Objective:To investigate the incidence and high-risk pathogenic factors of cardiovascular disease（CVD）in patients with rheumatic and autoimmune diseases，and to construct and validate a predictive model for the risk of CVD occurrence in these patients.Methods:A retrospective analysis was conducted on 239 patients with rheumatic and autoimmune diseases who underwent treatment and echocardiography at the Affiliated Hospital of Inner Mongolia Medical University between June 2020 and June 2023. General patient data，laboratory test results，and echocardiographic findings were collected. Follow-up was performed via electronic medical records or telephone surveys until December 2024 to determine the incidence of CVD，starting from the date of the first echocardiographic examination. Predictive factors were screened using univariate analysis and Lasso regression，and a Logistic regression model was constructed. Internal validation was performed using the Bootstrap method. The model's accuracy and clinical utility were assessed using the Hosmer-Lemeshow test，calibration curve，and decision curve analysis.Results:Among the 239 patients，111 developed CVD. Logistic regression analysis identified age，diastolic blood pressure，use of immunosuppressants，lymphocyte count（LYM），α-hydroxybutyrate dehydrogenase（α-HBDH）level，serum cystatin C（CysC），and right ventricular fractional area change（RVFAC）as independent predictive factors for CVD in these patients（all P<0.05）. The area under the ROC curve（AUC）for the prediction model was 0.895（95% CI = 0.856 - 0.935），and after Bootstrap validation，it was 0.894（95% CI = 0.861-0.925）. The Hosmer-Lemeshow test，calibration curve，and decision curve analysis all indicated that the model had good accuracy and clinical utility. Conclusions:Age，diastolic blood pressure，use of immunosuppressants，LYM，α-HBDH，CysC，and RVFAC may serve as independent risk factors for CVD in patients with rheumatic and autoimmune diseases. The prediction model based on echocardiography combined with laboratory indicators can，to some extent，predict the risk of CVD occurrence in these patients.

Objective:To explore the clinical effect of vitamin A in the adjuvant treatment of bronchial asthma in children and its influence on serum transforming growth factor-β1 (TGF-β1), eosinophils (EOS) and interleukin-17 (IL-17) levels.Methods:A prospective study was conducted on 110 children with bronchial asthma who received treatment in Department of Pediatrics, Xi'an Central Hospital from January 2022 to December 2023. Based on the principle of balanced and comparable baseline characteristics between groups, they were randomly divided into a control group and an observation group, with 55 cases in each group, using a random number table method. The control group was treated with routine pediatric bronchial asthma therapy, while the observation group was added with vitamin A adjuvant therapy on the basis of the control group. After 15 days of continuous treatment, the scores of asthma control condition (Childhood-Asthma Control Test (C-ACT), Asthma Control Questionnaire (ACQ)) in the two groups were evaluated. The pulmonary ventilation function (forced expiratory volume in one second (FEV 1), forced expiratory volume in one second/forced vital capacity (FEV 1/FVC), peak expiratory flow (PEF)), serum inflammatory factors (TGF-β1, EOS, IL-17) and immune function indicators (T helper 17 cell (Th17), T helper 2 cell (Th2), regulatory T cell (Treg) ) were compared between groups of children before treatment and after 15 days of treatment. Measurement data with normal or approximate distribution were expressed as xˉ± s, and independent sample t test was used for comparison between groups. Enumeration data were expressed as percentage, and chi-square test was adopted for between-group comparison. Results:After 15 days of treatment, the C-ACT score with (16.20±3.14) points in observation group was higher than (14.80±2.62) points in control group while the ACQ score with (30.30±4.14) points was lower than (34.60±6.23) points in control group, with statistical differences between groups (t values were 2.54 and 4.26; P values were 0.012 and <0.001). The pulmonary ventilation function indicators in observation group and control group after 15 days of treatment (FEV 1: (1.76±0.34) L与(1.54±0.32) L, FEV 1/FVC:(76.89±5.76)%与(70.25±6.42)%, PEF(2.89±0.35) L/s与(2.68±0.39) L/s) were higher than those before treatment (FEV 1:(1.12±0.31) L与(1.20±0.33) L, FEV 1/FVC:(56.96±4.35)%与(58.12±3.48)%, PEF(2.15±0.66) L/s与(2.34±0.56) L/s), and the differences were statistically significant ( t values were 10.32, 5.49, 20.48, 10.43, 7.35, 3.70, respectively; all P<0.001), and the indicators in observation group were higher compared to control group, the differences were statistically significant ( t values were 3.49, 5.71, and 2.97; P values were 0.001, <0.001, and 0.004). After 15 days of treatment, the levels of serum inflammatory factors (TGF-β1:(6.32±1.36) ng/L与(8.75±1.81) ng/L, EOS:(3.56±0.65)%与(4.28±0.82)%, IL-17:(5.53±1.22) ng/L与(6.42±1.51) ng/L) and CD4 + T lymphocyte immune function indicators (Th17:(0.97±0.26) ng/L与(1.23±0.35) ng/L, Th2:(2.32±0.64) ng/L与(3.15±0.52) ng/L, Treg:(5.41±0.76) ng/L与(5.86±0.23) ng/L ) were lower in observation group and control group than those before treatment (TGF-β1: (14.35±2.23)与(15.26±3.05) ng/L, EOS: (6.32±1.33)%与(6.41±1.27)%, IL-17:(8.86±1.68)与(9.03±1.89) ng/L, Th17:(1.82±0.75)与(1.67±0.68) ng/L, Th2:(4.15±1.49)与(3.98±1.28) ng/L, Treg: (7.26±1.35)与(6.92±1.72) ng/L), and the differences were statistically significant ( t values were 22.80, 13.61, 13.83, 10.45, 11.90, 8.08, 7.94, 4.27, 8.37, 4.46, 8.86, 4.58, respectively; all P<0.001). However, the above indicators in the observation group were lower than those in the control group ( t values were 7.96, 5.10, 3.40, 4.42, 7.47, 4.20, and P-values were <0.001, <0.001, 0.001, <0.001, <0.001, and <0.001 respectively). Conclusion:Vitamin A adjuvant therapy is helpful to the control of bronchial asthma, and it can effectively improve the pulmonary function, reduce the inflammatory reaction and enhance the body's immunity.

Objective To investigate the knowledge,attitude,and practice(KAP)related to medication use among pregnant and lactating women in Hubei province,to comprehend the specific requirements of pregnant and lactating women for pharmaceutical assistance,to assess the critical stages in the process of medication,and to furnish factual backing for devising a secure medication education framework tailored to pregnant and lactating women.Methods Through a multi-center study design,with pregnant and lactating women as the research subjects,a questionnaire survey was carried out to gather fundamental information and assess their knowledge,attitude,and practices towards medication use.Data analysis involved utilizing one-way analysis of variance,non-parametric tests,and multiple linear regression.Results A total of 548 valid questionnaires were collected.The average scores for knowledge,practice and attitude among pregnant and lactating women were(58.26±30.68),(52.18±22.32),and(46.60±14.66)points,respectively.Overall,the scores for medication knowledge and behavior were good,while the attitude scores were passable.These results suggest that pregnant and lactating women have a certain level of understanding about safe medication practices and hold a positive attitude towards receiving medication education.However,there are still potential safety hazards in their daily medication behavior.The results of multiple linear regression indicate that age,educational level,and occupation are the main factors influencing the knowledge,attitude,and practice of medication use among pregnant and lactating women.Conclusions Pregnant and lactating women require urgent education on the safe use of medication.It is recommended that targeted drug education should be carried out based on the knowledgegaps and medication misconceptions of different objects.Additionally,it is crucial to effectively utilize new media platforms,such as WeChat official accounts and channels,and to engage in offline scientific outreach activities,such as offering free consultations and giving lectures on rational drug use.This will provide pregnant and lactating women with convenient and practical educational content on safe medication.

Objective:To explore the clinical effect of vitamin A in the adjuvant treatment of bronchial asthma in children and its influence on serum transforming growth factor-β1 (TGF-β1), eosinophils (EOS) and interleukin-17 (IL-17) levels.Methods:A prospective study was conducted on 110 children with bronchial asthma who received treatment in Department of Pediatrics, Xi'an Central Hospital from January 2022 to December 2023. Based on the principle of balanced and comparable baseline characteristics between groups, they were randomly divided into a control group and an observation group, with 55 cases in each group, using a random number table method. The control group was treated with routine pediatric bronchial asthma therapy, while the observation group was added with vitamin A adjuvant therapy on the basis of the control group. After 15 days of continuous treatment, the scores of asthma control condition (Childhood-Asthma Control Test (C-ACT), Asthma Control Questionnaire (ACQ)) in the two groups were evaluated. The pulmonary ventilation function (forced expiratory volume in one second (FEV 1), forced expiratory volume in one second/forced vital capacity (FEV 1/FVC), peak expiratory flow (PEF)), serum inflammatory factors (TGF-β1, EOS, IL-17) and immune function indicators (T helper 17 cell (Th17), T helper 2 cell (Th2), regulatory T cell (Treg) ) were compared between groups of children before treatment and after 15 days of treatment. Measurement data with normal or approximate distribution were expressed as xˉ± s, and independent sample t test was used for comparison between groups. Enumeration data were expressed as percentage, and chi-square test was adopted for between-group comparison. Results:After 15 days of treatment, the C-ACT score with (16.20±3.14) points in observation group was higher than (14.80±2.62) points in control group while the ACQ score with (30.30±4.14) points was lower than (34.60±6.23) points in control group, with statistical differences between groups (t values were 2.54 and 4.26; P values were 0.012 and <0.001). The pulmonary ventilation function indicators in observation group and control group after 15 days of treatment (FEV 1: (1.76±0.34) L与(1.54±0.32) L, FEV 1/FVC:(76.89±5.76)%与(70.25±6.42)%, PEF(2.89±0.35) L/s与(2.68±0.39) L/s) were higher than those before treatment (FEV 1:(1.12±0.31) L与(1.20±0.33) L, FEV 1/FVC:(56.96±4.35)%与(58.12±3.48)%, PEF(2.15±0.66) L/s与(2.34±0.56) L/s), and the differences were statistically significant ( t values were 10.32, 5.49, 20.48, 10.43, 7.35, 3.70, respectively; all P<0.001), and the indicators in observation group were higher compared to control group, the differences were statistically significant ( t values were 3.49, 5.71, and 2.97; P values were 0.001, <0.001, and 0.004). After 15 days of treatment, the levels of serum inflammatory factors (TGF-β1:(6.32±1.36) ng/L与(8.75±1.81) ng/L, EOS:(3.56±0.65)%与(4.28±0.82)%, IL-17:(5.53±1.22) ng/L与(6.42±1.51) ng/L) and CD4 + T lymphocyte immune function indicators (Th17:(0.97±0.26) ng/L与(1.23±0.35) ng/L, Th2:(2.32±0.64) ng/L与(3.15±0.52) ng/L, Treg:(5.41±0.76) ng/L与(5.86±0.23) ng/L ) were lower in observation group and control group than those before treatment (TGF-β1: (14.35±2.23)与(15.26±3.05) ng/L, EOS: (6.32±1.33)%与(6.41±1.27)%, IL-17:(8.86±1.68)与(9.03±1.89) ng/L, Th17:(1.82±0.75)与(1.67±0.68) ng/L, Th2:(4.15±1.49)与(3.98±1.28) ng/L, Treg: (7.26±1.35)与(6.92±1.72) ng/L), and the differences were statistically significant ( t values were 22.80, 13.61, 13.83, 10.45, 11.90, 8.08, 7.94, 4.27, 8.37, 4.46, 8.86, 4.58, respectively; all P<0.001). However, the above indicators in the observation group were lower than those in the control group ( t values were 7.96, 5.10, 3.40, 4.42, 7.47, 4.20, and P-values were <0.001, <0.001, 0.001, <0.001, <0.001, and <0.001 respectively). Conclusion:Vitamin A adjuvant therapy is helpful to the control of bronchial asthma, and it can effectively improve the pulmonary function, reduce the inflammatory reaction and enhance the body's immunity.

Objective To investigate the knowledge,attitude,and practice(KAP)related to medication use among pregnant and lactating women in Hubei province,to comprehend the specific requirements of pregnant and lactating women for pharmaceutical assistance,to assess the critical stages in the process of medication,and to furnish factual backing for devising a secure medication education framework tailored to pregnant and lactating women.Methods Through a multi-center study design,with pregnant and lactating women as the research subjects,a questionnaire survey was carried out to gather fundamental information and assess their knowledge,attitude,and practices towards medication use.Data analysis involved utilizing one-way analysis of variance,non-parametric tests,and multiple linear regression.Results A total of 548 valid questionnaires were collected.The average scores for knowledge,practice and attitude among pregnant and lactating women were(58.26±30.68),(52.18±22.32),and(46.60±14.66)points,respectively.Overall,the scores for medication knowledge and behavior were good,while the attitude scores were passable.These results suggest that pregnant and lactating women have a certain level of understanding about safe medication practices and hold a positive attitude towards receiving medication education.However,there are still potential safety hazards in their daily medication behavior.The results of multiple linear regression indicate that age,educational level,and occupation are the main factors influencing the knowledge,attitude,and practice of medication use among pregnant and lactating women.Conclusions Pregnant and lactating women require urgent education on the safe use of medication.It is recommended that targeted drug education should be carried out based on the knowledgegaps and medication misconceptions of different objects.Additionally,it is crucial to effectively utilize new media platforms,such as WeChat official accounts and channels,and to engage in offline scientific outreach activities,such as offering free consultations and giving lectures on rational drug use.This will provide pregnant and lactating women with convenient and practical educational content on safe medication.

Objective:To investigate the incidence and high-risk pathogenic factors of cardiovascular disease（CVD）in patients with rheumatic and autoimmune diseases，and to construct and validate a predictive model for the risk of CVD occurrence in these patients.Methods:A retrospective analysis was conducted on 239 patients with rheumatic and autoimmune diseases who underwent treatment and echocardiography at the Affiliated Hospital of Inner Mongolia Medical University between June 2020 and June 2023. General patient data，laboratory test results，and echocardiographic findings were collected. Follow-up was performed via electronic medical records or telephone surveys until December 2024 to determine the incidence of CVD，starting from the date of the first echocardiographic examination. Predictive factors were screened using univariate analysis and Lasso regression，and a Logistic regression model was constructed. Internal validation was performed using the Bootstrap method. The model's accuracy and clinical utility were assessed using the Hosmer-Lemeshow test，calibration curve，and decision curve analysis.Results:Among the 239 patients，111 developed CVD. Logistic regression analysis identified age，diastolic blood pressure，use of immunosuppressants，lymphocyte count（LYM），α-hydroxybutyrate dehydrogenase（α-HBDH）level，serum cystatin C（CysC），and right ventricular fractional area change（RVFAC）as independent predictive factors for CVD in these patients（all P<0.05）. The area under the ROC curve（AUC）for the prediction model was 0.895（95% CI = 0.856 - 0.935），and after Bootstrap validation，it was 0.894（95% CI = 0.861-0.925）. The Hosmer-Lemeshow test，calibration curve，and decision curve analysis all indicated that the model had good accuracy and clinical utility. Conclusions:Age，diastolic blood pressure，use of immunosuppressants，LYM，α-HBDH，CysC，and RVFAC may serve as independent risk factors for CVD in patients with rheumatic and autoimmune diseases. The prediction model based on echocardiography combined with laboratory indicators can，to some extent，predict the risk of CVD occurrence in these patients.

Objective:To evaluate myocardial microcirculation perfusion with myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction after percutaneous coronary intervention (PCI), and to explore the prognostic value of different types of myocardial microcirculation perfusion.Methods:This is a prospective cohort study. Patients with acute myocardial infarction who underwent successful PCI in Nanfang Hospital of Southern Medical University and Kanghua Hospital of Dongguan City from October 2019 to June 2021 were selected. All the enrolled patients completed MCE examination within 72 hours after PCI. According to the examination results, the patients were divided into normal microcirculation perfusion group, delayed microcirculation perfusion group, and blocked microcirculation perfusion group. Adverse cardiovascular events including all-cause death, cardiovascular death, and angina re-hospitalization were followed up, and left ventricular ejection fraction (LVEF) review results were collected at six months to one year after surgery. Kaplan-Meier survival curve was used to investigate the difference in the incidence of adverse cardiovascular events in different myocardial perfusion groups, and Cox regression analysis was used to evaluate the effect of myocardial perfusion on adverse cardiovascular events.Results:A total of 113 patients with acute myocardial infarction were included, aged (56.3±11.5) years, with 88(78%) males. There were 31 cases in the normal microcirculation perfusion group, 43 cases in the delayed microcirculation perfusion group and 39 cases in the blocked microcirculation perfusion group. LVEF was reviewed in 49 patients, and LVEF in the delayed microcirculation perfusion group was significantly improved compared with baseline at follow-up ((63.3±1.2) % vs. (58.6±1.8) %, P=0.043), and there was no statistically significant difference between the other two groups (all P>0.05). The median follow-up time was 473 days, during follow-up period 30 adverse cardiovascular events occurred. Kaplan-Meier survival curve analysis showed that there was a statistically significant difference in the incidence of adverse cardiovascular events among the three groups ( Plog-rank=0.029). Cox regression analysis showed that abnormal microcirculation perfusion (defined as delayed and blocked microcirculation perfusion) was an independent predictor of adverse cardiovascular events in patients with acute myocardial infarction after PCI ( HR=1.90, 95% CI1.16-3.12, P=0.011). Conclusions:Microcirculatory perfusion decrease or lost is common in patients with acute myocardial infarction after PCI. Timely restoration of blood flow reconstruction can save heart function when microcirculatory perfusion decreases. Microcirculatory perfusion is a predictor of adverse cardiovascular events in patients with acute myocardial infarction, and patients with poor myocardial perfusion are more likely to experience adverse cardiovascular events.

BACKGROUND:Collagen is the most abundant extracellular matrix component,which is closely related to the structure and function of the extracellular matrix of skeletal muscle,but the effect and mechanism of recombinant human collagen(rhC)produced by bioengineering technology on the extracellular matrix of skeletal muscle are unclear. OBJECTIVE:To investigate the effect of rhC supplementation on the remodeling of skeletal muscle extracellular matrix after eccentric exercise,thereby revealing the possible mechanism by which rhC improves the injury of skeletal muscle extracellular matrix and promote the recovery after exercise. METHODS:A total of 104 healthy male C57 mice aged 8 weeks old were randomly divided into control group(normal saline),low-dose rhC group(0.2 g/kg),medium-dose rhC group(1.0 g/kg),and high-dose rhC group(2.0 g/kg).Two mice in each group were selected after continuous 7 days of intragastric intervention,and organs were dissected for hematoxylin-eosin staining to determine inflammatory infiltrates.On the 8th day,the remaining mice were subjected to eccentric exercise.The structural changes of the skeletal muscle extracellular matrix were observed under scanning electron microscopy immediately(0),24,48,and 96 hours after eccentric exercise.Meanwhile,grip strength,creatine kinase activity,and protein levels of matrix metalloproteinases 2,9,14 and tissue inhibitor of metalloproteinase-2 in skeletal muscle were detected by western blot assay. RESULTS AND CONCLUSION:Hematoxylin-eosin staining results indicated that short-term rhC supplementation showed no significant effects on the morphology of the heart,liver,spleen and kidney.After one-time eccentric exercise,the recovery rate of grip strength in the medium-and high-dose rhC groups was significantly increased(P＜0.01).The trend of creatine kinase changes was consistent in all groups and there was no significant difference between groups.The recovery process of the extracellular matrix in the low-dose rhC group was faster than that in the control group,and the muscle tract membrane in the medium-and high-dose rhC groups was more complete.The protein level of matrix metalloproteinase 9 in the high-dose rhC group was significantly decreased(P＜0.05).The protein levels of matrix metalloproteinase 14 in the medium-and high-dose rhC groups were significantly decreased(P＜0.05).The protein levels of matrix metalloproteinase 2 in the medium-and high-dose rhC groups were significantly decreased(P＜0.05).Tissue inhibitor of metalloproteinase-2 protein levels in the medium-and high-dose rhC groups were significantly increased(P＜0.05).The ratio of matrix metalloproteinase 2 to tissue inhibitor of metalloproteinase-2 in each rhC group was significantly decreased(P＜0.05).To conclude,pre-supplementation of 1.0 and 2.0 g/kg rhC for 7 days can inhibit extracellular matrix degradation in skeletal muscle after exercise by modulating matrix metalloproteinases and matrix metalloproteinase inhibitors,thereby promoting recovery of skeletal muscle strength in mice.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

Objective To investigate the expression of circular ribonucleic acid carnitine palmitoyltrans-ferase 1A(circRNA CPT1A)in patients with diabetic retinopathy(DR)and its mechanism of action on neuropathy.Methods To-tally 80 patients(102 eyes)with type 2 diabetes admitted to our hospital from January 2019 to January 2022 were selected,including 22 patients(28 eyes)with no DR(NDR group),38 patients(48 eyes)with non-proliferative DR(NPDR group),and 20 patients(26 eyes)with proliferative DR(PDR group).Optical coherence tomography angiography was used to measure the thickness of the peripapillary retinal nerve fiber layer(pRNFL)and macular ganglion cell complex(GCC),the level of phosphatase and tensin homolog(PTEN)in peripheral blood was detected by Western blot,and the circRNA CPT1A level in peripheral blood was detected by fluorescence quantitative polymerase chain reaction.The levels of circRNA CPT1A and PTEN in peripheral blood,as well as the thickness of pRNFL and GCC,were compared among three groups,and Pearson correlation analysis was used to investigate the correlation between circRNA CPT1A and PTEN,pRNFL and GCC thickness.Results The circRNA CPT1A in the peripheral blood of the PDR group was higher than that in the NDR group and NPDR group;the PTEN in the peripheral blood of the PDR group was lower than that in the NDR group and NP-DR group(all P＜0.05).There was no statistically significant difference in the expression of circRNA CPT1A and PTEN be-tween NDPR group and NDR group(all P＞0.05).The Pearson correlation analysis showed that the expression level of cir-cRNA CPT1A in peripheral blood was negatively correlated with PTEN(P＜0.05).With the increase in disease severity,the thickness of pRNFL and GCC showed a decreasing trend;the thickness of pRNFL and GCC in the whole,upper and lower parts of eyes in the NDR group were higher than those in the NPDR group(all P＜0.05),while those in the NPDR group were higher than the PDR group(all P＜0.05).Pearson correlation analysis showed that the expression level of cir-cRNA CPT1A in peripheral blood was negatively correlated with the thickness of pRNFL and GCC in the whole,upper and lower parts of the observed eyes(all P＜0.05).Conclusion With the increase in the severity of DR,circRNA CPT1A in the peripheral blood of DR patients shows an increasing trend and is negatively correlated with peripheral blood PTEN lev-el,as well as macular pRNFL and GCC thickness.The mechanism of action may be that circRNA CPT1A negatively regu-lates the expression of PTEN and thus participates in the occurrence and development of DR.