Seven days triple therapy for eradication of Helicobacter pylori does not alter the disease activity of patients with inflammatory bowel disease

BACKGROUND/AIMS: The influences of Helicobacter pylori eradication therapy on the disease course of inflammatory bowel disease (IBD) are still unclear. We therefore conducted a multicenter, retrospective cohort study to evaluate the safety of H. pylori eradication therapy for IBD patients. METHODS: IBD patients with H. pylori eradication from 2005 to 2015 (eradication group) and control patients (non-eradication group; 2 paired IBD patients without H. pylori eradication matched with each eradicated patient) were included. IBD exacerbation (increased/additional IBD drug or IBD-associated hospitalization/surgery) and disease improvement based on the physicians’ global assessment were investigated at baseline, and at 2 and 6 months after eradication or observation. RESULTS: A total of 429 IBD (378 ulcerative colitis, 51 Crohn’s disease) patients, comprising 144 patients in the eradication group and 285 patients in the non-eradication group, were enrolled at 25 institutions. IBD exacerbation was comparable between groups (eradication group: 8.3% at 2 months [odds ratio, 1.76; 95% confidence interval, 0.78–3.92; P=0.170], 11.8% at 6 months [odds ratio, 1.60; 95% confidence interval, 0.81–3.11; P=0.172]). Based on the physicians’ global assessment at 2 months, none of the patients in the eradication group improved, whereas 3.2% of the patients in the non-eradication group improved (P=0.019). Multivariate analysis revealed that active disease at baseline, but not H. pylori eradication, was an independent factor for IBD exacerbation during 2 months’ observation period. The overall eradication rate was 84.0%–comparable to previous reports in non-IBD patients. CONCLUSIONS: H. pylori eradication therapy does not alter the short-term disease activity of IBD.

NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

BACKGROUND/AIMS: Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). METHODS: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. RESULTS: None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. CONCLUSIONS: Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

Prevalence of Irritable Bowel Syndrome–like Symptoms in Japanese Patients with Inactive Inflammatory Bowel Disease

BACKGROUND/AIMS: Few studies are available that have investigated the risk factors for overlapping irritable bowel syndrome (IBS)-like symptoms in patients with inactive inflammatory bowel disease (IBD). The present study has 3 objectives: (1) to assess the prevalence of IBS-like symptoms in Japanese patients with inactive IBD using Rome III criteria, (2) to examine the relationship of IBS-like symptoms to health related quality of life (HR-QOL), and (3) to investigate associations for developing IBS-like symptoms in patients with inactive IBD. METHODS: IBS-like symptoms were evaluated using the Rome III questionnaire for functional gastrointestinal disorders. HR-QOL and hospital anxiety and depression scale were evaluated. RESULTS: IBS-like symptoms were found in 17.5% (7/40) of patients with inactive ulcerative colitis, 27.1% (29/107) of patients with inactive Crohn’s disease (CD), and 5.3% (23/438) of healthy control subjects. The QOL level was significantly lower and anxiety score was significantly higher in inactive CD patients with IBS-like symptoms than in those without such symptoms (P = 0.003, P = 0.009). Use of anti-anxiety drugs was associated with the presence of IBS symptoms (P = 0.045). HR-QOL score was lower and anxiety score was higher in patients with inactive ulcerative colitis, but the difference was not statistically significant. CONCLUSIONS: The prevalence of IBS-like symptoms in inactive IBD patients was significantly higher than in healthy controls. Inactive CD patients with IBS-like symptoms has low QOL and anxiety; suggesting that anxiety may be associated with symptom development in such patients.

A blended learning program providing core competency in clinical research / 医学教育

  In Japan, few health care professionals have a basic understanding（core competency）of the design of clinical research and statistical analysis. We developed a blended distance–learning program comprising face–to–face lectures with e–learning for busy health care professionals who work in the clinical settings to achieve core competency in clinical research. The purpose of this study was to examine the educational effects of this program.<br>1）Four months after the end of the program, 64％ of the participants had started to conduct clinical research.<br>2）This program may increase the number of research colleagues that can discuss clinical research.<br>3）This program could enhance the confidence（self–efficacy）of health care professionals in clinical research.

Adsorptive Granulocyte/Monocyte Apheresis for the Maintenance of Remission in Patients with Ulcerative Colitis: A Prospective Randomized, Double Blind, Sham-Controlled Clinical Trial

BACKGROUND/AIMS: Weekly granulocyte/monocyte adsorption (GMA) to deplete elevated and activated leucocytes should serve as a non-pharmacological intervention to induce remission in patients with ulcerative colitis (UC). This trial assessed the efficacy of monthly GMA as a maintenance therapy to suppress UC relapse. METHODS: Thirty-three corticosteroid refractory patients with active UC received 10 weekly GMA sessions as a remission induction therapy. They were then randomized to receive one GMA session every 4 weeks (True, n=11), extracorporeal circulation without the GMA column every 4 weeks (Sham, n=11), or no additional intervention (Control, n=11). The primary endpoint was the rate of avoiding relapse (AR) over 48 weeks. RESULTS: At week 48, the AR rates in the True, Sham, and Control groups were 40.0%, 9.1%, and 18.2%, respectively. All patients were steroid-free, but no statistically significant difference was seen among the three arms. However, in patients who could taper their prednisolone dose to <20 mg/day during the remission induction therapy, the AR in the True group was better than in the Sham (p<0.03) or Control (p<0.05) groups. CONCLUSIONS: Monthly GMA may potentially prevent UC relapse in patients who have achieved remission through weekly GMA, especially in patients on <20 mg/day PSL at the start of the maintenance therapy.

Qualitative research for investigating the factors that facilitate or interfere / 医学教育

Mentorship in academic medicine in the United States and Europe has been recognized as an effective system for increasing a mentee's research productivity, career success, and ability to obtain research grants. Therefore, to promote mentoring programs in Japanese academic medicine, it is important to investigate factors that facilitate or interfere with mentoring.<br>1)We interviewed 12 physicians who have performed clinical research under existing mentoring programs in Japan and asked them about factors that, in their experience, had facilitated or interfered with mentoring.<br>2)We qualitatively analyzed transcripts of interviews to identify these factors.<br>3)Factors identified as facilitating mentoring were: appropriate evaluation of a mentee's research skill, knowledge of a mentee's career goals, mutual communication between mentor and mentee, and the presence of senior researchers close to a mentee.<br>4)Factors identified as interfering with mentoring were: the busyness of a mentor, a mentee's concerns about giving offense by consulting the mentor about trivial matters, and the hierarchically organized social relationship in which the mentor is superior and the mentee is inferior.<br>5)Assessment of the mentoring process and education programs for mentors were expected to be necessary measures to promote mentoring programs.

Infliximab Therapy Impacts the Peripheral Immune System of Immunomodulator and Corticosteroid Naive Patients with Crohn's Disease

BACKGROUND/AIMS: Infliximab (IFX), an antibody to tumor necrosis factor, (TNF)-alpha has efficacy in treating Crohn's disease (CD). However, knowledge of the potential effects of IFX on patients' immune profiles is lacking. The purpose of this study was to reveal the immunological effects of IFX. METHODS: Twenty-two patients with a CD activity index (CDAI) of 194.2+/-92.9 and an average duration of disease of 3.26 months and 21 healthy controls were included. Patients were to have their first IFX remission induction therapy with 3 infusions (5 mg/kg) at weeks 0, 2, and 6. Oral 5-aminosalicylic acid was the only ongoing medication in the patient population. Blood samples at baseline, 12 hours after the first infusion and at week 14 were labeled with anti-CD4/CD25 antibodies for immunohistochemical measurement of regulatory T-cells (Treg). Serum cytokines and chemokines were measured by suspension array and ELISA. RESULTS: CDAI significantly decreased prior to the second IFX infusion (p<0.001). Clinical remission rates were 77.3% and 91% by the second and third infusions, respectively. At baseline, interleukin (IL)-6 (p<0.03), IL-8 (p<0.03), IL-10 (p=0.050), IL-13 (p<0.01), transforming growth factor-beta1 (p<0.01), and 'regulated on activation, normal T cell expressed and secreted' (RANTES) (p<0.01) were elevated in patients. After the initial IFX infusion, TNF-alpha (p<0.04), IL-6 (p<0.03), interferon (IFN)-gamma (p<0.04), IFN-gamma-inducible protein-10 (p<0.01), monocyte chemoattractant protein-1 (p<0.01), macrophage inflammatory protein-1beta (p<0.01), and RANTES (p<0.01) were decreased. IFX infusion was associated with an increase in Treg (p<0.01) and a decrease in the Th1 (IFN-gamma)/Th2 (IL-4) ratio (p<0.03). CONCLUSIONS: IFX use was associated with restoration of the Th1/Th2 balance after a single infusion and seemed to promote induction of naive Th0 lymphocytes to Treg. This knowledge should have clinical relevance.

Challenges in the conduct of clinical research / 医学教育

The promotion of clinical research in Japan requires the establishment of a formal and systematic education and training program for clinicians to ensure they become effective clinician investigators. The first of its kind in Japan, a formal 1-year masters-degree-level training program (MCR course) was started at Kyoto University School of Medicine and Public Health. The first 28 students graduated in 2008, with most returning to their original clinical institutions. <br>1) As follow-up, we conducted a self-administered questionnaire survey of all 28 graduates (response rate, 86%) concerning the current status of clinical research and problems encountered at their institutions.<br>2) Almost 40% of respondents (n=24) reported &quot;no time&quot; or &quot;no research collaborators&quot; for clinical research.<br>3) Twenty respondents (83%) have attempted to promote clinical research at their hospital or workplace, but only 1 has received institutional support.<br>4) Over half of the respondents (54%) would like to be working in both clinical research and clinical practice at their hospital in the future (10-year timescale). Forty-two percent of respondents had a concrete image of the clinical researcher's career path. <br>5) Although open to improvement, the MCR program presents a concrete model for the education of clinical researchers. These findings suggest that promoting the conduct of clinical research requires the implementation of a support system and adjustment of personal and physical infrastructure.

A survey of hospital managers' interest in conducting clinical research and clinical research education / 医学教育

Background: In Japan, although clinicians have been extremely interested in conducting clinical research, the shortage of clinical researchers is a serious problem. Therefore, it is important to explore barriers to conducting clinical research.1) We mailed a cross-sectional survey to hospital managers asking about their interest in and barriers to conducting clinical research and training clinical researchers at their hospitals.2) Of 810 eligible hospital managers, 301 completed questionnaires (response rate: 37.2%).3) The managers of university hospitals and national medical centers were more interested in conducting clinical research than were managers of other hospitals.4) Furthermore, 60.6% of managers of university hospital and 18.8% of managers of other hospitals reported the need to employ physicians who specialized in clinical research. However, given public research grants, about 50% of hospital managers were willing to employ research residents.5) Our results suggest there are still barriers to conducting clinical research, such as a lack of time set aside for clinicians and specialists to teach clinical research. A substantial strategy is needed to address the shortage of clinical researchers in Japan.

A survey of clinicians' interest in performing clinical research and in education for clinical research / 医学教育

Background: Because of a severe shortage of clinical researchers in Japan, training clinical physicians to perform clinical research is an important issue in medical education. Although education has started to provide a foundation for clinical research, it is unclear whether clinicians, who should play a central role in a clinical research, are interested in performing clinical research and participating in a training program for clinical research.1) We performed a cross-sectional Internet survey to determine the interest of clinicians' interest in performing a clinical research and participating in a clinical-research training program.2) A total of 2176 clinicians were sent emails requesting their participation in this survey, and 310 responded (response rate, 14.6%). Eighty-five percent of the respondents were interested in conducting clinical research, and 78% were willing to participate in a clinical-research training program.3) Most respondents were willing to participate in a training program as part of an educational seminar or a training course after a few years of clinical practice. The respondents desired an educational system that would allow them to learn about clinical research while continuing their clinical practice.4) Although the rate of willingness to participate in a training program was highest (90%) among respondents who wanted to earn a doctorate, the rates were also high among those who did not want to earn a doctorate (76%) and those who had already earned a doctorate (74%).5) An educational system for clinical research should allow graduate schools to play leading role in training and should be flexible enough for clinicians who do not want to earn a doctorate.