Enhancing antitumor immunity and achieving tumor eradication with IL11RA mRNA immunotherapy.

Current methods for delivering genes to target tumors face significant challenges, including off-target effects and immune responses against delivery vectors. In this study, we developed a novel approach using messenger RNA (mRNA) to encode IL11RA for local immunotherapy, aiming to harness the immune system to combat tumors. Our research uncovered a compelling correlation between IL11RA expression and CD8 + T cell levels across multiple tumor types, with elevated IL11RA expression correlating with improved overall survival. Examination of the Pan-Cancer Atlas dataset showed a significant reduction in IL11RA expression in various cancer types compared to normal tissue, raising questions about its potential role in tumorigenesis. To achieve efficient in vivo expression of IL11RA, we synthesized two mRNA sequences mimicking the wild-type protein. These mRNA sequences were formulated and capped to ensure effective delivery, resulting in robust expression within tumor sites. Our investigation into IL11RA mRNA therapy demonstrated its effectiveness in controlling tumor growth when administered both intratumorally and intravenously in mouse models. Additionally, IL11RA mRNA treatment significantly stimulated the expansion of CD8 + T cells within tumors, draining lymph nodes, and the spleen. Transcriptome analysis revealed distinct transcriptional patterns associated with T cell functions. Using multiple deconvolution algorithms, we found substantial infiltration of CD8 + T cells following IL11RA mRNA treatment, highlighting its immunomodulatory effects within the tumor microenvironment. In conclusion, IL11RA mRNA therapy presents a promising strategy for tumor regression with potential immunomodulatory effects and clinical implications for improved survival outcomes.

Mechanical thrombectomy for symptomatic stent thrombosis after carotid artery stenting.

Background: As there is still no consensus on the treatment of carotid stent thrombosis (CST), we would like to describe our experience with the revascularization of CST by mechanical thrombectomy. Methods: We retrospectively studied patients who underwent mechanical thrombectomy after CST at Xuzhou Municipal First People's Hospital and Xuzhou Central Hospital between January 2020 and November 2022. The results of the procedures, complications, and clinical and imaging follow-up were recorded. Results: A total of six patients were included in this study. The stenosis grade before stent implantation was ≥85% in all patients, and the stenosis length ranged from 7 to 20 mm. Patients experienced CST within 6 days to 45 months after carotid artery stenting (CAS); the median admission on the National Institutes of Health Stroke Scale (NIHSS) at CST was 12 (range 8-25). Mechanical thrombectomy was successfully performed in all patients. There was no periprocedural death, and the modified Rankin Scale (mRS) at the 3-month follow-up was 0-2. All patients showed recovery from their neurological deficits. Conclusion: The treatment of symptomatic CST with mechanical thrombectomy resulted in satisfactory clinical outcomes. This regimen could be effective and safe, and future prospective and randomized studies are warranted.

Combined ultrasound and low temperature pretreatment improve the content of anthocyanins, phenols and volatile substance of Merlot red wine.

Ultrasound combined with low temperature treatment is a new food processing technology. In this study, low temperature, three ultrasound power levels, and their combinations were adopted in the must before fermentation to study their effects on Merlot red wine. The results showed that ultrasound combined with low temperature pretreatment increased the total and monomer contents of anthocyanins and phenols, affected the color of the wine, and significantly increased its antioxidant capacity. In particular, 240 W of ultrasound combined with low temperature pretreatment reduced the bad odors (caprylic acid, benzaldehyde, and 1-ethanol content) and improved the flower and fruit aroma (1-octanol and phenethyl acetate), as well as the aftertaste, thus improving the quality of the wine. Ultrasound combined with low temperature pretreatment positively affected the quality of Merlot red wine.

Cholangiokines: undervalued modulators in the hepatic microenvironment.

The biliary epithelial cells, also known as cholangiocytes, line the intra- and extrahepatic bile ducts, forming a barrier between intra- and extra-ductal environments. Cholangiocytes are mostly known to modulate bile composition and transportation. In hepatobiliary diseases, bile duct injury leads to drastic alterations in cholangiocyte phenotypes and their release of soluble mediators, which can vary depending on the original insult and cellular states (quiescence, senescence, or proliferation). The cholangiocyte-secreted cytokines (also termed cholangiokines) drive ductular cell proliferation, portal inflammation and fibrosis, and carcinogenesis. Hence, despite the previous consensus that cholangiocytes are bystanders in liver diseases, their diverse secretome plays critical roles in modulating the intrahepatic microenvironment. This review summarizes recent insights into the cholangiokines under both physiological and pathological conditions, especially as they occur during liver injury-regeneration, inflammation, fibrosis and malignant transformation processes.

Effects of forage type on the rumen microbiota, growth performance, carcass traits, and meat quality in fattening goats.

Forages fed to goats influence ruminal microbiota, and further contribute to affect growth performance, meat quality and its nutritional composition. Our objective for current study was to investigate the effects of different forages on growth performance, carcass traits, meat nutritional composition, rumen microflora, and the relationships between key bacteria and amino acids and fatty acids in the longissimus dorsi and semimembranosus muscles of goats. Boer crossbred goats were separately fed commercial concentrate diet supplemented with Hemarthria altissima (HA), Pennisetum sinese (PS), or forage maize (FG), and then slaughtered 90 days after the beginning of the experiment. Growth performances did not vary but carcass traits of dressing percentage, semi-eviscerated slaughter percentage, and eviscerated slaughter percentage displayed significant difference with the treatment studied. Meats from goats fed forage maize, especially semimembranosus muscles are rich in essential amino acids, as well as an increase in the amount of beneficial fatty acids. Our 16S rRNA gene sequencing results showed that the Firmicutes, Bacteroidetes, and Proteobacteria were the most dominant phyla in all groups but different in relative abundance. Further, the taxonomic analysis and linear discriminant analysis effect size (LEfSe) identified the specific taxa that were differentially represented among three forage treatments. The spearman's correlation analysis showed that rumen microbiota was significantly associated with the goat meat nutritional composition, and more significant positive correlations were identified in semimembranosus muscles when compared with longissimus dorsi muscles. More specifically, the lipid metabolism-related bacteria Rikenellaceae_RC9_gut_group showed positively correlated with meat amino acid profile, while genera Oscillospiraceae_UCG-005 were positively correlated with fatty acid composition. These bacteria genera might have the potential to improve nutritional value and meat quality. Collectively, our results showed that different forages alter the carcass traits, meat nutritional composition, and rumen microflora in fattening goats, and forage maize induced an improvement in its nutritional value.

Petal-like Mn-doped α-Ni(OH)2 nanosheets for high-performance Li-S cathode material.

Lithium-sulphur (Li-S) batteries are high-energy-density and cost-effective batteries. Herein, petal-like Ni1-x Mn x (OH)2 (x ≈ 0.04) nanosheets were synthesised using a hydrothermal method and the electrical conductivity of Ni(OH)2 was improved by applying the cathode functional materials in Li-S batteries. With up to 5 mg cm-2 of S content in the cathode, the fabricated Ni1-x Mn x (OH)2 electrode exhibited specific discharge capacities up to 1375 and 1150 mA h g-1 at 0.2 and 0.5C, and retained this capacity at 813 and 714 mA h g-1 after 200 cycles, respectively. Electrochemical measurement results show that Ni1-x Mn x (OH)2 plays a critical role in Li-S batteries as it has a larger specific surface area than Ni(OH)2, which has superior adsorption performance toward lithium polysulphides. Moreover, the conductivity performance of Ni1-x Mn x (OH)2 is significantly better than that of Ni(OH)2, which improves the electrochemical reaction kinetics of the Li-S batteries.

Learning Response-Consistent and Background-Suppressed Correlation Filters for Real-Time UAV Tracking.

With the advantages of discriminative correlation filter (DCF) in tracking accuracy and computational efficiency, the DCF-based methods have been widely used in the field of unmanned aerial vehicles (UAV) for target tracking. However, UAV tracking inevitably encounters various challenging scenarios, such as background clutter, similar target, partial/full occlusion, fast motion, etc. These challenges generally lead to multi-peak interferences in the response map that cause the target drift or even loss. To tackle this problem, a response-consistent and background-suppressed correlation filter is proposed for UAV tracking. First, a response-consistent module is developed, in which two response maps are generated by the filter and the features extracted from adjacent frames. Then, these two responses are kept to be consistent with the response from the previous frame. By utilizing the l2-norm constraint for consistency, this module not only can avoid sudden changes of the target response caused by background interferences but also enables the learned filter to preserve the discriminative ability of the previous filter. Second, a novel background-suppressed module is proposed, which makes the learned filter to be more aware of background information by using an attention mask matrix. With the introduction of this module into the DCF framework, the proposed method can further suppress the response interferences of distractors in the background. Finally, extensive comparative experiments have been conducted on three challenging UAV benchmarks, including UAV123@10fps, DTB70 and UAVDT. Experimental results have proved that our tracker has better tracking performance compared with 22 other state-of-the-art trackers. Moreover, our proposed tracker can run at ∼36 FPS on a single CPU for real-time UAV tracking.

Low-dose versus standard-dose computed tomography-guided biopsy for pulmonary nodules: a randomized controlled trial.

BACKGROUND: To assess relative safety and diagnostic performance of low- and standard-dose computed tomography (CT)-guided biopsy for pulmonary nodules (PNs). MATERIALS AND METHODS: This was a single-center prospective randomized controlled trial (RCT). From June 2020 to December 2020, consecutive patients with PNs were randomly assigned into low- or standard-dose groups. The primary outcome was diagnosis accuracy. The secondary outcomes included technical success, diagnostic yield, operation time, radiation dose, and biopsy-related complications. This RCT was registered on 3 January 2020 and listed within ClinicalTrials.gov (NCT04217655). RESULTS: Two hundred patients were randomly assigned to low-dose (n = 100) and standard-dose (n = 100) groups. All patients achieved the technical success of CT-guided biopsy and definite final diagnoses. No significant difference was found in operation time (n = 0.231) between the two groups. The mean dose-length product was markedly reduced within the low-dose group compared to the standard-dose group (31.5 vs. 333.5 mGy-cm, P < 0.001). The diagnostic yield, sensitivity, specificity, and accuracy of the low-dose group were 68%, 91.5%, 100%, and 94%, respectively. The diagnostic yield, sensitivity, specificity, and accuracy were 65%, 88.6%, 100%, and 92% in the standard-dose group. There was no significant difference observed in diagnostic yield (P = 0.653), diagnostic accuracy (P = 0.579), rates of pneumothorax (P = 0.836), and lung hemorrhage (P = 0.744) between the two groups. CONCLUSIONS: Compared with standard-dose CT-guided biopsy for PNs, low-dose CT can significantly reduce the radiation dose, while yielding comparable safety and diagnostic accuracy.

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer-Challenges and opportunities.

Chronic liver diseases from varying etiologies generally lead to liver fibrosis and cirrhosis. Among them, non-alcoholic fatty liver disease (NAFLD) affects roughly one-quarter of the world population, thus representing a major and increasing public health burden. Chronic hepatocyte injury, inflammation (non-alcoholic steatohepatitis, NASH) and liver fibrosis are recognized soils for primary liver cancer, particularly hepatocellular carcinoma (HCC), being the third most common cause for cancer-related deaths worldwide. Despite recent advances in liver disease understanding, therapeutic options on pre-malignant and malignant stages remain limited. Thus, there is an urgent need to identify targetable liver disease-driving mechanisms for the development of novel therapeutics. Monocytes and macrophages comprise a central, yet versatile component of the inflammatory response, fueling chronic liver disease initiation and progression. Recent proteomic and transcriptomic studies performed at singular cell levels revealed a previously overlooked diversity of macrophage subpopulations and functions. Indeed, liver macrophages that encompass liver resident macrophages (also named Kupffer cells) and monocyte-derived macrophages, can acquire a variety of phenotypes depending on microenvironmental cues, and thus exert manifold and sometimes contradictory functions. Those functions range from modulating and exacerbating tissue inflammation to promoting and exaggerating tissue repair mechanisms (i.e., parenchymal regeneration, cancer cell proliferation, angiogenesis, fibrosis). Due to these central functions, liver macrophages represent an attractive target for the treatment of liver diseases. In this review, we discuss the multifaceted and contrary roles of macrophages in chronic liver diseases, with a particular focus on NAFLD/NASH and HCC. Moreover, we discuss potential therapeutic approaches targeting liver macrophages.

Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression.

BACKGROUND AND AIMS: The progression of chronic liver diseases towards liver cirrhosis is accompanied by drastic tissue changes. This study combines elaborate transcriptomic and histological methods aiming at spatially resolving the hepatic immune microenvironment in NAFLD (including NASH, primary sclerosing cholangitis, primary biliary cholangitis, and severe alcoholic hepatitis). APPROACH AND RESULTS: Human liver samples were subjected to RNA-sequencing (n=225) and imaging cytometry (n=99) across 3 independent patient cohorts. Liver samples from alcoholic hepatitis and primary biliary cholangitis patients were used for comparison. Myeloid populations were further characterized in corresponding mouse models. Imaging, clinical, and phenotypical data were combined for multidimensional analysis. NAFLD/NASH and primary sclerosing cholangitis disease stages were associated with loss of parenchymal areas, increased ductular cell accumulation, and infiltration of immune cells. NASH patients predominantly exhibited myeloid cell accumulation, whereas primary sclerosing cholangitis patients additionally had pronounced lymphoid cell responses. Correlating to disease stage, both etiologies displayed intense IBA1 + CD16 low CD163 low macrophage aggregation in nonparenchymal areas, with a distinct spatial proximity to ductular cells. Mouse models revealed that disease-associated IBA1 + hepatic macrophages originated from bone marrow-derived monocytes. Using an unbiased, machine learning-based algorithm, IBA1 in combination with hepatocyte and ductular cell immunostaining-predicted advanced cirrhosis in human NASH, primary sclerosing cholangitis, and alcoholic hepatitis. CONCLUSIONS: Loss of hepatocytes and increased ductular reaction are tightly associated with monocyte-derived macrophage accumulation and represent the most prominent common immunological feature revealing the progression of NAFLD, primary sclerosing cholangitis, primary biliary cholangitis, and alcoholic hepatitis, suggesting IBA1 + CD163 low macrophages are key pathogenic drivers of human liver disease progression across diverse etiologies.

Characterizing the macrostructure of electronic health record work using raw audit logs: an unsupervised action embeddings approach.

Raw audit logs provide a comprehensive record of clinicians' activities on an electronic health record (EHR) and have considerable potential for studying clinician behaviors. However, research using raw audit logs is limited because they lack context for clinical tasks, leading to difficulties in interpretation. We describe a novel unsupervised approach using the comparison and visualization of EHR action embeddings to learn context and structure from raw audit log activities. Using a dataset of 15 767 634 raw audit log actions performed by 88 intern physicians over 6 months of EHR use across inpatient and outpatient settings, we demonstrated that embeddings can be used to learn the situated context for EHR-based work activities, identify discrete clinical workflows, and discern activities typically performed across diverse contexts. Our approach represents an important methodological advance in raw audit log research, facilitating the future development of metrics and predictive models to measure clinician behaviors at the macroscale.

Bioinformatics analysis to obtain critical genes regulated in subcutaneous adipose tissue after bariatric surgery.

Bariatric surgery (BS) is a dependable method for managing obesity and metabolic diseases, however, the regulatory processes of lipid metabolism are still not well elucidated. Differentially expressed genes (DEGs) were analysed through three transcriptomic datasets of GSE29409, GSE59034 and GSE72158 from the GEO database regarding subcutaneous adipose tissue (SAT) after BS, and 37 DEGs were identified. The weighted gene co-expression network analysis (WGCNA), last absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms further screened four key genes involved in the regulation of STMN2, SFRP4, APOE and MXRA5. The GSE53376 dataset was used to further confirm the differential expression of SFRP4, APOE and MXRA5 in the postoperative period. GSEA analysis reveals activation of immune-related regulatory pathways after surgery. Finally, the silencing of MXRA5 was found by experimental methods to affect the expression of PPARγ and CEBPα during the differentiation of preadipocytes, as well as to affect the formation of lipid droplets. In conclusion, SAT immunoregulation was mobilized after BS, while MXRA5 was involved in the regulation of lipid metabolism.

Vertical distributions and potential sources of wintertime atmospheric pollutants and the corresponding ozone production on the coast of Bohai Sea.

This study investigated the wintertime vertical distributions and source areas of aerosols, NO2, and HCHO in a coastal city of Dongying from December 2020 to March 2021, using ground-based multi-axis differential optical absorption spectroscopy (MAX-DOAS) and a potential source contribution function (PSCF) model, respectively. Moreover, the chemical production sensitivity of O3 at different height layers was analyzed using HCHO/NO2 ratios. The results revealed that the wintertime averaged highest concentrations of aerosol (1.25 km-1), NO2 (14.81 ppb), and HCHO (2.32 ppb) were mainly distributed at the surface layer, 100-200 m layer, and 200-300 m layer, respectively. Regarding the diurnal cycles, high concentrations of aerosol (>1.4 km-1) and NO2 (>16.0 ppb) usually appeared in the early morning and late afternoon, while high concentrations of HCHO (>2.5 ppb) usually occurred during 12:00-15:00. The PSCF model revealed that the wintertime aerosol mainly originated from Shandong, northern Jiangsu, Korea, and the northwestern Mongolian Plateau. Below 200 m, NO2 was mainly from western Shandong, whereas above 600 m, it was mainly from northern Shandong and the Beijing-Tianjin-Hebei (BTH) region. The corresponding sources for HCHO were central and southern Shandong (below 200 m) and northern Shandong, northern Jiangsu, and southeastern BTH (above 600 m). In addition, the chemical production sensitivity of O3 below 100 m was observed only in the VOC-limited regime. The percentages of O3 production under the NOx-limited, NOx-VOC-limited, and VOC-limited regimes were 10.75% (31.18%), 4.30% (19.35%), and 84.95% (49.47%) at the 500-600 m (900-1000 m) layer. This study has guiding significance for the coordinated control of PM2.5 and O3, and can assist in the implementation of regional joint prevention and control strategies for air pollutants.

The macrophage-associated microRNA-4715-3p / Gasdermin D axis potentially indicates fibrosis progression in nonalcoholic fatty liver disease: evidence from transcriptome and biological data.

Nonalcoholic fatty liver disease (NAFLD) is highly possible to progress to cirrhosis, malignancy, and liver failure through fibrogenesis. The enormous potential of pathogenetic and therapeutic targets in NAFLD has been revealed. This study aimed to explore novel factors potentially indicating or mediating NAFLD progression. Multiple bulk and single-cell RNA sequencing datasets were used, in which landscapes of cell populations were clarified to characterize immune cell infiltration. Significantly high infiltration of macrophages (MPs) was discovered during NAFLD progression. Samples in bulk NASH datasets were regrouped by MP level. Highly differentially expressed genes (DEGs) were identified in the Ctrl vs. NASH comparison, low MP vs. high MP comparison, and the weighted gene co-expression network analysis (WGCNA) clusters. Eight hub genes were identified as promising targets by protein-protein interaction analysis and validated in fibrosis progression, microRNA (miR)-protein interactions were predicted, and the hub genes were verified in a free fatty acid (FFA)-induced macrophage injury model. The results showed that Gasdermin D (GSDMD) was upregulated with fibrosis progression in NAFLD and was associated with macrophage infiltration. In addition, a potential regulator (miR-4715-3p) was correlated with GSDMD. The miR-4715-3p/GSDMD axis potentially modulates macrophage-associated immunity and indicates fibrosis progression in NAFLD.

Engineered RBCs Encapsulating Antigen Induce Multi-Modal Antigen-Specific Tolerance and Protect Against Type 1 Diabetes.

Antigen-specific therapies that suppress autoreactive T cells without inducing systemic immunosuppression are a much-needed treatment for autoimmune diseases, yet effective strategies remain elusive. We describe a microfluidic Cell Squeeze® technology to engineer red blood cells (RBCs) encapsulating antigens to generate tolerizing antigen carriers (TACs). TACs exploit the natural route of RBC clearance enabling tolerogenic presentation of antigens. TAC treatment led to antigen-specific T cell tolerance towards exogenous and autoantigens in immunization and adoptive transfer mouse models of type 1 diabetes (T1D), respectively. Notably, in several accelerated models of T1D, TACs prevented hyperglycemia by blunting effector functions of pathogenic T cells, particularly in the pancreas. Mechanistically, TACs led to impaired trafficking of diabetogenic T cells to the pancreas, induced deletion of autoreactive CD8 T cells and expanded antigen specific Tregs that exerted bystander suppression. Our results highlight TACs as a novel approach for reinstating immune tolerance in CD4 and CD8 mediated autoimmune diseases.

Systematic molecular analysis of the human secretome and membrane proteome in gastrointestinal adenocarcinomas.

The human secretome and membrane proteome are a large source of cancer biomarkers. Membrane-bound and secreted proteins are promising targets for many clinically approved drugs, including for the treatment of tumours. Here, we report a deep systematic analysis of 957 adenocarcinomas of the oesophagus, stomach, colon and rectum to examine the cancer-associated human secretome and membrane proteome of gastrointestinal tract adenocarcinomas (GIACs). Transcriptomic data from these GIACs were applied to an innovative majority decision-based algorithm. We quantified significantly expressed protein-coding genes. Interestingly, we found a consistent pattern in a small group of genes found to be overexpressed in GIACs, which were associated with a cytokine-cytokine interaction pathway (CCRI) in all four cancer subtypes. These CCRI associated genes, which spanned both one secretory and one membrane isoform were further analysed, revealing a putative biomarker, interleukin-1 receptor accessory protein (IL1RAP), which indicated a poor overall survival, a positive correlation with cancer stemness and a negative correlation with several kinds of T cells. These results were further validated in vitro through the knockdown of IL1RAP in two human gastric carcinoma cell lines, which resulted in a reduced indication of cellular proliferation, migration and markers of invasiveness. Following IL1RAP silencing, RNA seq results showed a consistent pattern of inhibition related to CCRI, proliferation pathways and low infiltration of regulatory T cells (Tregs) and CD8 naive cells. The significance of the human secretome and membrane proteome is elucidated by these findings, which indicate IL1RAP as a potential candidate biomarker for cytokine-mediated cancer immunotherapy in gastric carcinoma.

Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic liver diseases in the global population that can lead to end-stage liver disease and hepatocellular carcinoma (HCC). NAFLD is closely linked to the metabolic syndrome, and comorbidities such as type 2 diabetes, obesity and insulin resistance aggravate liver disease, while NAFLD promotes cardiovascular risk in affected patients. The pathomechanisms of NAFLD are multifaceted, combining hepatic factors including lipotoxicity, mechanisms of cell death and liver inflammation with extrahepatic factors including metabolic disturbance and dysbiosis. Nuclear receptors (NRs) are a family of ligand-controlled transcription factors that regulate glucose, fat and cholesterol homeostasis and modulate innate immune cell functions, including liver macrophages. In parallel with metabolic derangement in NAFLD, altered NR signaling is frequently observed and might be involved in the pathogenesis. Therapeutically, clinical data indicate that single drug targets thus far have been insufficient for reaching patient-relevant endpoints. Therefore, combinatorial treatment strategies with multiple drug targets or drugs with multiple mechanisms of actions could possibly bring advantages, by providing a more holistic therapeutic approach. In this context, peroxisome proliferator-activated receptors (PPARs) and other NRs are of great interest as they are involved in wide-ranging and multi-organ activities associated with NASH progression or regression. In this review, we summarize recent advances in understanding the pathogenesis of NAFLD, focusing on mechanisms of cell death, immunometabolism and the role of NRs. We outline novel therapeutic strategies and discuss remaining challenges.

Personalized Surgical Transfusion Risk Prediction Using Machine Learning to Guide Preoperative Type and Screen Orders.

BACKGROUND: Accurate estimation of surgical transfusion risk is essential for efficient allocation of blood bank resources and for other aspects of anesthetic planning. This study hypothesized that a machine learning model incorporating both surgery- and patient-specific variables would outperform the traditional approach that uses only procedure-specific information, allowing for more efficient allocation of preoperative type and screen orders. METHODS: The American College of Surgeons National Surgical Quality Improvement Program Participant Use File was used to train four machine learning models to predict the likelihood of red cell transfusion using surgery-specific and patient-specific variables. A baseline model using only procedure-specific information was created for comparison. The models were trained on surgical encounters that occurred at 722 hospitals in 2016 through 2018. The models were internally validated on surgical cases that occurred at 719 hospitals in 2019. Generalizability of the best-performing model was assessed by external validation on surgical cases occurring at a single institution in 2020. RESULTS: Transfusion prevalence was 2.4% (73,313 of 3,049,617), 2.2% (23,205 of 1,076,441), and 6.7% (1,104 of 16,053) across the training, internal validation, and external validation cohorts, respectively. The gradient boosting machine outperformed the baseline model and was the best- performing model. At a fixed 96% sensitivity, this model had a positive predictive value of 0.06 and 0.21 and recommended type and screens for 36% and 30% of the patients in internal and external validation, respectively. By comparison, the baseline model at the same sensitivity had a positive predictive value of 0.04 and 0.144 and recommended type and screens for 57% and 45% of the patients in internal and external validation, respectively. The most important predictor variables were overall procedure-specific transfusion rate and preoperative hematocrit. CONCLUSIONS: A personalized transfusion risk prediction model was created using both surgery- and patient-specific variables to guide preoperative type and screen orders and showed better performance compared to the traditional procedure-centric approach.

Predicting physician burnout using clinical activity logs: Model performance and lessons learned.

BACKGROUND: Burnout is a significant public health concern affecting more than half of the healthcare workforce; however, passive screening tools to detect burnout are lacking. We investigated the ability of machine learning (ML) techniques to identify burnout using passively collected electronic health record (EHR)-based audit log data. METHOD: Physician trainees participated in a longitudinal study where they completed monthly burnout surveys and provided access to their EHR-based audit logs. Using the monthly burnout scores as the target outcome, we trained ML models using combinations of features derived from audit log data-aggregate measures of clinical workload, time series-based temporal measures of EHR use, and the baseline burnout score. Five ML models were constructed to predict burnout as a continuous score: penalized linear regression, support vector machine, neural network, random forest, and gradient boosting machine. RESULTS: 88 trainee physicians participated and completed 416 surveys; greater than10 million audit log actions were collected (Mean [Standard Deviation] = 25,691 [14,331] actions per month, per physician). The workload feature set predicted burnout score with a mean absolute error (MAE) of 0.602 (95% Confidence Interval (CI), 0.412-0.826), and was able to predict burnout status with an average AUROC of 0.595 (95% CI 0.355-0.808) and average accuracy 0.567 (95% CI 0.393-0.742). The temporal feature set had a similar performance, with MAE 0.596 (95% CI 0.391-0.826), and AUROC 0.581 (95% CI 0.343-0.790). The addition of the baseline burnout score to the workload features improved the model performance to a mean AUROC of 0.829 (95% CI 0.607-0.996) and mean accuracy of 0.781 (95% CI 0.587-0.936); however, this performance was not meaningfully different than using the baseline burnout score alone. CONCLUSIONS: Current findings illustrate the complexities of predicting burnout exclusively based on clinical work activities as captured in the EHR, highlighting its multi-factorial and individualized nature. Future prediction studies of burnout should account for individual factors (e.g., resilience, physiological measurements such as sleep) and associated system-level factors (e.g., leadership).

Bariatric Surgery Associates with Nonalcoholic Steatohepatitis/Hepatocellular Carcinoma Amelioration via SPP1 Suppression.

Nonalcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases worldwide and no effective drugs or treatments have been approved for disease management. Recently, bariatric surgery (BS) is considered to be a novel disease-modifying therapy for NASH and liver metabolic diseases, according to clinical follow-up studies. Despite the revealment of physiopathological alterations, underlying mechanisms and key factors remain indeterminate. This study included multiple bulk RNA-sequencing datasets to investigate transcriptome variation in one-year follow-up BS and diet management (Diet) NASH patients' liver biopsies. Liver functions, fibrosis, and carcinogenesis were predicted in liver samples via hallmark-based function enrichment analysis. Key factors generated from multi-dataset comparison were further assessed with hepatocellular carcinoma (HCC) progression and prognosis. BS leads to active gene expression alterations in NASH liver in comparison to diet management (Diet). Both approaches reduce cell stress and immune response, whereas BS contributes to higher metabolic levels and lower apoptosis levels. The macrophage infiltration, adipose accumulation, and fibroblast activation were revealed to be lower in post-BS NASH livers, further demonstrating positive correlations mutually. Seven key genes (MNDA, ALOX5AP, PECAM1, SPP1, CD86, FGF21, CSTA) were screened out as potential macrophage-associated and carcinogenetic factors suppressed by BS. SPP1 was identified as a crucial factor participating in BS intervened NASH-HCC progression. This study determined that BS exerts potentially superior protective functions in NASH livers compared to diet management. SPP1 may serve as a novel factor to study the functionalities of BS on NASH patients.