Diverticulosis, Adenomas, and Cancer in the Colon: A Systematic Review and Meta-Analysis of Endoscopic Studies.

GOALS: To perform a systematic review and meta-analysis of endoscopic studies to evaluate an association between diverticulosis and neoplastic lesions in the colon. BACKGROUND: Some epidemiological observations suggest an association between diverticulosis and adenoma/cancer in the colon. However, an increased risk of colon neoplastic lesions in diverticulosis subjects was found to be increased in some studies, but not in others, puzzling data interpretation. STUDY: From the retrieved studies, prevalence of adenomas, advanced adenomas, cancer or neoplasia (advanced adenoma or cancer) was compared between subjects with or without diverticulosis, and comparisons in subgroups were also performed. RESULTS: Data of 26 studies with a total of 419,623 patients were eventually considered, including 27,092 patients with diverticulosis. Data analysis found a statistically significant association between diverticulosis and adenomas (OR: 1.88; 95% CI: 1.50-2.25), advanced adenomas (OR: 1.49; 95% CI: 1.02-2.16), and neoplasia (OR: 1.50; 95% CI: 1.11-2.02), but not with cancer alone (OR: 1.01; 95% CI: 0.70-1.47). These associations were confirmed in the subgroup analyses, by considering Caucasian and Asian populations, prospective and retrospective studies, screening or symptoms settings, and between good or fair quality studies. CONCLUSIONS: A statistically significant association between diverticulosis and adenomas, advanced adenomas and neoplasia, but not with cancer alone was found. However, the strength of association seems to be insufficient to impact on clinical practice.

[Non-distinctive abdominal pain: is it diverticular disease or not?] / Unklare Bauchschmerzen: Wann ist es eine Divertikelkrankheit und wann nicht?

Acute abdominal pain may relate to specific organ systems and needs an interdisciplinary approach with close collaboration between internal and surgical disciplines. Main objective is to shorten the diagnostic work-up between the beginning of the symptoms and their therapy. After clarifying of the five w-questions: when, how, how long, why, and where, abdominal ultrasound, ECG, laboratory diagnostics and early application of computed tomography should be performed.For the most part, chronic abdominal pain is caused by disorders of the gut-brain-axis such as the irritable bowel syndrome. Because of the synaptic plasticity, the processing of pain is dynamic and cannot be related to a single organ system. This problem is obvious in patients with irritable bowel syndrome and colonic diverticula, which may be interpreted as symptomatic uncomplicated diverticular disease (SUDD, type 3a). However, a reliable clinical differentiation between both groups is not possible. The establishment of SUDD (type 3a) considerable widened the application area of mesalazine.

Colonic Diverticulosis at Colonoscopy in Africa: A Systematic Review and Meta-Analysis of Pooled Estimates.

INTRODUCTION: There is need to ascertain any epidemiologic shift of diverticulosis among Africans with traditionally high fiber diet consumption patterns and rare diverticulosis prevalence. METHODS: We systematically searched PubMed, Scopus, Cochrane Library, African Journal Online (AJOL), and Google Scholar. Eligibility criteria included full-text observational and experimental human colonoscopy studies on asymptomatic and symptomatic African population from 1985 to 2022. Case reports, conference abstracts, dissertations, systematic reviews, and studies lacking colonoscopy findings were excluded. NIH quality assessment tool for observational cohort and cross-sectional studies was used to assess risk of bias. Meta-analysis was performed using the random-effect model. Heterogeneity was assessed using inconsistency (I2) statistics. RESULTS: Thirty studies were included. Pooled prevalence rate of colonic diverticulosis in the last decade (2012-2022) has increased to 9.7% (95% CI 6.5-13.4; I2 = 97.3%) from 3.5% (95% CI 1.4-6.4; I2 = 62.7%). The highest regional prevalence rate was in West African studies at 11.3% (95% CI 7.6-14.9; I2 = 96.2%). Proportion of individuals with diverticulosis ≥50 years and male sex were 86.9% (95% CI 80.5-92.1) and 65.2% (95% CI 55.0-74.8), respectively. The left colon had the highest diverticulosis frequency (37% [148/400]). Bleeding/inflammation complications were sparingly detected (OR 0.2 [95% CI 0.03-0.75; p < 0.0001]). CONCLUSION: An increasing utilization of colonoscopy revealed approximately a threefold increase in the prevalence rate of colonic diverticulosis in Africa. This pathology was most common in males aged >50. Left colon was predominantly affected. Further studies are needed to demonstrate the effect of westernization of diet.

Diverticular Inflammation and Complication Assessment classification, CODA score and fecal calprotectin in clinical assessment of patients with diverticular disease: A decision curve analysis.

BACKGROUND AND AIMS: The Diverticular Inflammation and Complication Assessment (DICA) classification and the Combined Overview on Diverticular Assessment (CODA) were found to be effective in predicting the outcomes of Diverticular Disease (DD). We ascertain whether fecal calprotectin (FC) can further aid in improving risk stratification. METHODS: A three-year international, multicentre, prospective cohort study was conducted involving 43 Gastroenterology and Endoscopy centres. Survival methods for censored observations were used to estimate the risk of acute diverticulitis (AD) in newly diagnosed DD patients according to basal FC, DICA, and CODA. The net benefit of management strategies based on DICA, CODA and FC in addition to CODA was assessed with decision curve analysis, which incorporates the harms and benefits of using a prognostic model for clinical decisions. RESULTS: At the first diagnosis of diverticulosis/DD, 871 participants underwent FC measurement. FC was associated with the risk of AD at 3 years (HR per each base 10 logarithm increase: 3.29; 95% confidence interval, 2.13-5.10) and showed moderate discrimination (c-statistic: 0.685; 0.614-0.756). DICA and CODA were more accurate predictors of AD than FC. However, FC showed high discrimination capacity to predict AD at 3 months, which was not maintained at longer follow-up times. The decision curve analysis comparing the combination of FC and CODA with CODA alone did not clearly indicate a larger net benefit of one strategy over the other. CONCLUSIONS: FC measurement could be used as a complementary tool to assess the immediate risk of AD. In all other cases, treatment strategies based on the CODA score alone should be recommended.

The connection between diverticulosis and colonic superficial neoplastic lesions in patients who underwent screening colonoscopy.

PURPOSE: If could be a potential pathophysiological connection between colonic diverticula and colonic superficial neoplastic lesions, beyond the shared risk factors, has been a subject of debate in the last years. This study tries to evaluate the association between diverticulosis and colonic neoplastic lesions. METHODS: This is a cross-sectional study including asymptomatic patients who underwent a screening colonoscopy (patients with a positive fecal occult blood test under the regional program of colorectal cancer (CRC) screening), surveillance after polypectomy resection, or familiarity (first-degree relatives) between 2020 and 2021 to evaluate the association between diverticula and colonic polyps. A multivariate analysis with multiple logistic regression and odds ratio (OR) to study the independent association between adenomas and adenocarcinomas was performed. RESULTS: One thousand five hundred one patients were included. A statistically significant association between adenomas or CRC alone and colonic diverticula was found (p = 0.045). On a multivariate analysis of demographic (age, gender) and clinical parameters (familiarity for diverticula and adenoma/CRC), only age was significantly associated with the development of colorectal adenomas or cancer (OR 1.05, 95% CI 1.03-1.07, p < 0.0001). CONCLUSIONS: This study showed a statistically significant association between diverticula and colonic adenomas. However, it is impossible to establish a cause-effect relationship due to the intrinsic characteristics of this study design. A study with a prospective design including both patients with diverticulosis and without colonic diverticula aimed at establishing the incidence of adenoma and CRC could help to answer this relevant clinical question, since a potential association could indicate the need for closer endoscopic surveillance.

Cardiovascular Risk Factors and Physical Fitness Among Subjects with Asymptomatic Colonic Diverticulosis.

BACKGROUND: The association between diverticular disease and atherosclerotic cardiovascular disease (ASCVD) has been demonstrated previously, mainly in symptomatic subjects. AIMS: To evaluate 10 years cardiovascular risk, exercise performance and association to ASCVD among subjects with asymptomatic diverticulosis. METHODS: A retrospective cross-sectional cohort of self-referred participants in a medical screening program, who underwent a screening colonoscopy. Demographics, clinical and laboratory variables, ASCVD score, and metabolic equivalents (METs) during treadmill stress test were compared between subjects with and without diverticulosis as diagnosed on screening colonoscopy. RESULTS: 4586 participants underwent screening colonoscopy; 799 (17.4%) had diverticulosis. Among 50-69 yo participants, diverticulosis subjects had a higher ASCVD score compared to non-diverticulosis subjects. Exercise performance was comparable between the groups, across all age groups. Using logistic regression analysis, advanced age group (50-59 yo Adjusted odds ratio (AOR) [95% confidence interval (CI)] 2.57 (1.52-4.34), p < 0.001; 60-69 yo, AOR 2.87 (2.09-3.95), p < 0.001; ≥ 70 yo AOR 4.81 (3.23-7.15), p < 0.001; compared to < 50 yo age group), smoking [AOR 1.27 (1.05-1.55), p = 0.016], HTN [AOR 1.27 (1.03-1.56), p = 0.022], obesity [AOR 1.36 (1.06-1.74), p = 0.014] and male sex [AOR 1.29 (1.02-1.64), p = 0.036] were associated with diverticular detection during screening colonoscopy. Among males, achieving METs score ≥ 10 was inversely associated with diverticular detection during screening colonoscopy [AOR 0.64 (0.43-0.95), p = 0.027]. CONCLUSIONS: Ten years probability for ASCVD estimated by the ASCVD score is higher among subjects with asymptomatic diverticulosis compared to subjects without diverticulosis. Improved exercise performance is demonstrated for the first time to correlate with decreased probability for diverticular disease in screening colonoscopy.

Diverticulosis Is Associated With Internal Hemorrhoids on Colonoscopy: Possible Clues to Etiology.

Hemorrhoids are a common but poorly understood gastrointestinal condition.1 Bowel habits and fiber consumption are frequently cited as risk factors for hemorrhoids, but research has been inconclusive.2 Recent genome-wide association studies (GWAS) have suggested an association between diverticular disease and hemorrhoids.3 We sought to investigate the association between colonic diverticulosis and internal hemorrhoids to validate the prediction from the GWAS.

Prevalence of and Risk Factors for Incidental Colonic Diverticulosis.

INTRODUCTION: The true prevalence and pathogenesis of diverticulosis is poorly understood. Risk factors for diverticulosis are presently unclear, with most clinicians attributing its development to years of chronic constipation. Previous studies have been limited by their failure to include young, ethnically diverse patient populations. METHODS: Patients who presented to the emergency department of our hospital from January-September 2019 and underwent abdominal computerized tomography (CT) scan for the evaluation of appendicitis were included. CT's were reviewed for the presence of diverticulosis. Risk factors for diverticulosis were determined for two age groups: >40 and ≤ 40. RESULTS: A total of 359 patients were included in the study. The median age was 38.57.1% were male. 81.6% were Hispanic. 43.5% had colonic diverticulosis on CT. 198 patients (55.1%) were ≤ age 40. The rate of diverticulosis in this group was 35.3% (n = 70). Those with diverticulosis were not significantly older (median age 29 versus 27, P = 0.061) but had a higher median body mass index (BMI) (28.4 versus 25.3, P = 0.003) compared to those without diverticulosis. On multivariate analysis, no characteristics were associated with the presence of diverticulosis for this group. Over age 40, 53.4% of patients (n = 86) had diverticulosis. Patients with diverticulosis were more likely to be Hispanic (95.3% versus 73.3%, P ≤ 0.001), less likely to be Asian (2.4% versus 16.0%, P = 0.004), had a higher median BMI (28.7 versus 25.5, P ≤ 0.001), and were more likely to use alcohol (30.2% versus 14.7%, P = 0.024) than those without diverticulosis. On multivariate analysis, characteristics associated with the presence of diverticulosis were BMI >30 (odds ratio OR 2.22, 95% confidence interval CI 1.03-4.80), Hispanic ethnicity (OR 10.05, 95% CI 1.74-58.26), and alcohol use (OR 3.44, 95% CI 1.26-9.39). CONCLUSIONS: There was a higher rate of asymptomatic diverticulosis in the <40 cohort than previously reported in the literature. Obesity, alcohol use, and Hispanic ethnicity were associated with the presence of diverticulosis in patients > age 40, but no risk factors for diverticulosis were identified for patients ≤ age 40, suggesting that diverticular pathogenesis may differ by age. Constipation was not a risk factor for diverticulosis in either age group. The data regarding the prevalence of diverticulosis in Hispanic patients is lacking and should be the focus of future inquiry.

Pathophysiology of Diverticular Disease: From Diverticula Formation to Symptom Generation.

Diverticular disease is a common clinical problem, particularly in industrialized countries. In most cases, colonic diverticula remain asymptomatic throughout life and sometimes are found incidentally during colonic imaging in colorectal cancer screening programs in otherwise healthy subjects. Nonetheless, roughly 25% of patients bearing colonic diverticula develop clinical manifestations. Abdominal symptoms associated with diverticula in the absence of inflammation or complications are termed symptomatic uncomplicated diverticular disease (SUDD). The pathophysiology of diverticular disease as well as the mechanisms involved in the shift from an asymptomatic condition to a symptomatic one is still poorly understood. It is accepted that both genetic factors and environment, as well as intestinal microenvironment alterations, have a role in diverticula development and in the different phenotypic expressions of diverticular disease. In the present review, we will summarize the up-to-date knowledge on the pathophysiology of diverticula and their different clinical setting, including diverticulosis and SUDD.

Efficacy of Early Video Capsule Endoscopy for Acute Overt Lower Gastrointestinal Bleeding with Colonic Diverticulosis: A Prospective Observational Study.

BACKGROUND/AIMS: Although most patients with presumptive colonic diverticular bleeding (CDB) do not undergo a small bowel investigation in clinical practice, no prospective study supports this management. We evaluated the utility of early small bowel capsule endoscopy (CE) after negative colonoscopy results. METHODS: This prospective study evaluated the diagnostic yield of early small bowel CE (≤3 days from visit) for consecutive patients with acute-onset hematochezia, when colonoscopy found colonic diverticulosis but did not identify the definite bleeding source (n = 51; presumptive CDB). As a matched control for comparing clinical outcomes, presumptive CDB patients without CE (n = 51) were retrospectively extracted. RESULTS: On CE for the prospective cohort, the rates of total positive findings, P2 findings (high bleeding potential according to the P classification), and blood pooling in the colon were 57%, 12% (ulceration, 8%; angioectasia, 4%), and 24%, respectively. The rates of rebleeding within 30 and 365 days were 16% and 29% in the prospective cohort with CE, respectively, and were not significantly different from those in the retrospective cohort without CE (10% and 25%, respectively). In addition, thromboembolism and mortality within 30 and 365 days were not significantly different between those with and without CE. CONCLUSION: Early CE detected a suspected small bowel bleeding source in 12% of acute-onset presumptive CDB patients but did not significantly improve major clinical outcomes. Therefore, routine CE is unnecessary for presumptive CDB patients after colonoscopy (UMIN000026676).

[Diagnosis and Treatment of Colonic Diverticular Disease].

Colonic diverticulosis is one of the most common conditions of the digestive system and patients generally remain asymptomatic. However, about 20% of patients develop symptomatic diverticular disease such as acute diverticulitis or diverticular hemorrhage, and these have become a huge burden on healthcare systems worldwide. Recent understanding of the pathophysiology of diverticulosis and diverticular disease suggests the role of multiple factors including genetic and environment. Based on this understanding, a preventive strategy to reduce the risk factors of diverticulosis and diverticular disease is highly recommended. The diagnosis of the acute diverticulitis relies on imaging modalities such as an abdominal-pelvic CT scan together with symptoms and signs. Treatment of diverticular disease should be individualized and include modification of lifestyle, use of antibiotics, and surgery. Recent guidelines recommend pursuing less aggressive treatment for patients with acute diverticulitis. This review will provide an overview of both the existing and evolving understanding regarding colonic diverticulosis and diverticular disease and can help clinicians in the management of their patients with diverticular disease.

Prognostic performance of the 'DICA' endoscopic classification and the 'CODA' score in predicting clinical outcomes of diverticular disease: an international, multicentre, prospective cohort study.

OBJECTIVE: To investigate the predictive value of the Diverticular Inflammation and Complication Assessment (DICA) classification and to develop and validate a combined endoscopic-clinical score predicting clinical outcomes of diverticulosis, named Combined Overview on Diverticular Assessment (CODA). DESIGN: A multicentre, prospective, international cohort study. SETTING: 43 gastroenterology and endoscopy centres located in Europe and South America. PARTICIPANTS: 2215 patients (2198 completing the study) at the first diagnosis of diverticulosis/diverticular disease were enrolled. Patients were scored according to DICA classifications. INTERVENTIONS: A 3-year follow-up was performed. MAIN OUTCOME MEASURES: To predict the acute diverticulitis and the surgery according to DICA classification. Survival methods for censored observation were used to develop and validate a novel combined endoscopic-clinical score for predicting diverticulitis and surgery (CODA score). RESULTS: The 3-year cumulative probability of diverticulitis and surgery was of 3.3% (95% CI 2.5% to 4.5%) in DICA 1, 11.6% (95% CI 9.2% to 14.5%) in DICA 2 and 22.0% (95% CI 17.2% to 28.0%) in DICA 3 (p<0.001), and 0.15% (95% CI 0.04% to 0.59%) in DICA 1, 3.0% (95% CI 1.9% to 4.7%) in DICA 2 and 11.0% (95% CI 7.5% to 16.0%) in DICA 3 (p<0.001), respectively. The 3-year cumulative probability of diverticulitis and surgery was ≤4%, and ≤0.7% in CODA A; <10% and <2.5% in CODA B; >10% and >2.5% in CODA C, respectively. The CODA score showed optimal discrimination capacity in predicting the risk of surgery in the development (c-statistic: 0.829; 95% CI 0.811 to 0.846) and validation cohort (c-statistic: 0.943; 95% CI 0.905 to 0.981). CONCLUSIONS: DICA classification has a significant role in predicting the risk of diverticulitis and surgery in patients with diverticulosis, which is significantly enhanced by the CODA score. TRIAL REGISTRATION NUMBER: NCT02758860.

Enfermedad diverticular de colon no complicada sintomática: revisión sistemática del diagnóstico y tratamiento / Management of symptomatic uncomplicated diverticular colon disease: A systematic review of diagnosis and treatment

La enfermedad diverticular de colon (EDC) no complicada sintomática (EDCNCS) es una patología con elevada prevalencia en nuestro medio que afecta de manera importante la calidad de vida de los pacientes que la padecen. Los cambios recientes en la comprensión de la historia natural de esta enfermedad y los avances tecnológicos y farmacológicos han incrementado sustancialmente las opciones disponibles tanto para su diagnóstico como para el tratamiento. Sin embargo, el consenso que existe en cuanto al uso de estas opciones es pobre y en algunas ocasiones carente de evidencia científica. El objetivo de esta revisión sistemática es esclarecer la evidencia científica existente y fundamentar la utilización de las diferentes opciones diagnósticas y terapéuticas en la EDCNCS, comparando las ventajas y desventajas entre estas, para sugerir finalmente un algoritmo diagnóstico-terapéutico para esta patología y al mismo tiempo proponer nuevas preguntas de investigación.(AU)

Symptomatic uncomplicated diverticular colon disease (SUDCD) is a highly prevalent disease in our setting, which significantly affects the quality of life of patients. Recent changes in understanding the natural history of this disease and technological and pharmacological advances have increased the available options for both diagnosis and treatment. However, consensus regarding the use of these options is scarce and sometimes lacks scientific evidence. The objective of this systematic review is to clarify the existing scientific evidence and analyse the use of the different diagnostic and therapeutic options for SUDCD, comparing their advantages and disadvantages, to finally suggest a diagnostic-therapeutic algorithm for this pathology and, at the same time, propose new research questions.(AU)

The Interrelationship Among Non-Alcoholic Fatty Liver Disease, Colonic Diverticulosis and Metabolic Syndrome.

Non-alcoholic fatty liver disease and colonic diverticulosis are widespread, obesity-related diseases. It has recently become clear that non-alcoholic fatty liver disease is a systemic disease and may play a key role in metabolic syndrome; therefore, the term metabolic-dysfunction-associated fatty liver disease has been introduced in the literature. Excess visceral adipose tissue is an important predictor of complications in both non-alcoholic fatty liver disease and colonic diverticulosis. Current evidence suggests that intestinal dysbiosis may be involved in the development of both non-alcoholic fatty liver disease and colonic diverticulosis, and that metabolic syndrome is a consequence rather than a cause of this complex relationship. In this review, our aim was to assess the current knowledge of the complex interplay between metabolic syndrome, non-alcoholic fatty liver disease, and colonic diverticulosis.

Management of symptomatic uncomplicated diverticular colon disease: A systematic review of diagnosis and treatment. / Enfermedad diverticular de colon no complicada sintomática: revisión sistemática del diagnóstico y tratamiento.

Symptomatic uncomplicated diverticular colon disease (SUDCD) is a highly prevalent disease in our setting, which significantly affects the quality of life of patients. Recent changes in understanding the natural history of this disease and technological and pharmacological advances have increased the available options for both diagnosis and treatment. However, consensus regarding the use of these options is scarce and sometimes lacks scientific evidence. The objective of this systematic review is to clarify the existing scientific evidence and analyse the use of the different diagnostic and therapeutic options for SUDCD, comparing their advantages and disadvantages, to finally suggest a diagnostic-therapeutic algorithm for this pathology and, at the same time, propose new research questions.

Rising prevalence of colonic diverticulosis in a westernized multi-ethnic Asian community.

BACKGROUND AND AIM: Singapore is a multi-ethnic country that has undergone rapid development over the last few decades, with increasing influence of western culture, and faces an aging population. Previously, a varying prevalence of colonic diverticulosis (CD) was reported by a few small studies. This study aims to evaluate the prevalence of CD in Singapore and identify associations with common gastrointestinal symptoms and risk factors. METHODS: We reviewed retrospective data of 20 395 consecutive colonoscopies performed from 2006 to 2016 for presence of CD and indications of screening, diarrhea, constipation, and abdominal pain. RESULTS: The prevalence of CD progressively increased from 2006 to 2016 (14.9% vs 23.9%, adjusted trend < 0.001), with an overall prevalence of 19.6%. Patients with CD were older and had higher body mass index (BMI). CD was significantly more prevalent in Chinese compared with Malay and Indian races (20.5% vs 18.9% vs 15.5%, P < 0.05), and in male patients compared with female patients (21.5% vs 17.6%, P < 0.05). Right-sided CD was more common than left-sided or pan diverticulosis (16.2% vs 8.3% vs 4.8%, P < 0.05). Age [odds ratio (OR), 1.060; 95% confidence interval (CI), 1.052-1.068], BMI (OR, 1.051; 95% CI, 1.028-1.075), male gender (OR, 1.317; 95% CI, 1.084-1.600), and abdominal pain (OR, 1.409; 95% CI, 1.168-1.699) were positively associated, while constipation (OR, 0.566; 95% CI, 0.452-0.709) was negatively associated with CD. CONCLUSION: The prevalence of CD in Singapore has progressively increased over the last decade and is associated with older age, higher BMI, and abdominal pain. These findings may provide insights for healthcare resource planning in the region.

Relationship between colonic diverticulosis and colon neoplasms in Japanese patients.

BACKGROUND AND AIM: Colonic diverticulosis (CD) has been reported to be associated with presence of colon neoplasms (CNs) in Western patients, since most of the associated risk factors are common between them. However, such correlation has not been fully investigated in Asian patients. In this study, the association of CNs with CD was evaluated in a multicenter investigation. METHODS: We enrolled 5633 patients who underwent both colonoscopy and esophagogastroduodenoscopy due to annual follow-up, screening for positive occult blood testing and abdominal symptoms between January 2016 and December 2017 at three institutions. The relationship between the presence of CNs and CD was investigated, and predictors for presence of CNs were determined by multivariate logistic analysis. RESULTS: The enrolled patients consisted of 1799 (31.9%) with CD (average age 70.0 years, male 64.0%) and 3834 without CD (66.0 years, male 52.9%), with the prevalence of CNs in those groups 46.6% and 44.2%, respectively (P = 0.090). Predictors for early colon cancer were shown to be age (OR 1.02, 95% CI 1.01-1.04, P = 0.010), laxatives use (OR 1.76, 95% CI 1.17-2.64, P = 0.007), gastric neoplasms (OR 2.16, 95% CI 1.23-3.81, P = 0.008), and CD (OR 1.64, 95% CI 1.16-2.31, P = 0.005). Early colon cancer in the distal colon was most frequently detected in patients with right-sided CD (RR 2.50, P = 0.001). CONCLUSION: In Japanese patients, early colon cancer was more frequently found in those with as compared to those without CD. The presence of CD may be an important indicator for an index colonoscopy examination to detect colon cancer. (Clinical-trial-registry: UMIN000038985).