Publications by authors named "Naoki Nakaya"

213 Publications

HO-1 in lymph node metastasis predicted overall survival in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiation therapy.

Cancer Rep (Hoboken) 2021 Jul 15:e1477. Epub 2021 Jul 15.

Department of Pathology, Tohoku University Hospital, Sendai, Japan.

Background: Lymph node metastasis is one of the pivotal factors of the clinical outcomes of patients with esophageal cancer receiving neoadjuvant chemoradiation therapy (NACRT). Both the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway and heme oxygenase-1 (HO-1) are frequently upregulated in various human malignancies and associated with resistance to chemoradiation therapy, subsequently resulting in adverse clinical outcomes. However, the Nrf2 and HO-1 status in lymph node metastasis and their differences between primary and metastatic lesions are unknown.

Aims: To examine the levels of Nrf2 signaling proteins and HO-1 in primary and metastatic lesions of patients with esophageal squamous cell carcinoma using immunohistochemistry.

Methods And Results: We immunolocalized Nrf2 signaling proteins in 69 patients with lymph node metastases, who received NACRT with 5-fluorouracil and cisplatin before esophagectomy. We also compared the findings between primary and metastatic lesions. Residual lymph node metastases were detected in 30 patients and among them, both primary and metastatic lesions were available for evaluation in 25 patients. Subsequently, we correlated the results with patients' survival. Nrf2, HO-1, and the Ki-67 labeling index were all significantly lower in the patients with lymph node metastases than in those with primary tumors. Carcinoma cells with high HO-1 levels were significantly associated with pathological resistance to NACRT. These results suggested that overall and disease-free survival of esophageal squamous cell carcinoma were significantly associated with both pN2 and high HO-1 levels, respectively.

Conclusions: Protein expression in the Nrf2 pathway was significantly lower in patients with lymph node metastases than in those with primary lesions. HO-1 levels in lymph node metastases could be used to predict the eventual clinical outcome of patients with esophageal cancer receiving NACRT.
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http://dx.doi.org/10.1002/cnr2.1477DOI Listing
July 2021

Encouraging participation in colorectal cancer screening for people with schizophrenia: A randomized controlled trial.

Acta Psychiatr Scand 2021 Jul 9. Epub 2021 Jul 9.

Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, 693-8501, Japan.

Objective: We examined the efficacy of a case management approach to improve participation in colorectal cancer screening among people with schizophrenia.

Methods: This was a randomized, parallel group trial. We recruited outpatients with schizophrenia aged 40 years or over from two psychiatric hospitals in Japan. Participants were randomly assigned (1:1) to treatment as usual or case management intervention plus treatment as usual using a web-based system. Attending clinicians and participants were unmasked to the allocation. Case management included education and patient navigation for colorectal cancer screening using a fecal occult blood test. Treatment as usual included direct mail government recommendations. The primary endpoint was participation in colorectal cancer screening assessed using municipal records. We also assessed the secondary endpoint of participation in other cancer screenings (lung, gastric, breast, and cervical).

Results: Between June 3 and September 9, 2019, 172 eligible participants were randomly assigned to the case management plus treatment as usual group (n=86) or treatment as usual group (n=86). One participant was ineligible and another withdrew consent; both were excluded from analysis. A significantly higher proportion of participants received colorectal cancer screening in the case management plus treatment as usual group than in the treatment as usual group (40 [47.1%] of 85 participants vs. 10 [11.8%] of 85 participants, P<0.0001). The proportion of lung cancer screening also increased. No serious adverse events associated with the study intervention occurred.

Conclusion: The case management intervention to encourage participation in colorectal cancer screening was effective for patients with schizophrenia.
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http://dx.doi.org/10.1111/acps.13348DOI Listing
July 2021

The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project.

J Hum Genet 2021 Jul 8. Epub 2021 Jul 8.

Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.
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http://dx.doi.org/10.1038/s10038-021-00952-8DOI Listing
July 2021

Association between the combined fat mass and fat-free mass index and hypertension: The Tohoku Medical Megabank Community-based Cohort Study.

Clin Exp Hypertens 2021 Jul 6:1-12. Epub 2021 Jul 6.

Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.

Background: A  higher body fat percentage is associated with hypertension, even in non-obese individuals. The difference in body composition may be related to hypertension. The fat mass index (FMI) and fat-free mass index (FFMI) are proposed indicators of body composition. This study aimed to examine the relationship of a combination of FMI and FFMI with hypertension.

Methods: We conducted a cross-sectional study of 5,058 men and 11,842 women aged ≥ 20 years in the Miyagi Prefecture, northeastern Japan. The FMI and FFMI were calculated as the fat mass and fat-free mass divided by the height squared, respectively. The indices were classified into quartiles and combined into 16 groups. Hypertension was defined as casual blood pressure ≥ 140/90 mmHg and/or self-reported treatment for hypertension. Multivariable logistic regression models, adjusted for potential confounders, were used to assess the relationship of a combination of FMI and FFMI with hypertension.

Results: Higher FMI was associated with hypertension in most of the FFMI subgroups. Similarly, a higher FFMI was associated with hypertension in most of FMI subgroups. For men, the association between FFMI and hypertension in the lowest FMI group was not significant.

Conclusions: Reducing the FMI and FFMI may be important in preventing hypertension. For men, the relationship between the FFMI and hypertension in the lowest FMI group might be weak.
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http://dx.doi.org/10.1080/10641963.2021.1925681DOI Listing
July 2021

miRNA Changes in Retinal Ganglion Cells after Optic Nerve Crush and Glaucomatous Damage.

Cells 2021 Jun 22;10(7). Epub 2021 Jun 22.

Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.

The purpose of this study was to characterize the miRNA profile of purified retinal ganglion cells (RGC) from healthy and diseased rat retina. Diseased retina includes those after a traumatic optic nerve crush (ONC), and after ocular hypertension/glaucoma. Rats were separated into four groups: healthy/intact, 7 days after laser-induced ocular hypertension, 2 days after traumatic ONC, and 7 days after ONC. RGC were purified from rat retina using microbeads conjugated to CD90.1/Thy1. RNA were sequenced using Next Generation Sequencing. Over 100 miRNA were identified that were significantly different in diseased retina compared to healthy retina. Considerable differences were seen in the miRNA expression of RGC 7 days after ONC, whereas after 2 days, few changes were seen. The miRNA profiles of RGC 7 days after ONC and 7 days after ocular hypertension were similar, but discrete miRNA differences were still seen. Candidate mRNA showing different levels of expression after retinal injury were manipulated in RGC cultures using mimics/AntagomiRs. Of the five candidate miRNA identified and subsequently tested for therapeutic efficacy, miR-194 inhibitor and miR-664-2 inhibitor elicited significant RGC neuroprotection, whereas miR-181a mimic and miR-181d-5p mimic elicited significant RGC neuritogenesis.
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http://dx.doi.org/10.3390/cells10071564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305746PMC
June 2021

Validity and Reliability of the Japanese Version of the 12-item Self-administered World Health Organization Disability Assessment Schedule (WHODAS) 2.0 in Patients with Schizophrenia.

Acta Med Okayama 2021 Jun;75(3):315-322

Department of Psychiatry, Faculty of Medicine, Shimane University.

It is necessary to assess functional impairment when treating schizophrenia. The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) has been adopted as a measure of functional disability in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This study was a secondary analysis from a cross-sectional study of health-related behaviors among patients with schizophrenia. We examined the validity and reliability of the Japanese version of the 12-item WHODAS 2.0 when self-administered by such patients. Participants were 350 outpatients with schizophrenia from a psychiatric hospital. The standard six-factor structure of the WHODAS 2.0 showed a good fit for these participants. The Cronbach's alpha coefficient was 0.858, showing good internal consistency. The WHODAS 2.0 showed moderate correlations with the modified Global Assessment of Functioning and Kessler 6 scales (r=-0.434 and 0.555, respectively). The results of this study show that the Japanese version of the 12-item self-administered WHODAS 2.0 has good internal consistency and convergent validity among patients with schizophrenia. Further exploration of the usefulness of WHODAS 2.0 in clinical settings is needed.
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http://dx.doi.org/10.18926/AMO/62226DOI Listing
June 2021

Five-year Psychosocial Impact of Living in Post-Disaster Prefabricated Temporary Housing.

Disaster Med Public Health Prep 2021 Jun 23:1-31. Epub 2021 Jun 23.

Department of Disaster Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan.

Objective: This study aims to evaluate the long-term impact of living in post-disaster prefabricated temporary housing on social interaction activities and mental health status.

Methods: A total of 917 adult residents in a coastal town, whose residences were destroyed by the tsunami caused by the Great East Japan Earthquake (GEJE), were enrolled for the assessment held five years after the disaster. They answered questions about their experience and consequence of living in prefabricated temporary housing after the disaster. Their present scores on five types of self-reported measures regarding the psychosocial or psychiatric status and their present and recalled social interaction activities were cross-sectionally collected.

Results: A total of 587 (64.0%) participants had a history of living in prefabricated temporary housing, while the other 330 (36.0%) had not. The prevalence of social interaction activities significantly decreased after the GEJE. However, the experience of living in prefabricated temporary housing did not adversely affect the subsequent social interaction activities or mental conditions of the participants five years after the disaster.

Conclusions: Living in post-disaster prefabricated temporary housing may not negatively impact subsequent psychosocial conditions or social interaction activities five years later.
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http://dx.doi.org/10.1017/dmp.2021.212DOI Listing
June 2021

Does a combination treatment of repetitive transcranial magnetic stimulation and occupational therapy improve upper limb muscle paralysis equally in patients with chronic stroke caused by cerebral hemorrhage and infarction?: A retrospective cohort study.

Medicine (Baltimore) 2021 Jun;100(24):e26339

Department of Rehabilitation Medicine, The Jikei University School of Medicine, Tokyo.

Abstract: The clinical presentation of stroke is usually more severe in patients with intracerebral hemorrhage (ICH) than in those with cerebral infarction (CI); recovery of stroke-related muscle paralysis is influenced and limited by the type of stroke. To date, many patients have been treated by neurorehabilitation; however, the changes in the recovery of motor paralysis depending on the type of stroke, ICH or CI, have not been established. This study aimed to determine this difference in improvement of upper extremity paralysis using 2-week in-hospital NovEl intervention Using Repetitive transcranial magnetic stimulation combined with Occupational therapy (NEURO).We scrutinized the medical records of all patients with poststroke (ICH or CI) upper extremity muscle paralysis using Fugl-Meyer assessments (FMAs) who had been admitted to 6 hospitals between March 2010 and December 2018 for rehabilitation treatment. This was a multiinstitutional, open-label, retrospective cohort study without control patients. We evaluated the effects of NEURO on patients with CI and ICH by dividing them into 2 groups according to the type of stroke, after adjustment for age, sex, dominant hand, affected hand side, time since stroke, and prediction of recovery capacity in the upper extremity.The study included 1716 (CI [n = 876] and ICH [n = 840]) patients who had undergone at least 2 FMAs and had experienced stroke at least 6 months before. The type of stroke had no effect on the outcomes (changes in the FMA-upper extremity score, F[4,14.0] = 2.05, P = .09, partial η2 = 0.01). Patients from all 5 groups equally benefited from the treatment (improvement in FMA scores) according to the sensitivity analysis-stratified analysis (F = 0.08 to 1.94, P > .16, partial η2 < 0.001).We conclude that NEURO can be recommended for chronic stroke patients irrespective of the type of stroke.
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http://dx.doi.org/10.1097/MD.0000000000026339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213260PMC
June 2021

[Role of Palliative Care in the Introduction of Chemotherapy in Patients with Poor Performance Status].

Gan To Kagaku Ryoho 2021 May;48(5):735-737

Dept. of Medical Oncology, Ageo Central General Hospital.

Chemotherapy for patients with poor performance status(PS)is not recommended because it increases the risk of death and shortens their survival. We report on 3 cases in which palliative care improved PS and enabled chemotherapy, resulting in a prolonged prognosis. Case 1 involves a 57‒year‒old woman with multiple lung, liver, and bone metastases from breast cancer who was administered celecoxib and oxycodone. She received Mohs paste therapy. Her PS improved from 3 to 2, and paclitaxel and trastuzumab were started; however, the patient died on day 861. Case 2 involves a 53‒year‒old woman with multiple lymph node metastases from carcinoma of an unknown primary cause. She was administered oxycodone, loxoprofen, and dexamethasone. Her PS improved from 4 to 3. The biopsy of her bone marrow showed diffuse large B‒cell lymphoma. The patient is still alive, 6 years and 10 months after the introduction of R‒CHOP. In case 3, a 57‒year‒old man with multiple bone metastases from small cell lung cancer was administered loxoprofen and betamethasone. His PS improved from 4 to 3. Etoposide and carboplatin were administered to him, but the patient died on day 692. Palliative care may enable the introduction of chemotherapy and consequently improve prognosis.
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May 2021

Association between the social isolation and depressive symptoms after the great East Japan earthquake: findings from the baseline survey of the TMM CommCohort study.

BMC Public Health 2021 05 15;21(1):925. Epub 2021 May 15.

Iwate Tohoku Medical Megabank Organization, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Shiwa, Iwate, 028-3694, Japan.

Background: Social isolation and mental health issues have become a severe problem in disaster areas in the Great East Japan Earthquake. This study examined whether the combination of the house damage and social isolation or the combination of the death of family members and social isolation is associated with depressive symptoms among survivors using the baseline study data of the Tohoku Medical Megabank Project Community-Based Cohort Study (TMM CommCohort Study).

Methods: We used cross-sectional data from a baseline survey of 48,958 participants (18,423 males, 30,535 females; aged 60.1 ± 11.2 years) to examine the association between social isolation measured by the Lubben social network scale 6 (LSNS-6) and depressive symptoms measured by the Center for Epidemiological Studies-Depressive Scale (CES-D). The presence of social isolation and depressive symptoms was defined by an LSNS-6 score of < 12 and a CES-D score of ≥16, respectively. We performed a logistic regression analysis to determine the multivariable-adjusted odds ratio (95% confidence interval) [AOR (95% CI)] for depressive symptoms according to sex in the social isolation in comparison to without social isolation, and the associations of the combination of the house damage or the death of family members and social isolation and depressive symptoms.

Results: Social isolation was significantly associated with depressive symptoms (males: OR = 1.87; 95% CI = 1.72-2.04, females: OR = 2.13; 95% CI = 2.00-2.26). Both males and females respondents with severe house damage and social isolation had a greater risk of depressive symptoms in comparison to those with an undamaged house and without social isolation (males: OR = 3.40; 95% CI = 2.73-4.24, females: OR = 2.92; 95% CI = 2.46-3.46). The risk of depressive symptoms was also higher in both males and females respondents with the death of family members and social isolation in comparison to those without the death of family members and without social isolation (males: OR = 2.18; 95% CI = 1.90-2.50, females: OR = 2.60; 95% CI = 2.35-2.88).

Conclusion: The findings suggested that a combination of social isolation and severe house damage and the death of family members caused by a large-scale natural disaster was associated with a higher risk of depressive symptoms although the interaction was not statistically significant.
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http://dx.doi.org/10.1186/s12889-021-10896-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122535PMC
May 2021

Effect of internet-based attention bias modification on the anxiety of Japanese workers: A randomized controlled trial.

J Occup Health 2021 Jan;63(1):e12229

Department of Health Sciences, Saitama Prefectural University, Saitama, Japan.

Objectives: This study comprised a randomized controlled trial to examine the effect of internet-based attention bias modification (iABM) on reducing workers' anxiety.

Methods: In total, 300 eligible participants were randomized according to sex and age; 180 were assigned to the intervention group and 120 to the control group. The word stimuli used in the iABM included eight positive words and eight neutral words. Participants were instructed to indicate the positive word's position as quickly and accurately as possible by tapping one of the two directions on display. The intervention included five sessions per participant over 1 month, resulting in a total of 600 trials. The main outcome measure was the total state anxiety score of the State-Trait Anxiety Inventory (STAI).

Results: There was no significant difference in the net change in STAI scores between the intervention and control groups. The mean reaction time of the fifth session was significantly shorter than the mean reaction time of the first session. Furthermore, although there was no effect on the index of effect size Δ, the paired t-test showed a significant decrease in the anxiety score.

Conclusions: The iABM intervention in this study did not enhance the amelioration of workers' anxiety when compared with the control condition.
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http://dx.doi.org/10.1002/1348-9585.12229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088281PMC
January 2021

Risk of metastatic recurrence after endoscopic resection for esophageal squamous cell carcinoma invading into the muscularis mucosa or submucosa: a multicenter retrospective study.

J Gastroenterol 2021 Jul 21;56(7):620-632. Epub 2021 Apr 21.

National University Corporation Hirosaki University, Hirosaki, Japan.

Background: We aimed to elucidate the risk of metastatic recurrence after endoscopic resection (ER) without additional treatment for esophageal squamous cell carcinomas (ESCCs) with tumor invasion into the muscularis mucosa (pT1a-MM) or submucosa (T1b-SM).

Methods: We retrospectively enrolled patients with pT1a-MM/pT1b-SM ESCC after ER at 21 institutions in Japan between 2006 and 2017. We compared metastatic recurrence between patients with and without additional treatment, stratified into category A (pT1a-MM with negative lymphovascular invasion [LVI] and vertical margin [VM]), B (tumor invasion into the submucosa ≤ 200 µm [pT1b-SM1] with negative LVI and VM), and C (others). Subsequently, using multivariate Cox analysis, we evaluated risk factors for metastatic recurrence after ER without additional treatment.

Results: We enrolled 593 patients, and metastatic recurrence occurred in 38 patients. Metastatic recurrence after additional treatment was significantly lower than that after no additional treatment in category C (9.1% vs. 23.6% in 5 years, p = 0.001), whereas no significant difference was noted in categories A (0.0% vs. 2.6%) and B (0.0% vs. 4.3%). In patients without additional treatment after ER, risk factors for metastatic recurrence were lymphatic invasion (hazard ratio [HR], 5.61), positive VM (HR, 4.55), and tumor invasion into the submucosa > 200 μm (HR, 3.25), and, but near half of the patients with metastatic recurrence had no further recurrence after salvage treatment, resulting in excellent 5-year disease-specific survival in categories A (99.6%) and B (100.0%).

Conclusions: Closed follow-up with no additional treatment may be an acceptable option after ER in pT1a-MM/pT1b-SM1 ESCC with negative LVI and VM.
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http://dx.doi.org/10.1007/s00535-021-01787-yDOI Listing
July 2021

Prevention of delayed bleeding with vonoprazan in upper gastrointestinal endoscopic treatment.

J Gastroenterol 2021 Jul 19;56(7):640-650. Epub 2021 Apr 19.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Background: Delayed bleeding is the major adverse event in upper gastrointestinal endoscopic treatment (UGET). We aimed to investigate the efficacy of vonoprazan, which is the novel strong antisecretory agent, to reduce the risk for delayed bleeding in comparison with proton pump inhibitors (PPIs) in UGET.

Methods: This retrospective population-based cohort study used the Diagnosis Procedure Combination database in Japan. We included patients on vonoprazan or PPI in UGET between 2014 and 2019. The primary outcome was delayed bleeding. We conducted propensity score matching to balance the comparison groups, and logistic regression analyses to compare the bleeding outcomes.

Results: We enrolled 124,422 patients, in which 34,822 and 89,600 were prescribed with vonoprazan and PPI, respectively. After propensity score matching, the risk for delayed bleeding was lower in vonoprazan than in PPI (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.71-0.80), consistent with sensitivity analysis results. In the subgroup analyses of seven UGET procedures, vonoprazan was significantly advantageous in esophageal endoscopic submucosal dissection (E-ESD) (OR, 0.71; 95% CI, 0.54-0.94) and gastroduodenal endoscopic submucosal dissection (GD-ESD) (OR, 0.70; 95% CI, 0.65-0.75), although correction for multiple testing of the outcome data removed the significance in E-ESD. These results were also consistent with sensitivity analysis results. In the five other procedures, no significant advantage was found.

Conclusions: This nationwide study found that, compared with PPI, vonoprazan can reduce delayed bleeding with approximately 30% in GD-ESD. Vonoprazan has the possibility to become a new treatment method for preventing delayed bleeding in this procedure.
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http://dx.doi.org/10.1007/s00535-021-01781-4DOI Listing
July 2021

Impacts of the urinary sodium-to-potassium ratio, sleep efficiency, and conventional risk factors on home hypertension in a general Japanese population.

Hypertens Res 2021 Jul 15;44(7):858-865. Epub 2021 Feb 15.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Recently, a high urinary sodium-to-potassium (Na/K) ratio and reduced sleep efficiency, in addition to conventional risk factors (obesity and excess alcohol intake), have been identified as risk factors for hypertension. We estimated the population attributable fraction (PAF) for home hypertension due to these risk factors in a general Japanese population. We conducted a cross-sectional study including 1384 participants (393 men and 991 women) to estimate the odds ratio (OR) and 95% confidence interval (CI) for the presence of any of the conventional risk factors using multivariable logistic regression analyses. The models were adjusted for sex, age, smoking status, and log-transformed average daily steps. We also estimated the OR and 95% CI for the presence of any of the overall risk factors. Furthermore, we calculated the PAF due to these risk factors. The results showed that the prevalence of home hypertension was 39.0% (540/1384). The presence of any of the conventional risk factors, as well as any of the overall risk factors, was significantly associated with an increased prevalence of hypertension (OR 2.80, 95% CI 2.15-3.65; OR 2.50, 95% CI 1.93-3.22, respectively). The PAF for hypertension due to the presence of any of the conventional risk factors and the PAF due to the presence of any of the overall risk factors were 30.2% and 39.0%, respectively. In conclusion, the impact of the overall risk factors, including the urinary Na/K ratio and sleep efficiency, on home hypertension was higher than that of conventional risk factors alone. The management of the urinary Na/K ratio and sleep efficiency as well as conventional risk factors might be important in the management of blood pressure.
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http://dx.doi.org/10.1038/s41440-021-00628-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255210PMC
July 2021

Predictors of Early and Late Mortality after Endoscopic Resection for Esophageal Squamous Cell Carcinoma.

Tohoku J Exp Med 2021 01;253(1):29-39

Division of Gastroenterology, Tohoku University Graduate School of Medicine.

In esophageal squamous cell carcinoma (ESCC) comprising 90% of cases with esophageal cancer, endoscopic resection (ER) is recommended for patients with negligible risk of ESCC-related mortality. In fact, a main cause of death in patients underwent ER is not ESCC. We thus aimed to clarify the predictors for early and late mortality among patients underwent ER of ESCC between 2005 and 2018 at our institution. In this retrospective cohort study, we investigated the prognosis and predictors of early and late mortality with the cut-off value of 3 years. We enrolled 407 patients with a median 69 months follow-up. The 5-year overall survival and disease-specific survival, an indicator of ESCC-related mortality, were 83.4% and 98.4%, respectively. In multivariate Cox analyses, Eastern Cooperative Oncology Group performance status (ECOG-PS), consisting of six grades by a patient's level of activity, ≥ 2 was a predictor for early and late morality [hazard ratio (HR), 7.21 (P = 0.007) and 15.62 (P = 0.021), respectively]. Charlson comorbidity index (CCI), which is an index for predicting mortality by comorbid conditions, ≥ 2 was also a predictor for both mortality [HR, 2.97 (P = 0.017) and 1.90 (P = 0.019), respectively]. However, age was a predictor only for late mortality [HR, 3.08 (P = 0.010) in 80-84 years and 8.38 (P < 0.001) in ≥ 85 years]. Considering the predictive ability for early mortality, we propose that ECOG-PS and/or CCI are better indices compared with age in deciding treatment strategy after ER for ESCC.
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http://dx.doi.org/10.1620/tjem.253.29DOI Listing
January 2021

Combined associations of liver enzymes and obesity with diabetes mellitus prevalence: The Tohoku Medical Megabank Community-based Cohort Study.

J Epidemiol 2020 Dec 26. Epub 2020 Dec 26.

Tohoku Medical Megabank Organization, Tohoku University.

Background: Alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) are enzymes associated with diabetes mellitus (DM) prevalence. However, limited information is available regarding the association of liver enzymes and DM consistently present in obese and non-obese individuals. We examined whether the combination of ALT and GGT enzymes is associated with the prevalence of DM regardless of obesity in a general Japanese population.

Methods: We conducted a cross-sectional study of 62,786 participants aged ≥20 years who lived in Miyagi and Iwate, Japan. We divided all the participants into eight groups according to the ALT level (low: <30 IU/L and high: ≥30 IU/L), GGT level (low: <50 IU/L and high: ≥50 IU/L), and the presence of obesity. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression analysis, adjusting for potential confounders, to determine associations of the combination of ALT and GGT levels and obesity with DM prevalence.

Results: Overall, 6,008 participants (9.6%) had DM. Compared to non-obese individuals with low ALT and GGT levels, the participants with high ALT and GGT levels had high ORs for DM in both obese (OR 4.06; 95% CI, 3.61-4.56) and non-obese groups (OR 2.19; 95% CI, 1.89-2.52). The obese group had high ORs for DM, even at low ALT and GGT levels.

Conclusion: High ALT and GGT levels are associated with DM prevalence in obese and non-obese participants. This finding suggests that correcting ALT and GGT levels and controlling obesity are important for the prevention of DM.
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http://dx.doi.org/10.2188/jea.JE20200384DOI Listing
December 2020

[Advanced Gastric Cancer with Tumor Shrinkage Persisting after the Discontinuation of Nivolumab-A Case Report].

Gan To Kagaku Ryoho 2020 Dec;47(12):1715-1717

Dept. of Medical Oncology, Ageo Central General Hospital.

The patient was a 65-year-old man with advanced gastric cancer, cT4bN3aM1, cStage Ⅳ. The SOX therapy was administered as the primary treatment but discontinued after 9 courses because of disease progression. The PTX plus RAM therapy was then administered for 1 courses as the secondary treatment but discontinued because of the development of peritoneal dissemination, increased number of ascites, and increased number of lymph node metastases. The nivolumab(NIV)therapy was initiated as the tertiary treatment, but the patient complained of fatigue and diplopia after 2 courses. Ptosis was observed, and transaminase and creatine kinase levels were elevated. Electrocardiography showed complete right bundle branch block. The patient showed immune-related adverse events and was diagnosed with myocarditis and myasthenia gravis due to NIV. Consequently, systemic steroids were administered. Although 2 course of CPT-11 was administered as the fourth-line treatment, the treatment was discontinued upon the patient's request. Ten months after the discontinuation of chemotherapy, the disease showed no progression. The patient is being followed-up as an outpatient. Here, we reported a case of gastric cancer with tumor shrinkage after the discontinuation of NIV.
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December 2020

Correction to: a Cross-sectional Study of Attention Bias for Facial Expression Stimulation in Patients with Stroke at the Convalescence Stage.

Int J Behav Med 2021 Jun;28(3):401

Department of Rehabilitation, Graduate School of Health Sciences, Saitama Prefectural University, Saitama, Japan.

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http://dx.doi.org/10.1007/s12529-020-09948-8DOI Listing
June 2021

A Cross-sectional Study of Attention Bias for Facial Expression Stimulation in Patients with Stroke at the Convalescence Stage.

Int J Behav Med 2021 Aug 1;28(4):511-522. Epub 2020 Dec 1.

Department of Rehabilitation, Graduate School of Health Sciences, Saitama Prefectural University, Saitama, Japan.

Background: Post-stroke depression increases the likelihood of adverse physical symptoms. Attentional bias (AB) for negative stimuli is important in depression onset, maintenance, and remission. Stroke is more likely in older adults, who can have reduced cognitive function. Individuals with mild cognitive impairment (MCI) can have delayed reaction times (RTs). We hypothesized that RT to select neutral facial expression is affected by depressive symptoms and cognitive function in patients with stroke.

Methods: This study analyzed 61 patients with stroke. Beck Depression Inventory-Second Edition (BDI-II) and Profile of Mood States (short version) scores were determined. Task stimuli comprised eight pairs of facial expressions containing affective (angry) and neutral faces. AB was measured as the RT to select the neutral face in two simultaneously presented images using attention bias modification (ABM) software. Patients were grouped according to depressive symptoms using BDI-II scores. Between-subject factors of depressive symptoms and cognitive function were determined by ANCOVA.

Results: No significant interaction was found between depressive symptoms and cognitive function on RT. There was a main effect of cognitive function, but not depressive symptoms. In patients with hemiparesis and depressive symptoms, RT was significantly shorter in patients without MCI compared with patients with MCI.

Conclusions: People with stroke and elevated depression symptoms with hemiparesis but without MCI quickly selected neutral facial expressions from neutral and aversive expressions, and thus do not need ABM to escape aversive stimuli. ABM in response to aversive stimuli may be useful in evaluating negative emotions in individuals with post-stroke depression without MCI.
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http://dx.doi.org/10.1007/s12529-020-09940-2DOI Listing
August 2021

Impact of the Great East Japan Earthquake on the Employment Status and Mental Health Conditions of Affected Coastal Communities.

Int J Environ Res Public Health 2020 11 3;17(21). Epub 2020 Nov 3.

Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-Machi, Aoba-ku, Sendai 980-8573, Japan.

The Great East Japan Earthquake devasted the old community in coastal areas characterized by primary industry. The number of unemployed people increased from 150,000 to 190,000 after the earthquake. All of the adult residents of Shichigahama (18 years old or older), located in the coastal area of the Miyagi prefecture, whose houses were totally or majorly damaged, were recruited for a survey conducted in October 2011. All of the residents who responded with written informed consent were included in this study. Among 904 individuals who had a job before the Great East Japan Earthquake, 19% became unemployed. Concerning gender and age, 9% of young men, 34% of elderly men, 21% of young women, and 49% of elderly women became unemployed. Concerning the type of industry, 38%, 15%, and 16% of people who had belonged to the primary, secondary, and tertiary industries, respectively, before the disaster became unemployed. Those who became unemployed exhibited a significantly higher risk of insomnia compared to those who maintained jobs. The study pointed out the severe impact of the Great East Japan Earthquake on populations who had belonged to the primary industry, especially among elderly women, and its effect on sleep conditions.
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http://dx.doi.org/10.3390/ijerph17218130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662503PMC
November 2020

Reproducibility and reliability of performance indicators to evaluate the therapeutic effectiveness of biofeedback therapy after elbow surgery: An observational case series.

Medicine (Baltimore) 2020 Aug;99(34):e21889

Department of Rehabilitation, Graduate School of Health Sciences, Saitama Prefectural University, Saitama.

Electromyographic biofeedback (EMG-BF) therapy provides information on the state of contraction of the targeted muscles and relaxation of their antagonists, which can facilitate early active range of motion (RoM) after elbow surgery. Our aim in this study was to calculate the minimum detectable change (MDC) during EMG-BF therapy, initiated in the early postoperative period after elbow surgery.This study is an observational case series. EMG-BF of muscle contraction and relaxation was provided during active elbow flexion and extension exercises. Patients completed 3 sets of 10 trials each of flexion and extension over 4 weeks. The total range of flexion-extension motion and scores on the Japanese Society for Surgery of the Hand version of the disability of the arm, shoulder, and hand questionnaire and the Japanese version of the Patient-Rated Elbow Evaluation were obtained at baseline and weekly during the 4-week intervention period. A prediction formula was developed from the time-series data obtained during the intervention period, using the least-squares method. The estimated value was calculated by removing the slope from the prediction formula and adding the initial scores to residuals between the measured scores and predicted scores individually. Systematic error, MDC at the 95th percentile cutoff (MDC95), repeatability of the measures, and the change from the baseline to each time-point of intervention were assessed.The MDC95 was obtained for all 3 outcome measures and the range of values was as follows: RoM, 8.3° to 22.5°; Japanese version of the Patient-Rated Elbow Evaluation score, 17.6 to 30.6 points; and disability of the arm, shoulder, and hand questionnaire subscale: disability and symptoms score, 14.2 to 22.9 points.The efficacy of EMG-BF after elbow surgery was reflected in earlier initiation of elbow RoM after surgery and improvement in patient-reported upper limb function scores. The calculated MDC95 cut-offs could be used as reference values to assess the therapeutic effects of EMG-BF in individuals.
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http://dx.doi.org/10.1097/MD.0000000000021889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447474PMC
August 2020

Sodium/potassium ratio change was associated with blood pressure change: possibility of population approach for sodium/potassium ratio reduction in health checkup.

Hypertens Res 2021 Feb 17;44(2):225-231. Epub 2020 Aug 17.

Division of Personalized Prevention and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Recently, the sodium (Na)/potassium (K) ratio was reported to be associated with blood pressure (BP). A Na/K ratio self-monitoring device using spot urine was established recently. Here, we assessed whether the urinary Na/K ratio change measured using the Na/K device was associated with BP change in a health checkup setting. We targeted 12,890 participants who attended the health checkup in Tome City, Miyagi between 2017 and 2018. Tome City introduced urinary Na/K ratio measurements during health checkups since 2017. For each year, we compared the baseline characteristics according to the urinary Na/K ratio and BP level. We assessed the relationship between change in urinary Na/K ratio and BP change using multiple regression analyses adjusted for age, sex, and change in body mass index (BMI) and alcohol intake. The average urinary Na/K ratio was significantly lower in 2018 than in 2017 (5.4 ± 3.0 to 4.9 ± 2.2, P < 0.01). The systolic BP of the participants in 2018 (130.9 ± 17.4 mmHg) was lower than that in 2017 (132.1 ± 17.9 mmHg). Moreover, the change in systolic BP and diastolic BP was positively associated with the change in urinary Na/K ratio. In conclusion, the association of the change in urinary Na/K ratio with hypertension and changes in systolic and diastolic BP can be explained by a change in alcohol intake, BMI, and urinary Na/K ratio. Therefore, measuring the urinary Na/K ratio in community settings is a potential population approach for counteracting hypertension.
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http://dx.doi.org/10.1038/s41440-020-00536-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815510PMC
February 2021

Low birth weight and abnormal pre-pregnancy body mass index were at higher risk for hypertensive disorders of pregnancy.

Pregnancy Hypertens 2020 Oct 5;22:119-125. Epub 2020 Aug 5.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address:

Low birth weight is known to be associated with hypertension, cardiovascular disease and hypertensive disorders of pregnancy (HDP); however, this association might vary by race/ethnicity. This study aimed to clarify the association between women's own birth weight and their subsequent risk for HDP in a Japanese population, in combination with pre-pregnancy body mass index (BMI). We conducted a cohort study as part of the Tohoku Medical Megabank Birth and Three-Generation Cohort Study in Miyagi, Japan. Our study's population included 4810 women. A multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (aOR) and the 95% confidence interval (CI) of the women's own birth weight for HDP, in the combination categories of birth weight and pre-pregnancy BMI. As a result, the group with a low birth weight of <2500 g had a significant association with HDP (the aOR, 1.50; 95% CI, 1.02-2.21). In the subtype analysis, the odds ratio for only preeclampsia was significantly increased in the low birth weight group (aOR, 3.37; 95% CI, 1.84-6.16). In the group with a low birth weight, the prevalence of HDP was higher in both the underweight and overweight groups. In conclusion, there was a significant association between low birth weight and subsequent HDP in Japanese women. Furthermore, a significant association with HDP was found for women born with a low birth weight who were underweight or overweight as adults. Maintaining a normal weight may be effective for preventing HDP even if a woman was born small.
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http://dx.doi.org/10.1016/j.preghy.2020.08.001DOI Listing
October 2020

Impaired Mucosal Integrity in Proximal Esophagus Is Involved in Development of Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease.

Digestion 2021 12;102(3):404-414. Epub 2020 Aug 12.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background And Objective: Weakly acidic reflux reaching to the proximal esophagus is closely related to the perception of gastroesophageal reflux in patients with nonerosive reflux disease despite treatment with a proton pump inhibitor (PPI). However, little is known about the involvement of the patients' mucosal integrity of the proximal esophagus.

Methods: We recruited 15 symptomatic nonerosive gastroesophageal reflux disease (GERD) patients with a positive symptom index despite PPI treatment and 11 healthy asymptomatic volunteers as controls. The biopsy specimens obtained from the proximal and distal esophagus were applied to a mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) against a pH 4 weak acid. The esophageal biopsy samples were subjected to quantitative real-time PCR and immunohistochemical analysis.

Results: In the proximal esophagus, the weak acid exposure reduced the TEER in the PPI-refractory patients compared to that in the controls. The frequency of the reflux extending to the proximal esophagus had a significant correlation with the reduction in the proximal esophageal TEER in the patients. The reduced TEER in the proximal esophagus was accompanied by an increase in IL-8 and IL-1β mRNA and a decrease in occludin mRNA levels. The proximal esophageal mucosa in the patients presented infiltration of CD3-positive lymphocytes and an increased expression of solute carrier organic anion transporter family member 2A1 (SLCO2A1), a passage gate of reflux symptom-evoking molecules.

Conclusions: The reflux perception is related to an impairment of the proximal esophageal mucosal integrity in patients with nonerosive reflux disease despite PPI.
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http://dx.doi.org/10.1159/000508661DOI Listing
August 2020

The Impact of Health Consciousness on the Association Between Walking Durations and Mental Health Conditions After a Disaster: a Cross-Sectional Study.

Sports Med Open 2020 Jul 16;6(1):30. Epub 2020 Jul 16.

Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-Machi, Aoba-ku, Sendai, 980-8573, Japan.

Background: In communities affected by a disaster, walking can be a feasible form of physical exercise to improve physical and mental health conditions. However, there is limited evidence to support relationships between walking habits and mental health conditions in post-disaster settings. Cross-sectional epidemiological data obtained from a questionnaire survey (conducted in October 2017) of a community affected by the 2011 Great East Japan Earthquake (GEJE) was analyzed to evaluate the relationships.

Methods: Participants included individuals over 20 years of age (N = 718) from Shichigahama town in Miyagi prefecture, whose houses were significantly damaged by the GEJE. Their mental health conditions were assessed by the Kessler Psychological Distress Scale (K6), the Center for Epidemiologic Studies Depression Scale (CES-D), and the Impact of Event Scale-Revised (IES-R). Additionally, the questionnaire asked the participants spent duration walking on average and their walking purpose by the following items: (1) longer than 60 min per day, (2) between 30 and 60 min per day, or (3) less than 30 min per day, and whether they walked to maintain healthy living habits (health-conscious walkers) or merely for transportation without considering health consequences (non-health-conscious walkers). These information and mental health indicators were analyzed using analysis of covariance (ANCOVA).

Results: Among the three walking duration groups of health-conscious walkers, there were significant differences in CES-D and K6 scores (p = 0.01 and p = 0.04), but not in IES-R scores, considering age, gender, and alcohol drinking habits as covariates. CES-D score was significantly higher among short walkers (p = 0.004). Among the three walking duration groups of non-health-conscious walkers, there were significant differences in avoidance symptoms, the subdomain of IES-R (p = 0.01), but not in CES-D, K6, and total IES-R scores, considering the variants.

Conclusion: Our study suggests that walking durations may positively affect mood, but not PTSR, only when walking is performed with the purpose of maintaining healthy living habits. Walking durations were negatively associated with avoidance symptoms among non-health-conscious walkers in the community affected by the GEJE, indicating that the disaster may have had a long-lasting impact on walking habits.
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http://dx.doi.org/10.1186/s40798-020-00259-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366311PMC
July 2020

Trends in smoking rates among individuals with serious psychological distress: Analysis of data from a Japanese national survey, 2007-2016.

Psychiatry Res 2020 09 12;291:113225. Epub 2020 Jun 12.

Department of Psychiatry, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. Electronic address:

To determine whether the downward trend in the smoking rate over time in Japan differs between individuals with and without serious psychological distress (SPD), we used nationally representative data sets from the 2007, 2010, 2013, and 2016 Comprehensive Survey of Living Conditions of Japan. SPD was defined as a score ≥ 13 on the six-item Kessler Psychological Distress Scale. We conducted multivariate logistic regression analyses including the interaction terms between SPD and survey year. A total 187,685 participants were included. The interaction terms between SPD and survey year among men were significant for 2010 and 2016 but not for 2013. Among women, the interaction terms between SPD and survey year were not significant for any year. In conclusion, we confirmed that the gap in the rate of smoking between men with SPD and those without SPD decreased from 2007 to 2016. Among women, the gap in the smoking rate between those with SPD and those without SPD remained unchanged. Our findings suggest a need for specific support strategies including pharmacological interventions, especially for women smokers with SPD. Further studies are warranted to identify factors contributing to these sex differences.
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http://dx.doi.org/10.1016/j.psychres.2020.113225DOI Listing
September 2020

Viral delivery of multiple miRNAs promotes retinal ganglion cell survival and functional preservation after optic nerve crush injury.

Exp Eye Res 2020 08 20;197:108071. Epub 2020 Jun 20.

Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address:

Bone marrow mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEV) but not fibroblast sEV provide retinal ganglion cell (RGC) neuroprotection both in vitro and in vivo, with miRNAs playing an essential role. More than 40 miRNAs were more abundant in BMSC-sEV than in fibroblast-sEV. The purpose of this study was to test the in vitro and in vivo neuroprotective and axogenic properties of six candidate miRNAs (miR-26a, miR-17, miR-30c-2, miR-92a, miR-292, and miR-182) that were more abundant in BMSC-sEV than in fibroblast-sEV. Adeno-associated virus 2 (AAV2) expressing a combination of three of the above candidate miRNAs were added to heterogenous adult rat retinal cultures or intravitreally injected into rat eyes one week before optic nerve crush (ONC) injury. Survival and neuritogenesis of βIII-tubulin RGCs was assessed in vitro, as well as the survival of RBPMS RGCs and regeneration of their axons in vivo. Retinal nerve fiber layer thickness (RNFL) was measured to assess axonal density whereas positive scotopic threshold response electroretinography amplitudes provided a readout of RGC function. Qualitative retinal expression of PTEN, a target of several of the above miRNAs, was used to confirm successful miRNA activity. AAV2 reliably transduced RGCs in vitro and in vivo. Viral delivery of miRNAs in vitro showed a trend towards neuroprotection but remained insignificant. Delivery of selected combinations of miRNAs (miR-17-5p, miR-30c-2 and miR-92a; miR-92a, miR-292 and miR-182) before ONC provided significant therapeutic benefits according to the above measurable endpoints. However, no single miRNA appeared to be responsible for the effects observed, whilst positive effects observed appeared to coincide with successful qualitative reduction in PTEN immunofluorescence in the retina. Viral delivery of miRNAs provides a possible neuroprotective strategy for injured RGCs that is conducive to therapeutic manipulation.
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http://dx.doi.org/10.1016/j.exer.2020.108071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484142PMC
August 2020

Prediction model of bleeding after endoscopic submucosal dissection for early gastric cancer: BEST-J score.

Gut 2021 Mar 4;70(3):476-484. Epub 2020 Jun 4.

Division of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Objective: Bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is a frequent adverse event after ESD. We aimed to develop and externally validate a clinically useful prediction model (BEST-J score: Bleeding after ESD Trend from Japan) for bleeding after ESD for EGC.

Design: This retrospective study enrolled patients who underwent ESD for EGC. Patients in the derivation cohort (n=8291) were recruited from 25 institutions, and patients in the external validation cohort (n=2029) were recruited from eight institutions in other areas. In the derivation cohort, weighted points were assigned to predictors of bleeding determined in the multivariate logistic regression analysis and a prediction model was established. External validation of the model was conducted to analyse discrimination and calibration.

Results: A prediction model comprised 10 variables (warfarin, direct oral anticoagulant, chronic kidney disease with haemodialysis, P2Y12 receptor antagonist, aspirin, cilostazol, tumour size >30 mm, lower-third in tumour location, presence of multiple tumours and interruption of each kind of antithrombotic agents). The rates of bleeding after ESD at low-risk (0 to 1 points), intermediate-risk (2 points), high-risk (3 to 4 points) and very high-risk (≥5 points) were 2.8%, 6.1%, 11.4% and 29.7%, respectively. In the external validation cohort, the model showed moderately good discrimination, with a -statistic of 0.70 (95% CI, 0.64 to 0.76), and good calibration (calibration-in-the-large, 0.05; calibration slope, 1.01).

Conclusions: In this nationwide multicentre study, we derived and externally validated a prediction model for bleeding after ESD. This model may be a good clinical decision-making support tool for ESD in patients with EGC.
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http://dx.doi.org/10.1136/gutjnl-2019-319926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873424PMC
March 2021
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