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Keywords:

  • dyspepsia;
  • functional gastrointestinal disorders;
  • irritable bowel syndrome;
  • overactive bladder

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Background  Overactive bladder syndrome (OAB) is defined as a symptom complex comprising urgency, with or without urge incontinence, and usually frequency and nocturia. The association between irritable bowel syndrome (IBS) and bladder symptoms has been reported. This study is designed to investigate whether functional dyspepsia (FD), like IBS, is associated with OAB.

Methods  A web surveys containing questions about OAB, FD, IBS, and demographics were completed by 5494 public individuals (2302 men and 3192 women) who have no history of severe illness. The prevalence and overlap of OAB, FD, and IBS were examined.

Key Results  Among participants with FD, 20.5% could also be diagnosed with OAB (odds ratio [OR]: 2.85; 95% confidence interval [CI]: 2.21–3.67). Although concomitant FD and IBS were more strongly associated with OAB (OR: 4.34; 95% CI: 2.81–6.73), OAB was also highly prevalent among participants with FD but without IBS (OR: 3.09; 95% CI: 2.29–4.18). Among participants with FD, an overlapping OAB condition was more prevalent in those with both postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) (OR: 3.75; 95% CI: 2.48–5.67) than in those with PDS or EPS alone. Among participants with OAB, the severity of bladder symptoms was greater in participants with dyspeptic symptoms than without them.

Conclusions & Inferences  Overactive bladder syndrome is common among FD patients, even if they do not have IBS. To improve FD patients’ quality of life, it will be important to provide management for OAB.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Overactive bladder syndrome (OAB) is defined as a symptom complex comprising urgency, with or without urge incontinence, and usually frequency and nocturia, in the absence of other local factors that would account for the symptoms. OAB is a complex of one or more of the following symptoms, which occur in the absence of other local factors that would account for their presence: urgency, urge incontinence, frequent urination, and nocturia.1 Functional gastrointestinal disorders (FGIDs), including irritable bowel syndrome (IBS) and functional dyspepsia (FD), are defined as chronic disorders of the digestive system in which symptoms cannot be explained by the presence of structural or tissue abnormality. Both OAB and FGIDs are significant health issues, as they are highly prevalent and have negative effects on quality of life.2 The association between IBS and bladder symptoms was documented as early as 1986,3,4 when Whorwell et al. reported that IBS patients frequently experienced symptoms of irritable bladder, including frequency, urgency, hesitancy, nocturia, and incomplete bladder emptying. Coyne et al. recently reported that chronic constipation occurs more frequently in patients with OAB.5 However, studies on the potential association between OAB and FD are generally lacking.

Functional dyspepsia impairs the health-related quality of life in patients, and the impact seems to be on all major variables of quality of life, namely mental, social, and physical functioning.6 A recent population-based study showed that postprandial distress syndrome (PDS) seems to impair the quality of life more than epigastric pain syndrome (EPS), while FD-IBS overlap has a significant impact on bodily pain.6 In addition, a large employee-based study showed that employees with FD had greater average annual medical and prescription drug costs than those without FD.7 The employees with FD were absent for an additional 0.83 days per year and produced 12% fewer units per hour than those without FD.7 On the other hand, patients with OAB tend to limit their fluid intake, avoid sexual intimacy, wear pads, and be more anxious about knowing the location of toilets. In particular, older OAB patients not only have an increased risk of injury and fractures,8 but also have a higher incidence of sleep disturbance, depression, and visits to physicians.9,10 Therefore, it is important to evaluate the frequency of overlap between FD and OAB to improve the patients’ quality of life and reduce the economic losses incurred.

The standard treatment for OAB is anti-muscarinic drugs, which have gastrointestinal side effects. Although the most well-known side-effect is constipation, patients may also experience dyspepsia and abdominal pain during treatment of OAB. In three phase III, randomized, placebo-controlled, 12-week trials that evaluated the efficacy, tolerability, and safety of once-daily controlled-release darifenacin for OAB, dry mouth (20.2%–35.5%), constipation (14.8%–21.3%), dyspepsia (2.7%–8.4%), abdominal pain (2.4%–3.9%), nausea (1.5%–2.7%), and diarrhea (0.9%–2.1%) were reported as adverse events.11 The high prevalence of gastrointestinal (GI) side effects also indicates that it is important to better understand the relationship not only between OAB and IBS, but also OAB and FD.

The aim of the present study was to investigate the frequency of overlap between OAB and FD. As the presence of IBS is a potential confounding factor, we also investigated overlap between OAB and IBS.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Study participants

The protocol for this study was approved by the ethics committee of Tokyo-Eki Center Building Clinic (TEC-C E-002, July 14, 2010). We conducted a web-based cross-sectional study including participants from a list of 177 615 individuals (age range, 20–75 years) who had previously provided informed consent and enrolled for unspecified clinical research trials conducted by the Tokyo-Eki Center-Building Clinic. No participants in the list have severe chronic or life-threatening illnesses, such as progressive malignant diseases or systemic autoimmune diseases, or serious mental illnesses, such as major depression or schizophrenia. Individuals with a history of prescription drug use were initially excluded. The questionnaires collected sufficient data for us to use the OABSS12 to evaluate OAB, and the Rome III criteria to evaluate FD13 and IBS.14 Using the questionnaires, the presence/absence of structural disease in the urinary tract was also determined. In the questionnaires, we also asked whether dyspeptic symptoms were relieved with defecation. In addition, prior receipt of an upper GI screening examination was elicited. If it was identified, the presence/absence of structural disease in the upper GI was abstracted. We also collected the following demographic information: age, gender, smoking and alcohol-drinking habits, height, and weight. Participants could select one of three smoking habit categories based on the number of cigarettes consumed per day (0 = ‘none’, 1–4 = ‘light’, ≥15 = ‘heavy’) and one of three alcohol intake categories based on the number of days per week on which alcohol was consumed (0 = ‘none’, 1–3 = ‘light’, 4–7 = ‘heavy’). We calculated body mass index (BMI) (weight height−2) using the morphometric data provided. Participants with urethral calculus, bladder cancer, or prostate cancer were excluded from the study.

Definitions of OAB, FD, and IBS

As OAB is a collection of symptoms, symptom assessment tools are used for quantitative assessment of the syndrome. The OABSS is a validated self-assessment questionnaire that provides a simple sum of 4 symptom scores that address daytime frequency, night-time frequency, urgency, and urgency incontinence. The maximum scores for each component are defined as 2, 3, 5, and 5, respectively.12,15 Here, OAB was defined as a urinary urgency score (third question of OABSS) of 2 or more, and a total OABSS of 3 or more, based on the clinical guidelines for OAB prepared by the Neurogenic Bladder Society.16

Based on the Rome III criteria, participants were defined as having dyspepsia if they had experienced one or more symptoms, such as postprandial fullness, early satiation, or epigastric pain or burning, for at least 6 months prior to the survey. Participants with only epigastric pain that was relieved by defecation were not included into those with dyspepsia, as their symptoms would be caused by unrecognized IBS. Participants with dyspepsia who had undergone upper gastrointestinal examination and had no evidence of structural disease to explain their symptoms were defined as having ‘FD’. Functional dyspepsia participants with postprandial fullness or early satiation were defined as having PDS, while those with epigastric pain or burning were defined as having EPS; some participants had both PDS and EPS.

Based on the Rome III criteria, participants were defined as having IBS if they had suffered recurrent abdominal pain or discomfort for more than 2 days in a week and also had two or more of the following: improvement with defecation, onset associated with a change (increased or decreased) in frequency of stool production, and onset associated with a change in stool consistency (hard or soft). Irritable bowel syndrome participants were subcategorized as having constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D), or mixed IBS (IBS-M). In IBS-C, onset was associated with decreased frequency of stool production or hard stool, while in IBS-D onset was associated with increased frequency of stool production or soft stool, including diarrhea; participants with IBS-M experienced both decreased and increased frequency of stool production or presence of both hard and soft stool at different times.

Statistical analysis

Differences between non-OAB and OAB, non-FD and FD, and non-IBS and IBS participants were examined with unpaired Student’s t-tests (for age and BMI) and Pearson’s chi-squared tests (for gender, smoking habits, and alcohol-drinking habits). Associations between OAB and FGIDs or other clinical factors were evaluated using univariate and multivariate logistic regression. Associations between the OABSS and dyspeptic symptoms were examined with unpaired Student’s t-tests. All statistical analyses were conducted using SPSS version 18.0 for Windows (SPSS Japan Inc., Tokyo, Japan). The data in the tables are expressed as mean ± standard deviation. Two-sided P-values were considered to be statistically significant at a level of less than 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Participant characteristics

A total of 5494 individuals completed the web-based surveys (Fig. 1). After we excluded 164 participants who had an organic urinary tract disease, our final sample size was 5330 participants (2187 men and 3143 women). OAB, FD, and IBS were diagnosed in 497 (9.3%), 438 (8.2%), and 728 (13.7%) participants, respectively. Among the 438 participants with FD, 267 (61.0%) were categorized as having PDS alone, 45 (10.3%) were classified as having EPS alone, and 126 (28.8%) were found to have both PDS and EPS. Among the 728 participants with IBS, 147 (20.2%) were categorized as having IBS-C, 456 (62.6%) were classified as having IBS-D, and 125 (17.2%) were found to have IBS-M.

image

Figure 1.  The study population. OAB, overactive bladder; FD, functional dyspepsia; IBS, irritable bowel syndrome; IBS-C, constipation-predominant irritable bowel syndrome; IBS-D, diarrhea-predominant irritable bowel syndrome; IBS-M, mixed irritable bowel syndrome; PDS, postprandial distress syndrome; EPS, epigastric pain syndrome.

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Participant characteristics are shown in Table 1. Both mean age and alcohol consumption levels were higher in OAB participants than in non-OAB participants. Alcohol consumption was more prevalent in FD participants than in non-FD participants. Mean age was lower in participants with IBS than in those without this condition.

Table 1.   Participant characteristics
 Non-OAB (n = 4833)OAB (n = 497)Non-FD (n = 4402)FD (n = 438)Non-IBS (n = 4602)IBS (n = 728)
  1. Bold values indicate significant differences between non-OAB and OAB, non-dyspepsia and FD, or non-IBS and IBS. Differences of age and BMI were analyzed by unpaired Student’s t-tests. Differences of gender, smoking habit, and alcohol habit were analyzed by Pearson’s chi-squared tests. OAB, overactive bladder; IBS, irritable bowel syndrome; BMI, body mass index; FD, functional dyspepsia.

Age, years (mean ± SD)42.5 ± 9.7 45.9 ± 10.2 42.9 ± 9.942.9 ± 8.443.2 ± 9.8 40.3 ± 9.7
Gender, n (%)
 Men1985 (41.1%)202 (40.6%)1820 (41.3%)188 (42.9%)1897 (41.2%)290 (39.8%)
 Women2848 (58.9%)295 (59.4%)2582 (58.7%)250 (57.1%)2705 (58.8%)438 (60.2%)
Smoking habit, n (%) (number of consumptions/day)
 None (0)3712 (76.8%)385 (77.5%)3412 (77.5%)328 (74.9%)3555 (77.2%)542 (74.5%)
 Light (1–14)453 (9.4%)51 (10.3%)395 (9.0%)45 (10.3%)433 (9.4%)71 (9.8%)
 Heavy (15 ≤ )668 (13.8%)61 (12.3%)595 (13.5%)65 (14.8%)614 (13.3%)115 (15.8%)
Alcohol habit, n (%) (number of days of consumption/week)
 None (0)1837 (38.0%) 176 (35.4%)1709 (38.8%) 133 (30.4%)1758 (38.2%)255 (35.0%)
 Light (1–3)1616 (33.4%) 145 (29.2%)1449 (32.9%) 158 (36.1%)1510 (32.8%)251 (34.5%)
 Heavy (4–7)1380 (28.6%) 176 (35.4%)1244 (28.3%) 147 (33.6%)1334 (29.0%)222 (30.5%)
 BMI, kg m−2 (mean ± SD)22.2 ± 3.522.4 ± 3.922.2 ± 3.522.2 ± 3.722.2 ± 3.622.1 ± 3.6

Overlap of OAB, FD, and IBS

The numbers of participants with OAB, FD, or IBS are shown in Fig. 2A. Among participants with either FD or OAB, 10.7% (90/844) had both FD and OAB. On the other hand, among participants with either IBS or OAB, 12.3% (134/1091) had both IBS and OAB. Overlap between FD and OAB was almost as often as overlap between FD and IBS (11.2%; 117/1049) (Fig. 2B–D).

image

Figure 2.  Overlap between OAB, FD, and IBS. (A) The number of participants in each partition. Each partition is painted in different colors to be classified using Overactive Bladder Symptom Score (OABSS). The symptoms of OAB were the most severe in OAB participants with both FD and IBS. The prevalence of overlap (B) between OAB and FD, (C) between OAB and IBS, and (D) between FD and IBS are shown. OAB; overactive bladder; FD, functional dyspepsia; IBS, irritable bowel syndrome.

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Logistic regression analyses showed that OAB was associated with FD (odds ratio [OR]: 2.85; 95% confidence interval [CI]: 2.21–3.67) almost at the same level as it was associated with IBS (OR: 2.63; 95% CI: 2.12–3.27) (Table 2). OAB was also significantly associated with all subcategories of FD (e.g., PDS alone, EPS alone, or concomitant PDS and EPS). In particular, OAB was more common in participants with both PDS and EPS (OR: 3.75; 95% CI: 2.48–5.67).

Table 2.   Symptom overlap of OAB with other conditions
 Non-OAB (n = 4833)OAB (n = 497)Odds ratio (95% CI)
  1. Analyzed by univariate logistic regression model. OAB, overactive bladder; CI, confidence interval; FD, functional dyspepsia; IBS, irritable bowel syndrome; PDS, postprandial distress syndrome; EPS, epigastric pain syndrome.

Non-FD4485 (92.8%)407 (81.9%)ref.
FD348 (7.2%)90 (18.1%)2.85 (2.21–3.67)
 PDS alone218 (4.5%)49 (9.9%)2.48 (1.79–3.43)
 EPS alone36 (0.7%)9 (1.8%)2.76 (1.32–5.76)
 PDS and EPS94 (1.9%)32 (6.4%)3.75 (2.48–5.67)
Non-IBS4239 (87.7%)363 (73.0%)ref.
IBS594 (12.3%)134 (27.0%)2.63 (2.12–3.27)
Neither FD nor IBS3979 (82.3%)302 (60.8%)ref.
FD without IBS260 (5.4%)61 (12.3%)3.09 (2.29–4.18)
IBS without FD506 (10.4%)105 (21.1%)2.73 (2.15–3.48)
Both FD and IBS88 (1.9%)29 (5.8%)4.34 (2.81–6.73)

OAB was strongly associated with the presence of both FD and IBS (OR: 4.34; 95% CI: 2.81–6.73). In addition, OAB was also commonly found even in participants with FD but without IBS (OR: 3.09; 95% CI: 2.29–4.18). This result shows that FD and IBS are independently associated with the presence of OAB.

Differences in FD participants with and without OAB

We compared demographic and symptomatic characteristics between participants with both FD and OAB and those with FD but without OAB (Table 3). The multivariate logistic regression analyses revealed that older age (OR: 1.04; 95% CI: 1.01–1.07) and the presence of IBS-C (OR: 3.08; 95% CI: 1.24–7.63) were independently associated with overlap of FD and OAB. However, IBS-D, IBS-M, gender, smoking, alcohol use, and BMI were not associated with overlap of these two conditions.

Table 3.   Difference between FD with and without OAB
FD (n = 438)FD without OAB (n = 348)FD with OAB (n = 90)Univariate analysis, Odds Ratio (95% CI)Multivariate analysis Odds Ratio (95% CI)
  1. Analyzed by multivariable logistic regression model with adjustment for IBS-C and age. Bold values indicate significant associations. FD, functional dyspepsia; OAB, overactive bladder; IBS, irritable bowel syndrome; CI, confidence interval; BMI, body mass index.

IBS-C, n (%)12 (3.4%)9 (10.0%) 3.11 (1.27–7.63) 3.08 (1.24–7.63)
IBS-D, n (%)55 (15.8%)17 (18.9%)1.24 (0.68–2.26)  
IBS-M, n (%)21 (6.0%)3 (3.3%)0.54 (0.16–1.84) 
Age, years (mean ± SD)42.4 ± 8.445.1 ± 8.2 1.04 (1.01–1.07) 1.04 (1.01–1.07)
Gender, men, n (%)147 (42.2%)41 (45.6%)1.14 (0.72–1.82)  
Smoking habit, n (%)
 None257 (73.9%)71 (78.9%)ref. 
 Light36 (10.3%)9 (10.0%)0.29 (0.42–1.97) 
 Heavy55 (15.8%)10 (11.1%)0.66 (0.32–1.37) 
Alcohol habit, n (%)
 None106 (30.5%)27 (30.0%)ref. 
 Light132 (37.9%)26 (28.9%)0.91 (0.42–1.40) 
 Heavy110 (31.6%)37 (41.1%)1.31 (0.75–2.30) 
BMI, kg m−2 (mean ± SD)22.3 ± 3.722.1 ± 3.70.99 (0.93–1.06) 

Influences of dyspeptic symptoms on the severity of OAB symptoms

Among participants with OAB, the severity of OAB symptoms in participants with and without dyspeptic symptoms (postprandial fullness, early satiation, epigastric pain, and epigastric burning) is shown in Table 4. The average score of total OABSS in OAB participants with postprandial fullness was significantly higher than that in OAB participants without postprandial fullness. The presence of early satiation, epigastric pain, and epigastric burning also enhanced the scores of total OABSS, although these differences were not significant. These results suggest that concomitant dyspeptic symptoms influence the symptom severity of OAB.

Table 4.   Associations between the severities of OAB and dyspeptic symptoms
OAB (n = 497)Total OABSS
Score (mean ± SD) P-value
  1. Bold values indicate significant associations. OAB, overactive bladder.

Postprandial fullness
 Absence (n = 283) 5.24 ± 1.93 0.03
 Presence (n = 214) 5.65 ± 2.20  
Early satiation
 Absence (n = 345)5.32 ± 1.950.14
 Presence (n = 152)5.64 ± 2.29 
Epigastric pain
 Absence (n = 405)5.35 ± 1.980.12
 Presence (n = 92)5.72 ± 2.37 
Epigastric burning
 Absence (n = 421)5.36 ± 2.020.13
 Presence (n = 76)5.75 ± 2.26 

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

This large-scale cross-sectional study of a Japanese population revealed a high frequency of overlap between FD and OAB. To our knowledge, this is the first evidence for an independent association between FD and OAB. In IBS patients, many extra-intestinal co-morbidities, such as migraine, fibromyalgia, chronic fatigue syndrome, chronic pelvic pain, and depression, are more common.4,17,18 According to the guidance on IBS from the National Institute for Health and Clinical Excellence (NICE), bladder symptoms are common in people with IBS, and may be used to support the diagnosis of IBS.19 However, the present study revealed that OAB is a significant co-morbidity not only in IBS, but also in FD.

Overlap between OAB and IBS, diagnosed using the modern criteria, has not been reported previously, although Nickel et al.20 recently documented the overlap of interstitial cystitis/painful bladder syndrome (IC/PBS) with IBS, diagnosed using the Rome III. Although IC/PBS and OAB have similar symptoms, such as urgency, frequency, and nocturia, IC/PBS is differentiated from OAB by the presence of pain. The present study also provides the first evidence for the high prevalence of overlap between IBS and OAB. In addition, our work has revealed that OAB is more prevalent in participants with both IBS and FD than in those with IBS but without FD. Usually, different specialists (e.g., gastroenterologists and urologists) independently treat FD and OAB; this often occurs in the setting of a tertiary care hospital. Both specialists must recognize the impact of overlap between FD and OAB.

We recently reported that FD patients with concomitant constipation or diarrhea show different characteristics from those without bowel symptoms.21 We reported that FD patients with bowel symptoms have greater symptom severity than those without bowel symptoms. There were a greater proportion of women, especially with low BMI, in constipation-predominant FD. Alcohol consumption was associated with diarrhea-predominant FD in both genders.21 The present study revealed that FD participants with IBS-C are likely to have concomitant OAB. Namely, high prevalence of concomitant OAB is thought to be one of the characteristics among constipation predominant FD patients. Previous studies also showed that there is a significant overlap between lower urinary tract symptoms and constipation.5,22,23 Charach et al. reported that medical relief of constipation significantly improves lower urinary tract symptoms in the elderly, and also improves the patient’s mood, sexual activity, and quality of life,24 suggesting that treatment for FD would also improve symptoms of OAB, or vice versa.

We were unable to use the web survey to investigate the mechanism driving the strong association among OAB, FD, and IBS. However, our findings suggest that these conditions may result from common pathogenic mechanisms such as visceral (gastrointestinal and bladder) hypersensitivity, dysfunction of the central or autonomic nervous system, genetic susceptibility, alterations in serotonin (5-HT) signalling and metabolism, and psychological factors including somatization and anxiety. In the present study, participants with early satiation have to urinate more frequently (Table 4), suggesting that impaired gastric accommodation and bladder accommodation might be caused by common mechanisms. Recent studies demonstrated that elevated levels of neurotrophins, namely nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), contribute to bladder overactivity in OAB patients.25 These factors might also contribute to visceral hypersensitivity in FGIDs.26 In addition, as gut inflammation is known to cause functional and structural changes in the central nervous system as a result of abnormal afferent input from the gut,27 it may alter urinary bladder smooth muscle function. Noronha et al. reported that a transient colonic inflammatory insult attenuates the amplitude of bladder detrusor muscle contractions in rats.28 Thus, investigating common mechanisms of OAB and FGIDs might be able to reveal new pathophysiology in these disorders. Further studies are warranted to define underlying mechanisms.

It is possible that our population was not representative of the general population. As patients who were prescribed any drugs were excluded, some of individuals who have more severe symptoms of FD or OAB may have been filtered out. A potential bias also exists if some individuals do not participate in a web-based panel because of concerns about the technology. However, recent Japanese study to clarify the difference between of the survey methods (electronic survey and postal survey) on the epidemiology of FGID symptoms showed that the proportions of symptom subtypes and the patterns of the overlaps were similar in the two methods, despite the difference in the prevalence.29 In the same way, it is believed that population biases would not have a large impact on the associations between diseases (odds ratios) shown in the present study.30

In conclusion, clinical overlap between OAB and FD is very common. This association was not confounded by coexisting IBS, although concomitant IBS-C increased the risk of OAB among participants with FD. Among participants with OAB, the severity of bladder symptoms was greater in participants with dyspeptic symptoms than without them. These results suggest that a subgroup of patients may show development of OAB and FD through the same pathophysiology, which may lead to the discovery of a novel mechanism in FD. Furthermore, potential OAB symptoms should be considered when evaluating and treating patients with FD.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

This study was supported by a Health and Labour Sciences Research Grant for Research on Health Technology Assessment (Clinical Research Promotion No. 47 to HS), grants from the Smoking Research Foundation (to HS), the Keio Gijuku Academic Development Fund (to HS), Grant-in-Aid for JSPS Fellows DC2 (to JM), a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (to JM), the Graduate School Doctoral Student Aid Program, Keio University (to JM).

Author Contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

HS and YF designed the research study, conducted the web survey, and collected the data; JM, HS, KH, SF, and SO analyzed and interpreted the data; JM and HS drafted the article; TH supervised and approved final publication.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References