Abstract Background Tacrolimus is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), encoded by the CYP3A and ATP-binding cassette subfamily B member 1 (ABCB1) genes, respectively. ...This study was aimed to investigate the impact of CYP3A and ABCB1 polymorphisms on the tacrolimus pharmacokinetics and clinical outcomes in Korean renal transplant recipients. Methods We analyzed data from a cohort of 70 renal transplant recipients receiving tacrolimus. CYP3A4*4, CYP3A4*5, CYP3A4*18, CYP3A5*3, ABCB1 C1236>T, ABCB1 G2677>T/A, and ABCB1 C3435>T polymorphisms were genotyped and correlated to dose-adjusted tacrolimus trough concentration at months 1, 3, 6, and 12 after transplantation. Results Patients with the CYP3A5*3 alleles showed higher dose-adjusted tacrolimus concentrations for 12 months and higher trough levels until 6 months after transplantation. ABCB1 polymorphisms and haplotypes were not associated with tacrolimus concentrations. In a multivariate analysis, the presence of ≥1 CYP3A5*3 allele was a significant independent variable affecting dose-adjusted tacrolimus concentrations. Glomerular filtration rate, acute rejection, opportunistic infection, and graft survival were not affected by CYP3A5 polymorphisms. Calcineurin inhibitor toxicity, which showed higher tendency in patients with CYP3A5*1 alleles, might be associated with higher tacrolimus dose per kilogram. Conclusions The CYP3A5 genotype is a major factor in determining the dose requirement of tacrolimus, and genotyping may be of value in individualization of immunosuppressive therapy of renal transplant patients.
Background
Although transarterial chemoembolization is recommended as the standard treatment for Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma (BCLC‐B HCC), other treatments ...including liver resection have been used. This study aimed to determine the survival benefit of treatment strategies including resection for BCLC‐B HCC compared with non‐surgical treatments.
Methods
The nationwide multicentre database of the Korean Liver Cancer Association was reviewed. Patients with BCLC‐B HCC who underwent liver resection as a first or second treatment within 2 years of diagnosis and patients who received non‐surgical treatment were selected randomly. Survival outcomes of propensity score‐matched groups were compared.
Results
Among 887 randomly selected patients with BCLC‐B HCC, 83 underwent liver resection as first or second treatment and 597 had non‐surgical treatment. After propensity score matching, the two groups were well balanced (80 patients in each group). Overall median survival in the resection group was better than that for patients receiving non‐surgical treatment (50·9 versus 22·1 months respectively; P < 0·001). The 1‐, 2‐, 3‐ and 5‐year overall survival rates in the resection group were 90, 88, 75 and 63 per cent, compared with 79, 48, 35 and 22 per cent in the no‐surgery group (P < 0·001). In multivariable analysis, non‐surgical treatment only (hazard ratio (HR) 3·35, 95 per cent c.i. 2·16 to 5·19; P < 0·001), albumin level below 3·5 g/dl (HR 1·96, 1·22 to 3·15; P = 0·005) and largest tumour size greater than 5·0 cm (HR 1·81, 1·20 to 2·75; P = 0·005) were independent predictors of worse overall survival.
Conclusion
Treatment strategies that include liver resection offer a survival benefit compared with non‐surgical treatments for potentially resectable BCLC‐B HCC.
Selected patients benefit
Summary
Background
Rifaximin might decrease the risk of portal hypertension‐related complications by controlling small intestinal bacterial overgrowth.
Aim
To evaluate whether rifaximin was ...associated with the risk of death and cirrhotic complications.
Methods
We conducted a retrospective study that included 1042 patients experiencing hepatic encephalopathy (HE): 421 patients without hepatocellular carcinoma (HCC; the non‐HCC cohort) and 621 patients with HCC (the HCC cohort). The primary endpoint was overall survival and secondary endpoints were recurrence of HE and the development of spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS) and variceal bleeding.
Results
In the non‐HCC cohort, 145 patients received rifaximin plus lactulose (the rifaximin group) and 276 patients received lactulose alone (the control group). The multivariate analysis revealed that rifaximin was significantly associated with lower risk of death (adjusted hazard ratio aHR, 0.697; P = .024) and reduced the risk of recurrent HE (aHR, 0.452; P < .001), SBP (aHR, 0.210; P < .001) and variceal bleeding (aHR, 0.425; P = .011) but not HRS (aHR, 0.598; P = .08). In the HCC cohort, 173 patients received rifaximin plus lactulose and 448 patients received lactulose. Rifaximin was not associated with the risk of death (aHR, 1.177; P = .121). Rifaximin was associated with lower risk of SBP (aHR, 0.323; P < .001) but not with variceal bleeding (aHR, 0.660; P = .104) or recurrent HE (aHR, 0.689; P = .057). The risk of Clostridium difficile‐associated diarrhoea was not different between the groups (aHR, 0.028; P = .338).
Conclusions
In patients without HCC, rifaximin treatment was significantly associated with prolonged overall survival and reduced risks of spontaneous bacterial peritonitis, variceal bleeding and recurrent hepatic encephalopathy.
Linked Content
This article is linked to Juang, Kang et al, Wang et al, and Borentain et al papers. To view these papers visit https://doi.org/10.1111/apt.14325, https://doi.org/10.1111/apt.14343, https://doi.org/10.1111/apt.14353 and https://doi.org/10.1111/apt.14516.
To explore potential biomarkers for amoxicillin/clavulanate‐induced liver injury (AC‐DILI), we conducted a clinical trial in 32 healthy subjects based on multi‐omics approaches. Every subject was ...administered amoxicillin/clavulanate for 14 days. The liver‐specific microRNA‐122 (miR‐122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase. This result indicates its potential as a sensitive early marker for AC‐DILI. We also identified urinary metabolites, such as azelaic acid and 7‐methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC‐DILI, including metabolic changes, increased miR‐122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration. In conclusion, this study provides potential biomarkers for AC‐DILI based on currently known mechanisms using comprehensive multi‐omics approaches.
Our aim was to investigate the association between the triglycerides/glucose index (TyG index) and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) in the prediction of insulin ...resistance (IR) among adolescents.
We conducted a cross-sectional study among 221 Korean adolescents (168 males and 53 females aged 9-13 years) from May to June 2014 in Chung-ju city. The TyG index was calculated as ln triglycerides (mg dl
) × fasting glucose (mg dl
)/2. IR was defined using HOMA-IR >95th percentile for age and sex.
In the IR group, weight, body mass index (BMI), waist circumference, body fat, fasting insulin, fasting plasma glucose, triglyceride levels and triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) were significantly higher than that in the non-IR group. The TG index was significantly different between the IR group (n=22) and non-IR group (n=199), at 8.43±0.45 and 8.05±0.41, respectively (P<0.001). The TyG index was well correlated with HOMA-IR (r=0.41; P<0.001) and showed a strong positive association with TG/HDL-C (r=0.84; P<0.001). The cut-off of the TyG index for diagnosis of insulin resistance was 8.18.
The TyG index is a simple, cost-effective surrogate marker of insulin resistance among adolescents compared with HOMA-IR.
Mixed Candida/bacterial bloodstream infections (BSIs) have been reported to occur in more than 23% of all episodes of candidaemia. However, the clinical implications of mixed Candida/bacterial BSIs ...are not well known. We performed a retrospective case-control study of all consecutive patients with candidaemia over a 5-year period to determine the risk factors for and clinical outcomes of mixed Candida/bacterial BSIs (cases) compared with monomicrobial candidaemia (controls). Thirty-seven (29%) out of 126 patients with candidaemia met the criteria for cases. Coagulase-negative staphylococci were the predominant bacteria (23%) in cases. In multivariate analysis, duration of previous hospital stay >7 weeks (odds ratio (OR), 2.86; 95% confidence interval (CI), 1.09–7.53), prior antibiotic therapy ≥7 days (OR, 0.33; 95% CI, 0.14–0.82) and septic shock at the time of candidaemia (OR, 2.60; 95% CI, 1.14–5.93) were significantly associated with cases. Documented clearance of candidaemia within 3 days after initiation of antifungal therapy was less frequent in cases (63% vs. 84%; p = 0.035). The difference in the rate of treatment failure at 2 weeks was not significant between cases (68%) and controls (62%; p = 0.55). The crude mortality at 6 weeks and survival through 100 days did not differ between the two patient groups (p = 0.56 and p = 0.80, respectively). Mixed Candida/bacterial BSIs showed a lower clearance rate of candidaemia during the early period of antifungal therapy, although the treatment response and survival rate were similar regardless of concurrent bacteraemia. Further studies on the clinical relevance of species-specific Candida-bacterial interactions are needed.
Summary
What is known and objective
There is a disparity between the Korean treatment guidelines and actual clinical prescription habits. This study was designed to evaluate the department‐specific ...disparities and achievement rates for low‐density lipoprotein cholesterol (LDL‐C) targets, based on each department's specific statin prescription patterns.
Methods
We retrospectively evaluated data from 31 718 patients who had been prescribed a statin at least once between January 2008 and June 2013 at our institution. Patients were classified into the high‐risk (target LDL‐C < 100 mg/dL) or moderate‐risk (target LDL‐C < 130 mg/dL) groups, according to the National Cholesterol Education Programme‐Adult Treatment Panel III guidelines.
Results and discussion
Statins were most commonly prescribed in the cardiology (32·0%) and endocrinology (26·6%) departments. For the high‐risk group, 70% of patients in the cardiology, endocrinology and cardiac surgery departments achieved their target LDL‐C levels (<100 mg/dL). However, the target achievement rates in most other departments were <70%. For the moderate‐risk group, 79·2% of patients achieved their target levels. Departments that prescribed a greater number of high‐ or intermediate‐potency statins were more likely to achieve their target LDL‐C levels. The group that achieved their target LDL‐C levels (<100 mg/dL) exhibited a significant positive relationship (Spearman's correlation coefficient = 0·8571, P = 0·0065), from low to high potency.
What is new and conclusion
Some departments tend to undertreat when prescribing statins. However, to reach to the target LDL‐C levels, physicians must overcome their tendency to undertreat with statins. We believe that the target achievement rate will increase if doctors are more actively aware of a patient's individual status and related risk factors before prescribing statins.
Some departments tend to undertreat when prescribing statins. To reach to the target LDL‐C levels, physicians must overcome their tendency to undertreat with statins.
A total of 244 patients including 100 (41%) autologous hematopoietic stem cell transplant (HCT) recipients and 144 (59%) allogeneic HCT recipients were enrolled over a 28‐month period. During the ...study period, no prophylaxis for latent tuberculosis (TB) infection was administrated. Of these, 201 (82%) had Bacillus Calmette‐Guérin (BCG) scars or prior histories of BCG vaccination. The tuberculin skin test (TST) and the QuantiFERON‐TB Gold In‐Tube (QFT‐GIT) test were performed simultaneously in all 244 patients. TST indurations were ≥ 5 mm in 39 of these patients (15%), and in 25 (10%) indurations were ≥ 10 mm. In addition, 40 (16%) had positive QFT‐GIT outcomes, and 34 (14%) indeterminate outcomes. If the 34 patients with indeterminate QFT‐GIT results were excluded from the overall agreement analysis, the agreement between the TST results (induration size ≥ 5 mm) and the QFT‐GIT results in the 210 patients with clear QFT results was poor (κ = 0.08, 95% confidence interval CI −0.06 to 0.24), as it was for the patients with indurations ≥ 10 mm (κ = 0.15, 95% CI −0.004 to 0.31). During follow up, 2 patients developed TB after HCT. The incidence of TB in the patients with positive QFT‐GIT outcomes was 2.80 per 100 person‐years (95% CI 0.07–15.81), whereas among those with positive TST (≥ 5 mm) results, it was 0 per 100 person‐years (95% CI 0–8.00). However, this finding should be cautiously interpreted because of the relatively short follow up and the fact that the sample size of the study cohort did not have adequate power. In conclusion, our data show that, although the frequencies of positive outcomes in the 2 TB screening tests were similar, the overall agreement between the TST and the QFT‐GIT test was poor, regardless of BCG vaccination history.
Summary
Background
The quality of reporting randomized controlled trials (RCTs) in the dermatology literature has not received much consideration since the late 2000s.
Objectives
We aimed to assess ...the quality of recently reported RCTs published in dermatology journals, focusing on randomization processes, blinding and trial registration.
Methods
We reviewed 2042 original articles and identified 141 primary reports of RCTs in four dermatology journals (Journal of the American Academy of Dermatology, JAMA Dermatology, Journal of Investigative Dermatology and British Journal of Dermatology) from January 2015 to December 2017. Details were extracted from articles, supplements and public trial registries. A multivariable logistic regression analysis was conducted to identify factors associated with optimal reporting quality.
Results
Among the 141 RCTs, 99 (70·2%), 82 (58·2%) and 69 (48·9%) described methods used for randomization, allocation concealment and implementation, respectively. Most trials (126, 89·4%) reported blinding status; however, one‐third did not state the similarity of the intervention. Furthermore, 52 RCTs (36·9%) were not registered prospectively. Trials published in the British Journal of Dermatology and using central randomization were significantly associated with optimal reporting quality after adjusting for covariates.
Conclusions
Several critical items in reporting RCTs, including allocation concealment, similarity of interventions in blinded trials and prospective trial registration, have remained unsatisfactory in the recent dermatology literature.
What's already known about this topic?
The adoption of the CONSORT statement by journals has been associated with improved quality of reporting randomized controlled trials (RCTs).
The quality of reporting RCTs in the dermatology literature was below an acceptable level in the early 2000s.
What does this study add?
Only 30·5% of RCTs recently published in four leading dermatology journals show optimal reporting quality.
Reporting on the randomization processes used and prospective trial registration was suboptimal, while blinding status was reported in the majority of RCTs.
Factors associated with optimal reporting quality on multivariable analysis included publication in the British Journal of Dermatology and use of central randomization.
Linked Editorial: Kwatra and Kang. Br J Dermatol 2019; 180:1277–1278.
Respond to this article
Summary
Background
Atrophic gastritis and intestinal metaplasia are premalignant conditions for gastric cancer. Their reversibility by Helicobacter pylori eradication remains controversial.
Aim
To ...evaluate the reversibility of atrophic gastritis and intestinal metaplasia by H. pylori eradication with long‐term follow‐up.
Methods
598 subjects were prospectively enrolled and followed for up to 10 years. They were categorised as H. pylori‐negative (n = 65), H. pylori non‐eradicated (n = 91), and H. pylori‐eradicated (n = 442). Histological assessment was performed for antrum and corpus by Sydney classification.
Results
Histological follow‐up was performed regularly at 1, 2, 3‐4 and ≥5 years, with mean follow‐up of 1.07 ± 0.21, 2.29 ± 0.83, 3.93 ± 1.02, and 6.45 ± 1.28 years, respectively. Atrophic gastritis in antrum and corpus gradually and significantly (both P < .05 for all timepoints) improved only in the H. pylori‐eradicated group compared to that at baseline. Significant difference in atrophic gastritis between H. pylori‐eradicated and H. pylori‐negative groups disappeared from 1‐year follow‐up. Similarly, intestinal metaplasia in antrum and corpus improved significantly (both P < .05 for all timepoints) only in the H. pylori‐eradicated group in comparison with that at baseline. Significant difference in intestinal metaplasia between H. pylori‐eradicated and H. pylori‐negative groups disappeared from ≥5 years of follow‐up in the antrum and from 3 years of follow‐up in the corpus.
Conclusion
H. pylori eradication may be a preventative strategy for intestinal‐type gastric cancer by regression of atrophic gastritis and intestinal metaplasia.
Linked ContentThis article is linked to Genta and Kim and Hwang papers. To view these articles visit https://doi.org/10.1111/apt.14491 and https://doi.org/10.1111/apt.14524.
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