Objective:To explore the predictive value of hepatitis B surface antibody (HBsAb) quantitative level for achieving hepatitis B surface antigen (HBsAg) seroclearance and serological conversion in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogs (NAs) or interferon (IFN).Methods:A two-center prospective cohort study was conducted, including CHB patients from Nanfang Hospital Southern Medical University and Eastern Theater General Hospital treated with NAs and IFN. All patients were followed up once every three to six months. Basic clinical information and test results were collected at each follow-up. The presence or absence of HBsAg seroclearance and serological conversion rate was evaluated. HBsAg serological conversion was defined as HBsAg quantification continuously below the detection limit (<0.05 IU/mL) at two detection time points at least six months apart. HBsAg serological conversion was defined as HBsAb positivity (≥10 IU/L) at the same time as the first HBsAg seroclearance. The Kruskal-Wallis test was used to compare the quantitative data of multiple groups, and the Wilcoxon rank-sum test was used to compare the data between groups. The chi-square test was used for the count data, and the Fisher exact test was used when the chi-square test was not met. Univariate and multivariate Cox analysis was used to determine the predictors of the study endpoints, and stepwise regression was used for variable screening.Results:A total of 2 266 CHB cases were included, of which 86.5% (1 959/2 266) were NA antiviral-received population. The median treatment duration before baseline was 10.5 (2.5, 37.6) months, and the baseline HBsAg quantification was 3.1 (2.6, 3.5) log 10 IU/mL. A total of 68 cases (3.0%) had HBsAg seroclearance, and 44 cases (1.9%) achieved serological conversion after 85.0 (62.7, 97.3) months of prospective follow-up. The level and positivity rate of HBsAb showed a progressive increase 36 months before and significantly after HBsAg seroclearance. Cox regression analysis results showed that baseline HBsAb level was an independent predictor of HBsAg serological conversion ( HR=2.26, P=0.002) in the overall population, especially in the subgroup with HBsAg between 100 and 1 000 IU/mL, suggesting HBsAb level had important predictive value. In addition, the serological conversion development rate was significantly higher in the GOLDEN model favourable patients than in the unfavourable patients (11.5% vs. 0, P<0.001). Conclusion:The baseline HBsAb quantitative level can predict HBsAg seroclearance and serological conversion for patients with CHB receiving antiviral treatment, which is of significant value in long-term treatment monitoring.

Objective:To explore the predictive value of hepatitis B surface antibody (HBsAb) quantitative level for achieving hepatitis B surface antigen (HBsAg) seroclearance and serological conversion in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogs (NAs) or interferon (IFN).Methods:A two-center prospective cohort study was conducted, including CHB patients from Nanfang Hospital Southern Medical University and Eastern Theater General Hospital treated with NAs and IFN. All patients were followed up once every three to six months. Basic clinical information and test results were collected at each follow-up. The presence or absence of HBsAg seroclearance and serological conversion rate was evaluated. HBsAg serological conversion was defined as HBsAg quantification continuously below the detection limit (<0.05 IU/mL) at two detection time points at least six months apart. HBsAg serological conversion was defined as HBsAb positivity (≥10 IU/L) at the same time as the first HBsAg seroclearance. The Kruskal-Wallis test was used to compare the quantitative data of multiple groups, and the Wilcoxon rank-sum test was used to compare the data between groups. The chi-square test was used for the count data, and the Fisher exact test was used when the chi-square test was not met. Univariate and multivariate Cox analysis was used to determine the predictors of the study endpoints, and stepwise regression was used for variable screening.Results:A total of 2 266 CHB cases were included, of which 86.5% (1 959/2 266) were NA antiviral-received population. The median treatment duration before baseline was 10.5 (2.5, 37.6) months, and the baseline HBsAg quantification was 3.1 (2.6, 3.5) log 10 IU/mL. A total of 68 cases (3.0%) had HBsAg seroclearance, and 44 cases (1.9%) achieved serological conversion after 85.0 (62.7, 97.3) months of prospective follow-up. The level and positivity rate of HBsAb showed a progressive increase 36 months before and significantly after HBsAg seroclearance. Cox regression analysis results showed that baseline HBsAb level was an independent predictor of HBsAg serological conversion ( HR=2.26, P=0.002) in the overall population, especially in the subgroup with HBsAg between 100 and 1 000 IU/mL, suggesting HBsAb level had important predictive value. In addition, the serological conversion development rate was significantly higher in the GOLDEN model favourable patients than in the unfavourable patients (11.5% vs. 0, P<0.001). Conclusion:The baseline HBsAb quantitative level can predict HBsAg seroclearance and serological conversion for patients with CHB receiving antiviral treatment, which is of significant value in long-term treatment monitoring.

Objective:To retrospectively analyze the viral levels and associated factors in patients with hepatitis B virus (HBV)-related primary liver cancer (PHC) in real-world settings and further explore the correlation between low viral load (LVL) and/or low-level viremia (LLV) and PHC.Methods:Five hundred twenty-four cases with HBV-related PHC with complete pathologically confirmed data from 2013 to 2020 were included. Percentages (%) were used to express their viral load, antiviral (oral) status, patient compliance, presence or absence of cirrhosis, family history of liver cancer, and others. LVL definition: After excluding detection errors by PCR method, serum HBV DNA <50-2 000 IU/ml, and those who had received antiviral drug treatment were called LLV. Antiviral treatment (AVT) rate definition: As of the confirmed diagnosis of PHC, those who had been regularly treated using oral antiviral drugs for six months or more (≥6 months).Results:General situation: The ratio of male to female enrolled patients was 15.90:1 (493/31). Patients aged >40 years accounted for 91.98% (482 cases). Hepatitis B surface antigen (HBsAg) positivity condition: The ratio of HBsAg-positive to HBsAg-negative/anti-HBc-positive (HBsAg-/anti-HBc+) PHC patients was 5.89:1 (448/76). Among the 76 HBsAg-/anti-HBc+patients, the ratio of HBsAg-/anti-HBs+/anti-HBc+ to HBsAg-/anti-HBs-/anti-HBc+ patients was 0.95:1 (37/39). Hepatitis B e antigen (HBeA) positivity condition: The ratio of HBeAg-negative to HBeAg-positive cases was 3.23:1 (400/124). HBV DNA level condition: The medical history records of 75.00% of patients (393/524) had traceable HBV DNA test reports. Out of 393 patients, 45.04% (177/393) accounted for undetectable HBV DNA, 13.49% (53/393) accounted for LVL, 41.48% (163/393) accounted for HBV DNA exceeding the upper limit of LVL, and 4.07% (16/393) accounted for LLV. Among HBsAg-positive and HBsAg-/anti-HBc+ patients, the HBV DNA positivity rates were 59.12% (214/362) and 6.45% (2/31), respectively. Antiviral treatment condition: Among the 448 HBsAg-positive PHC patients, the total AVT rate was 18.08% (81/448), of which seven patients did not have their HBV DNA results traced back. Among them, the AVT rate of 148 patients with HBV DNA lower than the lowest detection value was 41.22% (61/148); the AVT rate of 53 patients with LVL was 18.87% (10/53); and the AVT rate of 163 patients with HBV DNA≥LVL upper limit was 1.84% (3/163). Liver cirrhosis and family history condition: 348 patients (66.41%) had liver cirrhosis. 67 patients (12.79%) had a distinct family history of HBV-related liver cirrhosis and liver cancer. Alpha-fetoprotein (AFP) condition: 514 patients underwent AFP testing, with 30.93% of the patients had normal AFP levels, and 69.07% had AFP levels exceeding the upper limit of normal values (355/514). Among them, 10 μg/L400 μg/L accounted for 34.44% (177/514) and 34.63% (178/514), respectively. Tissue typing condition: 99.05% (519/524) were hepatocellular carcinoma, and well-differentiated and moderately differentiated cases accounted for only 8.59%.Conclusions:In the real world, comprehensive, timely screening, standardized, and effective antiviral treatment have not yet been achieved for patients with chronic hepatitis B, resulting in the persistence of HBsAg and/or HBV DNA positivity (especially LVL and/or LLV). Although LVL does not account for a high proportion among all HBV-related PHC populations, the vast majority of LVL populations have not received any antiviral treatment. In addition, some PHC populations with HBV DNA>2 000 IU/ml have not received standard antiviral treatment before the onset of the disease, which should be paid attention to. At the same time, HBsAg-/anti-HBc+ populations may have latent HBV infection and may even progress to PHC. Notably, PHC may still occur after HBeAg seronegative conversion.

Objective:To systematically evaluate the efficacy of Fuzheng Huayu (FZHY) tablets/capsules on hepatitis B-associated liver fibrosis or cirrhosis based on randomized controlled trials (RCTs) in order to provide more accurate evidence-based medicine for clinical rational drug use.Methods:Randomized controlled clinical trial research reports related to the treatment of hepatitis B-associated liver fibrosis or cirrhosis with FZHY published in SCI and statistical source core journals were retrieved from databases such as PubMed, Cochrane Library, and China National Knowledge Infrastructure (CNKI). RevMan 5.3 and Stata18.0 software were used to conduct a meta-analysis of the improvement rate of liver tissue inflammatory activity (HAI) and Ishak stage of liver fibrosis, the decrease value of liver stiffness measurement (LSM), hyaluronic acid (HA), laminin (LN), type Ⅲ procollagen (PC-Ⅲ), type Ⅳ collagen (IV-C), total bilirubin (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (Alb). The Q test was used for the heterogeneity test, with a random-effect model selected for large heterogeneity and a fixed-effect model for less heterogeneity.Results:A total of 852 articles were retrieved. Duplicate articles, non-RCT articles, non-SCI/statistical source/core journal articles, and other articles that did not meet the inclusion criteria were sequentially excluded. Finally, a total of 2 746 cases (1 382 cases in the FZHY group and 1 364 cases in the control group) were included from 25 studies. The results of statistical analysis showed that the improvement rates of HAI grade of liver inflammation were 75.56% (68/90) and 42.22% (38/90, P<0.001) in the FZHY group and the control group at 24-48 weeks of treatment, while the improvement rates of Ishak stage of liver fibrosis were 67.90% (110/162) and 40.91% (63/154, P=0.005), respectively. Compared with the control group (95% CI -5.10-1.77, P<0.001) the mean △LSM of the FZHY group decreased by 3.43 kPa ( P<0.001)and 0.30 kPa ( P=0.93) at 48 and 72 weeks of treatment. The standardized mean differences (SMDs) of △HA, △LN, △PC-Ⅲ and △Ⅳ-C were -1.12, -1.00, -0.89 and -1.10 ( P<0.001) after 24 weeks of treatment between the FZHY group and the control group. The SMDs of △HA, △IV-C, △LN and △PC-Ⅲ were -1.13 ( P=0.01), -1.51 ( P<0.001), -0.53 ( P=0.14) and -0.42 ( P=0.19) after 48 weeks of treatment between the two groups. The △TBil, △ALT, △AST, and △ALB was -12.99 μmol/L ( P=0.007), -36.91 U/L ( P<0.001), -22.05 U/L ( P=0.12), and 6.09 g/L ( P=0.05) after 24 weeks of treatment between the two groups. The observation on indicators such as aspartate aminotransferase and platelet ratio index, fibrosis-4 index, and hepatocellular carcinoma incidence in current RCT studies remained deficient. Conclusion:FZHY can significantly improve the degree of histologic liver inflammation and fibrosis, LSM values, reduce serum liver fibrosis indexes, and serum bilirubin and transaminase levels in patients with hepatitis B-associated liver fibrosis or cirrhosis. Therefore, it is necessary to further explore the optimal course of FZHY and its long-term effects on the risk of complications of cirrhosis such as hepatocellular carcinoma, ascites, and esophageal varicose bleeding, through prospective large-sample multicenter real-world cohort studies.

Objective:To evaluate the efficacy and safety profile of tenofovir amibufenamide (TMF) at 48 weeks in patients with hepatitis B virus-related compensated and decompensated stage cirrhosis.Methods:Patients with treatment-na?ve or treatment-experienced hepatitis B virus-related cirrhosis with nucleos(t)ide analogues (NA) who met the inclusion and exclusion criteria from 2022 to 2024 were retrospectively collected and divided into the tenofovir amibufenamide group (TMF, n=25) and the tenofovir alafenamide fumarate group (TAF, n=14). The conditional changes in hepatitis B virus DNA (HBV DNA), hepatitis B surface antigen (HBsAg), liver function indexes, serum creatinine (Cr), estimated glomerular filtration rate (eGFR), serum phosphorus, blood lipid profiles, and other variables were compared between and within the groups at baseline and 48 weeks. The t-test or Kruskal-Wallis H test was used to compare the measurement data among the groups. The χ2 test was used for the enumeration data. Results:There were no statistically significant differences in baseline, age, gender, proportion of compensated/decompensated stage cirrhosis, proportion of NA-naive/treatment experienced, liver function indexes, serum Cr, and eGFR between the two groups ( P>0.05). There was no statistically significant difference in the proportion of patients with HBV DNA<30 IU/ml ( P=1.00) between the two groups, regardless of whether they were NA-naive ( P=0.52) or treatment experienced ( P=1.00) at 48 weeks. There was no statistically significant difference in HBsAg levels between the TMF and TAF groups ( P=0.18) at 48 weeks. There was no statistically significant difference in the decline of HBsAg within each group ( P>0.05). The levels of alanine aminotransferase ( P<0.001) and aspartate aminotransferase ( P=0.045) were significantly lower at 48 weeks than those at baseline, while the albumin level was higher than that at baseline ( P=0.004) among the TMF group. There were no statistically significant differences in the rest of the liver function indicators among the TMF and the TAF groups between baseline and 48 weeks ( P>0.05). There were no statistically significant differences in Cr ( P=0.34) and eGFR levels ( P=0.60) at 48 weeks between the TMF and TAF groups.There were no statistically significant differences in Cr ( P=0.89) and eGFR levels ( P=0.57) at 48 weeks in patients aged<40 years ( n=8) compared with baseline in the TMF group. There were no statistically significant differences ( P=0.09, P=0.13) in patients with similar aged≥40 years ( n=17). The reduction in Cr level ( P<0.001) and the increase in eGFR ( P<0.001) at 48 weeks were statistically significant in patients aged<40 years ( n=3) among the TAF group. There were no statistically significant differences in Cr ( P=0.30) and eGFR ( P=0.13) at 48 weeks in patients aged≥40 years compared with baseline. There were no statistically significant differences in serum phosphorus, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, and blood glucose levels at baseline and 48 weeks in the TMF and TAF groups ( P>0.05). Conclusion:TMF has a relatively better efficacy and safety profile than TAF at 48 weeks in patients with hepatitis B virus-related cirrhosis.

Objective:To systematically evaluate the efficacy of Fuzheng Huayu (FZHY) tablets/capsules on hepatitis B-associated liver fibrosis or cirrhosis based on randomized controlled trials (RCTs) in order to provide more accurate evidence-based medicine for clinical rational drug use.Methods:Randomized controlled clinical trial research reports related to the treatment of hepatitis B-associated liver fibrosis or cirrhosis with FZHY published in SCI and statistical source core journals were retrieved from databases such as PubMed, Cochrane Library, and China National Knowledge Infrastructure (CNKI). RevMan 5.3 and Stata18.0 software were used to conduct a meta-analysis of the improvement rate of liver tissue inflammatory activity (HAI) and Ishak stage of liver fibrosis, the decrease value of liver stiffness measurement (LSM), hyaluronic acid (HA), laminin (LN), type Ⅲ procollagen (PC-Ⅲ), type Ⅳ collagen (IV-C), total bilirubin (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (Alb). The Q test was used for the heterogeneity test, with a random-effect model selected for large heterogeneity and a fixed-effect model for less heterogeneity.Results:A total of 852 articles were retrieved. Duplicate articles, non-RCT articles, non-SCI/statistical source/core journal articles, and other articles that did not meet the inclusion criteria were sequentially excluded. Finally, a total of 2 746 cases (1 382 cases in the FZHY group and 1 364 cases in the control group) were included from 25 studies. The results of statistical analysis showed that the improvement rates of HAI grade of liver inflammation were 75.56% (68/90) and 42.22% (38/90, P<0.001) in the FZHY group and the control group at 24-48 weeks of treatment, while the improvement rates of Ishak stage of liver fibrosis were 67.90% (110/162) and 40.91% (63/154, P=0.005), respectively. Compared with the control group (95% CI -5.10-1.77, P<0.001) the mean △LSM of the FZHY group decreased by 3.43 kPa ( P<0.001)and 0.30 kPa ( P=0.93) at 48 and 72 weeks of treatment. The standardized mean differences (SMDs) of △HA, △LN, △PC-Ⅲ and △Ⅳ-C were -1.12, -1.00, -0.89 and -1.10 ( P<0.001) after 24 weeks of treatment between the FZHY group and the control group. The SMDs of △HA, △IV-C, △LN and △PC-Ⅲ were -1.13 ( P=0.01), -1.51 ( P<0.001), -0.53 ( P=0.14) and -0.42 ( P=0.19) after 48 weeks of treatment between the two groups. The △TBil, △ALT, △AST, and △ALB was -12.99 μmol/L ( P=0.007), -36.91 U/L ( P<0.001), -22.05 U/L ( P=0.12), and 6.09 g/L ( P=0.05) after 24 weeks of treatment between the two groups. The observation on indicators such as aspartate aminotransferase and platelet ratio index, fibrosis-4 index, and hepatocellular carcinoma incidence in current RCT studies remained deficient. Conclusion:FZHY can significantly improve the degree of histologic liver inflammation and fibrosis, LSM values, reduce serum liver fibrosis indexes, and serum bilirubin and transaminase levels in patients with hepatitis B-associated liver fibrosis or cirrhosis. Therefore, it is necessary to further explore the optimal course of FZHY and its long-term effects on the risk of complications of cirrhosis such as hepatocellular carcinoma, ascites, and esophageal varicose bleeding, through prospective large-sample multicenter real-world cohort studies.

Objective:To evaluate the efficacy and safety profile of tenofovir amibufenamide (TMF) at 48 weeks in patients with hepatitis B virus-related compensated and decompensated stage cirrhosis.Methods:Patients with treatment-na?ve or treatment-experienced hepatitis B virus-related cirrhosis with nucleos(t)ide analogues (NA) who met the inclusion and exclusion criteria from 2022 to 2024 were retrospectively collected and divided into the tenofovir amibufenamide group (TMF, n=25) and the tenofovir alafenamide fumarate group (TAF, n=14). The conditional changes in hepatitis B virus DNA (HBV DNA), hepatitis B surface antigen (HBsAg), liver function indexes, serum creatinine (Cr), estimated glomerular filtration rate (eGFR), serum phosphorus, blood lipid profiles, and other variables were compared between and within the groups at baseline and 48 weeks. The t-test or Kruskal-Wallis H test was used to compare the measurement data among the groups. The χ2 test was used for the enumeration data. Results:There were no statistically significant differences in baseline, age, gender, proportion of compensated/decompensated stage cirrhosis, proportion of NA-naive/treatment experienced, liver function indexes, serum Cr, and eGFR between the two groups ( P>0.05). There was no statistically significant difference in the proportion of patients with HBV DNA<30 IU/ml ( P=1.00) between the two groups, regardless of whether they were NA-naive ( P=0.52) or treatment experienced ( P=1.00) at 48 weeks. There was no statistically significant difference in HBsAg levels between the TMF and TAF groups ( P=0.18) at 48 weeks. There was no statistically significant difference in the decline of HBsAg within each group ( P>0.05). The levels of alanine aminotransferase ( P<0.001) and aspartate aminotransferase ( P=0.045) were significantly lower at 48 weeks than those at baseline, while the albumin level was higher than that at baseline ( P=0.004) among the TMF group. There were no statistically significant differences in the rest of the liver function indicators among the TMF and the TAF groups between baseline and 48 weeks ( P>0.05). There were no statistically significant differences in Cr ( P=0.34) and eGFR levels ( P=0.60) at 48 weeks between the TMF and TAF groups.There were no statistically significant differences in Cr ( P=0.89) and eGFR levels ( P=0.57) at 48 weeks in patients aged<40 years ( n=8) compared with baseline in the TMF group. There were no statistically significant differences ( P=0.09, P=0.13) in patients with similar aged≥40 years ( n=17). The reduction in Cr level ( P<0.001) and the increase in eGFR ( P<0.001) at 48 weeks were statistically significant in patients aged<40 years ( n=3) among the TAF group. There were no statistically significant differences in Cr ( P=0.30) and eGFR ( P=0.13) at 48 weeks in patients aged≥40 years compared with baseline. There were no statistically significant differences in serum phosphorus, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, and blood glucose levels at baseline and 48 weeks in the TMF and TAF groups ( P>0.05). Conclusion:TMF has a relatively better efficacy and safety profile than TAF at 48 weeks in patients with hepatitis B virus-related cirrhosis.

In March 2022, EASL released a new version of the clinical practice guidelines on haemochromatosis. Haemochromatosis is characterized by elevated transferrin saturation (TSAT) and progressive iron overload mainly involving the liver, and early diagnosis and venesection can prevent liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, and other complications. For patients with p.Cys282Tyr homozygous mutation of the hemochromatosis gene HFE , haemochromatosis can be diagnosed if serum iron parameters show TSAT > 45% and ferritin > 200 μg/L in female patients, or TSAT > 50% and ferritin > 300 μg/L in male patients and postmenopausal female patients. If a patient has elevated TSAT and ferritin and belongs to other HFE genotypes, magnetic resonance or liver biopsy is needed to confirm iron overload in the liver. Liver fibrosis stage and damage to other organs should be carefully assessed at the time of diagnosis, which will help to determine management strategies. Hepatocellular carcinoma should be screened for patients with progressive liver fibrosis. The goal of venesection is to achieve ferritin < 50 μg/L during the induction stage and ferritin < 100 μg/L during the maintenance stage.

In patients with liver disease such as viral hepatitis and liver cirrhosis, renal injury and renal insufficiency can be generally classified as acute kidney injury (AKI), chronic kidney disease, and acute-on-chronic nephropathy. AKI can be classified as stage 1 (risk stage), stage 2 (injury stage), and stage 3 (failure stage). Traditionally hepatorenal syndrome is classified as types Ⅰ and Ⅱ, and in recent years, type Ⅲ hepatorenal syndrome with organic renal injury has been proposed. Hepatorenal disorder(HRD) is used to describe any renal disease which occurs in patients with liver cirrhosis. At present, sensitive and accurate biochemical parameters used to evaluate renal function in patients with liver disease in clinical practice include estimated glomerular filtration rate, increase in serum creatinine within unit time, and serum cystatin C level, and urinary microalbumin level also plays an important role in the early diagnosis of nephropathy. Causes of liver disease, severity, complications including infection, nutritional status, therapeutic drugs, and underlying nephropathy may be associated with renal injury and renal insufficiency in patients with liver disease and should be differentiated.

OBJECTIVETo analyze the etiology, clinical features and prognosis of liver injuries caused by different drugs.

METHODSThe types of suspected drugs related to liver injury, clinical manifestations, liver biochemical parameters, clinical outcomes and other associated data were retrospectively assessed for 140 patients with drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method (RUCAM) was used to assess the causality between drugs and liver injury.

RESULTSThe most prevalent agents inducing DILI were Chinese traditional drugs (62.1%), followed by antipyretic analgesic drugs (10%) and antibiotics (5%). The ratio of male to female patients in the study cohort was 1:1.69, with 71 of the total patients (50.7%) being between the ages of 40 and 60 years-old. The RUCAM scale was not less than 3 points for any of the patients.In general, the clinical manifestations and biochemical results were not specific. The percentages of hepatocellular injury type, cholestatic injury type and mixed injury type were 51.4%, 30.7% and 17.9% respectively. The median age of patients with cholestatic liver injury was 55.6 years, which was older than that of patients with hepatocellular injury (47.1 years) or mixed injury (49.9 years).

CONCLUSIONAlthough antipyretic analgesics and antibiotics are considered as common drugs that can induce DILI, Chinese traditional drugs have emerged as another important group of liver injurious agents. Cholestatic DILI was found to occur more often in elderly patients than in younger patients.

Adult ; Anti-Bacterial Agents ; Chemical and Drug Induced Liver Injury ; Cholestasis ; Female ; Humans ; Male ; Medicine, Chinese Traditional ; Middle Aged ; Prevalence ; Prognosis ; Retrospective Studies