Most patients with differentiated thyroid cancer have a good prognosis after radioiodine-131 therapy,but a small number of patients are insensitive to radioiodine-131 therapy and even continue to develop disease.At present,some targeted drugs can improve progression-free survival in patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC),such as sorafenib and levatinib,have been approved for the treatment of RAIR-DTC.However,due to the presence of primary and acquired drug resistance,drug efficacy in these patients is unsatisfactory.This review introduces the acquired drug resistance mechanism of sorafenib in the regulation of mitogen-activated protein kinase(MAPK)and phosphatidylinositol-3-kinase(PI3K)pathways and proposes related treatment strategies,in order to provide a reference for similar drug resistance mechanism of sorafenib and effective treatment of RAIR-DTC.

Objective To study the changes of volume and cognitive function in hypothalamic subregions based on automated MRI segmentation at various stages of adult life and the correlation between them.Methods Totally 314 healthy subjects aged 20-89 years old were selected from the public database of Dallas Lifespan Brain Study(DLBS),and then divided into a youth group(20-35 years old),an early-middle age group(36-50 years old),a late-middle age group(51-65 years old)and an elderly age group(66-89 years old).The structural magnetic resonance imaging(sMRI)images of the 314 subjects were treated with Freesurfer software to determine the volumes of the anterosuperior,anterior-inferior,middle-superior,middle-inferior and posterior subregions of the right and left sides of the hypothalamus.Differences in hypothalamic subregion volumes between the 4 groups were compared using analysis of covariance,and multiple comparisons between the 4 groups were performed using Bonferroni correction.Pearson's correlation coefficients were used to analyze the correlations of the hypothalamic subregion volumes with the scores of mini mental state examination(MMSE),digit comparison(DC)test,digit symbol(DS)test,and Hopkins verbal learning test(HVLT).Results The volumes of all the hypothalamic subregions except the right anterior inferior part decreased significantly with age(P＜0.05).All the hypothalamic subregions except the right anterior inferior part had the volumes correlated with MMSE scores positively(P＜0.05);the DC test scores were correlated positively with all the hypothalamic subregion volumes(P＜0.05);the DS test scores were correlated positively with the volumes of the hypothalamic subregions except the bilateral anterior-inferior part(P＜0.05);the scores of HVLT immediate memory test were positively correlated with the anterior-superior,middle-superior and posterior subregion volumes of the right and left sides of the hypothalamus(P＜0.05);the scores of HVLT delayed memory test were correlated positively with the volumes of the bilat-eral anterior-superior and left-middle-superior subregions(P＜0.05);the scores of HVLT delayed recognition test did not cor-relate with all the hypothalamic subregions(P＞0.05);the volumes of the bilateral hypothalamus were positively correlated with the scores of MMSE,DC test,DS test and HVLT immediate memory test(P＜0.05).Conclusion Volume changes in some hy-pothalamic subregions are associated with age-related memory decline during adult aging,which can be used to assess the risk of memory loss throughout adulthood.[Chinese Medical Equipment Journal,2024,45(5):8-15]

Background::There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods::In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12.Results::At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician’s Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs. 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs. 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. Conclusion::Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration::ClinicalTrials.gov, NCT05108766.

Objective To estimate adolescents and children age using stepwise regression and machine learning methods based on the pulp and tooth volumes of the left maxillary central incisor and cuspid on cone beam computed tomography(CBCT)images,and to compare and analyze the estimation re-sults.Methods A total of 498 Shanghai Han adolescents and children CBCT images of the oral and maxillofacial regions were collected.The pulp and tooth volumes of the left maxillary central incisor and cuspid were measured and calculated.Three machine learning algorithms(K-nearest neighbor,ridge regression,and decision tree)and stepwise regression were used to establish four age estimation models.The coefficient of determination,mean error,root mean square error,mean square error and mean ab-solute error were computed and compared.A correlation heatmap was drawn to visualize and the monotonic relationship between parameters was visually analyzed.Results The K-nearest neighbor model(R2=0.779)and the ridge regression model(R2=0.729)outperformed stepwise regression(R2=0.617),while the decision tree model(R2=0.494)showed poor fitting.The correlation heatmap demon-strated a monotonically negative correlation between age and the parameters including pulp volume,the ratio of pulp volume to hard tissue volume,and the ratio of pulp volume to tooth volume.Con-clusion Pulp volume and pulp volume proportion are closely related to age.The application of CBCT-based machine learning methods can provide more accurate age estimation results,which lays a founda-tion for further CBCT-based deep learning dental age estimation research.

Objective To investigate the clinical efficacy and surgical experience of modified posterior fossa decompression combined with dural expansion repair in the treatment of type Ⅰ Chiari malformation complicated with syringomyelia.Methods The clinical data of 47 patients with Chiari type Ⅰ malformation complicated with syringomyelia treated by modified posterior fossa decompression combined with dural expansion repair in our hospital were analyzed retrospectively.The changes of posterior cranial fossa volume,cerebellar tonsil and syringomyelia were evaluated by MRI after operation.The scores of Japanese Orthopaedic Association(JOA)were used to evaluate the improvement of neurological function,and the complications were recorded.Results All the 47 patients successfully completed modified posterior fossa decompression combined with dural expansion repair.The main postoperative complications were unilateral limb numbness,incision pain,fever,subcutaneous effusion and so on,all of which were cured after symptomatic treatment.During the follow-up period,the clinical symptoms and neurological function of the patients were improved in varying degrees,and there was no deterioration of neurological function or death cases.The JOA score of the patients 3 months after operation was(15.83±1.31),which was higher than that of(14.66±2.06)before operation,the difference was statistically significant(P<0.05).MRI showed the extent of syringomyelia was reduced or disap-peared 6 after surgery in all 47 patients.Conclusion Modified posterior fossa decompression combined with dural expansion repair for the treatment of type Ⅰ Chiari malformation complicated with syringomyelia can not only ensure the decompression effect,but also increase the support of the contents of the posterior fossa,effectively prevent postoperative local adhesions,and restore the normal physiological circulation of cerebrospinal fluid in the cisterna magnum,which is an effective treatment method for type Ⅰ Chiari malformation complicated with syringomyelia.

Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Aim This study aimed to assess the therapeutic potential of ACT001, a micheliolide derivative, in the treatment of acute lung injury ( ALI) induced by sepsis and investigate its pharmacological mechanisms. Methods At the animal level, an ALI model was established in mice through intraperitoneal injection of li-popolysaccharide (LPS). Subsequently, ACT001 was administered to the ALI-afflicted mice. The therapeutic effects of ACT001 were assessed by evaluating factors such as individual survival rate, lung inflammation, and pulmonary edema. At the cellular level, RAW264. 7 cells were stimulated with LPS to explore the pharmacological mechanism of ACT001. The study examined inflammatory response and oxidative stress levels, and proteomics analysis was conducted to investigate the underlying molecular mechanisms. Results At the animal level, ACT001 can improve the survival of mice with ALI, reduce lung inflammation, and reduce the levels of inflammatory cytokines in serum. At the cellular level, ACT001 promotes the polarization of RAW264. 7 cells toward an anti-inflammatory pheno-type by inhibiting MHC-II related pathways, inhibiting the production of NO and related inflammatory cytokines while increasing SOD content and scavenging ROS. Conclusions ACT001 exhibited the potential to alleviate ALI via its anti-inflammatory and antioxidative activity, mainly by inhibiting the STAT1/ CIITA/ MHC-II pathway. ACT001 holds promise as a novel therapeutic candidate for the treatment of ALI induced by sepsis.

Objective: To evaluate the household secondary attack rates of the SARS-CoV-2 Delta variant and the associated factors. Methods: A COVID-19 outbreak caused by the Delta variant occurred in Nanjing in July 2021. A total of 235 cases with current addresses in Nanjing were reported from 171 households. The subjects in this study were selected from household close contact(s) of infected cases. The information on household index cases and their contacts were collected, and the household secondary attack rate (HSAR) and the risk factors were analyzed by the multi-factor logistic regression model. Results: A total of 234 cases of household close contacts and 64 household secondary cases were reported from 103 households, and the HSAR was 27.4% (64/234, 95%CI:22.0% to 33.4%). The proportions of household size for 2 to 3, 4 to 5, and 6 to 9 were 64.1% (66), 26.2% (27) and 9.7% (10), respectively. A total of 35 cases of household cluster outbreaks were reported (35/103, 34.0%). The number of the first case in the household (FCH) was 103 and males accounted for 27.2% (28 cases), with the median age (Q₁, Q₃) of 49 (9, 56). The number of household close contacts was 234 and males accounted for 59.0% (138 cases), with the median age (Q₁, Q₃) of 42 (20, 55) and the median exposure period (Q₁, Q₃) of 3 (1, 3) days. The multi-factor logistic regression model showed that the higher HSAR was observed in the FCH with the features of airport staff (OR=2.913, 95%CI:1.469-5.774), detection from home quarantine screening (OR=6.795, 95%CI:1.761-26.219) and detection from mass screening (OR=4.239, 95%CI:1.098-16.368). Meanwhile, higher HSAR was observed in cases with longer household exposure (OR=1.221, 95%CI:1.040-1.432), non-vaccination (OR=2.963, 95%CI:1.288-6.813) and incomplete vaccinations (OR=2.842, 95%CI:0.925-8.731). Conclusion: The generation interval of the Delta variant is shortened, and the ability of transmission within the household is enhanced. In the outbreak in Nanjing, the associated factors of HSAR are occupation, detection route, vaccination and exposure period.
Male ; Humans ; SARS-CoV-2 ; COVID-19/epidemiology* ; Incidence ; Family Characteristics

The present study was aimed to investigate whether Gasdermin D (GSDMD)-mediated pyroptosis participated in lipopolysaccharide (LPS)-induced sepsis-associated acute kidney injury (AKI), and to explore the role of caspase-1 and caspase-11 pyroptosis pathways in this process. The mice were divided into four groups: wild type (WT), WT-LPS, GSDMD knockout (KO) and KO-LPS. The sepsis-associated AKI was induced by intraperitoneal injection of LPS (40 mg/kg). Blood samples were taken to determine the concentration of creatinine and urea nitrogen. The pathological changes of renal tissue were observed via HE staining. Western blot was used to investigate the expression of pyroptosis-associated proteins. The results showed that the concentrations of serum creatinine and urea nitrogen in the WT-LPS group were significantly increased, compared with those in the WT group (P < 0.01); whereas serum creatinine and urea nitrogen in the KO-LPS group were significantly decreased, compared with those in the WT-LPS group (P < 0.01). HE staining results showed that LPS-induced renal tubular dilatation was mitigated in GSDMD KO mice. Western blot results showed that LPS up-regulated the protein expression levels of interleukin-1β (IL-1β), GSDMD and GSDMD-N in WT mice. GSDMD KO significantly down-regulated the protein levels of IL-1β, caspase-11, pro-caspase-1, caspase-1(p22) induced by LPS. These results suggest that GSDMD-mediated pyroptosis is involved in LPS-induced sepsis-associated AKI. Caspase-1 and caspase-11 may be involved in GSDMD cleavage.
Animals ; Mice ; Acute Kidney Injury ; Caspase 1 ; Caspases/metabolism* ; Creatinine ; Lipopolysaccharides ; Mice, Knockout ; Nitrogen ; Sepsis ; Urea ; Gasdermins/metabolism*