Performance of Bayesian Propensity Score Adjustment for Estimating Causal Effects in Small Clinical Trials

Propensity score (PS) adjustment can control confounding effects and reduce bias when estimating treatment effects in non-randomized trials or observational studies. PS methods are becoming increasingly used to estimate causal effects, including when the sample size is small compared to the number of confounders. With numerous confounders, quasi-complete separation can easily occur in logistic regression used for estimating the PS, but this has not been addressed. We focused on a Bayesian PS method to address the limitations of quasi-complete separation faced by small trials. Bayesian methods are useful because they estimate the PS and causal effects simultaneously while considering the uncertainty of the PS by modelling it as a latent variable. In this study, we conducted simulations to evaluate the performance of Bayesian simultaneous PS estimation by considering the specification of prior distributions for model comparison. We propose a method to improve predictive performance with discrete outcomes in small trials. We found that the specification of prior distributions assigned to logistic regression coefficients was more important in the second step than in the first step, even when there was a quasi-complete separation in the first step. Assigning Cauchy (0, 2.5) to coefficients improved the predictive performance for estimating causal effects and improving the balancing properties of the confounder.

Application of Scanning Acoustic Microscopy for Detection of Dental Caries Lesion

Introduction: A scanning acoustic microscope (SAM) is an apparatus for imaging acoustic properties. This apparatus can non-invasively and rapidly evaluate the hardness of materials in the elastic region. This device shows great potential for the diagnosis of dental caries in the clinical setting. However, since the tissue elastic modulus measured using a SAM is a property of the elastic region and the Knoop hardness is a property of the plastic region, the hardness properties differ completely. Therefore, we investigated whether the acoustic impedance measured using a SAM is related to the Knoop hardness, which is used as the standard for removal of carious dentin. Method: Polished sections were prepared from 20 extracted carious wisdom teeth. The acoustic impedance and Knoop hardness were measured for each section. In addition to comparing carious and healthy dentin in SAM images, we evaluated the difference between the carious and healthy dentin in terms of the acoustic impedance and Knoop hardness. We also evaluated the correlation between the Knoop hardness and acoustic impedance. Results: The SAM images were visualized as two-dimensional color images based on the acoustic impedance values. The mean acoustic impedance of carious dentin was significantly lower than that of healthy dentin, showing a similar trend as Knoop hardness. A strong correlation was observed between the two. Discussion: The acoustic impedance values obtained through acoustic microscopy differed significantly between carious and sound dentin. Both types of dentins were visualized using two-dimensional color images. A strong correlation was observed between the acoustic impedance value, which indicates the hardness of the elastic region, and the Knoop hardness, which indicates the hardness of the plastic region. The results of the present study indicate that acoustic impedance accurately reflects the hardness of dentin.

Radiation therapy has been shown to be adaptable for various stages of hepatocellular carcinoma

In addition to surgical procedures, radiofrequency ablation is commonly used for the treatment of hepatocellular carcinomas(HCCs) of limited size and number. Transcatheter arterial chemoembolization(TACE), using iodized poppy seed oil, Lipiodol and anticancer drugs, has been actively performed for the treatment of unresectable HCC, particularly in Asian countries. Recently, Sorafenib become available for advanced HCCs when the liver is still sufficiently functional. Sorafenib is an oral multikinase inhibitor with antiproliferative and antiangiogenic effects. However, the effect of sorafenib seems to be inadequate to control the progression of HCC. Radiation therapy(RT)for HCC has a potential role across all stages of HCC. However, RT is generally not considered an option in HCC consensus documents or national guidelines, primarily because of insufficient supporting evidence. However, the method of RT has much improved because of advances in technology. Moreover, combined treatment of RT plus other treatments(TACE, sorafenib and chemotherapy etc.) has become one of the alternative therapies for HCC. Therefore, we should understand the various kinds of RT available for HCC. In this review, we focus on various kinds of external beam radiation therapy.

Useful strategies to prevent severe stricture after endoscopic submucosal dissection for superficial esophageal neoplasm

The minimal invasiveness of endoscopic submucosal dissection(ESD) prompted us to apply this technique to large-size early esophageal squamous cell carcinoma and Barrett's adenocarcinoma, despite the limitationsin the study population and surveillance duration. A post-ESD ulceration of greater than three-fourths of esophageal circumference was advocated as an important risk factor for refractory strictures that require several sessions of dilation therapy. Most of the preoperative conditions are asymptomatic, but dilatation treatment for dysphagia associated with the stricture has potential risks of severe complications and a worsening of quality of life. Possible mechanisms of dysphasia were demonstrated based on dysmotility and pathological abnormalities at the site:(1) delayed mucosal healing;(2) severe inflammation and disorganized fibrosis with abundant extracellular matrices in the submucosa; and(3) atrophy in the muscularis proper. However, reports on the administration of anti-scarring agents, preventive dilation therapies, and regenerative medicine demonstrated limited success in stricture prevention, and there were discrepancies in the study designs and protocols of these reports. The development and consequent long-term assessments of new prophylactic technologies on the promotion of wound healing and control of the inflammatory/tumor microenvironment will require collaboration among various research fields because of the limited accuracy of preoperative staging and high-risk of local recurrence.

Gastric cancer development after the successful eradication of Helicobacter pylori

Gastric cancer(GC) develops as a result of inflammationassociated carcinogenesis due to Helicobacter pylori(H. pylori) infection and subsequent defects in genetic/epigenetic events. Although the indication for eradication therapy has become widespread, clinical studies have revealed its limited effects in decreasing the incidence of GC. Moreover, research on biopsy specimens obtained by conventional endoscopy has demonstrated the feasibility of the restoration of some genetic/epigenetic alterations in the gastric mucosa. Practically, the number of sporadic cases of primary/metachronous GC that emerge after successful eradication has increased, while on-going guidelines recommend eradication therapy for patients with chronic gastritis and those with background mucosa after endoscopic resection for GC. Accordingly, regular surveillance of numerous individuals who have received eradication therapy is recommended despite the lack of biomarkers. Recently, the focus has been on functional reversibility after successful eradication as another cue to elucidate the mechanisms of restoration as well as those of carcinogenesis in the gastric mucosa after H. pylori eradication. We demonstrated that Congo-red chromoendoscopy enabled the identification of the multifocal distribution of functionally irreversible mucosa compared with that of restored mucosa after successful eradication in individuals at extremely high risk for GC. Further research that uses functional imaging may provide new insights into the mechanisms of regeneration and carcinogenesis in the gastric mucosa post-eradication and may allow for the development of useful biomarkers.

Recent development of optical coherence tomography for preoperative diagnosis of esophageal malignancies

Endoscopic diagnosis with histological evidence is necessary to decide the best strategy for treating esophageal squamous cell carcinoma and Barrett's-associated neoplasia, and the recent development of endoscopic technologies have made possible real-time information of malignant hallmarks. We focused on the development of optical coherence tomography(OCT), the only technology that can depict real-time cross-sectional images with high resolution. With the improvements in image resolution, acquisition rate and demonstrable area of three-dimensional devices with Doppler capability, OCT imaging was shown to enable visualization of structural/functional alterations in the mucosal/submucosal tissue of the esophagus, resulting in more accurate preoperative diagnosis of such malignancies. Moreover, it approved to be useful for targeting malignant areas for biopsy and treatment as well as for predicting the treatment effects. Therefore, further development of this technology is expected to overcome the current clinical issues in management strategies of esophageal malignancies.

Stronger inhibition of gastric acid secretion by lafutidine, a novel H_2 receptor antagonist, than by the proton pump inhibitor lansoprazole

AIM: To compare the antisecretory activity and plasma drug concentrations of a single oral dose of 10 mg lafutidine, a novel H2 receptor antagonist, with those of the proton pump inhibitor lansoprazole (LPZ) 30 mg. METHODS: Ten volunteers without H pylori infection participated in this crossover study comparing lafutidine 10 mg with LPZ 30 mg. Intragastric pH was monitored for 6 h in all participants, and blood samples were collected from four randomly selected individuals after single-dose administration of each drug. RESULTS: The median intragastric pH was significantly higher in individuals who received lafutidine 10 mg than in those who received LPZ 30 mg 2, 3, 4, 5, and 6 h after administration. Maximal plasma drug concentration was reached more promptly with lafutidine 10 mg than with LPZ 30 mg. CONCLUSION: In H pylori-negative individuals, gastric acid secretion is more markedly inhibited by lafutidinethan by LPZ.

Role of nitric oxide in the pathogenesis of Barrett's-associated carcinogenesis

Barrett's esophagus(BE), a premalignant condition to Barrett's adenocarcinoma(BAC), is closely associated with chronic inflammation due to gastro-esophageal reflux. Caudal type homeobox 2(CDX2), a representative marker of BE, is increased during the metaplastic and neoplastic transformation of BE. Nitric oxide(NO) has been proposed to be a crucial mediator of Barrett's carcinogenesis. We previously demonstrated that CDX2 might be induced directly under stimulation of large amounts of NO generated around the gastroesophageal junction(GEJ) by activating epithelial growth factor receptor in a ligand-independent manner. Thus, we reviewed recent developments on the role of NO in Barrett's carcinogenesis. Notably, recent studies have reported that microbial communities in the distal esophagus are significantly different among groups with a normal esophagus, reflux esophagitis, BE or BAC, despite there being no difference in the bacterial quantity. Considering that microorganism components can be one of the major sources of large amounts of NO, these studies suggest that the bacterial composition in the distal esophagus might play an important role in regulating NO production during the carcinogenic process. Controlling an inflammatory reaction due to gastro-esophageal reflux or bacterial composition around the GEJ might help prevent the progression of Barrett's carcinogenesis by inhibiting NO production.

亚太地区胃食管反流病的处理共识:更新版

背景与目的:自从2004年亚太地区胃食管反流病(GERD)共识发表以来,更多关于GERD流行病学和处理的文献资料相继出现。有必要对这些资料进行循证综述,对共识作出更新。方法:由多学科专家组应用德尔菲(Delphi)法制定共识条文,提呈相关资料,并对证据质量、推荐力度和共识水平进行分级。结果:亚洲GERD发生率日益增加。其危险因素包括老年、男性、种族、家族史、社会经济地位高、体重指数增加和吸烟。对于有典型症状而无报警症状的患者,对质子泵抑制剂(PPI)试验有症状应答具有诊断意义。如PPI试验失败,停止治疗后pH监测结果阴性可排除GERD。窄带成像、胶囊内镜检查和无线pH监测的作用尚未明确。亚洲诊断策略的制定须考虑到并存的胃癌和消化性溃疡。减轻体质量和抬高床头可改善反流症状。PPIs是最有效的内科治疗手段。对于非糜烂性反流病(NERD)患者,按需治疗较为适宜。有慢性咳嗽、喉炎和典型GERD症状的患者在排除非GERD病因后,应予PPI每天两次治疗。如有经验丰富的外科医师,GERD患者可行胃底折叠术。除临床试验外,GERD不应采用内镜治疗。结论:新的诊断方法和内镜治疗的作用有待进一步研究阐明。亚洲GERD诊断策略的制定须考虑到并存的胃癌和消化性溃疡。PPIs仍为治疗的基石。

Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

AIM:To evaluate the efficacy of pegylated interferon α-2b(peg-IFNα-2b) plus ribavirin(RBV) therapy in Japanese patients with chronic hepatitis C(CHC) genotype Ib and a high viral load.METHODS:One hundred and twenty CHC patients(58.3% male) who received peg-IFNα-2b plus RBV therapy for 48 wk were enrolled.Sustained virological response(SVR) and clinical parameters were evaluated.RESULTS:One hundred(83.3%) of 120 patients completed 48 wk of treatment.53 patients(44.3%) achieved SVR.Early virological response(EVR) and end of treatment response(ETR) rates were 50% and 73.3%,respectively.The clinical parameters(SVR vs non-SVR) associated with SVR,ALT(108.4 IU/L vs 74.5 IU/L,P = 0.063),EVR(76.4% vs 16.4%,P < 0.0001),adherence to peg-IFN(≥ 80% of planned dose) at week 12(48.1% vs 13.6%,P = 0.00036),adherence to peg-IFN at week 48(54.7% vs 16.2%,P < 0.0001) and adherence to RBV at week 48(56.1% vs 32.1%,P = 0.0102) were determined using univariate analysis,and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis.In the older patient group(> 56 years),SVR in females was significantly lower than that in males(17% vs 50%,P = 0.0262).EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR.CONCLUSION:Peg-IFNα-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%.Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFNα-2b is important in improving the SVR rate.

Stimulatory effect on the transport mediated by organic anion transporting polypeptide 2B1

Drug-drug interaction(DDI)is one of causes of adverse drug events and can result in lifethreatening consequences.Organic anion-transporting polypeptide(OATP)2B1 is a major uptake transporter in the intestine and contributes to transport various clinically used therapeutic agents.The intestine has a high risk of DDI,because it has a special propensity to be exposed to a high concentration of drugs.Thus,understanding drug interaction mediated by OATP2B1 in the absorption process is important for the prevention of adverse drug events,including decrease in the therapeutic effect of co-administered drugs.Acute drug interaction occurs through the direct inhibitory effect on transporters,including OATP2B1.Moreover,some compounds such as clinically used drugs and food components have an acute stimulatory effect on transport of co-administered drugs by OATP2B1.This review summarizes the acute stimulatory effect on the transport mediated by OATP2B1 and discusses the mechanisms of the acute stimulatory effects of compounds.There are two types of acute stimulatory effects,substrate-independent and-dependent interactions on OATP2B1 function.The facilitating translocation of OATP2B1 to the plasma membrane is one of causes for the substrate-independent acute stimulatory effect.On the contrary,the substrate-dependent effect is based on the direct binding to the substrate-binding site or allosteric progesterone-binding site of OATP2B1.

Early effects of Lansoprazole orally disintegrating tablets on intragastric pH in CYP2C19 extensive metabolizers

AIM: To compare rabeprazole (RPZ; 10 mg) with Lansoprazole orally disintegrating tablets (LPZ; 30 mg OD) in terms of antisecretory activity and blood drug concentration after a single dose. METHODS: Eight H pylori-negative cytochrome P450 (CYP) 2C19 extensive metabolizers were assigned to receive a single oral dose of RPZ 10 mg or LPZ 30 mg OD. Twelve hour intragastric pH monitoring was perform- ed on the day of treatment. Blood samples were also collected after the administration of each drug. RESULTS: LPZ 30 mg OD induced a significantly earlier rise in blood drug concentration than RPZ 10 mg; consequently, LPZ 30 mg OD induced a significantly earlier rise in median pH in the third and fourth hours of the study. CONCLUSION: In H pylori-negative CYP2C19 extensive metabolizers, LPZ 30 mg OD induced a significantly faster inhibition of gastric acid secretion than RPZ 10 mg.

Osmotic pressure of serum and cerebrospinal fluid in patients with suspected neurological conditions

Interstitial fluid movement in the brain parenchyma has been suggested to contribute to sustaining the metabolism in brain parenchyma and maintaining the function of neurons and glial cells.The pulsatile hydrostatic pressure gradient may be one of the driving forces of this bulk flow.However,osmotic pressure- related factors have not been studied until now.In this prospective observational study,to elucidate the relationship between osmolality (mOsm/kg) in the serum and that in the cerebrospinal fluid (CSF),we simultaneously measured the serum and CSF osmolality of 179 subjects with suspected neurological conditions.Serum osmolality was 283.6 ± 6.5 mOsm/kg and CSF osmolality was 289.5 ± 6.6 mOsm/kg.Because the specific gravity of serum and CSF is known to be 1.024–1.028 and 1.004–1.007,respectively,the estimated average of osmolarity (mOsm/L) in the serum and CSF covered exactly the same range (i.e.,290.5–291.5 mOsm/L).There was strong correlation between CSF osmolality and serum osmolality,but the difference in osmolality between serum and CSF was not correlated with serum osmolality,serum electrolyte levels,protein levels,or quotient of albumin.In conclusion,CSF osmolarity was suggested to be equal to serum osmolarity.Osmolarity is not one of the driving forces of this bulk flow.Other factors such as hydrostatic pressure gradient should be used to explain the mechanism of bulk flow in the brain parenchyma.This study was approved by the Institutional Review Board of the Tohoku University Hospital (approval No.IRB No.2015-1-257) on July 29,2015.

Chronic exposure to excess iron promotes EMT and cancer via p53 loss in pancreatic cancer

Based on the evidence that hemochromatosis, an iron-overload disease, drives hepatocellular carcinoma, we hypothesized that chronic exposure to excess iron, either due to genetic or environmental causes, predisposes an individual to cancer. Using pancreatic cancer as our primary focus, we employed cell culture studies to interrogate the connection between excess iron and cancer, and combined in vitro and in vivo studies to explore the connection further. Ferric ammonium citrate was used as an exogenous iron source. Chronic exposure to excess iron induced epithelial-mesenchymal transition(EMT) in normal and cancer cell lines, loss of p53, and suppression of p53 transcriptional activity evidenced from decreased expression of p53 target genes(p21, cyclin D1, Bax, SLC7A11). To further extrapolate our cell culture data, we generated EL-KrasG12D( EL-Kras) mouse(pancreatic neoplastic mouse model) expressing Hfe+/+ and Hfe-/- genetic background. p53 target gene expression decreased in EL-Kras/Hfe-/- mouse pancreas compared to EL-Kras/Hfe+/+ mouse pancreas. Interestingly, the incidence of acinar-to-ductal metaplasia and cystic pancreatic neoplasms(CPN) decreased in EL-Kras/Hfe-/- mice, but the CPNs that did develop were larger in these mice than in EL-Kras/Hfe+/+ mice. In conclusion, these in vitro and in vivo studies support a potential role for chronic exposure to excess iron as a promoter of more aggressive disease via p53 loss and SLC7A11 upregulation within pancreatic epithelial cells.

Urinary type IV collagen excretion predicts an increased urinary albumin-to-creatinine ratio in normoalbuminuric patients with diabetes

Aims: We evaluated whether urinary excretion of type IV collagen (U-COL) may predict an increase in the urinary albumin-to-creatinine ratio (ACR) and what factors regulate U-COL in 145 normoalbuminuric patients with type 2 diabetes. Methods: We measured HbA1c, systolic blood pressure (SBP), urinary 8-hydroxydeoxyguanosine (8-OHdG) and monocyte chemoattractant protein (MCP)-1 at start of this study (Baseline), ACR and U-COL in addition to these measurements at one year later (Evaluation-1), and ACR and SBP after two years of the Evaluation-1 (Evaluation-2). The relationships were investigated between the increase of ACR and the U-COL. The effect of angiotensin receptor blockers (ARB) treatment on the correlations between U-COL and ACR at Evaluation-2 on one hand, and between U-COL and percent change of ACR on the other, was also analyzed. Furthermore, we investigated whether the increase in 8-OHdG and in MCP-1 in a year prior to the Evaluation-1 were risk factors of the rise in U-COL levels. Results: Both U-COL and SBP at Evaluation-1, but not ARB treatment, were independent risk factors for an increased ACR after 2 years. ARB treatment significantly suppressed the increase in ACR after 2 years in patients with higher U-COL excretion. The percentage changes in 8-OHdG (%8-OHdG) and MCP-1 (%MCP-1) in one year prior to Evaluation-1 measurements are independent risk factors for U-COL. HbA1c and SBP values one year prior to Evaluation-1 are independent risk factors not only for %8-OHdG but also, for baseline U-COL. The %8-OHdG is an independent risk factor for %MCP-1. Conclusions: U-COL may predict an increase in the ACR. The U-COL seems to be increased with oxidative stress and inflammation induced by past hyperglycemia.

Annual meeting of the Japan Traditional Chinese Medicine Association: Quantifying and objectifying traditional Chinese medicine

Five researchers reported on their studies to quantify and objectify traditional medicine at the symposium 'Verification of Traditional Chinese Medicine' during the 2016 annual meeting of the Japan Traditional Chinese Medicine Association.Takao Namiki reported on a methodology to quantify tongue diagnosis.Tetsuhiro Yoshino presented work on predictive prescribing two Kampo formulas for dysmenorrhea,Tangkuei and Peony Powder (Danggui Shaoyao San) and Cinnamon Twig and Poria Pill (Guizhi Fuling Wan).Koh Iwasaki presented work on validation of a questionnaire for assessing qi stagnation and Mitsuyuki Takamura reported on application of the questionnaire to evaluate the efficacy of Pinellia and Magnolia Bark Decoction (Banxia Houpo Tang).Kaoru Sakatani presented research on near-infrared spectroscopy as a diagnostic tool for wei bing,a concept of pre-symptomatic state in traditional Chinese medicine.

Highly Selective Molecular Recognition of Biologically Active Substances Using Liquid Phase Separation

The development of new chiral stationary phases has been very important in the a ccurate analysis of drug enantiomers and their metabolites in biological samples during drug discovery and development. New chiral stationary phases have been d eveloped using conalbumin and flavoprotein from chicken egg whites, which have b een applied to a broad range of drug enantiomers. The application and characteri zation of these two chiral columns for high-performance liquid chromatograp hy have been documented. Both specific and non-specific interactions, based on the silica gel surface and linker moiety, influenced retention and chiral separa tion of solutes. Interactions between drug enantiomers and proteins, as a pseudo chiral stationary phase, were investigated with affinity capillary electrophore sis, in order to avoid the effects of non-specific interactions. The chiral dis crimination region for ketoprofen on the flavoprotein surface was concluded to c onsist of an α-helix structure. Studies with chemically modified flavoprot ein indicated that two types of interactions at the chiral discrimination region were required for chiral separation: a π-π interaction between a tryptophan residue and the aromatic ring of ketoprofen, and an ionic interaction between th e carboxyl group of ketoprofen and an amino and carboxyl group of the protein. I n the bod y, drugs and biologically active substances having a carboxyl group have been kn own to transform various metabolites such as acyl glucuronide. The acyl adenylat e has also been noted as a chemically active intermediate of coenzyme A ligation . Both the acyl adenylate and the acyl glucuronide produced protein adducts by r eacting with nucleophilic groups such as amino groups on protein molecules. To c haracterize both active intermediates and protein adducts, analytical techniques conferring highly selective molecular recognition, such as high-performance li quid chromatography and mass spectrometry, were required.

Liver cell adenoma showing sequential alteration of radiological findings suggestive of well-differentiated hepatocellular carcinoma

A liver tumor 35 mm in diameter was found incidentally in a 40-year-old woman who had no history of liver diseases or the use of oral contraceptives.Radiological diagnostics showed the typical findings of liver cell adenoma(LCA).Dynamic computed tomography revealed that the tumor showed a homogenous enhancement in the arterial phase and almost the same enhancement as the surrounding liver parenchyma in the delayed phase.The tumor was found to contain fat on magnetic resonance imaging.A benign fat containing liver tumor was suggested.However,radiological findings altered,which caused us to suspect that a welldifferentiated hepatocellular carcinoma(HCC)containing fat was becoming dedifferentiated.Partial hepatectomy was performed and the pathological findings showed the typical findings of LCA.This case was an extremely rare LCA,which had no background of risk for LCA and developed the sequential alteration of the radiological findings to suspect well-differentiated HCC.

Compared with insulin glargine, insulin degludec narrows the day-to-day variability in the glucose-lowering effect rather than lowering blood glucose levels

Background: Changes in the day-to-day variability in the glucose-lowering effect of insulin [fluctuations of blood glucose levels (BG) seen during the same time period] that occur when insulin glargine (glargine) is replaced with insulin degludec (degludec) have not been sufficiently evaluated. Subjects: Five diabetics with unstable BG undergoing basal-bolus treatment using insulin glargine as basal insulin. Methods: Basal insulin was changed from glargine to same-dose degludec. The subjects’ HbA1c, glycoalbumin, and 1.5-anhydro-D-glucitol were measured before and after the switchover. Fasting blood glucose concentration (FBG) and predinner blood glucose concentration (PDBG) were measured continuously for 28 days immediately before the switchover, and 28 days immediately thereafter, to compare and evaluate 1) the changes in their mean values and standard deviations (SDs) before and after the switchover, and 2) the frequency of appearance of BG of over 180 mg/dL (BG ≥ 180) and under 70 mg/dL (BG Results: The levels of HbA1c, glycoalbumin, FBG’s mean value, SDs, BG ≥ 180 and BG Conclusion: The possibility was shown that degludec, to a greater extent than glargine, suppressed daily fluctuations of FBG and PDBG, suppressed the occurrence frequency of hyperglycemia and hypoglycemia, and exerted more steady hypoglycemic actions.