ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir,Deleobuvir, and Ribavirin for HCV Infection

Background & Aim

Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin.

Methods

HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression.

Results

In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12.

Conclusions

The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01132313","term_id":"NCT01132313"}}NCT01132313     

Performance of Two HCV RNA Assays during Protease Inhibitor-Based Triple Therapy in Patients with Advanced Liver Fibrosis and Cirrhosis

Introduction

On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance.

Aim

To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis.

Methods

We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays.

Results

Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR.

Conclusion

Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.     

Multimodality Imaging to Predict Response to Systemic Treatment in Patients with Advanced Colorectal Cancer

Aim

Aim of this study was to investigate the potential of ¹⁸F-FDG PET, diffusion weighted imaging (DWI) and susceptibility-weighted (T2*) MRI to predict response to systemic treatment in patients with colorectal liver metastases. The predictive values of pretreatment measurements and of early changes one week after start of therapy, were evaluated.

Methods

Imaging was performed prior to and one week after start of first line chemotherapy in 39 patients with colorectal liver metastases. ¹⁸F-FDG PET scans were performed on a PET/CT scanner and DWI and T2* were performed on a 1.5T MR scanner. The maximum standardized uptake values (SUV), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC) and T2* value were assessed in the same lesions. Up to 5 liver metastases per patient were analyzed. Outcome measures were progression free survival (PFS), overall survival (OS) and size response.

Results

Pretreatment, high SUV_max, high TLG, low ADC and high T2* were associated with a shorter OS. Low pretreatment ADC value was associated with shorter PFS. After 1 week a significant drop in SUV_max and rise in ADC were observed. The drop in SUV was correlated with the rise in ADC (r=-0.58, p=0.002). Neither change in ADC nor in SUV was predictive of PFS or OS. T2* did not significantly change after start of treatment.

Conclusion

Pretreatment SUV_max, TLG, ADC, and T2* values in colorectal liver metastases are predictive of patient outcome. Despite sensitivity of DWI and ¹⁸F-FDG PET for early treatment effects, change in these parameters was not predictive of long term outcome.     

The Development of the Pediatric NAFLD Fibrosis Score (PNFS) to Predict the Presence of Advanced Fibrosis in Children with Nonalcoholic Fatty Liver Disease

Background

Noninvasive hepatic fibrosis scores that predict the presence of advanced fibrosis have been developed and validated in adult patients with NAFLD. The aims of our study were to assess the utility of commonly used adult fibrosis scores in pediatric NAFLD and to develop a pediatric specific fibrosis score that can predict advanced fibrosis.

Methods

Consecutive children with biopsy-proven NAFLD were included. Fibrosis was determined by an experienced pathologist (F0–4). Advanced fibrosis was defined as fibrosis stage ≥3. The following adult fibrosis scores were calculated for each child: AST/ALT ratio, AST/platelet ratio index (APRI), NAFLD fibrosis score (NFS), and FIB-4 Index. Multivariable logistic regression analysis was performed to build a new pediatric model for predicting advanced fibrosis.

Results

Our cohort consisted of 242 children with a mean age of 12.4±3.1 years and 63% were female. 36 (15%) subjects had advanced fibrosis. APRI and FIB-4 were higher in patients with advanced fibrosis compared to those with fibrosis stage 0–2; however, AST/ALT ratio and NFS were not different between the two groups. We used our data to develop a new model to predict advanced fibrosis which included: ALT, alkaline phosphatase, platelet counts and GGT. The multivariable logistic regression model (z) was defined as follows: z = 1.1+(0.34*sqrt(ALT))+(0.002*alkaline phosphatase) – (1.1*log(platelets) – (0.02*GGT). This value was then converted into a probability distribution (p) with a value between 0 to 100 by the following formula: p = 100×exp(z)/[1+exp(z)]. The AUCROC for this model was 0.74 (95% CI: 0.66, 0.82). This was found to be significantly better than APRI, NAFLD Fibrosis Score and FIB-4 Index.

Conclusion

Noninvasive hepatic fibrosis scores developed in adults had poor performance in diagnosing advanced fibrosis in children with NAFLD. We developed a new pediatric NAFLD fibrosis score with improved performance characteristics.     

The Effect of Iron Treatment on Adhesion Molecules in Patients with Iron Deficiency Anemia

The present study was aimed to determine the effect of iron supplementation on levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients with iron deficiency anemia (IDA). In this study, 26 female patients diagnosed with iron deficiency were treated approximately 3 months of oral iron supplementation (99 ± 10 days; ferrous glycine sulfate; 100 mg/day of elemental iron). Levels of sICAM-1 and sVCAM-1 were assessed prior to treatment and after approximately 3 months of treatment and compared with 26 healthy female subjects. A significant increase in sVCAM levels was found in the patients with iron deficiency at the end of the treatment relative to pretreatment levels compared to controls, whereas no significant differences were determined in sICAM levels. In the posttreatment period, no significant change was observed in sICAM levels compared to the pretreatment levels, whereas sVCAM levels decreased. However, after the treatment period, the sVCAM, hemoglobin, mean corpuscular volume (MCV), and serum ferritin levels did not return to the normal range compared to the controls. Pretreatment sVCAM-1 levels were inversely correlated with levels of hemoglobin, hemotocrit, MCV, serum iron, and ferritin. After treatment, the sVCAM-1 levels were negatively correlated with ferritin levels. Levels of sVCAM were significantly higher in patients with IDA than controls. After the treatment period, the sVCAM levels were not completely normalized in patients with IDA compared to controls, regardless of the presence of inadequate levels of hemoglobin, MCV, and serum ferritin. Thus, iron supplementation not only ameliorates anemia, but may also reduce the inflammation markers in cases with IDA.     

Risk of Cancer in Patients with Iron Deficiency Anemia: A Nationwide Population-Based Study

ObjectiveThis study evaluated the risk of cancer among patients with iron deficiency anemia (IDA) by using a nationwide population-based data set.MethodPatients newly diagnosed with IDA and without antecedent cancer between 2000 and 2010 were recruited from the Taiwan National Health Insurance Research Database. The standardized incidence ratios (SIRs) of cancer types among patients with IDA were calculated.ResultsPatients with IDA exhibited an increased overall cancer risk (SIR: 2.15). Subgroup analysis showed that patients of both sexes and in all age groups had an increased SIR. After we excluded patients diagnosed with cancer within the first and first 5 years of IDA diagnosis, the SIRs remained significantly elevated at 1.43 and 1.30, respectively. In addition, the risks of pancreatic (SIR: 2.31), kidney (SIR: 2.23), liver (SIR: 1.94), and bladder cancers (SIR: 1.74) remained significantly increased after exclusion of patients diagnosed with cancer within 5 years after IDA diagnosis.ConclusionThe overall cancer risk was significantly elevated among patients with IDA. After we excluded patients diagnosed with IDA and cancer within 1 and 5 years, the SIRs remained significantly elevated compared with those of the general population. The increased risk of cancer was not confined to gastrointestinal cancer when the SIRs of pancreatic, kidney, liver, and bladder cancers significantly increased after exclusion of patients diagnosed with IDA and cancer within the first 5 years. This finding may be caused by immune activities altered by IDA. Further study is necessary to determine the association between IDA and cancer risk.     

Multi-Purpose Utility of Circulating Plasma DNA Testing in Patients with Advanced Cancers

Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5–1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical ‘hot-spot’ mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.     

NIKEI: A New Inexpensive and Non-Invasive Scoring System to Exclude Advanced Fibrosis in Patients with NAFLD

Aims

To develop, validate and compare a non-invasive fibrosis scoring system for non-alcoholic fatty liver disease (NAFLD) derived from routinely obtained clinical and biochemical parameters.

Methods

267 consecutive patients with biopsy proven fatty liver or non-alcoholic steatohepatitis were randomly assigned to the estimation (2/3) or validation (1/3) group to develop a model for the prediction of advanced fibrosis. Univariate statistics were performed to compare patients with and without advanced fibrosis, and following a multivariate logistic regression analysis a new scoring system was constructed. This non-invasive Koeln-Essen-index (NIKEI) was validated and compared to the FIB-4 index by calculating the area under the receiver operating characteristic curve (AUC). We evaluated a stepwise combination of both scoring systems for the precise prediction of advanced fibrosis. To set in contrast, we additionally tested the diagnostic accuracy of the AST/ALT ratio, BARD score and the NAFLD fibrosis score in our cohort.

Results

Age, AST, AST/ALT ratio, and total bilirubin were identified as significant predictors of advanced fibrosis and used to construct the NIKEI with an AUC of 0.968 [0.937; 0.998] compared to 0.929 [0.869; 0.989] for the FIB-4 index. The absence of advanced fibrosis could be confirmed with excellent accuracy (99–100%). The positive predictive value of the FIB-4 index was higher (100% vs. 60%), however, the false negative rate was also high (33%). With a stepwise combination of both indices 82%–84% of biopsies would have been avoidable without a single misclassification. The AUROC for AST/ALT ratio, the NAFLD fibrosis score, and the BARD score were 0.81 (95% CI, 0.72–0.90), 0.96 (95% CI 0.92–0.99), and 0.67 (95% CI 0.55–0.78), respectively.

Conclusion

The NIKEI can reliably exclude advanced fibrosis in subjects with NAFLD. In combination with the FIB-4 index misclassification with inadequate clinical management can be avoided while the need for liver biopsies can be reduced.     

Hemostatic Dysfunction Is Increased in Patients with Hepatosplenic Schistosomiasis Mansoni and Advanced Periportal Fibrosis

Background

Schistosomiasis mansoni is an endemic parasitic disease and a public health problem in Northeast Brazil. In some patients, hepatic abnormalities lead to periportal fibrosis and result in the most severe clinical form, hepatosplenic schistosomiasis. This study aimed to evaluate whether abnormal blood coagulation and liver function tests in patients with hepatosplenic schistosomiasis (n = 55) correlate with the severity of their periportal fibrosis.

Methodology/Principal Findings

Blood samples were used for liver function tests, hemogram and prothrombin time (International Normalized Ratio, INR). The blood coagulation factors (II, VII, VIII, IX and X), protein C and antithrombin IIa (ATIIa), plasminogen activator inhibitor 1 (PAI-1) and D-dimer were measured by photometry or enzyme linked immunosorbent assay. Hyperfibrinolysis was defined on the basis of PAI-1 levels and a D-dimer concentration greater than a standard cut-off of 483 ng/mL. Standard liver function tests were all abnormal in the patient group compared to healthy controls (n = 29), including raised serum transaminases (p<0.001) and lower levels of albumin (p = 0.0156). Platelet counts were 50% lower in patients, while for coagulation factors there was a 40% increase in the INR (p<0.001) and reduced levels of Factor VII and protein C in patients compared to the controls (both p<0.001). Additionally, patients with more advanced fibrosis (n = 38) had lower levels of protein C compared to those with only central fibrosis (p = 0.0124). The concentration of plasma PAI-1 in patients was one-third that of the control group (p<0.001), and D-dimer levels 2.2 times higher (p<0.001) with 13 of the 55 patients having levels above the cut-off.

Conclusion/Significance

This study confirms that hemostatic abnormalities are associated with reduced liver function and increased liver fibrosis. Of note was the finding that a quarter of patients with hepatosplenic schistosomiasis and advanced periportal fibrosis have hyperfibrinolysis, as judged by excessive levels of D-dimer, which may predispose them to gastrointestinal bleeding.     

Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging.     

Humoral Immune Responses to EGFR-Derived Peptides Predict Progression-Free and Overall Survival of Non-Small Cell Lung Cancer Patients Receiving Gefitinib

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, in patients with non-small cell lung cancer (NSCLC). However, humoral immune responses to EGFR in NSCLC patients have not been well studied. In this study, we investigated the clinical significance of immunoglobulin G (IgG) responses to EGFR-derived peptides in NSCLC patients receiving gefitinib. Plasma IgG titers to each of 60 different EGFR-derived 20-mer peptides were measured by the Luminex system in 42 NSCLC patients receiving gefitinib therapy. The relationships between the peptide-specific IgG titers and presence of EGFR mutations or patient survival were evaluated statistically.IgG titers against the egfr_481–500, egfr_721–740, and egfr_741–760 peptides were significantly higher in patients with exon 21 mutation than in those without it. On the other hand, IgG titers against the egfr_841–860 and egfr_1001–1020 peptides were significantly lower and higher, respectively, in patients with deletion in exon 19. Multivariate Cox regression analysis showed that IgG responses to egfr_41_ 60, egfr_61_80 and egfr_481_500 were significantly prognostic for progression-free survival independent of other clinicopathological characteristics, whereas those to the egfr_41_60 and egfr_481_500 peptides were significantly prognostic for overall survival. Detection of IgG responses to EGFR-derived peptides may be a promising method for prognostication of NSCLC patients receiving gefitinib. Our results may provide new insight for better understanding of humoral responses to EGFR in NSCLC patients.     

Development and Validation of a Bedside Score to Predict Early Death in Cancer of Unknown Primary Patients

Background

We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients.

Methods

Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4).

Results

The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5×the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0–1], 2 and [3]–[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values.

Conclusions

We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy.     

The Diagnostic Accuracy and Clinical Utility of Three Noninvasive Models for Predicting Liver Fibrosis in Patients with HBV Infection

AimTo evaluate the diagnostic accuracy and clinical utility of the fibrosis index based on the four factors (FIB-4), aspartate aminotransferase -to-platelet ratio index (APRI), and aspartate aminotransferase–alanine aminotransferase ratio index (AAR) for predicting liver fibrosis in patients with HBV infection.MethodsFrom January 2006 to December 2010,a total of 1543 consecutive chronic hepatitis B(CHB) patients who underwent liver biopsies were enrolled. FIB-4,APRI, and AAR were calculated.The areas under the receiver-operating characteristic curves (AUROCs) were calculated to assess the diagnostic accuracy of these models.The AUROCs of these models were compared by DeLong’s test.For further comparisons in different studies,the AUROCs were adjusted to conduct Adjusted AUROCs(ADjAUROCs) according to the prevalence of fibrosis stages using the difference between advanced and nonadvanced fibrosis (DANA).ResultsFor prediction of significant fibrosis,severe fibrosis,and cirrhosis,the AUROCs of FIB-4 were 0.646(ADjAUROC 0.717),0.670(ADjAUROC 0.741), and 0.715(ADjAUROC 0.786) respectively;whereas it were 0.656(ADjAUROC 0.727),0.653(ADjAUROC 0.724) and 0.639(ADjAUROC 0.710) for APRI, 0.498(ADjAUROC 0.569),0.548(ADjAUROC 0.619) and 0.573(ADjAUROC 0.644) for AAR. The further comparisons demonstrated that there were no significant differences of AUROCs between FIB-4 and APRI in predicting significant and severe fibrosis(P > 0.05),while FIB-4 was superior to APRI in predicting cirrhosis(P < 0.001). Further subgroup analysis demonstrated that the diagnostic accuracy of FIB-4 and APRI in patients with normal alanine aminotransferase(ALT) were higher than that in patients with elevated ALT.ConclusionsThe results demonstrated that FIB-4 and APRI are useful for diagnosis of fibrosis. FIB-4 and APRI have similar diagnostic accuracy in predicting significant and severe fibrosis,while FIB-4 is superior to APRI in predicting cirrhosis. The clinical utility of FIB-4 and APRI for fibrosis need further external validation in a large population before it was used for prediction of fibrosis in patients with HBV infection.     

Three Cases of Hemolytic Anemia with Erythrocyte Pyruvate Kinase Deficiency in Alberta

Erythrocyte pyruvate kinase (PK) activity was determined by the lactate dehydrogenase-coupled spectrophotometric assay. The effects of modifications in the buffer and in substrate concentrations were studied. Three patients with congenital non-spherocytic hemolytic anemia were deficient in erythrocyte PK, and were evidently homozygous for this deficiency. The daughter of one patient and the parents of another had intermediate PK levels and were probably heterozygous. The erythrocyte adenosine triphosphate (ATP) level was low in one patient, high in another. Adenosine triphosphatase activity of the erythrocyte membranes of one patient was normal.     

生血宁片联合琥珀酸亚铁片治疗妊娠期缺铁性贫血患者的疗效及对铁代谢的影响

目的:探讨生血宁片联合琥珀酸亚铁片治疗妊娠期缺铁性贫血患者的疗效及对铁代谢的影响。方法:选取2015年2月-2017年2月我院收治的妊娠期缺铁性贫血患者200例为研究对象。将其以随机数字表法分成对照组(n=100)和研究组(n=100)。对照组予以口服琥珀酸亚铁片治疗,研究组则予以生血宁片联合琥珀酸亚铁片治疗,两组均连续治疗4周。分别比较两组临床疗效、治疗前后血液学指标、治疗前后铁代谢指标以及不良妊娠结局情况。结果:研究组治疗总有效率明显较对照组升高(P0.05)。治疗后两组患者血红蛋白(Hb)、红细胞(RBC)、平均红细胞体积(MCV)以及平均红细胞血红蛋白浓度(MCHC)水平均明显高于治疗前,且研究组高于对照组(P0.05)。治疗后两组患者血清铁、转铁蛋白饱和度(TSAT)水平均明显高于治疗前,且研究组又明显高于对照组(P0.05)。与对照组比较,研究组不良妊娠结局发生率降低(P0.05)。结论:生血宁片联合琥珀酸亚铁片治疗妊娠期缺铁性贫血患者的临床疗效显著,改善患者血液学指标以及铁代谢水平,降低不良妊娠结局发生风险,值得临床推广应用。     

Impact of Type 2 Diabetes on Nonalcoholic Steatohepatitis and Advanced Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Objective: Type 2 diabetes mellitus (T2DM) is a risk factor for nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the effect of T2DM on nonalcoholic steatohepatitis (NASH) and advanced fibrosis.Methods: A total of 221 NAFLD patients who had undergone a liver biopsy were included in this study. Subjects were divided into a non-T2DM group and a T2DM group based on glycemic control. NASH was diagnosed by the joint presence of steatosis, ballooning, and lobular inflammation. The steatosis, activity, and fibrosis (SAF) score and NAFLD activity score (NAS) were used to evaluate the severity of NAFLD. The severity of liver fibrosis was evaluated based on the fibrosis stage.Results: The total percentages of NASH and advanced fibrosis in this study were 95.0% and 50.2%, respectively. The percentages of NASH and advanced fibrosis in NAFLD patients with T2DM were 96.1% and 56.5%, respectively, which were higher than those in the non-T2DM group. SAF score (especially activity and fibrosis stage) and NAS (especially ballooning) were higher in NAFLD patients with T2DM than in NAFLD patients without T2DM. Glycemic control and insulin resistance were positively associated with SAF, NAS, and fibrosis stage. Additionally, T2DM elevated the risk of a high NAS and advanced fibrosis.Conclusion: T2DM increases the risk of serious NASH and advanced fibrosis in patients with NAFLD. Liver biopsy can be performed in NAFLD patients with T2DM to confirm the stage of NAFLD. Screening of NASH and advanced fibrosis in NAFLD patients with T2DM is needed.Abbreviations: ALT = alanine aminotransferase; APO = apolipoprotein; AST = aspartate aminotransferase; BMI = body mass index; CI = confidence interval; FPG = fasting plasma glucose; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HDL-c = high-density-lipoprotein cholesterol; ¹H-MRS = proton magnetic resonance spectroscopy; HOMA-IR = homeostasis model assessment of insulin resistance; 2hPG = postprandial plasma glucose at 2 hours; LDL-c = low-density-lipoprotein cholesterol; LFC = liver fat content; NAFLD = nonalcoholic fatty liver disease; NAS = NAFLD activity score; NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; OR = odds ratio; T2DM = type 2 diabetes mellitus; TC = total cholesterol; TG = triglyceride; SAF = steatosis, activity, and fibrosis; US-FLI = ultrasonographic fatty liver indicator     

The Clinical Utility of Informants' Appraisals on Prospective and Retrospective Memory in Patients with Early Alzheimer's Disease

Increasing studies suggest the importance of including prospective memory measures in clinical evaluation of dementia due to its sensitivity and functional relevance. The Prospective and Retrospective Memory Questionnaire (PRQM) is originally a self-rated memory inventory that offers a direct comparison between prospective and episodic memory. However, the informant''s report has been recognized as a more valid source of cognitive complaints. We thus aimed to examine the validity of the informant-rated form of the PRMQ in assessing memory function of the patients and in detecting individuals with early dementia. The informants of 140 neurological outpatients with memory complaints completed the Taiwan version of the PRMQ. Tests of prospective memory, short-term memory, and general cognitive ability were also administered to non-demented participants and patients with early stages of Alzheimer''s disease (AD). Results showed significant relationships between the PRMQ ratings and objective cognitive measures, and showed that higher ratings on the PRMQ were associated with increasing odds of greater dementia severity. Receiver operative characteristic (ROC) curves showed an adequate ability of the PRMQ to identify patients with dementia (93% sensitivity and 84% specificity). Hierarchical regression revealed that the PRMQ has additional explanatory power for dementia status after controlling for age, education and objective memory test results, and that the prospective memory subscale owns predictive value for dementia beyond the retrospective memory subscale. The present study demonstrated the external validity and diagnostic value of informants'' evaluation of their respective patients'' prospective and retrospective memory functioning, and highlighted the important role of prospective memory in early dementia detection. The proxy-version of the PRMQ is a useful tool that captures prospective and episodic memory problems in patients with early AD, in combination with standardized cognitive testing.     

Usefulness of Midregional Proadrenomedullin to Predict Poor Outcome in Patients with Community Acquired Pneumonia

Background

midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP). We sought to confirm whether MR-proADM added to Pneumonia Severity Index (PSI) improves the potential prognostic value of PSI alone, and tested to what extent this combination could be useful in predicting poor outcome of patients with CAP in an Emergency Department (ED).

Methods

Consecutive patients diagnosed with CAP were enrolled in this prospective, single-centre, observational study. We analyzed the ability of MR-proADM added to PSI to predict poor outcome using receiver operating characteristic (ROC) curves, logistic regression and risk reclassification and comparing it with the ability of PSI alone. The primary outcome was “poor outcome”, defined as the incidence of an adverse event (ICU admission, hospital readmission, or mortality at 30 days after CAP diagnosis).

Results

226 patients were included; 33 patients (14.6%) reached primary outcome. To predict primary outcome the highest area under curve (AUC) was found for PSI (0.74 [0.64-0.85]), which was not significantly higher than for MR-proADM (AUC 0.72 [0.63-0.81, p > 0.05]). The combination of PSI and MR-proADM failed to improve the predictive potential of PSI alone (AUC 0.75 [0.65-0.85, p=0.56]). Ten patients were appropriately reclassified when the combined PSI and MR-proADM model was used as compared with the model of PSI alone. Net reclassification improvement (NRI) index was statistically significant (7.69%, p = 0.03) with an improvement percentage of 3.03% (p = 0.32) for adverse event, and 4.66% (P = 0.02) for no adverse event.

Conclusion

MR-proADM in combination with PSI may be helpful in individual risk stratification for short-term poor outcome of CAP patients, allowing a better reclassification of patients compared with PSI alone.     

Impairment of Bone Health in Pediatric Patients with Hemolytic Anemia

Introduction

Sickle cell anemia and thalassemia result in impaired bone health in both adults and youths. Children with other types of chronic hemolytic anemia may also display impaired bone health.

Study Design

To assess bone health in pediatric patients with chronic hemolytic anemia, a cross-sectional study was conducted involving 45 patients with different forms of hemolytic anemia (i.e., 17 homozygous sickle cell disease and 14 hereditary spherocytosis patients). Biochemical, radiographic and anamnestic parameters of bone health were assessed.

Results

Vitamin D deficiency with 25 OH-vitamin D serum levels below 20 ng/ml was a common finding (80.5%) in this cohort. Bone pain was present in 31% of patients. Analysis of RANKL, osteoprotegerin (OPG) and osteocalcin levels indicated an alteration in bone modeling with significantly elevated RANKL/OPG ratios (control: 0.08+0.07; patients: 0.26+0.2, P = 0.0007). Osteocalcin levels were found to be lower in patients compared with healthy controls (68.5+39.0 ng/ml vs. 118.0+36.6 ng/ml, P = 0.0001). Multiple stepwise regression analysis revealed a significant (P<0.025) influence of LDH (partial r² = 0.29), diagnosis of hemolytic anemia (partial r² = 0.05) and age (partial r² = 0.03) on osteocalcin levels. Patients with homozygous sickle cell anemia were more frequently and more severely affected by impaired bone health than patients with hereditary spherocytosis.

Conclusion

Bone health is impaired in pediatric patients with hemolytic anemia. In addition to endocrine alterations, an imbalance in the RANKL/OPG system and low levels of osteocalcin may contribute to this impairment.