[Health economic evaluation of telemedicine diabetic retinopathy examination using a non-mydriatic fundus camera in China].

Objective: To perform a health economic evaluation of telemedicine diabetic retinopathy (DR) examination with a non-mydriatic fundus camera in China and to investigate the optimal examination interval. Methods: Based on 18 peer-reviewed articles related to epidemiology, clinical trial, and health economic evaluation of DR, surveys from 9 ophthalmologists in 3 tertiary hospitals in China, price lists for medical services in each province, and the negotiated price in 2021, a Markov model was conducted to evaluate the cost utility of telemedicine eye examination for diabetes mellitus patients aged 45 and older from the health system perspective. Separate analyses were performed for no examination and for examination intervals of every 1 to 5 years to predict the lifetime health gain, including cumulative days of blindness, cumulative life years, and quality-adjusted life years (QALYs), and costs for unilateral and bilateral direct medication with a 3.5% discount rate. Results: The cumulative days of blindness in the absence of a DR screening were 2 375.00 days, and ranged from 701.00 to 738.00 days for five different DR screening interval programs. The cumulative life years for no screening and five DR screening programs ranged from 27.120 34 to 28.005 00 years, with QALYs ranging from 9.502 96 to 9.875 02. The direct medication costs in the absence of a DR screening program were 72 785.00 yuan for both unilateral and bilateral scenarios. For the five DR screening intervals, the direct medication costs ranged from 52 065.00 to 52 408.00 yuan for unilateral and 79 100.00 to 79 603.00 yuan for bilateral. Comparing the incremental cost-effectiveness ratios between the DR screening intervals and no screening, the 1-to 5-year intervals were dominant in the unilateral scenario (between -56 368.54 and -55 523.75 yuan/QALY). In the bilateral scenario, the ratios ranged from 17 469.07 to 18 325.15 yuan/QALY. Using a willingness-to-pay threshold equal to the per capita GDP (80 976 yuan/QALY), the 1-year DR screening interval had an 85.9% probability of being cost-effective and a 55.2% probability of being dominant in the unilateral scenario. In the bilateral scenario, the 2-year interval held a 61.4% probability of being cost-effective. Conclusions: Analyses on the remote fundus consultation in diabetic patients and health economics based on the Markov model indicate that telemedicine DR examination through a non-mydriatic fundus camera can be effectively employed for diabetes mellitus patients in China. DR examination every two years is recommended for general diabetic patients, and DR examination every year may be chosen in developed areas.

[Effect of dietary water-soluble vitamins on the poor prognosis of low-grade cervical intraepithelial neoplasia-a prospective cohort study].

Objective: To explore the effect of dietary water-soluble vitamins on the poor prognosis of low-grade cervical intraepithelial neoplasia (CINⅠ). Methods: A total of 564 participants with CINⅠ were selected from a community-based married women cohort established in 2014. The general baseline information was collected, and HPV genotyping was detected. A food frequency questionnaire was used to investigate dietary water-soluble vitamins' consumption and determine their exposure levels. The follow-up program was carried out for 12 months, and the regression, persistence, and progression of CINⅠ was determined according to histopathological results at 12-month. Results: The low-levels of dietary water-soluble vitamins could promote CINⅠ's persistence and progression, showing the increasing tendency of CINⅠ poor prognosis with the decrease of water-soluble vitamin levels. Especially folate, VB1, VB2, VB6, niacin, biotin, and VC (RR values were 15.22, 1.86, 1.92, 2.11, 2.98, 2.14, 2.19, respectively) played an important role. Considering the status of high-risk human papillomavirus (HR-HPV) infection, our results showed that the low levels of folate, niacin, biotin could promote the poor prognosis of CINⅠ. Conclusions: The low-level of dietary water-soluble vitamins could facilitate the poor prognosis of CINⅠ. In addition, folate, niacin, biotin were more effective on HR-HPV positive women.

[Prognosis of high-risk HPV infection and its influences by vaginal micro-environmental factors].

Objective: To describe the characteristics of high-risk human papillomavirus (HR-HPV) infection and its influences by vaginal micro-environmental factors. Methods: A total of 421 women with HR-HPV infection and normal cervix diagnosed by pathology were selected from a community cohort established earlier by our research group for a 24-month follow-up. The baseline data were collected at enrollment. The vaginal micro-environmental factors were detected by using the combined detection kit of aerobic vaginitis and bacterial vaginosis. And the HPV was detected by using the flow-through hybridization technology. According to the HR-HPV infection status in baseline and 24 months of follow-up, with the prognosis characteristics of HR-HPV infection described, the impact of vaginal micro-environmental factors on the prognosis of HR-HPV infection was explored as well. Results: Among 390 HR-HPV infected women who completed 24 months of follow-up, the top five types of persistent HR-HPV infection rate appeared as HPV16 (24.1%), HPV58 (22.2%), HPV53 (21.7%), HPV52 (20.0%), and HPV39 (11.8%), respectively. The results showed that women with abnormal vaginal pH (aOR=1.74, 95%CI: 1.08-2.80), abnormal neuraminidase (aOR=2.70, 95%CI: 1.52-4.83), or abnormal leucocyte esterase (aOR=3.41, 95%CI: 2.13-5.44), the risk of HR-HPV persistent infection increased. The abnormalities of neuraminidase and leukocyte esterase could increase the risk of persistent infection of homotype and heterotypic HR-HPV. Conclusions: HPV16 was prone to persistent infection. Abnormalities of vaginal pH, neuraminidase, and leukocyte esterase might increase the risk of HR-HPV persistent infection. Both the abnormalities of neuraminidase and leukocyte esterase play an essential role in the HR-HPV persistent infection.

[The optimal model of diagnosis to low-grade cervical intraepithelial neoplasia by combined detecting vaginal micro-environmental factors, based on the high-risk HPV infection].

Objective: To investigate the diagnostic value of different vaginal micro-environmental factors in low-grade cervical intraepithelial neoplasia (CIN Ⅰ) and determine the optimal model in high-risk human papillomavirus (HR-HPV) infection. Methods: A total of 926 women, including 623 with normal cervical (NC) condition and 303 CINⅠ patients, had undergone pathological examinations, and were enrolled in the study. All the women were from a community previously established cohort. Vaginal cleanliness, pH, H2O2, ß-glucuronidase, coagulase, sialidase, and leukocyte esterase (LE) were detected by the combined detection method aerobic vaginitis/bacterial vaginosis in vaginal secretions. HPV genotyping was performed by using the flow-through hybridization technology. The data were analyzed by SAS 9.2 and SPSS 23.0. Results: The vaginal cleanliness, pH, sialidase, and LE were determined as the representative vaginal micro-environment factors by principal component analysis. Based on logistic regression theory to analyze the ROC curve, the results showed that the highest sensitivity was with pH value (76.2%), and the highest specificity was with sialidase (90.9%). The area under ROC curve were higher in combination detection modes of sialidase+LE (0.714), pH+sialidase+LE (0.719), vaginal cleanness+sialidase+LE (0.713) and pH+vaginal cleanness+sialidase+LE (0.709). According to HR-HPV infection status, the TOPSIS method was used to analyze the combined detection optimal model. Specifically, we found that the best diagnostic model was pH+sialidase +LE (Ci=0.585) in the HR-HPV positive group and vaginal cleanness+sialidase+LE (Ci=0.641) in the negative group. Conclusions: The combined detection of vaginal microenvironment factors could be used for auxiliary diagnosis for CINⅠ. It would be more effective when detecting pH, sialidase, and LE in HR-HPV positive women while vaginal cleanness, sialidase, and LE in HR-HPV negative women at the same time.

[Relationship between serum folate and CIN1 prognosis and its interaction with HR-HPV infection].

Objective: To evaluate the relationship between serum folate and the prognosis of cervical intraepithelial neoplasia grade I (CIN1) and the interaction between folate and high risk human papillomavirus (HR-HPV) infection. Methods: From a community-based married women cohort established in Jiexiu and Yangqu County of Shanxi Province from June to December 2014, a total of 564 eligible women with CIN1 by pathologically diagnosed were recruited. The pathological examination was performed again 12 months later. According to the prognosis of CIN1, participants were divided into CIN1 regression group, persistence and progression group, respectively. Nested case-control study was used to explore the relationship between serum folate and CIN1 prognosis, and additive model was used to analyze the interaction between serum folate and HR-HPV infection. Results: Among 564 CIN1 patients, 479 cases underwent pathological examination again, 331 were divided in CIN1 regression group and other 148 in persistence and progression group. The levels of serum folate in CIN1 regression group and persistence and progression group were (18.890±8.360) and (15.640±5.550) nmol/L, respectively, and the difference was statistically significant (Z=-6.937, P<0.001). HPV infection was detected in 154 patients, including 148 cases of HR-HPV infection and 6 cases of low risk human papillomavirus (LR-HPV) infection. Univariate analysis showed that there were significant differences in the age, passive smoking, frequency of pudendal cleaning, frequency of cleaning after sex, frequency of changing underwear, serum folate and HR-HPV infection between regression group and persistence and progression group (P<0.05). Multivariate logistic regression analysis showed that the frequency of pudendal cleaning (OR=0.422, 95%CI: 0.238-0.750), frequency of changing underwear (OR=0.574, 95%CI: 0.355-0.928), serum folate (13.06-16.78nmol/L: OR=4.806, 95%CI: 2.355-9.810; ≤13.05nmol/L: OR=8.378, 95%CI: 4.024-17.445), HR-HPV infection (OR=1.852, 95%CI: 1.170-2.933) were the independent influencing factors of CIN1 prognosis. Interaction analysis showed that the relative excess risk of low serum folate level and HR-HPV infection for the CIN1 persistence and progression was 4.992 (95%CI: 0.189-9.796), attributable proportion due to interaction was 0.552 (95%CI: 0.279-0.824), synergy index was 2.632 (95%CI: 1.239-5.588), aOR of serum folate≤16.78 nmol/L and HR-HPV infection positive was 9.055 (95%CI: 4.878-16.807). Conclusion: Low serum folate level could increase the risk of CIN1 persistence and progression, and might enhance the risk when combined with HR-HPV infection.

[Considerations of the non-inferior clinical researches on the anti-vascular endothelial growth factor therapy for fundus diseases].

In evidence-based medicine, randomized controlled clinical trials are considered as the gold standard to evaluate the curative effect of the anti-vascular endothelial growth factor drugs on fundus diseases. The non-inferiority design is widely used due to the existence of the "ceiling effect" if vision improvement is used as the primary outcome. It is critical to make several issues clear before non-inferiority studies are performed. For example, patients can benefit from the new therapy other than efficacy; the determination of the non-inferiority margin should be based on the comprehensive consideration of clinical and statistical meanings; the traditional significance test method is not suitable for non-inferiority tests; the superiority test could be further performed if the non-inferiority conclusion has been reached. This article aims to elaborate these hot issues and to provide guidance for clinical researchers to carry out research designs and interpret findings objectively and scientifically. (Chin J Ophthalmol, 2020, 56: 895-898).

Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication.

Background: Previous studies have shown that industry funded trials are associated with pro-industry conclusions and publication bias. Less is known about the role of industry funders and their influence on trial conclusions and time to publication. Methods: We identified all industry funded RCTs published in six high-impact clinical journals between 2014 and 2016 to estimate the prevalence of the role of industry funders in trial design, data collection, data analyses, data interpretation and manuscript writing. Ordinal logistic regression was used to assess the association between the role of industry funders and trial conclusions, which was classified on a five-point scale. Cox proportional-hazards were used to examine the effect of role of funder on time to publication. Results: Of the 255 eligible RCTs, industry funders had a role in trial design in 179 (70.2%) trials, data collection in 160 (62.7%) trials, data analyses in 173 (67.8%) trials, data interpretation in 135 (52.9%) trials and manuscript writing in 168 (65.9%) trials. Trials with any role of industry funders had 3.6 times (95% CI 2.0-6.6) higher odds of having positive conclusions compared with those without role of industry funders. In trials with any role of industry funders, positive trials were published more rapidly than negative trials (hazard ratio = 4.3; 95% CI 2.7-6.7, P < 0.001), while for trials without role of industry funders, there was no association (hazard ratio = 1.07; 95% CI 0.57-1.99, P = 0.84). Conclusion: The involvement of industry funders is common in all stages of clinical trials and was associated with more positive conclusions and more rapid publication of RCTs with positive results.

[Impacts of EGFR 19 exon mutations on brain metastases in treatment-naïve patients with lung adenocarcinoma].

Objective: To investigate the relationship between the status of epidermal growth factor receptor (EGFR) mutations and brain metastases in patients with lung adenocarcinoma. Methods: From August 2010 to May 2015, a total of 1 063 lung adenocarcinoma patients with identified status of EGFR mutations in Shanxi Cancer Hospital were enrolled, of which 456 patients had EGFR mutations. Multivariate Logistic regression model was used to analyze the correlation between EGFR mutation status and brain metastases in patients with lung adenocarcinoma. Results: In 125 patients with brain metastases before initial treatment, 65 patients had EGFR mutations, including 36 patients with deletion mutations in exon 19. The frequency of EGFR 19 exon mutation was 28.8% (36/125). Among 456 patients with EGFR mutations, 65(14.3%) patients were with brain metastases, in which 36(55.0%) had deletion mutations in exon 19. The multivariate analysis showed that age, Eastern Cooperative Oncology Group (ECOG) score, EGFR mutations and N staging were associated with brain metastases(P<0.05). Further subgroup multivariate analyses showed that age, ECOG score, mutation status in exon 19 and N staging were associated with brain metastases (P<0.05). Conclusions: EGFR mutation status is related to brain metastases. Mutations in EGFR exon 19 is an independent risk factor for brain metastases.

[Study on the contribution rate of follow-up formula to the nutrient intake of infants and young children aged 7-24 months in China].

Objective: To determine the contribution of follow-up formula (FUF) to the nutrient intake of 7-24-month-old infants and young children. Methods: The cluster random sampling method and the convenience sampling method were used in combination, and geographic and economic factors were taken into consideration. Four areas of China (Beijing, Hebei, Guangxi, Guangdong) were selected, with 120 infants chosen from each of these areas (half of which were 7-12 months old, and half were 13-24 months old). A dietary survey was completed by a continuous 24-hour weighing method over two days. Questionnaires were completed by their caregivers which included weighing the FUF and supplementary food given to the infant, and recording the frequency of breast feeding and any supplementary nutrients. A total of 518 questionnaires were distributed, and 472 questionnaires qualified for inclusion. Nutrient intake was calculated using the China food composition, infant formula food nutrient content and infant nutrition supplement brand-label information databases, and then the nutrient intake proportion (the percentage of estimated energy requirement (EER%), recommended nutrient intake (RNI%) or adequate intake (AI%)), and the contribution rate of FUF were analyzed. Results: A total of 472 infants were investigated (227 infants aged 7-12 months old, 245 infants aged 13-24 months old). The findings revealed that the median energy intake of 7- 12-month-old and 13- 24-month-old infants were 2 530.08 kJ and 3 445.48 kJ, respectively, which accounted for 85.18% and 94.14% of EER, respectively; and the median intake of protein reached 91.50% and 105.88% of their RNI/AI, respectively. For micronutrients, the median intake of vitamin B1, vitamin B2, niacin, vitamin E, potassium, zinc and manganese in 7- 12-month-old infants and vitamin B2, vitamin E, potassium, magnesium, iron and manganese in 13-24-month-old children accounted for 82.00% and 114.29% of RNI/AI (RNI%/AI%), respectively. The intake of vitamin B6, iron and selenium in 7-12-month-old infants and vitamin B1, vitamin B6, vitamin C, calcium and selenium in 13-24-month-old children was less than 80% RNI/AI. Furthermore, some nutrients showed higher intake levels, such as vitamin A, calcium, phosphorus and magnesium in 7-12-month-old infants and vitamin A and phosphorus in 13-24-month-old children, which were higher than 130% RNI/AI. In total, 40.53% (92) of infants aged 7-12 months and 52.65% (129) of children aged 13- 24 months were fed FUF as part of their diet, and its contribution rate to macronutrients was 29.69% for carbohydrates and 51.77% for fats, and to micronutrients was 2.04% for manganese and 74.24% for vitamin C. Conclusion: FUF contributes to the nutrient intake of infants and young children aged from 7-24 months old at different rates depending on the macronutrient or micronutrient analyzed.

Correlation between molybdenum target mammography signs and pathological prognostic factors of breast cancer.

This study explores the correlation between molybdenum target (mo-target) mammography signs and pathological prognostic factors of breast cancer. We selected 320 breast cancer patients who were treated between January 2014 and January 2016; using single-factor and multiple-factor logistic regression method, we made correlation analysis on their clinical features, pathological features and mo-target mammography signs. Among mo-target mammography signs, lumps accompanied with calcification and blurry edge were associated with high histologic grades; lumps accompanied with calcification and clear edge were associated with Ki-67 positive; compared with the patients who had lumps with non-stellate edges, positive rates of estrogen receptor (ER) and progesterone receptor (PR) were significantly higher for the patients who had lumps with stellate edges (p < 0.01), while positive rate of human epidermal growth factor receptor-2 (HER-2) and tumor proliferative activity were significantly lower (p < 0.05, p < 0.01). According to the study, we can conclude that mo-target mammography signs mainly include lumps and calcification. Mo-target mammography can improve the accuracy of diagnosis and reduce misdiagnosis or missed diagnosis. Part of mo-target mammography signs are associated with clinical pathology prognostic factors; by grasping the relation, breast cancer patient conditions are expected to be relieved.

[Comparison study of subcutaneous immunotherapy and sublingual immunotherapy in patients with allergic rhinitis].

Objective: To observe the compliance, efficacy and safety of subcutaneous immunotherapy(SLIT) and sublingual immunotherapy(SCIT) in patients with allergic rhinitis(AR).Method:One hundred and fifteen patients sensitized to house dust mites were recruited in this study. The standardized extract of house dust mites was used for SLIT in 64 cases, and the standardized extract of dual house dust mites was used for SCIT in the other 51 cases. The compliance, nasal symptom scores, the medication scores, the quality of life and the adverse reaction were evaluated before and 2 years after immunotherapy. SPSS 19.0 was used for data analysis. Result:Forty patients out of 64 completed the 2 years-SLIT, and the compliance rate was 62.50%. Forty three patients out of 51 completed the 2 years-SCIT and the compliance rate was 84.31%.The compliance rate of SLIT was significantly lower than that of SCIT(P <0.05). The nasal symptom scores, the anti-allergic medication, the scores in quality of life decreased significantly after receiving SLIT or SCIT for 2 years（P <0.05）. However, the changed values of scores between the two groups had no significant differences（P >0.05）. There was no moderate or severe adverse reactions occurred in SLIT group but a total of 6 moderate or severe adverse reactions occurred in SCIT group.Conclusion:SLIT has same effect compared with SCIT with a lower compliance rate but a significantly higher safety.

Investigation of several biomarkers associated with diabetic nephropathy.

OBJECTIVE: The aim of this study was to facilitate the systematic discovery of diagnostic biomarkers of diabetic nephropathy (DN). METHODS: 3 publicly available independent cohorts were got from Gene Expression Omnibus database. Gene expression array were used to screen for genome-wide relative significance (GWRS) and genome-wide global significance (GWGS). The most significant up- and down-regulated top 100 gene signatures were identified using a fold change based model. Then the protein-protein interaction (PPI) network was constructed, while the hub genes in this PPI network were identified by centrality analysis. Modules detection was performed to explore the functions of the modules. Meanwhile, gene enrichment analysis was performed to illuminate the biological pathways and processes associated with DN. RESULTS: The most significant up- and down-regulated top 100 gene signatures were identified and a PPI network was established. Several hub genes (VEGFA, IL8, MYC, CD14, ALB) were discovered. Several functional modules were revealed. Biological pathways including cytokine-cytokine receptor interaction and p53 signaling pathway, and processes including inflammatory response, response to wounding and enzyme linked receptor protein signaling pathway were identified. CONCLUSION: Our study displayed underlying biomarkers including biological pathways and several hub genes of DN.