BMAL1 moonlighting as a gatekeeper for LINE1 repression and cellular senescence in primates.

Aging in humans is intricately linked with alterations in circadian rhythms concomitant with physiological decline and stem cell exhaustion. However, whether the circadian machinery directly regulates stem cell aging, especially in primates, remains poorly understood. In this study, we found that deficiency of BMAL1, the only non-redundant circadian clock component, results in an accelerated aging phenotype in both human and cynomolgus monkey mesenchymal progenitor cells (MPCs). Unexpectedly, this phenotype was mainly attributed to a transcription-independent role of BMAL1 in stabilizing heterochromatin and thus preventing activation of the LINE1-cGAS-STING pathway. In senescent primate MPCs, we observed decreased capacity of BMAL1 to bind to LINE1 and synergistic activation of LINE1 expression. Likewise, in the skin and muscle tissues from the BMAL1-deficient cynomolgus monkey, we observed destabilized heterochromatin and aberrant LINE1 transcription. Altogether, these findings uncovered a noncanonical role of BMAL1 in stabilizing heterochromatin to inactivate LINE1 that drives aging in primate cells.

SIRT3 consolidates heterochromatin and counteracts senescence.

Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

Epidemiological and spatiotemporal analysis of severe fever with thrombocytopenia syndrome in Eastern China, 2011-2021.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease, which is caused by severe fever with thrombocytopenia syndrome virus (SFTSV) with high fatality. Recently, the incidence of SFTS increased obviously in Jiangsu Province. However, the systematic and complete analysis of spatiotemporal patterns and clusters coupled with epidemiological characteristics of SFTS have not been reported so far. METHODS: Data on SFTS cases were collected during 2011-2021. The changing epidemiological characteristics of SFTS were analyzed by adopting descriptive statistical methods. GeoDa 1.18 was applied for spatial autocorrelation analysis, and SaTScan 10.0 was used to identify spatio-temporal clustering of cases. The results were visualized in ArcMap. RESULTS: The annual incidence of SFTS increased in Jiangsu Province from 2011 to 2021. Most cases (72.4%) occurred during May and August with the obvious peak months. Elderly farmers accounted for most cases, among which both males and females were susceptible. The spatial autocorrelation and spatio-temporal clustering analysis indicated that the distribution of SFTS was not random but clustered in space and time. The most likely cluster was observed in the western region of Jiangsu Province and covered one county (Xuyi county) (Relative risk = 8.18, Log likelihood ratio = 122.645, P < 0.001) located in southwestern Jiangsu Province from January 1, 2017 to December 31, 2021. The Secondary cluster also covered one county (Lishui county) (Relative risk = 7.70, Log likelihood ratio = 94.938, P < 0.001) from January 1, 2017 to December 31, 2021. CONCLUSIONS: The annual number of SFTS cases showed an increasing tendency in Jiangsu Province from 2011 to 2021. Our study elucidated regions with SFTS clusters by means of ArcGIS in combination with spatial analysis. The results demonstrated solid evidences for the orientation of limited sanitary resources, surveillance in high-risk regions and early warning of epidemic seasons in future prevention and control of SFTS in Jiangsu Province.

ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin.

Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) has long been known as a master transcriptional repressor of autophagy. Here, we identify a novel role for ZKSCAN3 in alleviating senescence that is independent of its autophagy-related activity. Downregulation of ZKSCAN3 is observed in aged human mesenchymal stem cells (hMSCs) and depletion of ZKSCAN3 accelerates senescence of these cells. Mechanistically, ZKSCAN3 maintains heterochromatin stability via interaction with heterochromatin-associated proteins and nuclear lamina proteins. Further study shows that ZKSCAN3 deficiency results in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, loss of heterochromatin, a more accessible chromatin status and consequently, aberrant transcription of repetitive sequences. Overexpression of ZKSCAN3 not only rescues premature senescence phenotypes in ZKSCAN3-deficient hMSCs but also rejuvenates physiologically and pathologically senescent hMSCs. Together, these data reveal for the first time that ZKSCAN3 functions as an epigenetic modulator to maintain heterochromatin organization and thereby attenuate cellular senescence. Our findings establish a new functional link among ZKSCAN3, epigenetic regulation, and stem cell aging.

Epidemiology of 631 Cases of COVID-19 Identified in Jiangsu Province Between January 1st and March 20th 2020: Factors Associated with Disease Severity and Analysis of Zero Mortality.

BACKGROUND This retrospective study aimed to investigate the factors associated with disease severity and patient outcomes in 631 patients with COVID-19 who were reported to the Jiangsu Commission of Health between January 1 and March 20, 2020. MATERIAL AND METHODS We conducted an epidemiological investigation enrolling 631 patients with laboratory-confirmed COVID-19 from our clinic from January to March 2020. Patients' information was collected through a standard questionnaire. Then, we described the patients' epidemiological characteristics, analyzed risk factors associated with disease severity, and assessed causes of zero mortality. Additionally, some key technologies for epidemic prevention and control were identified. RESULTS Of the 631 patients, 8.46% (n=53) were severe cases, and no deaths were recorded (n=0). The epidemic of COVID-19 has gone through 4 stages: a sporadic phase, an exponential growth phase, a peak plateau phase, and a declining phase. The proportion of severe cases was significantly different among the 4 stages and 13 municipal prefectures (P<0.001). Factors including age >65 years old, underlying medical conditions, highest fever >39.0°C, dyspnea, and lymphocytopenia (<1.0×109/L) were early warning signs of disease severity (P<0.05). In contrast, earlier clinic visits were associated with better patient outcomes (P=0.029). Further, the viral load was a potentially useful marker associated with COVID-19 infection severity. CONCLUSIONS The study findings from the beginning of the COVID-19 epidemic in Jiangsu Province, China showed that patients who were more than 65 years of age and with comorbidities and presented with a fever of more than 39.0°C developed more severe disease. However, mortality was prevented in this initial patient population by early supportive clinical management.

A case-control study on the risk factors for hemorrhagic fever with renal syndrome.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is an endemic communicable disease in China, accounting for 90% of total reported cases worldwide. In this study, the authors want to investigate the risk factors for HFRS in recent years to provide the prevention and control advices. METHODS: A community-based, 1:2 matched case-control study was carried out to investigate the risk factors for HFRS. Cases were defined as laboratory-confirmed cases that tested positive for hantavirus-specific IgM antibodies. Two neighbourhood controls of each case were selected by sex, age and occupation. Standardized questionnaires were used to collect information and identify the risk factors for HFRS. RESULTS: Eighty-six matched pairs were investigated in the study. The median age of the cases was 55.0 years, 72.09% were male, and 73.26% were farmers. In the multivariate logistic regression analysis, cleaning spare room at home (OR = 3.310, 95%CI 1.335-8.210) was found to be risk factor for infection; storing food and crops properly (OR = 0.279 95%CI 0.097-0.804) provided protection from infection. CONCLUSION: Storing food and crops properly seemed to be protective factor, which was important for HFRS prevention and control. More attention should be paid to promote comprehensive health education and behaviour change among high-risk populations in the HFRS endemic area.

iASPP-Mediated ROS Inhibition Drives 5-Fu Resistance Dependent on Nrf2 Antioxidative Signaling Pathway in Gastric Adenocarcinoma.

AIMS: Inhibitor for the apoptosis-stimulating protein of p53 (iASPP) has been reported to be correlated with 5-fluorouracil (5-Fu) resistance in renal cell carcinoma. Here, we uncover mechanisms of iASPP-Nrf2-ROS regulation of 5-Fu resistance which are important for the development of alternative treatment strategies for gastric adenocarcinoma treatment. METHODS: We analyzed iASPP and Nrf2 through TCGA RNA-seq data, UALCAN analysis, and cBioPortal datasets. Intracellular ROS generation was determined by 2',7'-dichloro-fluorescin diacetate staining. Transwell was used to evaluate the invasion. The expression of iASPP, Nrf2, HO-1, and GSTP1 was tested using western blot. RESULTS: We found that iASPP KD led to an apparent 5-Fu-induced ROS accumulation in MGC803 and SCG790 cells. Accompanied by iASPP KD, Nrf2 was markedly decreased. iASPP-induced ROS inhibition relies on Nrf2, and due to both knocked down iASPP and Nrf2, the level of ROS did not show an obvious difference with Nrf2 KD solely. Similarly, iASPP KD failed to enhance the Nrf2 KD-mediated ROS accumulation after 5-Fu treatment, suggesting that iASPP-induced antioxidative effects related to 5-Fu resistance are partially dependent on Nrf2. Also, the combination of iASPP KD and Nrf2 KD did not show any synergistic effect on apoptosis after 5-Fu treatment in MGC803 and SCG790 cells. Further studies revealed that iASPP KD or Nrf2 KD could decrease the expression of HO-1 and GSTP1. CONCLUSIONS: Our data highlight that iASPP plays a crucial role in the inhibition of 5-Fu-induced apoptosis resistance by removing ROS accumulation in gastric adenocarcinoma, and that the removal of ROS induced by iASPP is Nrf2 signaling dependent.

Evaluation of pharmacist interventions as part of a multidisciplinary cancer pain management team in a Chinese academic medical center.

OBJECTIVE: The objective of this study was to evaluate pharmacist interventions in the cancer pain management of hospitalized patients, focusing on a clinically meaningful change in drug-related problems and pain score. METHODS: A retrospective data analysis was performed at a single academic comprehensive cancer center. Hospitalized patients with moderate to severe pain who had already received analgesic medication for at least 3 consecutive days were included. For patients who met the criteria for admission, a pharmacist followed up daily during hospitalization and evaluated the patient during pre- (first) and postintervention (second, third, and fourth) visits. Medication problems, medication changes, and changes in pain scores were assessed. RESULTS: A total of 195 patients were included in the study. The pharmacist identified 12 types of pharmacotherapeutic drug-related problems. The top 3 problems were nonadherence or missed doses (27.69%), inappropriate opioid selection (22.56%), and inappropriate dosage (16.41%). After the intervention of pharmacists, these drug-related problems decreased by 74.54% on average. Across all visits, the changes in pain scores (mean ± SD: 2.80 ± 1.92 vs. 1.90 ± 1.58, P < 0.05) and the number of patients with mild (172 vs. 128, P < 0.05), moderate (58 vs. 21, P < 0.05), and severe pain (9 vs. 2, P < 0.05) indicated a marked decrease in patients' pain levels after the inclusion of pharmacist in the cancer pain multidisciplinary management team (CPMMT). CONCLUSION: Participation by the pharmacist in the CPMMT led to a marked reduction in most of the drug-related problems and a statistically significant change in pain score during the 4 visits, indicating that pharmacists play an active role in CPMMT.

Nurses' Attitudes Toward Internet-Based Home Care: A Survey Study.

Internet-based home care has emerged as a way to relieve the burden of hospitals and meet patients' need for home care. This study aims to explore nurses' attitudes toward Internet-based home care. A cross-sectional online survey was conducted in Ningbo City in China. A self-designed Internet-based home care attitudes questionnaire for nurses (23 items) was used. There were 2039 nurses from 13 hospitals who participated in this online survey. Results reveal that, 1369 nurses (67.1%) were willing to provide Internet-based home care. However, there were significant differences in the attitudes of nurses with different ages (H = 11.86, P = .001), years of work experience (H = 24.257, P = .000), positions (H = 8.850, P = .031), and types of phones (H = 13.096, P = .001). More than 80% of nurses were willing to provide hypodermic and intramuscular injection. But there was a significant difference in the attitudes toward hypodermic injection, intramuscular injection, and pressure ulcer care in nurses with different ages (H = 13.039, P = .005; H = 9.178, P = .027; H = 10.997, P = .012) and a significant difference in the attitudes toward pressure ulcer care in nurses with different years of work experience (H = 15.259, P = .002). Results also indicated that most nurses were worried about their own safety and personal rights protection during Internet-based home care.

Influenza activity prediction using meteorological factors in a warm temperate to subtropical transitional zone, Eastern China.

Influenza activity is subject to environmental factors. Accurate forecasting of influenza epidemics would permit timely and effective implementation of public health interventions, but it remains challenging. In this study, we aimed to develop random forest (RF) regression models including meterological factors to predict seasonal influenza activity in Jiangsu provine, China. Coefficient of determination (R2) and mean absolute percentage error (MAPE) were employed to evaluate the models' performance. Three RF models with optimum parameters were constructed to predict influenza like illness (ILI) activity, influenza A and B (Flu-A and Flu-B) positive rates in Jiangsu. The models for Flu-B and ILI presented excellent performance with MAPEs <10%. The predicted values of the Flu-A model also matched the real trend very well, although its MAPE reached to 19.49% in the test set. The lagged dependent variables were vital predictors in each model. Seasonality was more pronounced in the models for ILI and Flu-A. The modification effects of the meteorological factors and their lagged terms on the prediction accuracy differed across the three models, while temperature always played an important role. Notably, atmospheric pressure made a major contribution to ILI and Flu-B forecasting. In brief, RF models performed well in influenza activity prediction. Impacts of meteorological factors on the predictive models for influenza activity are type-specific.

Forecasting incidence of hand, foot and mouth disease using BP neural networks in Jiangsu province, China.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a rising public health problem and has attracted considerable attention worldwide. The purpose of this study was to develop an optimal model with meteorological factors to predict the epidemic of HFMD. METHODS: Two types of methods, back propagation neural networks (BP) and auto-regressive integrated moving average (ARIMA), were employed to develop forecasting models, based on the monthly HFMD incidences and meteorological factors during 2009-2016 in Jiangsu province, China. Root mean square error (RMSE) and mean absolute percentage error (MAPE) were employed to select model and evaluate the performance of the models. RESULTS: Four models were constructed. The multivariate BP model was constructed using the HFMD incidences lagged from 1 to 4 months, mean temperature, rainfall and their one order lagged terms as inputs. The other BP model was fitted just using the lagged HFMD incidences as inputs. The univariate ARIMA model was specified as ARIMA (1,0,1)(1,1,0)12 (AIC = 1132.12, BIC = 1440.43). And the multivariate ARIMAX with one order lagged temperature as external predictor was fitted based on this ARIMA model (AIC = 1132.37, BIC = 1142.76). The multivariate BP model performed the best in both model fitting stage and prospective forecasting stage, with a MAPE no more than 20%. The performance of the multivariate ARIMAX model was similar to that of the univariate ARIMA model. Both performed much worse than the two BP models, with a high MAPE near to 40%. CONCLUSION: The multivariate BP model effectively integrated the autocorrelation of the HFMD incidence series. Meanwhile, it also comprehensively combined the climatic variables and their hysteresis effects. The introduction of the climate terms significantly improved the prediction accuracy of the BP model. This model could be an ideal method to predict the epidemic level of HFMD, which is of great importance for the public health authorities.

Scrub typhus in Jiangsu Province, China: epidemiologic features and spatial risk analysis.

BACKGROUND: With the increasing incidence of scrub typhus in recent years, it is of great value to analyse the spatial and temporal distribution of scrub typhus by applying micro-geographical studies at a reasonably fine scale, and to guide the control and management. METHODS: We explored the use of maximum entropy modelling method to confirm the spatial and temporal distribution of scrub typhus according to the occurrence locations of human cases in Jiangsu Province. The risk prediction map under specific environmental factors was therefore drawn by projecting the training model across China. The area under the curve and the omission rate were used to validate the model. Meanwhile, Jackknife tests were applied to enumerate the contribution of different environmental variables, then to predict the final model. The predicted results were validated by using China's known occurrence locations. RESULTS: A total of 566 occurrence locations with known 4865 scrub typhus occurrence records were used in our study. The number of female cases was higher than male cases, with a proportion of 1.17:1, and people in any age group could be infected. The number of cases presented an inverted-U relation with age. The percentage of cases aged from 60 to 69 years old was the highest, accounting for 30.50% of all cases. Ecological niche modelling results indicated that the locations of scrub typhus cases, which was of great importance in the disease transmission cycle, had a certain ecological niche with environmental elements in many dimensions. Moreover, the key environmental factors for determining scrub typhus occurrence were temperature (including temperature seasonality, min temperature of coldest month, mean diurnal range, and monthly mean temperature), precipitation of wettest month, and land cover types. The risk prediction maps indicated that mid-eastern China was the potential risk areas for scrub typhus of "autumn type". Meanwhile, in our results, Guangdong Province was the high-risk region for "autumn type" scrub typhus, where cases were mainly reported as "summer type". CONCLUSION: The combination of climatic and geographic factors with GIS methods is an appropriate option to analyse and estimate the spatial and temporal distribution of scrub typhus.

The role of RhoA in retrograde neuronal death and axon regeneration after spinal cord injury.

Paralysis following spinal cord injury (SCI) is due to interruption of axons and their failure to regenerate. It has been suggested that the small GTPase RhoA may be an intracellular signaling convergence point for several types of growth-inhibiting extracellular molecules. Even if this is true in vitro, it is not clear from studies in mammalian SCI, whether the effects of RhoA manipulations on axon growth in vivo are due to a RhoA-mediated inhibition of true regeneration or only of collateral sprouting from spared axons, since work on SCI generally is performed with partial injury models. RhoA also has been implicated in local neuronal apoptosis after SCI, but whether this reflects an effect on axotomy-induced cell death or an effect on other pathological mechanisms is not known. In order to resolve these ambiguities, we studied the effects of RhoA knockdown in the sea lamprey central nervous system (CNS), where after complete spinal cord transection (TX), robust but incomplete regeneration of large axons belonging to individually identified reticulospinal (RS) neurons occurs, and where some RS neurons show unambiguous delayed retrograde apoptosis after axotomy. RhoA protein was detected in neurons and axons of the lamprey brain and spinal cord, and its expression was increased post-TX. Knockdown of RhoA in vivo by retrogradely-delivered morpholino antisense oligonucleotides (MOs) to the RS neurons significantly reduced retrograde apoptosis signaling in identified RS neurons post-SCI, as indicated by Fluorochrome Labeled Inhibitor of Caspases (FLICA) in brain wholemounts. In individual RS neurons, the reduction of caspase activation by RhoA knockdown began at 2weeks post-TX and was still seen at 8weeks. RhoA knockdown slowed axon retraction and possibly increased early axon regeneration in the proximal stump. The number of axons regenerating beyond the lesion more than 5mm at 10weeks post-TX also was increased. Thus RhoA knockdown both enhanced true axon regeneration and inhibited retrograde apoptosis signaling after SCI.

Catalytic decomposition of toxic chemicals over iron group metals supported on carbon nanotubes.

This study explores catalytic decomposition of phosphine (PH3) using iron group metals (Co, Ni) and metal oxides (Fe2O3, Co(3)O4, NiO) supported on carbon nanotubes (CNTs). The catalysts are synthesized by means of a deposition-precipitation method. The morphology, structure, and composition of the catalysts are characterized using a number of analytical instrumentations, including high-resolution transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, BET surface area measurement, and inductively coupled plasma. The activity of the catalysts in the PH3 decomposition reaction is measured and correlated with their surface and structural properties. The characterization results show that phosphidation occurs on the catalyst surface, and the resulting metal phosphides act as an active phase in the PH3 decomposition reaction. Cobalt phosphide, CoP, is formed on Co/CNTs and Co(3)O4/CNTs, whereas iron phosphide, FeP, is formed on Fe2O3/CNTs. In contrast, phosphorus-rich phosphide NiP2 is formed on Ni/CNTs and NiO/CNTs. The initial activities of the catalysts are shown in the following sequence: Ni/CNTs > Co/CNTs > Co(3)O4/CNTs >NiO/CNTs > Fe2O3/CNTs, whereas activities of metal phosphides are shown in the following order: CoP > NiP2 > FeP. The catalytic activity of metal phosphides is attributed to their electronic properties. Cobalt phosphide formed on Co/CNTs and Co(3)O4/CNTs exhibits not only the highest activity, but also long-term stability in the PH3 decomposition reaction.

Unlocking Syngas Synthesis from the Catalytic Gasification of Lignocellulose Pinewood: Catalytic and Pressure Insights.

Modern technologies transform biomass into commodity chemicals, biofuels, and solid charcoal, making it appear as a renewable resource rather than organic waste. The effectiveness of Mo, Fe, Co, and Ni metal catalysts was investigated during the gasification of lignocellulosic pinewood. The primary goal was to compare the performance of iron and nickel catalysts in the low- and high-pressure production of syngas from pinewood. This is the first study that has reported high-pressure gasification of pinewood without the use of an external gasifying agent, producing syngas containing hydrogen, carbon monoxide, and carbon dioxide along with considerable amounts of methane with or without a catalyst. Also, the same gasification at low pressures was compared. In this study, the iron catalyst produces syngas more efficiently at higher pressure and 800 °C, and contains 43 mol % H2, 22 mol % CO2, 26 mol % CH4, and 8 mol % CO in comparison to the nickel catalyst. High pressure produces a large amount of methane too. The nickel catalyst produces higher syngas at low pressure and 850 °C, and contains 55 mol % H2, 9 mol % CO2, 5 mol % CH4, and 30 mol % CO. Low-pressure gasification produces less amounts of CH4 and CO2. Also, the H2/CO ratio is ∼1.81 using the nickel catalyst at low pressures, which is good for utilizing syngas as a feedstock. These results highlight the importance of catalyst selection, reactor configuration, and operating circumstances in adjusting gasification product composition. The study's findings provide information about optimizing syngas production from pinewood, which is critical for the development of sustainable and efficient energy conversion technologies.

Changes in prevalence of anxiety and depression among COVID-19 patients during a two-year recovery period: A systematic review and meta-analysis.

OBJECTIVE: To analyze the temporal trend of anxiety and depression prevalences up to 2 years of follow-up for COVID-19 patients during the recovery period and to compare regional differences. METHODS: We performed a systematic review from PubMed, Embase, Web of Science, CNKI, Wanfang, and VIP using keywords such as "COVID-19", "anxiety", "depression", and "cohort study". Meta-analysis was performed to estimate the pooled prevalence of anxiety and depression at five follow-up time intervals. Subgroup analyses were conducted by different regions. RESULTS: 34 cohort studies were included in the meta-analyses. The pooled anxiety prevalence rates at 0-1 month, 1-3 months, 3-6 months, 6-12 months and 12-24 months were 18% (95% CI: 11% to 28%), 18% (95% CI: 12% to 28%), 22% (95% CI: 16% to 29%), 15% (95% CI: 11% to 21%), and 10% (95% CI: 0.05% to 20%), respectively, and the pooled depression prevalence rates were 22% (95%CI: 15% to 33%), 19% (95% CI: 13% to 29%), 21% (95% CI: 15% to 28%), 15% (95% CI: 11% to 20%), and 9% (95% CI: 0.4% to 21%) respectively. The prevalence of depression in Asian and non-Asian countries was statistically different at 0-1 month (χ2 = 15.248, P < 0.001) and 1-3 months (χ2 = 28.298, P < 0.001), and prevalence of anxiety was statistically different at 3-6 months (χ2 = 9.986, P = 0.002) and 6-12 months (χ2 = 7.378, P = 0.007). CONCLUSION: The prevalence of anxiety and depression in COVID-19 patients generally tends to decrease after 2 years of recovery, but may temporarily increase at 3-6 months. There are regional differences in the changes in prevalence of anxiety and depression.

Efficacy and safety of SBRT combined with sintilimab and IBI305 in patients with advanced HCC and previously failed immunotherapy: study protocol of a phase 2 clinical trial.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors, has been recommended as first-line treatment for advanced HCC. However, two-thirds of patients did not benefit from this form of immunotherapy. Currently, data on the subsequent regimen for patients previously treated with ICIs are lacking. Studies have shown that the combination of radiotherapy (RT) and ICIs is a potentially effective second-line therapy for HCC. This study aims to assess the efficacy and safety of combined therapy with stereotactic body RT (SBRT), sintilimab and IBI305 (a biosimilar of bevacizumab) in patients with HCC following the progression of first-line ICI therapy. METHODS AND ANALYSIS: This study is an open-label, single-arm, single-centre, phase 2 trial of 21 patients with advanced HCC in whom previous ICI therapy has failed. Participants will receive approximately 30-40 Gy/5-8F SBRT, followed by 200 mg sintilimab and 15 mg/kg IBI305 intravenously every 3 weeks. Treatment will continue until the development of unacceptable toxicity or disease progression. We will use Simon's two-stage design, with the objective response rate (ORR) as the primary endpoint. Secondary endpoints include ORR of lesions without RT, disease control rate, progression-free survival, overall survival and safety. ETHICS AND DISSEMINATION: The study was authorised by the Medical Ethics Committee. Dissemination of results will occur via a peer-reviewed publication and other relevant media. TRIAL REGISTRATION NUMBER: ChiCTR2200056068.

Opioid Nonadherence Risk Prediction of Patients with Cancer-Related Pain Based on Five Machine Learning Algorithms.

Objectives: Opioid nonadherence represents a significant barrier to cancer pain treatment efficacy. However, there is currently no effective prediction method for opioid adherence in patients with cancer pain. We aimed to develop and validate a machine learning (ML) model and evaluate its feasibility to predict opioid nonadherence in patients with cancer pain. Methods: This was a secondary analysis from a cross-sectional study that included 1195 patients from March 1, 2018, to October 31, 2019. Five ML algorithms, such as logistic regression (LR), random forest, eXtreme Gradient Boosting, multilayer perceptron, and support vector machine, were used to predict opioid nonadherence in patients with cancer pain using 43 demographic and clinical factors as predictors. The predictive effects of the models were compared by the area under the receiver operating characteristic curve (AUC_ROC), accuracy, precision, sensitivity, specificity, and F1 scores. The value of the best model for clinical application was assessed using decision curve analysis (DCA). Results: The best model obtained in this study, the LR model, had an AUC_ROC of 0.82, accuracy of 0.82, and specificity of 0.71. The DCA showed that clinical interventions for patients at high risk of opioid nonadherence based on the LR model can benefit patients. The strongest predictors for adherence were, in order of importance, beliefs about medicines questionnaire (BMQ)-harm, time since the start of opioid, and BMQ-necessity. Discussion. ML algorithms can be used as an effective means of predicting adherence to opioids in patients with cancer pain, which allows for proactive clinical intervention to optimize cancer pain management. This trial is registered with ChiCTR2000033576.