comprised of one extracellular region, one transmembrane region, and one intracellular region. There were 48 potential functional sites in the protein, including glycosylation, phosphorylation, and acetylation sites. A homology analysis among 9 primate species, including the Tibetan macaque, human, chimpanzee, gibbon, rhesus macaque, cynomolgus monkey, pig-tailed monkey, squirrel monkey, and small-eared galago, showed that the homology of the nucleotide and AA sequences ranged from 60.9-99.5% and 51.4- 99.0%, respectively. Higher variability was identified in the extracellular region of the TLR4 protein, and its variable sites accounted for 88.79% (AA) of the total variable sites. Additionally, the number of AAs at the 3' end of the intracellular region was notably different among the primate lineages. The phylogenetic tree based on TLR4 gene exons of 9 primate species showed that the Tibetan macaque clustered with the rhesus macaque, cynomolgus monkey, and pig-tailed monkey; it was most distant from the small-eared galago. This study will provide an important basis for further study on the expression, regulation, and polymorphism of the TLR4 gene and the relationship between polymorphisms and host disease susceptibility.

Uneven evolutionary rate of the melatonin-related receptor gene (GPR50) in primates.

The melatonin-related receptor GPR50 plays an important role in mammalian adaptive thermogenesis in response to calorie intake. The evolutionary history of the GPR50 gene is poorly understood in primates; however, it has been reported that GPR50 is the mammalian ortholog of Mel1c, which has been well characterized. In this study, the complete coding sequences of the GPR50 gene in the Sichuan snub-nosed monkeys (Rhinopithecus roxellana) and Tibetan macaques (Macaca thibetana) were sequenced, and the orthologous nucleotide acid sequences of the GPR50 gene in 11 other primate species were downloaded from GenBank. Thirteen species representing 6 major primate lineages (human, great ape, lesser ape, Old World monkey, New World monkey, and prosimian monkey) were subjected to statistical analyses. A selective test showed that the entire GPR50 gene sequence is under strong purifying selection in these primates but has a significantly different evolutionary rate among the 6 major primate lineages. Notably, both the Homo and Pan branches exhibited an ω ratio >1, indicating accelerated evolution of the two lineages. Further analysis of different domains revealed that the acceleration trend was more significant in the C-terminal domain (CTD). Interestingly, in the alignment of 13 primate GPR50 nucleotide acid sequences, numerous insertions or deletions were only found in the CTD region, implying that this region may play a key role in the process of primate GPR50 evolution. The results provide deeper insight into the functional evolution of GPR50 in mammals at the molecular level.

Phytotreatment of sewage sludge contaminated by heavy metals and PAHs by co-planting Sedum alfredii and Alocasia marorrhiza.

High concentrations of heavy metals and organic pollutants in municipal sewage sludge are key factors limiting its use in agriculture. The objectives of this study were to decrease the heavy metal and polycyclic aromatic hydrocarbon concentrations in sewage sludge by phytotreatment and to determine, in a field experiment, whether co-planting is more effective than using a mono-crop of Sedum alfredii. Four treatments were used in the plot experiment: no sludge, no plants, S. alfredii and co-planting S. alfredii and Alocasia marorrhiza. The results showed that co-planting produced tubers and shoots of A. marorrhiza that were suitable as a safe animal feed and good organic K fertilizer, respectively. Co-planting was more effective than mono-planting at reducing concentrations of total Zn and diethylenetriaminepentaacetic acid (DTPA)-extractable Zn, Cd, and Cu in the sludge. Co-planting decreased the concentrations of DTPA-extractable heavy metals and benzo[a]pyrene (B[a]P) in the sludge significantly compared with the unplanted sludge. Decreases of 87, 75, 85, 31, and 64% were obtained for B[a]P and DTPA-extractable Zn, Cd, Cu, and Pb, respectively, compared with the fresh sludge. These results indicate that co-planting can reduce significantly the environmental risks associated with heavy metals and B[a]P in sewage sludge for further disposal.

Identification and characterization of the major histocompatibility complex class II DQB (MhcMath-DQB1) alleles in Tibetan macaques (Macaca thibetana).

Tibetan macaque (Macaca thibetana), an endangered primate species endemic to China, have been used as experimental animal model for various human diseases. Major histocompatibility complex (MHC) genes play a crucial role in the susceptibility and/or resistance to many human diseases, but little is known about Tibetan macaques. To gain an insight into the MHC background and to facilitate the experimental use of Tibetan macaques, the second exon of Mhc-DQB1 gene was sequenced in a cohort of wild Tibetan macaques living in the Sichuan province of China. A total of 23 MhcMath-DQB1 alleles were identified for the first time, illustrating a marked allelic polymorphism at the DQB1 locus for these macaques. Most of the sequences (74%) observed in this study belong to DQB1*06 (9 alleles) and DQB1*18 (8 alleles) lineages, and the rest (26%) belong to DQB1*15 (3 alleles) and DQB1*17 (3 alleles) lineages. The most frequent alleles detected among these macaques were MhcMath-DQB1*15:02:02 (17.9%), followed by Math-DQB1*06:06, 17:03 and 18:01, which were detected in 9 (16.1%) of the monkeys, respectively. Non-synonymous substitutions occurred at a significantly higher frequency than synonymous substitutions in the peptide-binding region, suggesting balancing selection for maintaining polymorphisms at the MHC class II DQB1 locus. Phylogenetic analyses confirms the trans-species model of evolution of the Mhc-DQB1 genes in non-human primates, and in particular, the extensive allele sharing is observed between Tibetan and other macaque species.

Associations of lifestyle-related factors, hsa-miR-149 and hsa-miR-605 gene polymorphisms with gastrointestinal cancer risk.

To explore the associations of SNPs within hsa-miR-605 (rs2043556) and hsa-miR-149 (rs2292832) and lifestyle-related factors with gastrointestinal cancer, a case-control study including 762 cases and 757 controls was conducted. Marginally significant associations were found both for hsa-miR-149 rs2292832 with gastric cancer risk (TC + CC vs. TT, OR = 0.68, 95% CI: 0.44-1.04) and for hsa-miR-605 rs2043556 with colorectal cancer risk (AG + GG vs. AA, OR = 0.70, 95% CI: 0.48-1.02) in males. Tea drinking showed a protective effect on gastric cancer risk (OR = 0.28, 95% CI: 0.13-0.60), while smoke inhalation increased the risk of gastric cancer (OR = 1.94, 95% CI: 1.08-3.47). Irritability was found to be a risk factor for both colorectal cancer (OR = 1.61, 95% CI: 1.02-2.53) and gastric cancer (OR = 1.96, 95% CI: 1.17-3.29). Among those that engaged in smoke inhalation, miR-149 CT/CC and miR-605 AG/GG genotype carriers had increased susceptibilities to colorectal cancer (OR = 1.90, 95% CI: 1.11-3.25) and gastric cancer (OR = 1.87, 95% CI: 1.03-3.42), respectively. Among the tea drinkers, there exists a marginally protective effect of miR-605 AG/GG genotypes on colorectal cancer incidence (OR = 0.71, 95% CI: 0.47-1.06) and a significantly protective effect of miR-149 CT/CC on gastric cancer incidence (OR = 0.47, 95% CI: 0.29-0.77). The SNPs of rs2292832 and rs2043556 might be able to modify the susceptibility to male gastric and colorectal cancers, respectively. Tea drinking is a protective factor, while smoke inhalation is a risk factor for gastric cancer, and they might have the potential to modify the associations between miR-149 and miR-605 polymorphisms with gastrointestinal cancer risk. In addition, irritability was shown to be a risk factor for both gastric and colorectal cancers.

[Genetic effects of mineral elements of Fe, Zn, Mn and P in black pericarp rice grains].

Complete diallel crosses with seven varieties of black pericarp rice were conducted in one year to analyze the genetic effects on main mineral elements of Fe, Zn, Mn and P contents in kernels of parents and their F1S and F2S, using the full genetic model including triploid endosperm, cytoplasmic and maternal effects on quantitative traits of seeds in cereal crops. The results indicated that the contents of all the four mineral elements were controlled by seed direct genetic effects, maternal genetic effects as well as by cytoplasmic effects. The seed direct genetic effects were more important than the maternal genetic effects for Fe, Zn, Mn contents, and seed direct additive effects constituted a major part of their genetic effects, whereas seed direct additive, maternal additive and dominant effects formed the main part in the inheritance of P content. The heritabilities of seed direct effects of the 4 mineral element contents were all highly significant. The estimate values of narrow heritabilites of seed direct genetic effects were high for Fe, Zn and Mn contents, while those of seed and maternal effects were intermediate for P content. Therefore, more attention should be paid to the single plant selection and single grain selection based on the seed mineral element contents of hybrid offspring.

[Effects of murine lymphokine-activated killer (LAK) cells on proliferation of myeloid progenitor cells (CFU-GM)].

Murine lymphokine-activated killer (LAK) cells were generated from spleen cells of C57/BL6 mice by culture of spleen cells in vitro for 72 hours in medium containing 500 units/ml recombinant human interleukin 2 (IL-2), and effects of these LAK cells on proliferation of syngenic myeloid progenitor cells (CFU-GM) were observed. After 3 days culture, LAK cells were assayed for their cytotoxicity in a 4 hours 51Cr-release test. Either natural killer (NK) cell sensitive YAC-1 lymphoma cells or NK cell resistant LP-3 and WEHI-164 fibrosarcoma cells were efficiently lysed by murine LAK cells. When LAK cells were added into culture system in a final concentration of 5 x 10(4)/ml, 2 x 10(5)/ml, 8 x 10(5)/ml, CFU-GM were increased by 55.2%, 165.5%, and 194.4% of control respectively. LAK-CM also showed augmentative effect on CFU-GM growth. When 10% (v/v) of LAK-CM were added into culture system, CFU-GM were increased by 51.4% of control, but LAK-CM alone could not stimulate CFU-GM growth. Again, effects of LAK-BMC interaction on CFU-GM formation were investigated. CFU-GM were inhibited to 27.6% of control when 1 x 10(5) BMC were mixed with 8 x 10(5) LAK cells and incubated for 4 hours prior to CFU-GM culture. These data suggest that (1) LAK cells may secrete co-CSF which showed synergistic effect with CSF on CFU-GM proliferation: (2) When LAK cells contact with BMC, they showed significant cytotoxicity to myeloid progenitor cells which mediated decrease of CFU-GM formation.

Modulating activity of B lymphocytes on haemopoiesis (II)--the purification of proliferation amplifying factor (PAF).

In recent years we have done a series of observations on the haemopoietic modulation effects of lymphocytes. Now we report here, for the first time, the purification of a modulating factor (proliferation amplifying factor, PAE) with affinity chromatography and HPLC from supernatant conditioned by a lymphoma cell line M12.4.1. RAF exhibits on SDS-PAGE only one band, the molecular weight is about 31,000, the specific activity is 20,000 times that in the conditioned medium. It may provide a direct evidence that the B lymphocyte also possesses some haemopoietic modulation effects.

Dynamic aspects of whole-body nitrogen metabolism in uremic patients on dietary therapy.

15N-glycine administered orally to 3 patients with chronic renal failure and 15N-ammonium chloride given by intravenous infusion to 5 patients were used as tracers in studying the total body nitrogen metabolism during the course of dietary therapy. Patients on a diet providing 1.2 g protein per kilogram body weight per day had significantly lowered total nitrogen flux (Q) and rates of total body protein synthesis (S) and catabolism (C) as compared with the normal controls. A reduction in daily protein intake to 0.6 g/kg/day resulted in marked increases in all these parameters, so that the values actually approached that of the normal controls. While in the normal subjects low-protein intake did not affect the total body protein turnover significantly, it tended to decrease Q and to raise S, C, and S/Q. The results of the present study suggest that the adaptive response to restriction in protein intake is a more efficient utilization of nitrogen entering the metabolic pool for anabolic purposes, and less nitrogen excreted as urea. This response becomes manifest and essential to patients with chronic renal failure and forms the basis for low-protein diet therapy.