Background and purpose:The ripple filter(RiFi)is a passive energy modulator used in particle beam therapy to broaden the Bragg peak.The 1D-RiFi features a wavy structure that can broaden a monoenergetic carbon ion beam to 3 mm,while the 2D-RiFi employs a two-dimensional groove structure to achieve a 6 mm beam broadening.This study aimed to evaluate the potential advantages of the 2D-RiFi over the 1D-RiFi in terms of dose distribution optimization,treatment efficiency,and organ at risk(OAR)dose control by comparing water phantom and clinical patient plans.Methods:Carbon ion treatment plans were designed for water phantoms and 20 patients using both 1D-RiFi and 2D-RiFi.The water phantom plans targeted a cubic region of interest(80 mm×80 mm×80 mm)at ranges of 95,105,190 and 290 mm.From patients who underwent carbon ion therapy at Shanghai Proton and Heavy Ion Center,20 cases were selected via simple random sampling with computer-generated random numbers,stratified by the proportion of different tumor sites(6 head and neck tumors,4 prostate tumors,4 lung tumors,2 pancreatic tumors,2 liver tumors and 2 shoulder tumors).Key dosimetric metrics,including homogeneity index(HI),conformity index(CI)and clinical target volume(CTV)coverage by 95%prescription dose(V95),were analyzed along with OAR doses.Energy layers,beam time,and irradiation time were compared between the two RiFi types.Statistical analysis was performed using the Wilcoxon rank-sum test,with a significance level of P＜0.05.This study was approved by the ethics committee of Shanghai Proton and Heavy Ion Center(approval number:240311EXP-01).Results:For water phantom plans,the 1D-RiFi plans achieved HI of 0.04±0.01,CI of 1.10±0.03,V95 of 99.92%±0.06%and flatness of 6.52%±0.61%,while the 2D-RiFi plans achieved HI of 0.04±0.01,CI of 1.11±0.04,V95 of 99.92%±0.06%,and flatness of 7.52%±0.81%.The mean doses to the distal and lateral block in 1D-RiFi plans were(1.34 Gy±0.43)Gy[relative biological effectiveness(RBE)]and(0.98±0.05)Gy(RBE),respectively,compared to(1.47±0.33)Gy(RBE)and(0.94±0.03)Gy(RBE)for 2D-RiFi plans.The use of 2D-RiFi reduced the average beam-on time by 43%and the number of energy layers by 48%.For clinical plans,the 1D-RiFi plans had HI of 0.07±0.04,CI of 1.94±0.67,and V95 of 98.81%±1.61%,compared to HI of 0.07±0.05,CI of 1.95±0.70,and V95 of 98.79%±1.69%for the 2D-RiFi plans,with no statistically significant differences(P=0.77,0.65 and 0.66,respectively).OAR mean doses increased slightly with the 2D-RiFi plans(average increase of 0.8%,P=0.62)but remained within clinically acceptable limits.The 2D-RiFi plans reduced energy layers by 45%-50%(average 48%),beam time by 32%-49%(average 44%),and irradiation time by 28%-41%(average 36%).Conclusion:Treatment plans using the 2D-RiFi achieved comparable target coverage to those using the 1D-RiFi,with a slight but clinically acceptable increase in OAR doses.The application of the 2D-RiFi significantly reduced the number of energy layers,beam time and irradiation time in carbon ion therapy,enhancing treatment efficiency.

Background and purpose:The ripple filter(RiFi)is a passive energy modulator used in particle beam therapy to broaden the Bragg peak.The 1D-RiFi features a wavy structure that can broaden a monoenergetic carbon ion beam to 3 mm,while the 2D-RiFi employs a two-dimensional groove structure to achieve a 6 mm beam broadening.This study aimed to evaluate the potential advantages of the 2D-RiFi over the 1D-RiFi in terms of dose distribution optimization,treatment efficiency,and organ at risk(OAR)dose control by comparing water phantom and clinical patient plans.Methods:Carbon ion treatment plans were designed for water phantoms and 20 patients using both 1D-RiFi and 2D-RiFi.The water phantom plans targeted a cubic region of interest(80 mm×80 mm×80 mm)at ranges of 95,105,190 and 290 mm.From patients who underwent carbon ion therapy at Shanghai Proton and Heavy Ion Center,20 cases were selected via simple random sampling with computer-generated random numbers,stratified by the proportion of different tumor sites(6 head and neck tumors,4 prostate tumors,4 lung tumors,2 pancreatic tumors,2 liver tumors and 2 shoulder tumors).Key dosimetric metrics,including homogeneity index(HI),conformity index(CI)and clinical target volume(CTV)coverage by 95%prescription dose(V95),were analyzed along with OAR doses.Energy layers,beam time,and irradiation time were compared between the two RiFi types.Statistical analysis was performed using the Wilcoxon rank-sum test,with a significance level of P＜0.05.This study was approved by the ethics committee of Shanghai Proton and Heavy Ion Center(approval number:240311EXP-01).Results:For water phantom plans,the 1D-RiFi plans achieved HI of 0.04±0.01,CI of 1.10±0.03,V95 of 99.92%±0.06%and flatness of 6.52%±0.61%,while the 2D-RiFi plans achieved HI of 0.04±0.01,CI of 1.11±0.04,V95 of 99.92%±0.06%,and flatness of 7.52%±0.81%.The mean doses to the distal and lateral block in 1D-RiFi plans were(1.34 Gy±0.43)Gy[relative biological effectiveness(RBE)]and(0.98±0.05)Gy(RBE),respectively,compared to(1.47±0.33)Gy(RBE)and(0.94±0.03)Gy(RBE)for 2D-RiFi plans.The use of 2D-RiFi reduced the average beam-on time by 43%and the number of energy layers by 48%.For clinical plans,the 1D-RiFi plans had HI of 0.07±0.04,CI of 1.94±0.67,and V95 of 98.81%±1.61%,compared to HI of 0.07±0.05,CI of 1.95±0.70,and V95 of 98.79%±1.69%for the 2D-RiFi plans,with no statistically significant differences(P=0.77,0.65 and 0.66,respectively).OAR mean doses increased slightly with the 2D-RiFi plans(average increase of 0.8%,P=0.62)but remained within clinically acceptable limits.The 2D-RiFi plans reduced energy layers by 45%-50%(average 48%),beam time by 32%-49%(average 44%),and irradiation time by 28%-41%(average 36%).Conclusion:Treatment plans using the 2D-RiFi achieved comparable target coverage to those using the 1D-RiFi,with a slight but clinically acceptable increase in OAR doses.The application of the 2D-RiFi significantly reduced the number of energy layers,beam time and irradiation time in carbon ion therapy,enhancing treatment efficiency.

Objective: To investigate a SARS-CoV-2 epidemic reported in Rongcheng City, Weihai, Shandong Province. Methods: The SARS-CoV-2 nucleic acid positive patients and their close contacts were investigated, and the whole genome sequencing and genetic evolution analysis of 9 variant viruses were carried out. An infection source investigation and analysis were carried out from two sources of home and abroad, and three aspects of human, material and environment. Results: A total of 15 asymptomatic infections were reported in this epidemic, including 13 cases as employees of workshop of aquatic products processing company, with an infection rate of 21.67% (13/60). Two cases were infected people's neighbors in the same village (conjugal relation). The first six positive persons were processing workers engaged in the first process of removing squid viscera in the workshop of the company. The nucleic acid Ct value of the first time were concentrated between 15 and 29, suggesting that the virus load was high, which was suspected to be caused by one-time homologous exposure. The whole genome sequence of 9 SARS-CoV-2 strains was highly homologous, belonging to VOC/Gamma (Lineage P.1.15). No highly homologous sequences were found from previous native and imported cases in China. It was highly homologous with the six virus sequences sampled from May 5 to 26, 2021 uploaded by Chile. The infection source investigation showed that the company had used the squid raw materials captured in the ocean near Chile and Argentina from May to June 2021 over the last 14 days. Many samples of raw materials, products and their outer packages in the inventory were tested positive for nucleic acid. Conclusion: This epidemic is the first local epidemic caused by the VOC/Gamma of SARS-CoV-2 in China. It is speculated that the VOC/Gamma, which was prevalent in South America from May to June 2021, could be imported into China through frozen squid.
Humans ; SARS-CoV-2 ; COVID-19 ; Epidemics ; China/epidemiology*

Objective:To assess the optimal cut-off value between early recurrence and late recurrence of patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA), and to construct a nomogram to predict early recurrence.Methods:A total of 119 patients with HCC who recurred after RFA in Cancer Hospital, Chinese Academy of Medical Sciences from January 2012 to December 2017 were identified. The optimal cut-off value to distinguish early and late recurrence was determined based on differences in post recurrence survival (PRS) by minimum P-value approach. The clinical and radiographic risk factors for early recurrence were identified by univariate and multivariate Logistic regression analysis. The predictive nomogram was constructed by these factors and internally validated. Results:The optimal cut-off value to distinguish early recurrence and late recurrence was 12 months after RFA ( P=0.005). The patients were divided into early recurrence group (47 cases) and late recurrence group (72 cases). The lower quartile PRS (Q1-PRS) and lower quartile overall survival (Q1-OS) were 11.1 and 19.1 months in the early recurrence group, which were shorter than 31.6 and 81.0 months in the late recurrence group ( P=0.005 and P<0.001, respectively). The independent risk factors of early recurrence were alpha fetoprotein (AFP) ( OR=8.459, 95% CI: 2.231-32.073), albumin(ALB) ( OR=0.251, 95% CI: 0.047-1.339), number of lesions ( OR=3.842, 95% CI: 1.424-10.365) and peritumoral enhancement ( OR=8.05, 95% CI: 1.23-52.80), which were further incorporated into constructing the predictive nomogram of early recurrence of HCC after RFA. Internal validation results showed the area under the curve, sensitivity, specificity of the receiver operating characteristic (ROC) curve were 0.839, 68.1% and 93.1%, respectively. The calibration curve showed the predicted curve of nomogram was close to the ideal curve. Hosmer-Lemeshow test showed there was no significant difference between the predicted results of nomogram and the actual results ( P=0.424). Conclusions:An interval of 12 months after RFA is the optimal cut-off value for defining early recurrence and late recurrence. The nomogram is integrated by clinical and radiographic features, which can potentially predict early recurrence of HCC after RFA and may offer useful guidance for individual treatment or follow up.

Objective:To assess the optimal cut-off value between early recurrence and late recurrence of patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA), and to construct a nomogram to predict early recurrence.Methods:A total of 119 patients with HCC who recurred after RFA in Cancer Hospital, Chinese Academy of Medical Sciences from January 2012 to December 2017 were identified. The optimal cut-off value to distinguish early and late recurrence was determined based on differences in post recurrence survival (PRS) by minimum P-value approach. The clinical and radiographic risk factors for early recurrence were identified by univariate and multivariate Logistic regression analysis. The predictive nomogram was constructed by these factors and internally validated. Results:The optimal cut-off value to distinguish early recurrence and late recurrence was 12 months after RFA ( P=0.005). The patients were divided into early recurrence group (47 cases) and late recurrence group (72 cases). The lower quartile PRS (Q1-PRS) and lower quartile overall survival (Q1-OS) were 11.1 and 19.1 months in the early recurrence group, which were shorter than 31.6 and 81.0 months in the late recurrence group ( P=0.005 and P<0.001, respectively). The independent risk factors of early recurrence were alpha fetoprotein (AFP) ( OR=8.459, 95% CI: 2.231-32.073), albumin(ALB) ( OR=0.251, 95% CI: 0.047-1.339), number of lesions ( OR=3.842, 95% CI: 1.424-10.365) and peritumoral enhancement ( OR=8.05, 95% CI: 1.23-52.80), which were further incorporated into constructing the predictive nomogram of early recurrence of HCC after RFA. Internal validation results showed the area under the curve, sensitivity, specificity of the receiver operating characteristic (ROC) curve were 0.839, 68.1% and 93.1%, respectively. The calibration curve showed the predicted curve of nomogram was close to the ideal curve. Hosmer-Lemeshow test showed there was no significant difference between the predicted results of nomogram and the actual results ( P=0.424). Conclusions:An interval of 12 months after RFA is the optimal cut-off value for defining early recurrence and late recurrence. The nomogram is integrated by clinical and radiographic features, which can potentially predict early recurrence of HCC after RFA and may offer useful guidance for individual treatment or follow up.

Objective:To propose a new robust optimization method, known as modified worst case method, was proposed, which can enable users to control the trade-off between nominal plan quality and plan robustness.Methods:In each iteration of the plan optimization process, the dose value of each voxel in nine scenarios, which corresponded to a nominal scenario and eight perturbed scenarios with range or set-up uncertainties, were calculated and the maximum of deviations of each scenario voxel dose from that of the nominal scenario was included as an additive robust optimization term in the objective function. A weighting factor p robust was used to this robust optimization term to balance the nominal plan quality and plan robustness. Results:The robust optimization methods were implemented and compared in an in-house developed robust optimization module. When p robust=0.8, compared with conventional optimization, the ΔD 95% of CTV was reduced from 9.8 Gy to 7.6 Gy. When p robust was reduced from 1 to 0, ΔD 95% was increased from 7.0 Gy to 9.8 Gy, whereas the D 95% and D max of CTV, and the D 5% and D max of organs at risk (OAR) in the nominal scenario were reduced. Conclusions:The proposed modified worst case method can effectively improve the robustness of the plan to the range and set-up uncertainties. Besides, the weighting factor p robust in this method can be adopted to control the trade-off between nominal plan quality and plan robustness.

Background and objective Background and objective Follow up by computed tomography (CT) and growth evaluation are routine methods for the differential diagnosis of indeterminate pulmonary nodules in clinical practice. Pulmonary nodules with diverse biological behaviors may show different growth patterns and velocities. The aim of this study is to identify the volume growth curve of both benign and malignant pulmonary nodules. This work also intends to determine these nodules' growth patterns and provide evidence for the establishment of a follow-up strategy. Methods The CT data of 111 pulmonary nodules (54 solid, 57 subsolid) were retrospectively evaluated using 3D volumetric software. All of these nod-ules have been followed up at least twice. Of these nodules, 35 were confirmed as lung cancers, whereas 5 were confirmed as benign by pathology or histology. Moreover, 71 nodules showed no growth in more than 2 years. Stable nodules were defined as low-risk nodules, as confirmed by reevaluation from experts. On the basis of their densities and diameters, the nodules were classified into four types: benign/low-risk solid nodules, malignant solid nodules (diameter ≤1 cm and >1 cm), benign/low-risk subsolid nodules, and malignant subsolid nodules (diameter ≤1 cm and >1 cm). The follow-up interval time (d) were plot-ted on the x-axis, and the nodules' volume (mm3) and logarithmic volume were plotted on the y-axis. Two radiologists subjec-tively determined the type of growth curve. Chi-square test was performed to compare the growth curves of benign/low-risk and malignant nodules. Results Of 18 solid cancers, 12 cases (66%) were found with steep ascendant growth curves. Those of 3 cases (16.7%) were flat ascendant, 2 cases (11.1%) slowly ascendant, and 1 (5.56%) case flat. Of 17 subsolid cancers, 8 cases (47.1%) manifested steep ascendant growth curves. Those of 4 cases (23.5%) were slowly ascendant, 3 (17.6%) flat, and 2 (11.8%) descendant–ascendant. Of 36 benign/low-risk solid nodules, 5 cases (13.9%) manifested descendant growth curves, 17 cases (47.2%) flat, 8 cases (21.6%) slowly ascendant, and 6 cases (16.7%) undulate. Of 40 benign/low-risk subsolid nod-ules, 4 cases (10%) manifested descendant growth curves, 21 cases (52.5%) flat, 9 cases (22.5%) slowly ascendant, and 6 cases (15%) undulate. The distribution of growth curve types significantly differed between benign/low-risk and malignant nodules (χ2=42.4, P<0.01). Conclusion The growth curves of lung cancers are heterogeneous. A steep ascendant curve is the main type for lung cancer, with the exception of flat, slowly ascendant, or even descendant curve. A slowly ascendant curve cannot exclude the diagnosis of lung cancer, especially for subsolid nodules.

Background and objective hTe management of pulmonary nodules relies on cancer risk assessment, in which the only widely accepted criterion is diameter. hTe development of volumetric computed tomography (CT) and three-dimensional (3D) sotfware enhances the clarity in displaying the nodules’ characteristics. hTis study evaluated the values of the nodules’ volume and 3D morphological characteristics (edge, shape and location) in cancer risk assessment.Methods hTe CT data of 200 pulmonary nodules were retrospectively evaluated using 3D volumetric sotfware. hTe malignancy or benignity of all the nodules was conifrmed by pathology, histology or follow up (>2 years).Logistic regression analysis was performed to calculate the odds ratios (ORs) of the 3D margin (smooth, lobulated or spiculated/irregular), shape (spherical or non-spherical), location (purely intraparenchymal, juxtavascular or pleural-attached), and nodule volume in cancer risk assessment for total and sub-centimeter nodules. hTe receiver operating characteristic (ROC) curve was employed to determine the opti-mal threshold for the nodule volume.Results Out of 200 pulmonary nodules, 78 were malignant, whereas 122 were benign. hTeLogistic regression analysis showed that the volume (OR=3.3;P<0.001) and the 3D margin (OR=13.4, 9.8; bothP=0.001) were independent predictive factors of malignancy, whereas the location and 3D shape exhibited no total predictive value (P>0.05). ROC analysis showed that the optimal threshold for malignancy was 666 mm3. For sub-centimeter nodules, the 3D margin was the only valuable predictive factor of malignancy (OR=60.5, 75.0;P=0.003, 0.007).Conclusion hTe volume and 3D margin are important factors considered to assess the cancer risk of pulmonary nodules. Volumes larger than 666 mm3 can be determined as high risk for pulmonary nodules; by contrast, nodules with lobulated, spiculated, or irregular margin present a high malignancy probability.

Objective To investigate the association between chronic kidney dysfunction and the complexity of coronary artery disease in elderly patients.Methods A prospective study was conducted on 1380 consecutive patients underwent coronary angiography for the first time in our hospital and with angiographically diagnosed coronary artery disease from January 2011 to June 2012.The complexity of coronary artery disease were classified according to the American College of Cardiology/American Heart Association (ACC/AHA) grading system as types A,B1,B2,and C.Estimated glomerular filtration rate (eGFR) was calculated by the simplified Modification of Diet in Renal Disease(MDRD)equation.Patients were classified into 3 stages according to eGFR as follows:normal renalfunction(n=234,eGFR≥90 ml· min-1 · 1.73 m-2),mild renaldysfunction(n=881,60≤eGFR＜90 ml · min-1 · 1.73 m-2,and moderate or severe renaldysfunction(n=265,eGFR＜60ml · min-1 · 1.73 m-2).Ordinal logistic regression was used to analyze the association between chronic kidney dysfunction and the complexity of coronary artery disease.Results Patients with mild,moderate or severe renal dysfunction were older (F=56.82,P＜0.001),more predominantly female (x2 =66.29,P＜ 0.001) and more likely to have history of hypertension (x2 =17.57,P ＜ 0.001),diabetes (x2=20.97,P＜0.001) and hyperlipidemia (x2=10.48,P 0.005) than those with normal renal function.The percentage of lesions of types B2 or C in moderate or severe renal dysfunction group was higher than that in normal renal function group (x2=175.03,P＜0.001).The ordinal logistic regression showed that age,male,hypertension,diabetes,C-reactive protein and eGFR were independent risk factors for the ACC/AHA lesion classification.Conclusions Age,male,hypertension,diabetes,C-reactive protein and eGFR are independent risk factors for the complexity of coronary artery disease.

Objective To investigate the best fermentation and induction models of the engineered Escherichia coli, in order to obtain the highest expression level of humanized anti HBsAg Fab. Methods The optimal condition governing the growth of the Escherichia coli, with the flask shaking method and the best fermentation and induction conditions to yield the highest production level were explored, and then E coli were grown in fermentor using the fed batch method following the same principle under flask shaking condition to ensure the best production. Results The data obtained from flask shaking conditions showed that when the induction procedure started the amount of anti HBsAg Fab would reach the highest level at mid log growth phase under the induction condition of 25℃ and 0 2% arabinose. Using the DO stat fed batch method, the OD 600 value of the culture would reach 55 2, which corresponded to 110g/L bacterial wet weight. The biological activity of Fab was proved to have well preserved. Conclusion We established the optimal production technic of HBsAg Fab, and lay a foundation to produce HBsAg Fab on a large scale