[Exploration and validation of optimal cut-off values for tPSA and fPSA/tPSA screening of prostate cancer at different ages].

Objective: To determine the total and age-specific cut-off values of total prostate specific antigen (tPSA) and the ratio of free PSA divided total PSA (fPSA/tPSA) for screening prostate cancer in China. Methods: Based on the Chinese Colorectal, Breast, Lung, Liver, and Stomach cancer Screening Trial (C-BLAST) and the Tianjin Common Cancer Case Cohort (TJ4C), males who were not diagnosed with any cancers at baseline since 2017 and received both tPSA and fPSA testes were selected. Based on Cox regression, the overall and age-specific (＜60, 60-＜70, and ≥70 years) accuracy and optimal cut-off values of tPSA and fPSA/tPSA ratio for screening prostate cancer were evaluated with time-dependent receiver operating characteristic curve (tdROC) and area under curve (AUC). Bootstrap resampling was used to internally validate the stability of the optimal cut-off value, and the PLCO study was used to externally validate the accuracy under different cut-off values. Results: A total of 5 180 participants were included in the study, and after a median follow-up of 1.48 years, a total of 332 prostate cancer patients were included. In the total population, the tdAUC of tPSA and fPSA/tPSA screening for prostate cancer were 0.852 and 0.748, respectively, with the optimal cut-off values of 5.08 ng/ml and 0.173, respectively. After age stratification, the age specific cut-off values of tPSA in the <60, 60-<70, and ≥70 age groups were 3.13, 4.82, and 11.54 ng/ml, respectively, while the age-specific cut-off values of fPSA/tPSA were 0.153, 0.135, and 0.130, respectively. Under the age-specific cut-off values, the sensitivities of tPSA screening for prostate cancer in males <60, 60-70, and ≥70 years old were 92.3%, 82.0%, and 77.6%, respectively, while the specificities were 84.7%, 81.3%, and 75.4%, respectively. The age-specific sensitivities of fPSA/tPSA for screening prostate cancer were 74.4%, 53.3%, and 55.9%, respectively, while the specificities were 83.8%, 83.7%, and 83.7%, respectively. Both bootstrap's internal validation and PLCO external validation provided similar results. The combination of tPSA and fPSA/tPSA could further improve the accuracy of screening. Conclusion: To improve the screening effects, it is recommended that age-specific cut-off values of tPSA and fPSA/tPSA should be used to screen for prostate cancer in the general risk population.

[ABC prognostic classification and MELD 3.0 and COSSH-ACLF â ¡ prognostic evaluation in acute-on-chronic liver failure].

Objective: To investigate the ABC prognostic classification and the updated version of Model for End-stage Liver Disease (MELD) score 3.0 and Chinese Group on the Study of Severe Hepatitis B ACLF Ⅱ score (COSSH-ACLF Ⅱ score) to evaluate the prognostic value in acute-on-chronic liver failure (ACLF). Methods: ABC classification was performed on a 1 409 follow-up cohorts. The area under the receiver operating characteristic curve (AUROC) was used to analyze MELD, MELD 3.0, COSSH-Ⅱ and COSSH-Ⅱ score after 3 days of hospitalization (COSSH-Ⅱ-3d). The prognostic predictive ability of patients were evaluated for 360 days, and the prediction differences of different classifications and different etiologies on the prognosis of ACLF were compared. Results: The survival curve of 1 409 cases with ACLF showed that the difference between class A, B, and C was statistically significant, Log Rank (Mantel-Cox) χ2=80.133, P<0.01. Compared with class A and C, χ2=76.198, P<0.01, the difference between class B and C, was not statistically significant χ2=3.717, P>0.05. AUROC [95% confidence interval (CI)] analyzed MELD, MELD 3.0, COSSH-Ⅱ and COSSH-Ⅱ-3d were 0.644, 0.655, 0.817 and 0.839, respectively (P<0.01). COSSH-Ⅱ had better prognostic predictive ability with class A ACLF and HBV-related ACLF (HBV-ACLF) for 360-days, and AUROC (95% CI) were 0.877 and 0.881, respectively (P<0.01), while MELD 3.0 prognostic predictive value was not better than MELD. Conclusion: ACLF prognosis is closely related to ABC classification. COSSH-Ⅱ score has a high predictive value for the prognostic evaluation of class A ACLF and HBV-ACLF. COSSH-Ⅱ score has a better prognostic evaluation value after 3 days of hospitalization, suggesting that attention should be paid to the treatment of ACLF in the early stage of admission.

[Clinical analysis of 2 820 cases of drug-induced liver injury].

Objective: To investigate the clinical characteristics, incidence trend, underlying diseases, causative drug and prognosis of drug-induced liver injury (DILI), so as to provide basis for its prevention and treatment. Methods: A retrospective study was conducted on 2 820 DILI cases who were admitted to our hospital from January 2002 to December 2015, and their clinical characteristics, incidence trends, underlying related diseases, causative drug, treatment and outcome were analyzed. Results: Among 2 820 DILI cases, the ratio of male to female was 1:1.44, and the age was (44.00±16.32) years old. According to the clinical classification of DILI, there were 2 353 cases (83.43%) of hepatocyte injury, 353 cases (12.51%) of cholestatic type and 114 cases (4.04%) of mixed type. In the three clinical classification of DILI, there was no statistically significant difference in the ratio of male to female (χ(2) = 3.032, P > 0.05). However, the difference in the ratio of male to female between different age groups was statistically significant (χ(2) = 48.367, P < 0.001). Among the patients with liver disease and acute liver disease admitted to our hospital from January 2002 to December 2015, the proportion of DILI and acute DILI showed an overall upward trend. The main underlying related diseases of 2 820 DILI cases were fever (15.14%), skin diseases (11.84%), cardiovascular and cerebrovascular diseases (11.17%). Chinese herbal patent medicines (37.49%), antibiotics (15.85%), antipyretic-analgesics (14.37%), and so on were the main causative drugs involved, and the prognostic differences among the three clinical classifications of DILI in terms of cure, improvement, ineffectiveness, and death were statistically significant (H = 61.300, P < 0.001). Conclusion: In recent years, among the patients with liver disease in our hospital, the proportion of DILI has shown an obvious upward trend, involving a variety of underlying diseases and causative drugs, and thus it needs clinical attention.

[Application values of genome-wide association studies in screening for breast cancer].

Objective: To investigate the potential application values of screening on breast cancer, using the single-nucleotide polymorphisms (SNPs) that were identified from the genome- wide association studies (GWASs). Methods: Two million Chinese women aged 35-69 years were simulated, based on both age distributions, age-specific incidence rates of breast cancer and the distribution of known risk factors, in 2013. Twenty-three SNPs identified from GWAS were further simulated. Both genetic-related risks explained by each SNPs and the improvement on the risks under reclassification, were used to select SNPs for the prediction on breast cancer among the targeted high-risk population. Further analyses were conducted to investigate the following items as: improvements on detection rates of breast cancer among the high-risk populations, areas under the curve (AUC) and the odds ratio (OR) among women at high risk. Results: A total of 12 SNPs were eligible for targeting the high-risk population of breast cancer. When high-risk populations were defined as women whose predicted risks were higher than the 95(th) predicted risk of the whole population, the detection rate (146.99/100 000) among high-risked women predicted by 12 SNPs would be significantly lower than 177.46/100 000, which was predicted by the known risk factors (P<0.001), among the high-risked women. Among those women at high risk, the detection rate (229.00/100 000) predicted by integrating known risk factors and 12 SNPs was significantly higher than that predicted by known risk factors (P<0.001). Also, the AUC increased from 64.4% to 67.8% (P<0.001), and the OR of increased from 3.32 to 4.33, predicted by integrating known risk factors and 12 SNPs, for women at high risk on breast cancer. Conclusion: Targeted SNPs that were identified from genome- wide association studies could be used to improve the detection rates as well as the overall accuracy of risk prediction so as to identify the potential high-risk women on breast cancer before carrying on the screening program.

Expression of Wnt-1 and TSLC1 in condyloma acuminatum.

BACKGROUND: Despite its high contagiousness, high recurrence rate and potential for malignant transformation, effective treatments for condyloma acuminatum (CA) have not yet been developed. Accordingly, it is necessary to clarify the mechanisms underlying CA development. AIM: To investigate the expression and significance of the proteins Wnt-1 and TSLC1 in patients with CA and in normal foreskin controls. METHODS: Wnt-1 and TSLC1 were assessed by immunohistochemistry in 45 patients with CA. RESULTS: Positive expression rates of Wnt-1 and TSLC1 were 82.22% (37/45) and 37.78% (17/45), respectively, in CA tissues, and 29.17% (7/24) and 91.67% (22/24), respectively, in normal foreskin controls. Wnt-1 expression intensity in CA was markedly higher (positive to strongly positive) than that in normal controls (negative to weakly positive), whereas TSLC1 expression intensity ranged from weakly positive to positive in CA, and nearly strongly positive in the normal control group. The differences in the positive expression rate and expression intensity of Wnt-1 and TSLC1 between the two groups were statistically significant (P < 0.05). In addition, Wnt-1 and TSLC1 were negatively correlated. (r = -0.336, P < 0.05). CONCLUSIONS: Overexpression of Wnt-1 and low expression of TSLC1 may be associated with the growth of CA. These findings may provide a basis for the development of therapies to prevent recurrence or malignant transformation of CA.

[Overdiagnosis in mammography screening for breast cancer].

Screening has been always considered as a double-edged sword. Cancer screening could save lives in some cases, however, in other cases, it might also turn people into overdiagnosis. Overdiagnosis is the diagnosis of cancer that will never cause symptoms or death during a patient's lifetime. Therefore, overdiagnosis might lead to unnecessary treatments and lifetime surveillance, and then increase economic burden and psychological burden. In this review, we focus on how to correctly evaluate the overdiagnosis rate, and how to avoid or reduce the harms caused by overdiagnosis in the future according to the reasons associated with overdiagnosis. After systematically reviewing the previous studies, we will try to identify the potential reasons associated with overdiagnosis in breast cancer screening with mammography, address how to correctly evaluate the overdiagnosis rate, and finally provide some suggestions to reduce the overdiagnosis.

Effectiveness of directly observed treatment of tuberculosis: a systematic review of controlled studies.

BACKGROUND: There is controversy about the effectiveness of directly observed treatment (DOT) for anti-tuberculosis treatment. This systematic review aimed to synthesise evidence from studies that compared DOT and self-administered treatment (SAT) or different types of DOT for anti-tuberculosis treatment. METHODS: Multiple databases were searched by two independent reviewers to identify relevant randomised (RCTs) and non-randomised studies. The risk of bias was independently assessed by two reviewers, and studies at high risk of bias were excluded. Data extraction was conducted by one reviewer and checked by a second reviewer. Primary outcome measures were cure and treatment success. RESULTS: We included eight RCTs and 15 non-randomised studies that were predominantly conducted in low- and middle-income countries. There was no convincing evidence that clinic DOT was more effective than SAT. Evidence from both RCTs and non-randomised studies suggested that community DOT was more effective than SAT. Community DOT was as effective as, or more effective than, clinic DOT. There was no statistically significant difference in results between family and non-family community DOT. CONCLUSIONS: Community DOT by non-family members might be the best option if it is more convenient to patients and less costly to health services than clinic DOT.

Implementation and community involvement in DOTS strategy: a systematic review of studies in China.

OBJECTIVE: To summarise data on the implementation of the DOTS strategy in China in terms of actual observation and treatment adherence, and to review the effectiveness of quality improvement interventions for tuberculosis (TB) control in China. DESIGN: We included survey studies that reported data on the implementation of DOTS in China and controlled studies that evaluated TB care in specified communities. We excluded studies outside mainland China, pharmacological intervention trials and reviews. RESULTS: We included 12 survey studies that reported on the performance of TB control services in China. The pooled analysis showed that more than half of TB patients were treated by self-administration (52%) and that only 20% actually had their treatment observed by health workers. We include 85 intervention studies that evaluated the effect of quality improvement interventions. Treatment observers were family members in 37 studies, and health workers in 20 studies. The pooled odds ratio (OR) for cure was 2.48 (95%CI 1.97-3.11, I(2) = 70.9%, P < 0.001); the pooled OR for treatment completion was 2.87 (95%CI 2.23-3.69, I(2) = 66.3%, P < 0.001). Sensitivity analysis found that the estimated treatment effects in meta-analyses using reported and imputed data were much reduced, but still statistically significant. CONCLUSION: The proportion of TB patients whose treatment was strictly observed was much lower than reported by official statistics in China. The treatment completion rate was not optimal, which may be an important reason for the reported increases in drug resistance. Community health personnel have become the main work force for TB control in China.

Study on association between polymorphism of HLA-DRB1 alleles and Behçet's disease.

BACKGROUND: Behçet's disease (BD) is known to be associated with human leucocyte antigen (HLA)-B*51 in many ethnic groups. However, the association of HLA class II gene with BD has been described to be different according to different countries and regions. OBJECTIVE: This study aims to investigate the association between polymorphism of HLA-DRB1 alleles and BD. METHODS: Forty patients with BD and 100 healthy controls were typed for HLA-DRB1 alleles by the LABType SSO method. RESULTS: The frequency of HLA-DRB1*14 was significantly higher in BD patients than in controls (P < 0.05), while the frequency of HLA-DRB1*15 was markedly lower in BD patients (P < 0.05). Regarding clinical manifestations, the frequency of HLA-DRB1*15 was significantly decreased in BD patients with genital ulcerations compared with controls (P < 0.05); the frequency of HLA-DRB1*14 was significantly increased in BD patients with erythema nodosum-like lesions and in BD patients with folliculitis-like lesions when compared to controls (P < 0.05, respectively). Moreover, the frequency of HLA-DRB1*14 was significantly increased in BD patients under 20 years of age at the onset of disease (P < 0.01), while the frequency of HLA-DRB1*15 was significantly decreased in them (P < 0.05), compared with controls. CONCLUSION: The results suggested that HLA-DRB1 alleles might play an important role in the onset and clinical manifestations of BD.

Identification and assessment of ongoing trials in health technology assessment reviews.

OBJECTIVES: To assess the importance of ongoing trials in health technology assessment reviews (HTARs) for the National Institute for Clinical Excellence and to provide practical recommendations for identifying ongoing trials and assessing their possible impact. DATA SOURCES: Electronic databases. REVIEW METHODS: Ongoing trials (or trials in progress) were defined as any trials that have started but where the results are not yet available or only interim results are available for HTARs. This methodological review included: (1) an assessment of ongoing trials in HTARs completed by the end of August 2002, (2) a survey and assessment of trial registers and other sources of ongoing trials and (3) a summary and assessment of available methods for assessing the possible impacts of ongoing trials. RESULTS: The identification of ongoing trials is a common phenomenon in reviews of health technology assessment. Twenty-three of the 32 HTARs identified one or more ongoing trials and in eight of these the information on identified ongoing trials was not considered in the evidence synthesis and research recommendations. All but one HTAR that considered the potential impact of ongoing trials adopted a narrative approach. Trial registers and grey literature are important sources of information on ongoing trials. All 32 HTARs explicitly or implicitly searched for unpublished studies, and/or ongoing trials and/or grey literature and trial registers. The assessment of six commonly used trial registers suggested that most registers provided sufficient information for reviewers to decide the relevance of identified ongoing trials. However, it is sometimes extremely difficult to know whether ongoing trials identified from different sources (registers) are the same trials or belong to the same multicentre trials. The ISRCTN (the International Standard Randomised Controlled Trial Number) is the most reliable system but it has not been widely adopted. The qualitative assessment of ongoing trials compared major features of completed and ongoing trials, providing information about the possible impact of ongoing trials in terms of relevance, validity, reliability and generalisability. Quantitative methods to assess the impact of ongoing trials include cumulative meta-analysis related methods, fail-safe N, Bayesian data monitoring, and Bayesian interim predictions. The most useful method may be the Bayesian predictive probability, which estimates predictive probabilities for any possible values of treatment effect. A case study indicated that the appropriate use of quantitative methods would strengthen findings from narrative assessment of possible impact of ongoing trials. CONCLUSIONS: Identification of ongoing trials is common in HTARs. Searching for ongoing trials in effectiveness reviews should be more thorough and explicit. Conversely, primary researchers, in particular those working with in multicentre trials, should label ongoing trials more clearly, preferably by ISRCTN. Qualitative assessment of identified ongoing trials is crucial and informative. Available quantitative methods could be used to strengthen findings from narrative assessment, although further research and more empirical examples are required. Information from ongoing trials may contribute to syntheses of results, conclusions and recommendations for future research. Future research is suggested into the identification and assessment of ongoing trials in other systematic reviews of effectiveness of health care interventions; existing and new methods for incorporating information on ongoing trials; comparing estimated impacts with the actual results of ongoing trials; and to incorporate findings from the assessment of ongoing trials into decision models.

Screening for fragile X syndrome: a literature review and modelling study.

OBJECTIVES: To compare the effectiveness, estimate the associated costs, and summarise available evidence about the feasibility and acceptability of different screening strategies in England and Wales. Also to establish a model for estimating effectiveness and costs of these different strategies. DATA SOURCES: Literature searches were restricted to MEDLINE and EMBASE, as well as citations in included papers. A broad search strategy was used involving all aspects of fragile X syndrome (FXS) and covered all relevant literature published between 1991 and 2001. REVIEW METHODS: An assessment was conducted of published literature and efforts focused on the development of a model that could be used to synthesise data from various sources, estimate cost-effectiveness of different strategies, and conduct sensitivity analyses according to different assumptions. RESULTS: The identified screening programmes were effective in detecting carriers, but a comparison of different strategies was not possible. Simulation results by the FXS Model showed that, over the first 10 years, 4% of premutation (PM) females and 70% of full mutation (FM) females could be detected by active cascade screening; it is 10% and 58%, respectively, by prenatal screening. The maximal detection rate for FM carriers by active cascade screening is higher than that by prenatal screening (91% versus 71%). However, the maximal rate of detection of female PM carriers by active cascade screening (6%) is much lower than that by prenatal screening (60%). During the first 10 years of simulation, the estimated direct cost per year to the NHS in England and Wales is 0.7-0.2 million pounds sterling by active cascade screening and 14.5-9.1 million pounds sterling by a programme of prenatal screening. The incremental cost per extra carrier detected (using current practice as the reference standard) is on average only 165 pounds sterling by active cascade screening and 7543 pounds sterling by prenatal screening. The incremental cost per FXS birth avoided is on average 8494 pounds sterling by active cascade screening and 284,779 pounds sterling by prenatal screening. CONCLUSIONS: The empirical evidence suggests that both prenatal screening and cascade screening are feasible and acceptable. Population-based prenatal screening is more efficacious, but it will cost more than active cascade screening. The active cascade screening of affected families is more efficient, cheaper, but less effective than a population-based prenatal screening. It is suggested that both strategies be evaluated in large-scale trials, which might also help to determine whether and how the different strategies could be simultaneously or sequentially combined.

[Evidence for involvement of NO/NOS-cGMP signal system in morphine dependence].

The present study was undertaken to observe changes in cGMP contents, calcium-dependent and non-calcium-dependent NOS activities in brain regions isolated from morphine-dependent mice as well as the effect of NOS inhibitor (L-NMMA) on the development of this dependence. It was found that (1) cGMP contents in cerebellum, striatum, hippocampus and cerebral cortex were significantly decreased. (2) Calcium-dependent NOS activity was noticeably increased in striatum and cerebral cortex, which was inhibited by PKA inhibitor. No similar changes were found in cerebellum and hippocampus. Changes of non-calcium-dependent NOS activity did not occur in morphine-dependent mice brain. (3) In the striatum and cerebral cortex of morphine-dependent mice, the level of 150 kD protein phosphorylation in vitro was noticeably decreased, which was inhibited by IP20 (PKA inhibitor). (4) NOS inhibitor injected (icv) 15 min prior to daily morphine injection could prevent the development of morphine dependence. (5) All the changes above were not observed in mice treated with naloxone 30 min prior to daily morphine injection. Our data suggest that the reduction of cGMP contents and the increase of calcium-dependent NOS activity in striatum and cerebral cortex isolated from morphine-dependent mice may be mediated by opioid receptors and involved in the development of morphine-dependence. Why the increase of NOS activity was in association with the reduction of cGMP contents remains to be answered and it implies that the effect of NO/NOS involved in morphine-dependence may be produced through other mechanisms other than those producing cGMP signal. NOS phosphorylation in some other brain regions, which may be regulated by PKA, probably contributes to the increase of NOS activity in morphine-dependent mice.

Association between HLA antigens and families with psoriasis vulgaris.

This paper typed HLA-A, B, C and DR antigens in patients with psoriasis vulgaris and healthy persons in 12 families. The phenotype frequencies of HLA-A1, B13, B17, Cw4 and Cw6 in the patients were higher than those in the controls. The analysis of haplotype segregation showed that HLA haplotypes in families with more psoriatic cases were marked deviation from random distribution. One or two HLA haplotypes sharing among affected siblings occurred more frequently than expected. The result of Lods score for six families showed that there was a close linkage between the gene of psoriasis vulgaris and HLA antigens. The gene of psoriasis was coincided with the recessive hereditary mode.