1.Analysis of alanine aminotransferase screening results in blood donors and quality management measures
Liang ZANG ; Lei ZHOU ; Le CHANG ; Lunan WANG
Chinese Journal of Blood Transfusion 2025;38(4):474-481
[Objective] To explore quality issues and quality management measures in alanine aminotransferase (ALT) testing, aiming to improve consistency and accuracy of ALT test results by analyzing the outcomes from different pre-donation screening methods and different sample sources. [Methods] Data were collected from 58 blood collection and supply institutions across China. ALT test results from donor samples analyzed by dry chemistry analyzers, semi-automatic biochemical analyzers, and automatic biochemical analyzers were compared, focusing on the influence of venous versus capillary blood samples on testing accuracy. By comparing results from pre-donation screening with laboratory testing, the current state of quality management for different methods and sample types was assessed. Differences in ALT unqualified rates between laboratories were analyzed, and quality improvement strategies were proposed accordingly. [Results] No significant differences were found in laboratory ALT unqualified rates between venous and capillary blood samples during pre-donation screening across different analytical methods (P>0.05). However, laboratory ALT unqualified rates were consistently lower for venous blood compared to capillary blood, regardless of the testing method used (P<0.05). Notable differences in quality control were observed among various blood collection and supply institutions (P<0.05). [Conclusion] Minimal differences were observed between pre-donation ALT screening results obtained by the three analytical methods and laboratory test outcomes; thus, blood stations can select an appropriate testing method according to their specific conditions. Pre-donation screening using venous blood samples demonstrated superior reliability in quality control compared to capillary blood samples. Significant variations in ALT unqualified rates among blood stations suggest that blood collection and supply institutions should emphasize quality management at both the pre-donation screening and laboratory testing stages. Measures such as optimized standardized operating procedures, regular equipment calibration and maintenance, proficiency testing, internal quality control, inter-system comparisons, and enhanced personnel training and evaluation should be implemented to ensure consistent and stable screening results, thereby reducing ALT unqualified rates.
2.Exploring the prognostic value of spatiotemporal heterogeneity in pathological grading during the dynamic progression of non-metastatic renal cancer
Lei CHANG ; Ge SILUN ; Zhou YE ; Chen HUI ; Wang LINHUI ; Qu LE
Chinese Journal of Clinical Oncology 2024;51(17):902-908
Objective:To investigate the characteristics of spatiotemporal heterogeneity in pathological grading during the latent and invas-ive growth phases of non-metastatic renal cell carcinoma(RCC)and its correlation with clinical outcomes.Methods:A retrospective analysis was conducted on the case data of 316 RCC patients with local recurrence(LR)and 429 RCC patients with venous tumor thrombus(VTT)who underwent surgical treatment at 13 medical centers in China from January 2003 to December 2023.Pathological grade differences between primary tumor(PT)and LR,and between PT and VTT were selected as scenarios for the application of spatiotemporal heterogen-eity in the dynamic progression of RCC.Pathological grading changes were defined according to a new four-tier scheme(upgrading,down-grading,stable low-grade,and stable high-grade).Stable low-or high-grade was defined as low-grade(WHO/ISUP grade Ⅰ or Ⅱ)or high-grade(WHO/ISUP grade Ⅲ or Ⅳ)in both PT and LR/VTT.Upgrading was defined as low-grade in the PT and high-grade in the LR/VTT;con-versely,downgrading was defined as high-grade in the PT and low-grade in the LR/VTT.The potential influencing factors of pathological grading changes and their impact on patient prognosis were analyzed.Results:The median cancer-specific survival(CSS)for RCC patients with VTT and RCC patients with LR was 83 months and 76 months,respectively.The 5-year CSS rates were 65.6%and 60.6%,respectively.Pathological grading changes were observed in 38.0%of patients with PT and VTT and in 43.6%of patients with PT and LR.Lasso-Logistic re-gression analysis revealed a close correlation between primary tumor necrosis and pathological grading changes.Kaplan-Meier survival curves indicated a significant correlation between pathological grading changes and prognosis.Replacing the pathological grading in Leibovich,UISS,and GRANT scores with pathological grading changes significantly improved the predictive performance of the models(P<0.05).Conclusions:Spatiotemporal heterogeneity in pathological grading exists during the dynamic progression of non-metastatic RCC.Compared to the pathological grading of isolated events,the spatiotemporal variation in pathological grading serves as a more accurate in-dependent prognostic factor for RCC patients with VTT and RCC patients with LR.Incorporating pathological grading changes can signific-antly improve the predictive performance of existing prognostic models.
3.Incidence of extrauterine growth retardation and its risk factors in very preterm infants during hospitalization: a multicenter prospective study.
Wei SHEN ; Zhi ZHENG ; Xin-Zhu LIN ; Fan WU ; Qian-Xin TIAN ; Qi-Liang CUI ; Yuan YUAN ; Ling REN ; Jian MAO ; Bi-Zhen SHI ; Yu-Mei WANG ; Ling LIU ; Jing-Hui ZHANG ; Yan-Mei CHANG ; Xiao-Mei TONG ; Yan ZHU ; Rong ZHANG ; Xiu-Zhen YE ; Jing-Jing ZOU ; Huai-Yu LI ; Bao-Yin ZHAO ; Yin-Ping QIU ; Shu-Hua LIU ; Li MA ; Ying XU ; Rui CHENG ; Wen-Li ZHOU ; Hui WU ; Zhi-Yong LIU ; Dong-Mei CHEN ; Jin-Zhi GAO ; Jing LIU ; Ling CHEN ; Cong LI ; Chun-Yan YANG ; Ping XU ; Ya-Yu ZHANG ; Si-Le HU ; Hua MEI ; Zu-Ming YANG ; Zong-Tai FENG ; San-Nan WANG ; Er-Yan MENG ; Li-Hong SHANG ; Fa-Lin XU ; Shao-Ping OU ; Rong JU
Chinese Journal of Contemporary Pediatrics 2022;24(2):132-140
OBJECTIVES:
To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China.
METHODS:
A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined.
RESULTS:
The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05).
CONCLUSIONS
It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.
Female
;
Fetal Growth Retardation
;
Gestational Age
;
Hospitalization
;
Humans
;
Incidence
;
Infant
;
Infant, Newborn
;
Infant, Premature
;
Infant, Very Low Birth Weight
;
Prospective Studies
;
Risk Factors
4.Outcomes at discharge of preterm infants born <34 weeks' gestation.
Ning Xin LUO ; Si Yuan JIANG ; Yun CAO ; Shu Jun LI ; Jun Yan HAN ; Qi ZHOU ; Meng Meng LI ; Jin Zhen GUO ; Hong Yan LIU ; Zu Ming YANG ; Yong JI ; Bao Quan ZHANG ; Zhi Feng HUANG ; Jing YUAN ; Dan Dan PAN ; Jing Yun SHI ; Xue Feng HU ; Su LIN ; Qian ZHAO ; Chang Hong YAN ; Le WANG ; Qiu Fen WEI ; Qing KAN ; Jin Zhi GAO ; Cui Qing LIU ; Shan Yu JIANG ; Xiang Hong LIU ; Hui Qing SUN ; Juan DU ; Li HE
Chinese Journal of Pediatrics 2022;60(8):774-780
Objective: To investigate the incidence and trend of short-term outcomes among preterm infants born <34 weeks' gestation. Methods: A secondary analysis of data from the standardized database established by a multicenter cluster-randomized controlled study "reduction of infection in neonatal intensive care units (NICU) using the evidence-based practice for improving quality (REIN-EPIQ) study". This study was conducted in 25 tertiary NICU. A total of 27 192 infants with gestational age <34 weeks at birth and admitted to NICU within the first 7 days of life from May 2015 to April 2018 were enrolled. Infants with severe congenital malformation were excluded. Descriptive analyses were used to describe the mortality and major morbidities of preterm infants by gestational age groups and different admission year groups. Cochran-Armitage test and Jonckheere-Terpstra test were used to analyze the trend of incidences of mortality and morbidities in 3 study-years. Multiple Logistic regression model was constructed to analyze the differences of outcomes in 3 study-years adjusting for confounders. Results: A total of 27 192 preterm infants were enrolled with gestational age of (31.3±2.0) weeks at birth and weight of (1 617±415) g at birth. Overall, 9.5% (2 594/27 192) of infants were discharged against medical advice, and the overall mortality rate was 10.7% (2 907/27 192). Mortality for infants who received complete care was 4.7% (1 147/24 598), and mortality or any major morbidity was 26.2% (6 452/24 598). The incidences of moderate to severe bronchopulmonary dysplasia, sepsis, severe intraventricular hemorrhage or periventricular leukomalacia, proven necrotizing enterocolitis, and severe retinopathy of prematurity were 16.0% (4 342/27 192), 11.9% (3 225/27 192), 6.8% (1 641/24 206), 3.6% (939/25 762) and 1.5% (214/13 868), respectively. There was a decreasing of the overall mortality (P<0.001) during the 3 years. Also, the incidences for sepsis and severe retinopathy of prematurity both decreased (both P<0.001). However, there were no significant differences in the major morbidity in preterm infants who received complete care during the 3-year study period (P=0.230). After adjusting for confounders, infants admitted during the third study year showed significantly lower risk of overall mortality (adjust OR=0.62, 95%CI 0.55-0.69, P<0.001), mortality or major morbidity, moderate to severe bronchopulmonary dysplasia, sepsis and severe retinopathy of prematurity, compared to those admitted in the first study year (all P<0.05). Conclusions: From 2015 to 2018, the mortality and major morbidities among preterm infants in Chinese NICU decreased, but there is still space for further efforts. Further targeted quality improvement is needed to improve the overall outcome of preterm infants.
Bronchopulmonary Dysplasia/epidemiology*
;
Gestational Age
;
Humans
;
Infant
;
Infant Mortality/trends*
;
Infant, Newborn
;
Infant, Premature
;
Infant, Premature, Diseases/epidemiology*
;
Patient Discharge
;
Retinopathy of Prematurity/epidemiology*
;
Sepsis/epidemiology*
5.Wuzhi Tablet protects against APAP-induced liver injury at different pretreated intervals in mice
Le-qian XU ; Yan-ying ZHOU ; Yi-ming JIANG ; Yun-hui XING ; Min HUANG ; Hui-chang BI
Acta Pharmaceutica Sinica 2021;56(4):1147-1154
Acetaminophen (APAP, also known as paracetamol)-induced liver injury is the leading cause of drug-induced liver injury in the world. Wuzhi Tablet (WZ, an ethanol extract of
6.A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation.
Le-Qing CAO ; Yang ZHOU ; Yan-Rong LIU ; Lan-Ping XU ; Xiao-Hui ZHANG ; Yu WANG ; Huan CHEN ; Yu-Hong CHEN ; Feng-Rong WANG ; Wei HAN ; Yu-Qian SUN ; Chen-Hua YAN ; Fei-Fei TANG ; Xiao-Dong MO ; Kai-Yan LIU ; Qiao-Zhen FAN ; Ying-Jun CHANG ; Xiao-Jun HUANG
Chinese Medical Journal 2021;134(10):1199-1208
BACKGROUND:
For patients with B cell acute lymphocytic leukemia (B-ALL) who underwent allogeneic stem cell transplantation (allo-SCT), many variables have been demonstrated to be associated with leukemia relapse. In this study, we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.
METHODS:
A total of 477 patients with B-ALL who underwent allo-SCT at Peking University People's Hospital from December 2010 to December 2015 were enrolled in this retrospective study. We aimed to evaluate the factors associated with transplant outcomes after allo-SCT, and establish a risk score to identify patients with different probabilities of relapse. The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables.
RESULTS:
All patients achieved neutrophil engraftment, and 95.4% of patients achieved platelet engraftment. The 5-year cumulative incidence of relapse (CIR), overall survival (OS), leukemia-free survival (LFS), and non-relapse mortality were 20.7%, 70.4%, 65.6%, and 13.9%, respectively. Multivariate analysis showed that patients with positive post-transplantation minimal residual disease (MRD), transplanted beyond the first complete remission (≥CR2), and without chronic graft-versus-host disease (cGVHD) had higher CIR (P < 0.001, P = 0.004, and P < 0.001, respectively) and worse LFS (P < 0.001, P = 0.017, and P < 0.001, respectively), and OS (P < 0.001, P = 0.009, and P < 0.001, respectively) than patients without MRD after transplantation, transplanted in CR1, and with cGVHD. A risk score for predicting relapse was formulated with the three above variables. The 5-year relapse rates were 6.3%, 16.6%, 55.9%, and 81.8% for patients with scores of 0, 1, 2, and 3 (P < 0.001), respectively, while the 5-year LFS and OS values decreased with increasing risk score.
CONCLUSION
This new risk score system might stratify patients with different risks of relapse, which could guide treatment.
B-Lymphocytes
;
Graft vs Host Disease
;
Hematopoietic Stem Cell Transplantation
;
Humans
;
Leukemia, Myeloid, Acute
;
Precursor Cell Lymphoblastic Leukemia-Lymphoma
;
Recurrence
;
Retrospective Studies
;
Risk Factors
;
Stem Cell Transplantation
7.A multi-center retrospective study of perioperative chemotherapy for gastric cancer based on real-world data.
Xue Wei DING ; Zhi Chao ZHENG ; Qun ZHAO ; Gang ZHAI ; Han LIANG ; Xin WU ; Zheng Gang ZHU ; Hai Jiang WANG ; Qing Si HE ; Xian Li HE ; Yi An DU ; Lu Chuan CHEN ; Ya Wei HUA ; Chang Ming HUANG ; Ying Wei XUE ; Ye ZHOU ; Yan Bing ZHOU ; Dan WU ; Xue Dong FANG ; You Guo DAI ; Hong Wei ZHANG ; Jia Qing CAO ; Le Ping LI ; Jie CHAI ; Kai Xiong TAO ; Guo Li LI ; Zhi Gang JIE ; Jie GE ; Zhong Fa XU ; Wen Bin ZHANG ; Qi Yun LI ; Ping ZHAO ; Zhi Qiang MA ; Zhi Long YAN ; Guo Liang ZHENG ; Yang YAN ; Xiao Long TANG ; Xiang ZHOU
Chinese Journal of Gastrointestinal Surgery 2021;24(5):403-412
Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.
Chemotherapy, Adjuvant
;
Female
;
Gastrectomy
;
Humans
;
Male
;
Neoadjuvant Therapy
;
Neoplasm Staging
;
Prognosis
;
Retrospective Studies
;
Stomach Neoplasms/surgery*
8.Clinical observation of warm moxibustion therapy to improve quadriceps weakness after total knee arthroplasty.
Chang-Jun JU ; Xin ZHOU ; Cheng-Cheng DONG ; Le-Qin LIN ; Hai-Ning LIU ; Yan HOU
Chinese Acupuncture & Moxibustion 2019;39(3):276-279
OBJECTIVE:
To evaluate the clinical efficacy of warm moxibustion therapy in the recovery of quadriceps muscle strength in patients undergoing total knee arthroplasty (TKA) with analgesia of the femoral nerve block (FNB).
METHODS:
A total of 174 patients with KOA were randomized into a warm moxibustion group and a rehabilitation group, 87 cases in each group. In the warm moxibustion group, warm moxibustion combined with conventional quadriceps strength training were used. In the rehabilitation group, conventional quadriceps strength training was given. The warm moxibustion was applied at Liangqiu (ST 34) and Zusanli (ST 36), the treatment was given twice a day, 7 days for one course, with a total of 2 courses.The quadriceps muscle strength of the two groups was recorded and compared at 24 h before FNB, 24, 48, 72 and 96 h after surgery, and the resting and exercise VAS pain scores were also recorded at the same time point. And the first time for standing up and the first straight raising time in the two groups were compared, and the occurrence of adverse reactions in the two groups were observed.
RESULTS:
At 24, 48, 72 and 96 h after FNB, the quadriceps muscle strength in the warm moxibustion group was better than that in the rehabilitation group (<0.05, <0.01). At 72 h and 96 h after FNB, the resting and exercise VAS scores of the warm moxibustion group were lower than those of the rehabilitation group (both <0.001). The average first straight leg raising time in the warm moxibustion group was postoperative (31.03±10.78) h, and the time in the rehabilitation group was postoperative (47.23±15.78) h. The difference was statistically significant (<0.001). The average time of the first time for standing up in the warm moxibustion group was postoperative (25.76±7.00) h, and postoperative (33.12±11.18) h in the rehabilitation group. The difference was also statistically significant (<0.001). No adverse reactions occurred in both groups.
CONCLUSION
Warm moxibustion combined with conventional quadriceps strength training can improve the symptoms of quadriceps weakness in patients with femoral nerve block after total knee arthroplasty, and accelerate the recovery of joint function, which is superior to conventional quadriceps strength training.
Arthroplasty, Replacement, Knee
;
Femoral Nerve
;
Humans
;
Moxibustion
;
Muscle Strength
;
Nerve Block
;
Pain, Postoperative
;
Quadriceps Muscle
;
Treatment Outcome
9.Study and Application Overview of Spectroscopy Method in TCM Tongue Diagnosis
Wen JIAO ; Ji CUI ; Chang-Le ZHOU ; Jia-Tuo XU
Chinese Journal of Information on Traditional Chinese Medicine 2018;25(11):130-134
Tongue diagnosis is one of unique techniques of TCM diagnosis. Its subjective and empirical description of written words, spoken language and pictures have been used until now, however, which cannot express the complete information of tongue image comprehensively and objectively. The development of modern technology provides new ideas and methods for the study of tongue diagnosis in TCM. For example, the application of spectroscopy is of great significance for restoring tongue image information. This article briefly introduced the spectroscopy method, summarized its research and application in the field of TCM tongue diagnosis, and put forward the problems and prospects to provide references for further research.
10.Ultrasound-guided diffuse optical tomography(DOT) differences and clinical characteristics of T1-T3 breast carcinoma
Wenxiang ZHI ; Min CHEN ; Yu WANG ; Shichong ZHOU ; Na HU ; Wei ZENG ; Xun ZHANG ; Jin ZHOU ; Jian LE ; Cai CHANG
Chinese Journal of Ultrasonography 2018;27(1):31-35
Objective To explore the ultrasound-guided diffuse optical tomography (DOT) distribution difference and clinical characteristics of T 1-T3 breast carcinoma. Methods Four hundred and forty-seven breast cancer patients with 455 breast lesions were enrolled.The lesion maximal diameter and total hemoglobin concentration(THC) were obtained by ultrasound-guided DOT before breast surgery biopsy.The patients age,body mass index(BMI),and the distances from lesion to skin and nipple were measured,lymph node status were also assessed.According to the 7th Edition of the AJCC Cancer Staging, all tumors were divided into T1( ≤ 2 cm),T2(2 cm < lesion ≤ 5 cm),and T3( > 5 cm) three groups according to maximum diameter on ultrasound.Results Out of 455 breast cancer lesions,148 lesions were stage T1,251 lesions were stage T2,56 lesions were T3.The age,lesion size,lesion THC and the distances between lesions and nipples of breast cancer patients were found that there were significant differences among T1,T2 and T3(all P = 0.000). With T stages increasing,the age of breast cancers patients decreased,the distance between lesions and nipples decreased,the THC increased.THC of breast cancer T 2 [(221.0 ± 56.0)μmol/L] and T3[(233.1 ± 54.0)μmol/L] were significant higher than that of T1 [(181.6 ± 70.4)μmol/L](all P = 0.000).There were all no significant difference for BMI and the distancefrom lesion to skin among different stages T( P > 0.05).With T stages increasing,the ratio of lymph node metastasis increased(T1 26.4%,T2 49.8%,T3 55.4%; P =0.000).Conclusions With breast cancer T stages increasing,T HC increases,the age of the patients decreases,lymph node metastasis rate increases.

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