Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective To explore the differences in therapeutic efficacy and possible mechanism of different routes of administration of fullerene nanoparticles in the treatment of radiation retinopathy.Methods Eight-week-old adult male SD rats were randomly divided into blank group(Control),irradiation group(X-Ray),irradiation+vitreous cavity administration group[X+F(IVT)],irradiation+ocular surface administration group[X+F(OS)],and irradiation+intravenous administration group[X+F(IV)],with 5 rats in each group.The blank group was not treated,the irradiation groups exposed to X-ray irradiation to establish the model,and fullerenol nanoparticles were given to the treatment groups through different routes after irradiation.At 7,14,and 28 d after modeling,body weight and fundus changes were measured to evaluate drug safety,retinal optical coherence tomography(OCT)was used to observe the change in retinal tissue structure,and electroretinography(ERG)was applied for oscillatory potentials(OPs)to evaluate visual function.CD31 immunofluorescence staining was carried out to evaluate retinal endothelial vascular status,and in vivo imaging was utilized to evaluate the accumulation of fullerenol nanoparticles in the eyes.Results The growth curves of body weight demonstrated that fullerenol nanoparticles did not affect the growth and development of rats,with no statistical difference between the treatment groups and the control group.Irradiation resulted in a significant reduction in visual function,decreased amplitudes of a-wave and b-wave,and declined OPs(P<0.01),and significantly increased thicknesses of the ganglion cell layer(GCL)and the inner nuclear layer(INL)in the retinas,as evidenced by OCT(P<0.01),along with a notably absent presence of CD31-positive cells(P<0.01).Notably,the X+F(IVT)group obtained significantly improved visual function after intravitreal administration,effectively maintained thickness of the GCL and INL,and prevention against the loss of CD31-positive cells(P<0.01).However,no such effective results were observed in the irradiated groups receiving intravenous either ocular surface administration.In vivo imaging revealed that intravitreal administration maintained high ocular accumulation of fullerene for 96 h,while ocular surface administration sustained these concentrations for only 12 h.Intravenous administration,in contrast,only led to a predominant drug distribution in vascular-rich areas,but reduced ocular accumulation.Conclusion Fullerene nanoparticles possess a therapeutic effect on radiation retinopathy,and the intravitreal administration route demonstrates better efficacy than ocular surface and intravenous administration.

With the rapid advancement of artificial intelligence(AI)in healthcare,clinical decision support system(CDSS)is gradually integrated into clinical workflows.While CDSS enhances diagnostic and therapeutic efficiency and accuracy,it has also sparked complex debates regarding accountability.This article systematically examines the current global landscape of accountability challenges associated with CDSS.It delves into the mechanisms underlying these challenges,focusing on 5 key dimensions:ambiguity in liability attribution,the"black-box"nature of algorithms,data bias,backward legal and regulatory systems,and heterogeneity in deployment environments.To address these issues,a collaborative governance framework centered on whole-lifecycle governance is proposed.Specifically,the framework advocates:enhancing AI trustworthiness through technical pathways;constructing innovative mechanisms such as risk-based tiered regulation and no-fault compensation funds through legal and regulatory pathways;strengthening institutional internal controls through organizational pathways;and reshaping a new professional paradigm of"human-AI collaboration"through ethical and educational pathways.The study argues that resolving CDSS accountability dilemmas is not only critical for fostering trustworthy AI in medicine but also essential for safeguarding patient safety,ensuring healthcare equity,and providing clinicians with clear liability boundaries and robust professional protections amid technological transformation.

Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are lacking.Methods:We conducted a single-center retrospective study to describe the clinical features,complications,and mortality rates of hospitalized KTRs infected with COVID-19 between Dec.16,2022 and Jan.31,2023.The patients were followed up until Mar.31,2023.Results:A total of 324 KTRs with COVID-19 were included.The median age was 49 years.The median time between the onset of symptoms and admission was 13 d.Molnupiravir,azvudine,and nirmatrelvir/ritonavir were administered to 67(20.7%),11(3.4%),and 148(45.7%)patients,respectively.Twenty-nine(9.0%)patients were treated with more than one antiviral agent.Forty-eight(14.8%)patients were treated with tocilizumab and 53(16.4%)patients received baricitinib therapy.The acute kidney injury(AKI)occurred in 81(25.0%)patients and 39(12.0%)patients were admitted to intensive care units.Fungal infections were observed in 55(17.0%)patients.Fifty(15.4%)patients lost their graft.The 28-d mortality rate of patients was 9.0%and 42(13.0%)patients died by the end of follow-up.Multivariate Cox regression analysis identified that cerebrovascular disease,AKI incidence,interleukin(IL)-6 level of>6.8 pg/mL,daily dose of corticosteroids of>50 mg,and fungal infection were all associated with an increased risk of death for hospitalized patients.Conclusions:Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality.The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival,while higher doses of corticosteroids may increase the death risk.

Objective:To explore the changes in acoustic features of 9-10-year-old primary school students with depressive symptoms, and based on these features and the random forest (RF) algorithm, construct a model for identifying depressive symptoms in primary school students, so as to provide an intelligent psychological health screening tool for schools and education departments.Methods:This was a case-control study.A total of 1 186 primary school students aged 9-10 from three primary schools in three regions of Jiangsu Province were selected as research subjects for psychological health screening from October 26, 2022 to February 13, 2023.Their demographic data, Depression-Anxiety-Stress Scale (DASS-21) scores, Insomnia Severity Index scores, and voice recordings were collected.Based on the DASS-21 scores, the participants were divided into a control group ( n=1 086) and a depression group ( n=100).Voice recordings were made using the neutral text " The North Wind and the Sun". openSMILE was used to extract 523 acoustic features from the pre-processed voice recordings.Group differences were assessed using independent-samples t-tests or chi-square tests.Pearson correlation analysis was conducted to examine the relationship between acoustic features and depression scores.Depressive symptoms were set as the dependent variable, and the correlated acoustic features were set as the independent variable to construct a classification model using the RF algorithm.The model performance was assessed using the receiver operating characteristic (ROC) curve, the area under the curve (AUC), precision, accuracy, recall, and F1 score. Results:Compared with the control group, the depression group showed significant differences in 105 acoustic features (44 spectral features, 49 source features, and 12 prosodic features) (all P<0.05).Correlation analysis showed that 12 acoustic features (7 spectral features, 4 source features, and 1 prosodic feature) were significantly correlated with the depression score (all P<0.05).Among the RF algorithm-based classification models, the spectral features demonstrated superior performance compared to source features and prosodic features (AUC=0.793), and the performance of the model based on the combination of these features was the best (AUC=0.818). Conclusions:Acoustic features may be an objective indicator to identify the depression of 9-10-year-old primary school students, and the classification model established based on acoustic features can identify the depressed primary school students.

Purpose: The interval between neoadjuvant chemotherapy (NAC) and surgery for locally advanced breast cancer (LABC) remains controversial. At the same time, the prognostic effect of delayed surgery in patients with poor responses is currently unclear. Methods: Data was collected from patients who had poor responses to NAC and underwent modified radical surgery from January 2013 to December 2018. The interval from completion of NAC to surgery was divided into two groups: a longer (greater than four weeks) or shorter (four weeks or less) interval. The associations of these interval groups with overall survival (OS) and recurrence-free survival (RFS) were evaluated by multivariable Cox models adjusting for the existing prognostic factors. Propensity score matching (PSM) was used to minimize election bias. Results: A total of 1,229 patients (mean age, 47.2 ± 8.9 years; median follow-up duration, 32.67 [6.57–52.63] months) were included. The 5-year OS rates were 73.2% and 60.8% in the shorter (n = 171) and longer interval group (n = 1,058), respectively, while the 3-year RFS rates were 80.8% and 71.7%, respectively. In multivariate Cox analysis, the longer interval was associated with an increased risk of mortality (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.01–2.02; p = 0.046) and recurrence (HR, 1.50; 95% CI, 1.12–1.99; p = 0.006).There was an interaction between the molecular subtype and the surgery interval for OS (pinteraction = 0.014) and RFS (pinteraction = 0.027). After PSM, no significant difference in OS (p = 0.180) and RFS (p = 0.069) was observed between the two groups. Conclusion Among LABC patients with a poor response, those with a longer interval between NAC and surgery had worse OS and RFS. The results indicate that these patients should receive modified radical surgery timely, which may in turn improve their prognosis.

Objective:To explore the efficacy and safety profile of sofosbuvir/velpatasvir/voxilaprevir ± ribavirin (SOF/VEL/VOX±RBV) for salvage treatment of chronic hepatitis C patients who have failed direct-acting antivirals (DAAs).Methods:Patients with chronic hepatitis C who failed DAAs±RBV treatment and were treated in five hospitals in Chongqing, Guangdong, Guizhou, and Guangxi from January 2022 to December 2023 were included in this retrospective study. One or more courses of DAAs±RBV therapy were evaluated for all patients who had been previously treated. Virological rebound occurrence was observed during the follow-up. SOF/VEL/VOX±RBV was used for one course of salvage treatment. Virological and biochemical indicators were analyzed before salvage therapy, post-treatment, and drug discontinuation at 12 weeks. Adverse drug events were recorded during treatment. Data between groups were compared using t-tests or non-parametric tests.Results:A total of 26 cases of chronic hepatitis C who had failed DAAs±RBV were included in this study, with an age of (52.9±9.6) years. Twenty-one cases (80.8%) were male, sixteen (61.5%) had a history of drug abuse, two (7.7%) had combined human immunodeficiency virus infection, and fourteen (53.8%) had combined cirrhosis. The previous DAA regimen of 21 cases (80.8%) included SOF/VEL. The baseline HCV RNA load of salvage treatment was (5.8±1.6) log 10 IU/ml, and 16 cases (61.5%) were genotype 3. All patients completed the 12-week SOF/VEL/VOX±RBV salvage treatment and achieved sustained virological response (SVR) at the end of treatment. All 22 cases were followed up for 12 weeks following treatment completion and attained SVR12, including patients with genotype 3 and cirrhosis. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) had normalized return rates of 94.1% and 93.8%, respectively, following therapy. ALT, AST, FIB-4 index, APRI, and aPMAP scores were significantly lower than those before treatment ( Z=-3.980, -3.875, -3.461, -3.582, P<0.05). The proportion of patients in the high-risk group of liver cancer dropped (52.6% before treatment and 33.3% after treatment), and more patients were reclassified to medium-and low-risk groups. Two cases (7.7%) experienced nausea and diarrhea, one case (3.8%) had a headache, and one case (3.8%) had fatigue, all of which were well managed during treatment. There were no serious adverse events, deaths, or interruptions of treatment due to adverse reactions. Conclusions:SOF/VEL/VOX is a safe and effective salvage treatment option for chronic hepatitis C patients who have failed DAAs therapy, and may be particularly beneficial to refractory populations infected with genotype 3 and combined with cirrhosis.

Objective:This study conducted mosquito-borne viruses RNA screening and analysis of virus evolution characteristics on mosquito specimens collected in 2023 from Hunchun city, Jilin province, China.Methods:Firstly, morphological method were employed for mosquito specimen classification. Then, real-time fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the RNA of six mosquito-borne viruses in the collected mosquitos, i. e., Banna virus (BAV), Kadipiro virus (KDV), Liaoning virus (LNV), Tahyna virus (TAHV), Getah virus (GETV) and Japanese encephalitis virus (JEV). And by sequencing, the viral genome sequence of positive samples was obtained.Results:A total of 5490 mosquito specimens were collected from Hunchun city, Jilin province, included 4400 Aedes vexans (80.15%), 1090 Anopheles sinensis (19.85%). A total of 41 groups were obtained by mixing samples according to the time, location, and mosquito species collected. qRT-PCR result showed that only the Aedes vexans sample with the number JLHC2321 was tested positive for LNV, while the remaining samples were tested negative for the detected viruses. According to the phylogenetic analysis of the segment 10 gene, this LNV strain had the closest genetic relationship with NE9731 and belonged to the type II branch. Meanwhile, the amino acid sequence analysis based on the coding sequence (CDS) in the segment 10 showed that JLHC2321 only had 2 amino acid differential sites with the GII reference strain NE9731.Conclusions:This study detected LNV for the first time in Aedes vexans in Hunchun city, and our result provide important basic data for the monitoring and prevention strategies of mosquito-borne viruses in the region.

Objective:This study conducted mosquito-borne viruses RNA screening and analysis of virus evolution characteristics on mosquito specimens collected in 2023 from Hunchun city, Jilin province, China.Methods:Firstly, morphological method were employed for mosquito specimen classification. Then, real-time fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the RNA of six mosquito-borne viruses in the collected mosquitos, i. e., Banna virus (BAV), Kadipiro virus (KDV), Liaoning virus (LNV), Tahyna virus (TAHV), Getah virus (GETV) and Japanese encephalitis virus (JEV). And by sequencing, the viral genome sequence of positive samples was obtained.Results:A total of 5490 mosquito specimens were collected from Hunchun city, Jilin province, included 4400 Aedes vexans (80.15%), 1090 Anopheles sinensis (19.85%). A total of 41 groups were obtained by mixing samples according to the time, location, and mosquito species collected. qRT-PCR result showed that only the Aedes vexans sample with the number JLHC2321 was tested positive for LNV, while the remaining samples were tested negative for the detected viruses. According to the phylogenetic analysis of the segment 10 gene, this LNV strain had the closest genetic relationship with NE9731 and belonged to the type II branch. Meanwhile, the amino acid sequence analysis based on the coding sequence (CDS) in the segment 10 showed that JLHC2321 only had 2 amino acid differential sites with the GII reference strain NE9731.Conclusions:This study detected LNV for the first time in Aedes vexans in Hunchun city, and our result provide important basic data for the monitoring and prevention strategies of mosquito-borne viruses in the region.

Objective:To explore the efficacy and safety profile of sofosbuvir/velpatasvir/voxilaprevir ± ribavirin (SOF/VEL/VOX±RBV) for salvage treatment of chronic hepatitis C patients who have failed direct-acting antivirals (DAAs).Methods:Patients with chronic hepatitis C who failed DAAs±RBV treatment and were treated in five hospitals in Chongqing, Guangdong, Guizhou, and Guangxi from January 2022 to December 2023 were included in this retrospective study. One or more courses of DAAs±RBV therapy were evaluated for all patients who had been previously treated. Virological rebound occurrence was observed during the follow-up. SOF/VEL/VOX±RBV was used for one course of salvage treatment. Virological and biochemical indicators were analyzed before salvage therapy, post-treatment, and drug discontinuation at 12 weeks. Adverse drug events were recorded during treatment. Data between groups were compared using t-tests or non-parametric tests.Results:A total of 26 cases of chronic hepatitis C who had failed DAAs±RBV were included in this study, with an age of (52.9±9.6) years. Twenty-one cases (80.8%) were male, sixteen (61.5%) had a history of drug abuse, two (7.7%) had combined human immunodeficiency virus infection, and fourteen (53.8%) had combined cirrhosis. The previous DAA regimen of 21 cases (80.8%) included SOF/VEL. The baseline HCV RNA load of salvage treatment was (5.8±1.6) log 10 IU/ml, and 16 cases (61.5%) were genotype 3. All patients completed the 12-week SOF/VEL/VOX±RBV salvage treatment and achieved sustained virological response (SVR) at the end of treatment. All 22 cases were followed up for 12 weeks following treatment completion and attained SVR12, including patients with genotype 3 and cirrhosis. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) had normalized return rates of 94.1% and 93.8%, respectively, following therapy. ALT, AST, FIB-4 index, APRI, and aPMAP scores were significantly lower than those before treatment ( Z=-3.980, -3.875, -3.461, -3.582, P<0.05). The proportion of patients in the high-risk group of liver cancer dropped (52.6% before treatment and 33.3% after treatment), and more patients were reclassified to medium-and low-risk groups. Two cases (7.7%) experienced nausea and diarrhea, one case (3.8%) had a headache, and one case (3.8%) had fatigue, all of which were well managed during treatment. There were no serious adverse events, deaths, or interruptions of treatment due to adverse reactions. Conclusions:SOF/VEL/VOX is a safe and effective salvage treatment option for chronic hepatitis C patients who have failed DAAs therapy, and may be particularly beneficial to refractory populations infected with genotype 3 and combined with cirrhosis.