Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial.

BACKGROUND: Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a PD-1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC. PATIENTS AND METHODS: In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1:1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by 2 cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either 6 cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or 6 cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS). RESULTS: Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in experimental arm and 118 patients in control arm, with surgery performed in 92% and 83.9%, respectively. At data cutoff (July 11, 2023), the pCR rate were 39.8% (95% CI, 30.7 to 49.5) in experimental arm compared to 15.3% (95% CI, 9.3 to 23.0) in control arm (difference, 24.6%; odds ratio, 3.7; 95% CI, 2.0 to 6.9; p < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, grade ≥ 3 treatment-related adverse events were 29.2% and 27.2%. 3-year EFS rate and OS continue to mature. CONCLUSIONS: In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.

[Bayesian network prediction study on the impact of occupational health psychological factors on insomnia among thermal power generation workers].

Objective: To explore the risk factors of insomnia among employees in the thermal power generation industry and the network relationships between their interactions, and to provide scientific basis for personalized interventions for high-risk groups with insomnia. Methods: In November 2022, 860 employees of a typical thermal power generation enterprise were selected as the research subjects by cluster sampling. On-site occupational health field surveys and questionnaire surveys were used to collect basic information, occupational characteristics, anxiety, depression, stress, occupational stress, and insomnia. The interaction between insomnia and occupational health psychological factors was evaluated by using structural equation model analysis and Bayesian network construction. Results: The detection rates of anxiety, depression and stress were 34.0% (292/860), 32.1% (276/860) and 18.0% (155/860), respectively. The total score of occupational stress was (445.3±49.9) points, and 160 workers (18.6%) were suspected of insomnia, and 578 workers (67.2%) had insomnia. Structural equation model analysis showed that occupational stress had a significant effect on the occurrence of insomnia in thermal power generation workers (standardized load coefficient was 0.644), and occupational health psychology had a low effect on insomnia (standardized load coefficient was 0.065). However, the Bayesian network model further analysis found that anxiety and stress were the two parent nodes of insomnia, with direct causal relationships, the arc strength was-8.607 and -15.665, respectively. The model prediction results showed that the probability of insomnia occurring was predicted to be 0 in the cases of no stress and anxiety, low stress without anxiety, and no stress with low anxiety. When high stress with low anxiety and low stress with high anxiety occurred, the predicted probability of insomnia occurring were 0.38 and 0.47, respectively. When both high stress and high anxiety occurred simultaneously, the predicted probability of insomnia occurring was 0.51. Conclusion: Bayesian network risk assessment can intuitively reveal and predict the insomnia risk of thermal power generation workers and the network interaction relationship between the risks. Anxiety and stress are the direct causal risks of insomnia, and stress is the main risk of individual insomnia of thermal power generation workers. The occurrence of insomnia can be reduced based on scientific intervention of stress conditions.

[Construction of CD138-targeted chimeric antigen receptor- modified T cells and their effect in multiple myeloma therapy].

Objective: To construct a novel chimeric antigen receptor T (CAR-T) cell targeting CD138 and to investigate its cytotoxicity against myeloma cells. Methods: The hybridoma strain that can stably secrete the CD138 monoclonal antibody (mAb) was prepared and obtained through monoclonal antibody screening technology. The hybridoma strain cells were intraperitoneally injected into mice to produce ascites containing monoclonal antibodies, which were then collected and purified to obtain pure CD138 mAb. Further examinations were performed to assess the biological characteristics of CD138 mAb. The variable region sequence of this antibody was amplified through reverse transcription polymerase chain reaction and was used as the antigen recognition domain of CD138 CAR, which was subsequently expressed on the surface of T cells by lentiviral infection. Flow cytometry was employed to assess the phenotype of CD138 CAR-T cells. In vitro cytotoxicity and degranulation assays were performed to evaluate their antitumor effects. Results: ① We successfully prepared anti-human CD138 antibody hybridoma cell lines and screened a hybridoma cell strain, 5G2, which could persistently and stably secrete the anti-CD138 antibody. ② The purified CD138 (5G2) mAb can especially recognize CD138(+) cells with a binding affinity constant (K(D)) of 6.011×10(-9) mol/L and showed no significant binding activity with CD138(-) cells. ③The variable region sequence of the CD138 (5G2) antibody was obtained using molecular cloning technology, and CD138 (5G2) CAR was successfully constructed and expressed on T cells through lentivirus infection and, concurrently, demonstrated effective binding to recombinant human CD138 protein.④ The proliferation of T cells transduced with the CD138 (5G2) CAR was highly efficient. The phenotype analysis revealed that CD138 (5G2) CAR-T cells exhibited a greater tendency to differentiate into central memory T cells and memory stem T cells, with a reduced proportion of terminally differentiated effector memory subsets. ⑤CD138 (5G2) CAR-T cells demonstrated specific cytotoxicity against CD138(+) myeloma cell line H929, whereas CD138(-) cell line K562 remained unaffected. The percentage of residual H929 cells was (12.92±8.02) % after co-culturing with CD138 (5G2) CAR-T cells, while (54.25±15.79) % was left in the Vector-T group (E∶T=1∶2; P<0.001). ⑥Results of degranulation assays demonstrated a significant activation of CD138 (5G2) CAR-T cells after co-culture with the H929 cell line, whereas no significant activation was observed in Vector-T cells [ (25.78±3.35) % vs (6.13±1.30) %, P<0.001]. ⑦After co-culturing with CD138(+) cells, CD138 (5G2) CAR-T cells exhibited a significant increase in cytokine secretion compared to the Vector-T group [interleukin-2: (1 697.52±599.05) pg/ml vs (5.07±1.17) pg/ml, P<0.001; interferon-γ: (3 312.20±486.38) pg/ml vs (9.28±1.46) pg/ml, P<0.001; and tumor necrosis factor-α: (1 837.43±640.49) pg/ml vs (8.75±1.65) pg/ml, P<0.001]. However, no significant difference was observed in cytokine secretion levels between the two groups after co-culturing with CD138(-) cells. Conclusion: This study successfully prepared a novel monoclonal antibody against CD138, and CAR-T cells constructed with the antigen recognition domain derived from this 5G2 mAb demonstrated effective antitumor activity against myeloma cells. This can be used as a new option for the detection of the CD138 antigen and proposes a novel strategy for multiple myeloma immunotherapy.

Draft genome sequence of Penicillium citrinum B9, a plant growth-promoting symbiont from barley rhizosphere.

Penicillium citrinum strain B9 is a plant growth-promoting fungus isolated from Barley (Hordeum vulgare) rhizosphere. We report the first draft genome of P. citrinum B9 assembled using single-molecule real-time sequencing and Illumina reads. The assembled genome spans 31.3 Mb comprising nine contigs and 10,106 protein-encoding genes.

[Value of histological activity in predicting endoscopic relapse among patients of ulcerative colitis in endoscopic remission].

Objective: To investigate the value of histological evaluation in predicting endoscopic relapse among patients with ulcerative colitis (UC) who were in endoscopic remission, and to compare the usefulness of various histological scoring systems. Methods: Histological sections from 61 patients with UC who were in endoscopic remission were retrospectively analyzed, at Peking University Third Hospital, Beijing, China from January 2015 to June 2021. They were subdivided into endoscopic persistent remission group (remission group, n=31, Mayo endoscopic score 0) and endoscopic relapse group (relapse group, n=30, Mayo endoscopic score≥1) according to the results of the first endoscopic reexamination after the biopsy. Histological evaluation was performed using the Geboes score (GS) and its simplified version (SGS), the Nancy index (NI) and the Robarts histopathological index (RHI). The median and maximum histological scores for each case in all biopsies were recorded. Univariate comparisons were performed using chi-squares and multivariate analysis using binary logistic regression. The values of four histological evaluation systems for predicting endoscopic relapse among UC patients in endoscopic remission were analyzed using receiver operating characteristic (ROC) curves. Results: Significant differences were observed between the remission and relapse groups. The differences were more pronounced in the maximum histological scores; the mean and highest results of area under the ROC curve scores (AUC) for GS, SGS, NI, and RHI were 0.657, 0.668, 0.682, 0.691, and 0.866, 0.863, 0.864, 0.869, respectively. The differences were statistically significant (P<0.05). The corresponding best cut-offs were GS≥2B.1, SGS≥2B.1, NI≥2, and RHI≥2.5, respectively, which meant mild active inflammation histologically, while there was no statistical difference of AUC among the four histological scoring indices (P>0.05). Univariate and multivariate analyses revealed statistically significant differences in the number of neutrophils in the epithelium and lamina propria (P<0.05). Conclusions: Biopsies from UC patients in endoscopic remission may still have histological active inflammation which appears to correlate with endoscopic relapse. Four commonly used histological scoring systems can be used to assess the risk of endoscopic relapse among UC patients in endoscopic remission. The patients who more likely have endoscopic relapse seem to have a histological score greater than the cut-off value (i.e., mild histological activity). The maximum histological scores can accurately predict the risk of endoscopic relapse, while the presence of epithelial and laminar propria neutrophil infiltrates can independently predict the endoscopic relapse in these patients. Considering the utility and convenience in routine practice, NI is recommended for evaluating histological inflammatory activity.

[Preliminary study on the role and mechanism of IL-6 receptor antagonists in improving post-infarction ventricular arrhythmia].

Objective: To investigate the effect of tocilizumab (TCZ) on ventricular arrhythmias (VAs) after myocardial infarction (MI) in Sprague-Dawley rats and explore its potential mechanism. Methods: The random number table method was used to divide 32 adult male Sprague-Dawley rats into 4 groups: Sham group, TCZ group, MI group and MI+TCZ group, with 8 rats in each group. The MI model was established by ligation of the left anterior descending branch of the coronary artery in the MI and MI+TCZ groups, and only sutured without ligation in the Sham and TCZ groups. TCZ was injected into the left superior cervical ganglion (SCG) of rats in the TCZ and MI+TCZ groups after successful modeling or sham operation, and the same amount of normal saline was injected in the Sham and MI groups. 24 h after successful modeling, ECG of rats in each group was recorded, heart rate variability (HRV, including low frequency power (LF), high frequency power (HF), LF/HF ratio), QT interval, QTc interval were calculated, and left ventricular effective refractory period (ERP) and VA inducibility were measured. Myocardial infarct size and tissue changes were observed with triphenyl tetrazolium chloride staining and HE staining. Real-time PCR analysis was used to detect the messager RNA (mRNA) expression of interleukin-6 (IL-6) and signal transducer and activator of transcription (STAT) 3 in SCG and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in myocardial infarction periphery. The expression of c-fos in SCG was detected by immunofluorescence staining. Results: Compared with Sham group and MI+TCZ group, rats in MI group had higher LF and LF/HF ratio, longer QT interval and QTc interval, more VAs induced, lower HF and shorter ERP (P all<0.05). Triphenyl tetrazolium chloride staining and HE staining showed that rats in the Sham and TCZ groups had normal myocardial tissue structure, those in the MI group had severe myocardial injury, and those in the MI+TCZ group had less myocardial injury than those in the MI group. Real-ime PCR analysis showed that compared with Sham group and MI+TCZ group, mRNA expression levels of IL-6 and STAT3 in SCG of rats in MI group were higher, and mRNA expression level of myocardial Kcnd2 was lower (P all<0.05). Immunofluorescence staining showed that the content of c-fos in SCG of rats in MI group was higher than that of Sham group and MI+TCZ group (P all<0.05). Conclusions: TCZ may reduce neural activity of the SCG after MI by inhibiting the IL-6/STAT3 signaling pathway, thereby alleviating myocardial injury and inhibiting VAs.

Label-free-based proteomics analysis reveals differential proteins of sheep, goat and cow milk.

Regarding the limited information on species protein differences between sheep, goat, and cow milk, the differentially expressed proteins in sheep, goat, and cow milk and their functional differences are analyzed using label-free proteomics technology to identify potential biomarkers. 770 proteins and 2914 peptide segments were identified. The statistical analysis showed significant differences in the relative abundances of the 74 proteins among the sheep, goat, and cow milk. CSN3 and LALBA can be used as potential biomarkers for goat milk, XDH can be used as potential biomarkers for cow milk, and CTSB and BPIFB1 can be used as potential biomarkers for sheep milk. The functional analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes showed that these significantly different proteins were enriched by different pathways including thyroid hormone synthesis and glycerol phospholipid metabolism. The data revealed differences in the amounts and physiological functions of the milk proteins of different species, which may provide an important basis for research on the nutritional composition of dairy products and adulteration identification technology.

[Study on the protection of gingival epithelial barrier by interleukin-22 through regulating microbiota and E-cadherin expression].

Objective: To investigate the regulatory effect and mechanism of interleukin-22 (IL-22) on the gingival epithelial barrier in the context of periodontal inflammation. Methods: IL-22 knockout (IL-22 KO) mice were constructed, and periodontitis mice models were established through oral gavage with polymicrobial inoculation. DNAs were extracted from the oral plaques of IL-22 KO periodontitis mice group (n=7) and their wild-type littermates periodontitis group (n=7) to establish a periodontitis-related oral microbiota database"PD-RiskMicroDB", determining the relationship between changes in oral microbiota and microbial function in two groups using 16S rRNA sequencing results. Gingival epithelial cells (GEC) were cultured by modified trypsinization method, and were stimulated with 100 µg/L IL-22, Porphyromonas gingivalis (Pg) (multiplicity of infection:100), separately or together for 3 and 12 hours. The experimental groups were as follows: control group (no stimulation), IL-22 group, Pg group and Pg+IL-22 group. The expression of barrier protein E-cadherin in each group at 3 h was detected by immunofluorescence, real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Fluorescein isothiocyanate-dextran-mediated epithelial cell permeability experiment was conducted to clarify the changes in permeability of GEC in each group at 3 and 12 h. The mRNA expressions of E-cadherin in the gingival epithelium of wild-type littermates periodontitis group and IL-22 KO periodontitis group were detected by RT-qPCR. Fifteen C57BL/6 wild-type mice were randomly divided into control group (n=5), periodontitis group (n=5) and periodontitis+IL-22 treatment group (n=5). RT-qPCR and immunohistochemistry (IHC) staining were used to detect the expression level of E-cadherin in the gingival epithelium of each group. Results: 16S rRNA sequencing results showed that the composition of oral microbiota changed in IL-22 KO periodontitis group, of which the abundance of bacterial genera related to periodontal tissue invasion was significantly increased (linear discriminant analysis score: 2.22, P=0.009), compared with wild-type littermates periodontitis group. In vitro cell experiments showed that after Pg infection for 3 hours, the cell connections of GEC in Pg group were interrupted, and the fluorescence intensity of E-cadherin was reduced in Pg group compared with the control group. Meanwhile, the mRNA and protein expression levels of E-cadherin (mRNA: 0.69±0.12; protein: 0.60±0.12) were downregulated compared with the control group [mRNA: 1.00±0.00 (P=0.043); protein: 1.04±0.08 (P=0.003)], respectively. The fluorescence intensity of E-cadherin in the Pg+IL-22 group was enhanced compared with Pg group, and expression levels of E-cadherin mRNA (1.16±0.10) and protein (0.98±0.07) in Pg+IL-22 group showed a significant increase compared with Pg group [mRNA: 0.69±0.12 (P=0.005); protein: 0.60±0.12 (P=0.007)]. The result of epithelial permeability test showed that there was no statistical difference in epithelial permeability among control group, Pg group, IL-22 group and Pg+IL-22 group with treatment for 3 hours (F=0.20, P=0.893). While when the treatment time turned to be 12 hours, the epithelial barrier permeability showed a significant increase in Pg group (1.39±0.15) compared with control group (1.00±0.00, P=0.027), and a decrease in Pg+IL-22 group (1.02±0.18) compared with Pg group (1.39±0.15, P=0.034). In vivo, the mRNA expression of E-cadherin in the gingival epithelium of IL-22 KO periodontitis group decreased significantly (0.32±0.21) compared with wild-type littermates periodontitis group (1.01±0.01) (t=5.70, P=0.005). Moreover, RT-qPCR and IHC staining results showed that the mRNA expression level of E-cadherin (0.40±0.07) and absorbance value of E-cadherin positive expression (0.02±0.00) in gingival epithelial tissue of periodontitis group were both significantly down-regulated compared with control group [mRNA: 1.00±0.00 (P=0.005); absorbance value of E-cadherin positive expression: 0.04±0.01 (P=0.006)]. Meanwhile, the mRNA expression level of E-cadherin (1.06±0.24) and the absorbance value of E-cadherin positive expression (0.03±0.01) were both observed increase in periodontitis+IL-22 treatment group compared with periodontitis group (P=0.003, P=0.039). Conclusions: IL-22 may exert a protective effect on the gingival epithelial barrier in an inflammatory environment by regulating the invasiveness of oral microbiota and the expression of host barrier protein.

[Preparation and biological characteristics of extracellular matrix vesicle mimetics].

Objective: To investigate the characteristics of extracellular matrix vesicle mimetics prepared by mechanical extrusion and their effects on the cell viability and osteogenic differentiation potential of human periodontal ligament stem cells (PDLSC). Methods: PDLSC derived extracellular matrix vesicles were prepared by collagenase digestion, while the cell derived vesicle mimetics were simulated by mechanical extrusion. The obtained extracellular matrix vesicles and parental cell derived vesicle mimetics were divided into 4 groups: matrix vesicles derived from PDLSC cultured in basic medium for 7 days (PDLSC matrix vesicles, MVs), vesicle mimetics derived from PDLSC cultured in basic medium for 7 days (PDLSC vesicle mimetics, CVMs), matrix vesicles derived from PDLSC cultured in osteogenic inducing medium for 7 days (osteogenic-induced PDLSC matrix vesicles, O-MVs) and vesicle mimetics derived from PDLSC cultured in osteogenic inducing medium for 7 days (osteogenic-induced PDLSC vesicle mimetics, O-CVMs). Vesicles morphologies and sizes were observed by transmission electron microscopy and nanoparticle tracking analysis. Vesicles uptake was detected by immunofluorescence. With PDLSC as the control group, the effects of vesicles on the viability of PDLSC were detected by cell activity assay (cell counting kit-8), and the effects of vesicles on the osteogenic differentiation potential of PDLSC were detected by alizarin red staining and Western blotting. Results: Vesicles in MVs, O-MVs, CVMs and O-CVMs were all observed with a round structure (size 50-250 nm), and could be taken up by PDLSC without affecting the cell viability. Under osteogenic inducing conditions, PDLSC incubated with O-MVs or O-CVMs could produce more mineralized nodules than those in the control group (PDLSC). MVs, O-MVs, CVMs and O-CVMs could promote the expression of osteogenic-related proteins in PDLSC. PDLSC in group O-CVMs showed significant higher expressions of osteogenic-related proteins, including alkaline phosphatase (ALP) (1.571±0.348), osteopontin (OPN) (1.827±0.627) and osteocalcin (OCN) (1.798±0.537) compared to MVs (ALP: 1.156±0.170, OPN: 1.260±0.293, OCN: 1.286±0.302) (P<0.05). Compared to CMVs-incubated PDLSC, O-CVMs-incubated PDLSC expressed more Runt-related transcription factor 2 (1.632±0.455 vs 1.176±0.128) and OPN (1.827±0.627 vs 1.428±0.427) (P<0.05). Moreover, there was no significant difference in the expression levels of osteoblast-related proteins in PDLSC cultured with MVs, O-MVs and CVMs (P>0.05). Conclusions: The vesicle mimetics prepared by mechanical extrusion method are similar in shape and size to the extracellular matrix vesicles. MVs, O-MVs, CVMs and O-CVMs do not affect the cell viability of PDLSC, and can promote the osteogenic differentiation potential of PDLSC to a certain extent.

[Spatial and temporal distribution characteristics research of esophageal cancer in China].

Objectives: To explore the spatial distribution characteristics, trend changes, and spatial clustering of esophageal cancer among residents in China at the county (city, district) scale, a spatial epidemiological approach was used, with the aim of providing localized evidence for the prevention and treatment of esophageal cancer in China. Methods: The data source was the incidence (crude rate) and mortality (crude rate) of esophageal cancer from 2005 to 2016 in the 2008-2019 edition of China Cancer Registration Annual Report published by the National Cancer Center. The Joinpoint model was used for time trend analysis. The tumor registration area in 2016 was selected as the study area for spatial feature analysis, with a total of 487 counties (cities and districts), covering 27.6% of the national population. Spatial autocorrelation analysis was performed to reveal spatial distribution characteristics by using Arcgis 10.6 software, and spatial scanning statistics was used to analyze spatial clustering characteristics by using SaTScan 9.5 software. The log-likelihood ratio (LLR) and relative risk (RR) were calculated in different windows, and the region with the largest LLR value represented the most likely cluster. Results: From 2005 to 2016, the incidence and mortality rate of esophageal cancer in China showed a trend of increasing at first and then decreasing. The incidence and mortality rate of esophageal cancer in 2016 were characterized by spatial positive correlation. High incidence and high mortality were mainly concentrated in the areas through which the Huaihe River flowed. The primary clusters (taking high incidence rate as an example LLR=6 374.41, RR=2.37, P＜0.001) were mainly distributed in Jiangsu, Anhui and Shandong in eastern China and eastern Henan and southern Hebei in central China, and secondary clusters (taking high incidence rate as an example LLR=1 971.19, RR=1.91, P＜0.001) in Gansu, Ningxia Hui Autonomous Region, Shaanxi, Sichuan and other central and western regions. Conclusions: The incidence and mortality of esophageal cancer in China have decreased since 2010. The disease burden of esophageal cancer has obvious spatial differences, and measures should be taken according to local conditions in high-risk cluster areas such as the Huaihe River basin.

Neuroendocrine Lesions Arising From Mediastinal Teratoma-A Case Report and Literature Review.

Background. Neuroendocrine lesions arising from mediastinal teratomas are rare tumors with only small number of patients reported in literature. The behavior of these lesions appears to be different from traditional neuroendocrine neoplasms. A comprehensive review will be valuable for histologic assessment and treatment planning for similar cases. Case presentation. We present an example of a 57-year-old man who presented with cough. Subsequent work-up revealed an anterior mediastinal mass of 2.1 cm on computed tomography. The patient underwent robot-assisted thoracoscopic thymectomy. Histological examination revealed a mature cystic teratoma with a neuroendocrine component consisting of clusters of tumor cells with round to oval nuclei and a "salt-and-pepper" chromatin pattern. The tumor cells were immunoreactive to cytokeratin, synaptophysin, chromogranin, and INSM1, with a Ki-67 proliferative index of 4%. A histological diagnosis was mature teratoma with well-differentiated low-grade neuroendocrine tumor (carcinoid) was made. The patient was well and without disease after complete surgical excision at 10 months. Literature review. Literature reviewed yielded 13 examples of neuroendocrine lesions arising from mediastinal teratomas. No disease-related mortality was reported, even in lesions with high-grade neuroendocrine, carcinomatous, or immature teratomatous components. Conclusions. Surgical removal is the mainstay of treatment of these lesions, and the presence of a neuroendocrine component does not appear to negatively affect prognosis.

Bimodal alteration of cognitive accuracy for spintronic artificial neural networks.

Spintronics-based artificial neural networks (ANNs) exhibiting nonvolatile, fast, and energy-efficient computing capabilities are promising neuromorphic hardware for performing complex cognitive tasks of artificial intelligence and machine learning. Early experimental efforts focused on multistate device concepts to enhance synaptic weight precisions, albeit compromising on cognitive accuracy due to their low magnetoresistance. Here, we propose a hybrid approach based on the tuning of tunnel magnetoresistance (TMR) and the number of states in the compound magnetic tunnel junctions (MTJs) to improve the cognitive performance of an all-spin ANN. A TMR variation of 33-78% is controlled by the free layer (FL) thickness wedge (1.6-2.6 nm) across the wafer. Meanwhile, the number of resistance states in the compound MTJ is manipulated by varying the number of constituent MTJ cells (n = 1-3), generating n + 1 states with a TMR difference between consecutive states of at least 21%. Using MNIST handwritten digit and fashion object databases, the test accuracy of the compound MTJ ANN is observed to increase with the number of intermediate states for a fixed FL thickness or TMR. Meanwhile, the test accuracy for a 1-cell MTJ increases linearly by 8.3% and 7.4% for handwritten digits and fashion objects, respectively, with increasing TMR. Interestingly, a multifarious TMR dependence of test accuracy is observed with the increasing synaptic complexity in the 2- and 3-cell MTJs. By leveraging on the bimodal tuning of multilevel and TMR, we establish viable paths for enhancing the cognitive performance of spintronic ANN for in-memory and neuromorphic computing.

Cytomorphologic comparison of upper urinary tract urothelial carcinomas and renal cell carcinomas on urine cytology.

INTRODUCTION: Compared to urothelial carcinomas (UCs), the cytomorphology of renal cell carcinomas (RCCs) is underdescribed. This study aims to investigate whether UCs and RCCS of the upper urinary tract can be differentiated cytologically, and to identify distinguishing cytomorphological features. METHODOLOGY: Consecutive urine cytology specimens with atypical/C3, suspicious/C4 or malignant/C5 diagnoses matched with a nephrectomy or ureterectomy specimen with UC or RCC over a 15-year period were reviewed for cellularity, architecture, background composition and cytomorphologic features. RESULTS: Totally 132 specimens were retrieved, comprising 24 RCCs and 108 UCs. Clear cell RCC (CCRCC) (n = 18) was the most common RCC. Urine cytology specimens from UC showed a trend of higher cellularity (p = 0.071) against RCC and was significant in subgroup analysis with CCRCC (p < .001). Epithelial structures in sheets, tubules, and papillae were exclusive in specimens of UC (p < .05). For background features, squamous cells were more common for RCC (p = .006) including CCRCC (p = .003), whereas polymorphs (p = .011) and necrotic material (p = .010) were associated with UC. Average nuclear size was larger and nuclear size variation (p < .001) and nuclear-cytoplasmic ratio (p = .001) were greater in UC (p = .001) than RCC. Comparing RCC to high-grade UCs only, nuclear-cytoplasmic ratio maintained statistical significance (p = .006) while average nuclear size showed a trend (p = .063). CONCLUSION: A clean background free of tumor necrosis and polymorphs, and the lack of complex tumor fragments favors RCC. UCs also display larger nuclear size, higher nuclear size variation and nuclear-cytoplasmic ratio. These cytomorphological features with corroboration of clinical/radiological findings, can aid in raising a diagnosis of RCC.

von Willebrand factor antigen, von Willebrand factor propeptide and ADAMTS13 activity in TIA or ischaemic stroke patients changing antiplatelet therapy.

Data are limited on the impact of commencing antiplatelet therapy on von Willebrand Factor Antigen (VWF:Ag) or von Willebrand Factor propeptide (VWFpp) levels and ADAMTS13 activity, and their relationship with platelet reactivity following TIA/ischaemic stroke. In this pilot, observational study, VWF:Ag and VWFpp levels and ADAMTS13 activity were quantified in 48 patients ≤4 weeks of TIA/ischaemic stroke (baseline), and 14 days (14d) and 90 days (90d) after commencing aspirin, clopidogrel or aspirin+dipyridamole. Platelet reactivity was assessed at moderately-high shear stress (PFA-100® Collagen-Epinephrine / Collagen-ADP / INNOVANCE PFA P2Y assays), and low shear stress (VerifyNow® Aspirin / P2Y12, and Multiplate® Aspirin / ADP assays). VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d in the overall population (P ≤ 0.03). In the clopidogrel subgroup, VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d (P ≤ 0.01), with an increase in ADAMTS13 activity between baseline vs. 90d (P ≤ 0.03). In the aspirin+dipyridamole subgroup, there was an inverse relationship between VWF:Ag and VWFpp levels with both PFA-100 C-ADP and INNOVANCE PFA P2Y closure times (CTs) at baseline (P ≤ 0.02), with PFA-100 C-ADP, INNOVANCE PFA P2Y and C-EPI CTs at 14d (P ≤ 0.05), and between VWF:Ag levels and PFA-100 INNOVANCE PFA P2Y CTs at 90d (P = 0.03). There was a positive relationship between ADAMTS13 activity and PFA-100 C-ADP CTs at baseline (R2 = 0.254; P = 0.04). Commencing/altering antiplatelet therapy, mainly attributed to commencing clopidogrel in this study, was associated with decreasing endothelial activation following TIA/ischaemic stroke. These data enhance our understanding of the impact of VWF:Ag and VWFpp especially on ex-vivo platelet reactivity status at high shear stress after TIA/ischaemic stroke.

Wildfires increasingly threaten oil and gas wells in the western United States with disproportionate impacts on marginalized populations.

The western United States is home to most of the nation's oil and gas production and, increasingly, wildfires. We examined historical threats of wildfires for oil and gas wells, the extent to which wildfires are projected to threaten wells as climate change progresses, and exposure of human populations to these wells. From 1984-2019, we found that cumulatively 102,882 wells were located in wildfire burn areas, and 348,853 people were exposed (resided ≤ 1 km). During this period, we observed a five-fold increase in the number of wells in wildfire burn areas and a doubling of the population within 1 km of these wells. These trends are projected to increase by late century, likely threatening human health. Approximately 2.9 million people reside within 1 km of wells in areas with high wildfire risk, and Asian, Black, Hispanic, and Native American people have disproportionately high exposure to wildfire-threatened wells.

[Prevalence and influencing factors on food allergy among children aged 0-5 years in China].

Objective: To describe the prevalence of food allergy among children aged 0-5 years in China and to explore related influencing factors. Methods: Multistage stratified random sampling method was used to collect data from 275 surveillance sites of the China National Nutrition and Health Survey of Chinese children and lactating mothers programs in 31 provinces (autonomous regions and municipalities) of China in 2016-2017. A total of 70 107 participants aged 0-5 years were included in this study. The study collected information of participants' demographic characteristics and food allergies by face-to-face questionnaire. The prevalence of food allergy was analyzed, using the complex data weighting method. The logistic regression models were used to analyze the influencing factors related to food allergy. Results: The overall prevalence of self-reported food allergy among children aged 0-5 years was 4.81%. Prevalence rates in infants aged 0-5 months, and 6-23 months and preschool children aged 2-5 years were 0.81%, 4.68% and 5.26%, respectively. The results of logistic analysis showed that there was a significantly positive correlation between factors including children from 6 months to 5 years old, urban area, southwest area, first-born, mothers with college education or above, and the prevalence of food allergy in children. Shrimp, poultry eggs, crab shellfish, fruit, milk and fish appeared the common allergic foods in children aged 0-5 years, with prevalence rates of self-reported food allergy as 1.55%, 1.25%, 0.99%, 0.97%, 0.87% and 0.86%, respectively. The proportion of single food allergy in children with allergies was 69.85%. Conclusions: Among children aged 0-5 years, the prevalence of self-reported food allergy increases with age, in China. Foods that is prone to allergies include fish, shrimp, crab, shellfish, poultry eggs, milk and fruits, etc. Most allergies were only caused by single food in children, under observation.

[Epidemiological characteristics and spatial aggregation of acute myocardial infarction in Shandong Province].

Objective: To understand the characteristics and trends of acute myocardial infarction (AMI) in Shandong Province and to provide evidence for formulating prevention and control strategies. Methods: Data were derived from the AMI incidence reports of Shandong Province's Chronic Disease Surveillance Information Management System in 2012-2021. The crude and standardized incidence rates were used as indicators to describe the incidence level of AMI. Joinpoint regression analysis was used to analyze the trends in the incidence and age of onset over the years. The contribution of population aging to the increase in AMI incidence was assessed using the rate difference decomposition method. The incidence of AMI in each district (county) in Shandong Province was visualized using ArcGIS 10.8 software, and global and local spatial autocorrelation analysis was performed using DeoDa 1.12 software. Results: From 2012 to 2021, 198 233 cases of AMI were reported from 19 provincial monitoring sites in Shandong Province, of which 53.13% were males and 97.12% were ≥45 years old. The reported crude incidence increased from 90.12 per 100 000 in 2012 to 176.54 per 100 000 in 2021, with an average annual increase of 7.01% (Z=7.35, P<0.001). There was no significant upward trend in standardized incidence (Z=1.64, P=0.140), but the standardized incidence of male residents showed an increasing trend (Z=2.76, P=0.028). Before 2014, the reported crude incidence of males was similar to that of females, but after 2014, the reported crude incidence of males was continuously higher than that of females. However, males' standardized incidence was higher than females in all years. Both crude and standardized incidence rates were higher in rural residents than in urban areas. The median onset of AMI increased from 71.6 years old in 2012 to 73.5 years old in 2021. The median age of onset in males was lower than that in females in all years, and in most years, the median age of onset in urban residents was lower than that in rural residents. The incidence of AMI in males showed a trend in younger age groups. According to the seasonal decomposition, the incidence peak of AMI was in January, and the trough was in September. The contribution of aging population to the increase in crude incidence of AMI increased from 8.63% in 2013 to 52.58% in 2021. The global spatial autocorrelation analysis showed that the incidence of AMI presented an obvious spatial clustering distribution. Local spatial autocorrelation analysis found that the high-incidence areas (counties) were mainly concentrated in Liaocheng City and Dezhou City in the northwest region of Shandong Province and Heze City in the southwest. Conclusions: The incidence of AMI among residents in Shandong Province was rising, with spatial clustering and seasonal clustering characteristics. People aged 45 years and older, male residents, and rural residents were at high risk of developing AMI. There was a certain trend of younger age at onset among men. Targeted prevention and control measures should be taken for high-incidence seasons, high-risk groups, and high-incidence clustering areas in northwestern Shandong Province.

Metered-Dose Inhaler Spacer with Integrated Spirometer for Home-Based Asthma Monitoring and Drug Uptake.

This work introduces Spiromni, a single device incorporating three different pressurised metered-dose inhaler (pMDI) accessories: a pMDI spacer, an electronic monitoring device (EMD), and a spirometer. While there are devices made to individually address the issues of technique, adherence and monitoring, respectively, for asthma patients as laid out in the Global Initiative for Asthma's (GINA) global strategy for asthma management and prevention, Spiromni was designed to address all three issues using a single, combination device. Spiromni addresses the key challenge of measuring both inhalation and exhalation profiles, which are different by an order of magnitude. Moreover, the innovative design prevents exhalation from entering the spacer chamber and prevents medication loss during inhalation using umbrella valves without a loss in flow velocity. Apart from recording the peak exhalation flow rate, data from the sensors allow us to extract other key lung volume and capacities measures similar to a medical pulmonary function test. We believe this low-cost portable multi-functional device will benefit both asthma patients and clinicians in the management of the disease.

Cytokeratin 15 is a novel and independent predictor of poor outcome in luminal B HER2-negative breast carcinomas.

Cytokeratin 15 (CK15) has been described as a stem cell marker in human organs and its expression is seen in breast tissue. CK15 expression is associated with aggressive features in endometrial and oesophageal cancers, but data on the breast are lacking. This study aims to investigate the clinicopathological associations and prognostic significance of CK15 in breast carcinomas. A multi-institute cohort of breast carcinomas were retrieved. Clinicopathological and outcome data were obtained and compared with immunohistochemical expression CK15 and a panel of biomarkers. In total, 1,476 cases were included, with an expression rate of 3.5%, preferentially expressed in luminal subtypes (p=0.024), with luminal B carcinomas being the highest (4.7%), as opposed to basal-like (1%) and HER2-overexpressed carcinomas (0%). Except for nodal stage (p=0.013) and nodal metastasis (p=0.048), oestrogen (p=0.035) and progesterone receptor (p=0.001) positivity, there were no associations with other clinicopathological parameters. A trend was observed with shorter breast cancer specific survival (BCSS) in CK15-positive luminal B carcinomas (p=0.062). On further subgroup multivariate analysis of luminal B HER2-negative carcinomas, CK15 expression exhibited robust correlation with shorter BCSS (HR=9.004, p=0.001) and disease-free survival (HR=7.085, p<0.001). Restricted to luminal breast carcinomas, specifically luminal B HER2-negative, CK15 is demonstrated to be a robust independent predictor of higher risk of recurrence and shorter survival, with potential as a clinical prognostic marker and an exclusive stem cell marker for this subgroup of carcinomas.