Nutrition Journal Nucleotide supplementation: a randomised double-blind placebo controlled trial of IntestAidIB in people with Irritable Bowel Syndrome [ISRCTN67764449]

C P Dancey
University of East London
UK

E A Attree
University of East London
UK

K F Brown
University of East London
UK

Nutrition Journal Nucleotide supplementation: a randomised double-blind placebo controlled trial of IntestAidIB in people with Irritable Bowel Syndrome [ISRCTN67764449]
10.1186/1475-2891-5-16BioMed Central Page 1 of 9 (page number not for citation purposes) Research * Corresponding author
Background: Dietary nucleotide supplementation has been shown to have important effects on the growth and development of cells which have a rapid turnover such as those in the immune system and the gastrointestinal tract. Work with infants has shown that the incidence and duration of diarrhoea is lower when nucleotide supplementation is given, and animal work shows that villi height and crypt depth in the intestine is increased as a result of dietary nucleotides. Dietary nucleotides may be semi-essential under conditions of ill-health, poor diet or stress. Since people with Irritable Bowel Syndrome tend to fulfil these conditions, we tested the hypothesis that symptoms would be improved with dietary nucleotide supplementation.Methods: Thirty-seven people with a diagnosis of Irritable Bowel gave daily symptom severity ratings for abdominal pain, diarrhoea, urgency to have a bowel movement, incomplete feeling of evacuation after a bowel movement, bloating, flatulence and constipation for 28 days (baseline). They were then assigned to either placebo (56 days) followed by experimental (56 days) or the reverse. There was a four week washout period before crossover. During the placebo and experimental conditions participants took one 500 mg capsule three times a day; in the experimental condition the capsule contained the nutroceutical substances. Symptom severity ratings and psychological measures (anxiety, depression, illness intrusiveness and general health) were obtained and analysed by repeated measures ANOVAs.Results:Symptom severity for all symptoms (except constipation) were in the expected direction of baseline>placebo>experimental condition. Symptom improvement was in the range 4 -6%. A feeling of incomplete evacuation and abdominal pain showed the most improvement. The differences between conditions for diarrhoea, bloating and flatulence were not significant at the p < .05 level. There were no significant differences between the conditions for any of the psychological measures.Conclusion:Dietary nucleotide supplementation improves some of the symptoms of irritable bowel above baseline and placebo level. As expected, placebo effects were high. Apart from abdominal pain and urgency to have a bowel movement, the improvements, while consistent, are modest, and were not accompanied by improvements in any of the psychological measures. We suggest that the percentage improvement over and above the placebo effect is a physiological effect of the nucleotide supplement on the gut. The mechanisms by which these effects might improve symptoms are discussed.

Background

Irritable Bowel Syndrome (IBS) is a chronic disorder affecting an estimated 15 -22% of western populations, and is the major cause of referrals to gastroenterology clinics in the western world [1]. The symptoms may include abdominal pain, diarrhoea, urgency to have a bowel movement, a feeling of incomplete evacuation after a bowel movement, flatulence and bloating. Some sufferers experience constipation, or an alternation between constipation and diarrhoea. IBS is more common among women than men, with a 2:1 female: male ratio [2]. Current medical treatments are directed at symptomatic relief, and although these can give some relief, there is no one treatment which has been shown to be lastingly effective. Although IBS is not a life-threatening disease, the symptoms and the effects of the symptoms on daily life can have a great impact on sufferers [3]. IBS is also associated with large healthcare and economic costs in terms of hospital investigations, repeated visits to GPs, prescription medicines, and loss of time from work [4]. Although hospital investigations for more serious diseases such as cancer or Inflammatory Bowel Disease are negative in people with IBS, some abnormalities in the gut have been found. For instance, some patients have been found to have a degree of mucosal inflammation, which may be in response to some foods [5]. It is possible that people with IBS have immunological reactions to dietary antigens as food elimination based on serum immunoglobulin G antibodies has been found to result in a significant decrease in symptoms of IBS. Both numbers of mast cells and their mediators have been shown to be increased in intestinal mucosa in patients with irritable bowel syndrome, especially in the close proximity of intestinal nerves [6]. Kalliomäki [6] suggests that food antigens induce mast cells to secrete mediators which regulate gastrointestinal motility, resulting in alterations in peristalsis and an increase in abdominal pain and discomfort. Furthermore, the mast cell-derived mediators have effects on immune cell functions. It may be then, that the nutrition of people with IBS is more important than has been traditionally thought. As people with IBS tend to believe that their symptoms are affected by diet, they often attempt to manage their disorder by dietary control. However, the only consistent advice given to people with IBS is usually simply to eat a "healthy" diet which includes fruit, vegetables and fibre. In an early study of people with IBS, Dancey & Backhouse [7] found that although the majority of their sample of 148 people (70%) stated that they were trying to follow a "healthy" diet with large amounts of fruit and vegetables; for many of these people, such a strategy had not led to symptom improvement, and in an attempt to control their IBS, 14% were eating very restricted diets. Some of these diets involved avoiding complete groups of foods, e.g. carbohydrates. Whilst such a strategy may reduce bloating, for instance, such a diet is not likely to enhance wellbeing. As well as eating a sufficient quantity of a wide variety of foods from each food group, micronutrients and nucleotides may also be important for health, especially in the sub-well. It is nucleotides which are the focus of this study.

Nucleotides are substances which are synthesised endogenously -they have important effects on the growth and development of cells which have a rapid turnover, such as those in the immune system and the gastrointestinal tract. The intestinal epithelium is a rapidly proliferating tissue with a high cellular turnover rate. A complete cell cycle in humans is 24 hours, with a replacement of the entire enteric epithelium within 3-6 days. In healthy people, dietary nucleotides are probably not essential, and in fact most will be metabolised and rapidly excreted from the system. However, under certain circumstances (e.g. in the sub-well, diseased, or under conditions of stress or poor diet) dietary nucleotides may be what Maldonado, Navorro, Narbona, & Gil [8] call "semi-essential", optimising the function of the gastrointestinal and immune systems. In relation to the gastrointestinal system work has shown that dietary nucleotides enhance the intestinal absorption of iron [9]. Dietary sources of nucleotides are nucleoproteins and nucleic acids, and these are found to varying degrees in many foods -lamb, liver, mushrooms (but not fruit and other vegetables) all are rich in nucleotides. Rapidly dividing tissue requires a constant supply of nucleotides in order to manufacture essential nucleic acids. Exogenous supplies of nucleotides may optimise tissue function particularly during recovery from mucosal injuries when the endogenous supply may limit the synthesis of nucleic acids.

Holen & Jonsson [10] found that dietary nucleotides had beneficial effects, especially when the nutrition supply was inadequate. Work with infants has shown that the incidence and duration of acute diarrhoea is lower in infants when dietary nucleotides are included in their diets [11]. Previous work on the effect of nucleotide supplementation in animals has found that such supplements are important for the repair mechanism of immune cells [12]. In piglets, nucleotide supplementation had effects on the gastrointestinal system by increasing villi height and crypt depth. [13]. Evans, Tian, Gu, Jones & Ziegler [14], using rats to model short-bowel syndrome, found that nucleotide supplementation is associated with increased jejunal adaptive growth after massive small bowel resection in rats. Dietary nucleotides have been found to help athletes by reducing the release of stress related hormones and chemicals in the body, and by maintaining a higher level of antibodies, which enables the immune system to work more effectively [15]. In people with a chronic illness such as IBS whose primary symptoms relate to the gastrointestinal tract, nucleotide supplementation may improve symptoms via improved gut function or by an enhancement of the immune system.

There are particular problems in assessing the benefits of treatments of people with IBS, and some of the problems of this patient group in relation to clinical trials have been discussed in detail by Spiller [16]. People with IBS show great variability in frequency and severity of symptoms, both when compared to others and also from day-to-day in their own symptoms. Spiller [16] has shown there are clear benefits to participating in clinical trials; people with IBS tend to be helped by placebo alone. This is thought to be due to a reduction in anxiety and/or depression as a result of help and reassurance given by the people running the trial. If this is the case, then anxiety and depression should reduce over the length of the trial. One would also expect that, if symptoms improve, then psychological well-being should in some way improve also. Thus although our primary aim was to determine whether nucleotide supplementation improved the symptoms of irritable bowel, we also wished to determine whether ratings of anxiety and/or depression would show any change as a result of symptom change.

Methods

Design

A double-blind randomised placebo cross-over study in which participants rated symptoms daily for six months in baseline, placebo, and experimental conditions. This study was approved by our university ethics committee and was in accordance with the code of conduct for psychologists (ethical principles for conducting research with human participants) produced by the British Psychological Society. The research was conducted only when written consent was received from the participant, and their G.P. had provided written confirmation of their diagnosis, and confirmation of no other co-existing conditions.

Participants

Thirty seven people with a diagnosis of Irritable Bowel Syndrome took part in the study. The inclusion criteria were that participants should be aged 18 -65, should have been diagnosed as having IBS by a qualified medical practitioner, and should have diarrhoea as a main symptom. The exclusion criteria were any other co-existing illnesses, and non-confirmation of the diagnosis by G.P. The participant flow is shown below (see Figure 1).

Thirty-seven participants completed the trial, during which they completed daily symptom diaries for four weeks (baseline) following by either the experimental condition (eight weeks) or the placebo condition (eight weeks). There was a four week washout period between conditions. The mucosal cell turn-over for the whole tract is approximately six days, with the majority of other cells in the body are also replaced over 30 days. For this reason a 30 day washout was selected. Although some of the participants rated some symptoms as not particularly bothersome over the baseline condition no person was excluded by us.

IBS symptoms

The symptoms of interest were: abdominal pain, diarrhoea, urgency to have a bowel movement, incomplete evacuation after a bowel movement, flatulence, bloating, and constipation. Participants rated symptoms every day on a scale of 1 ("no discomfort at all today") to 7 ("very severe discomfort today"). Reliability for these symptoms has been previously established [17].

Participants were given a pack containing a month's supply of daily diaries in which to record their symptoms. The next month's supply were sent to the participants once the previous completed pack had been returned.

Neutroceutical product

Participants took one 500 mg capsule three times a day with meals -in the experimental condition these contained the neutroceutical product IntestAidIB which consists of the following active substances: nucleotides & RNA (concentrated extracts of Saccharomyces cerevisae), hydroxypropyl methycellulose, FOS (fructo-olligosaccharides), Methionine, Glutamine, Inositol, Lysine, Pantothenic acid (Vitamin B5 as Calcium d-pantothenate), Sodium citrate, Riboflavin (Vitamin B2), Vanillin, Folic acid, and Biotin. Flow agents are magnesium stearate and silicic acid. The capsules are carbohydrate based. RNA and the specific, purified nucleotides are the natural extracts of yeast. There are no yeast cells carried over from the extraction process into the product. The daily diaries contained space where participants confirmed that they had taken each capsule, and at what time of day.

Procedure

Recruitment was by a variety of sources. Notices asking for people with diagnosed IBS interested in taking part in a trial for a neutroceutical product were sent to people with IBS who had previously expressed an interest in IBSrelated research; a request was included in one issue of Gut Reaction (a quarterly journal sent to people with IBS by The IBS Network, a British self-help organisation), and notices were placed in doctors' surgeries and libraries. Such a recruitment strategy was considered necessary, as strict inclusion and exclusion criteria, plus the burden of completing daily diaries for six months meant recruitment might be difficult. We wished to have a mixed group of people with IBS, representative of the general population of people with IBS. Recruiting from tertiary centres does not allow generalisation to the wider population of people with this condition.

Participants were invited to respond to these recruitment methods by telephone or e-mail. During this initial con-participant flow through the trial Figure 1 participant flow through the trial.

tact, the researcher ensured that potential participants met the inclusion criteria. Eligible individuals were then given full information relating to the study. They were advised at this stage of their right to withdraw their participation and/or any data already provided, at any time, without giving any notice or reason to the research team.

Participants were then asked to provide contact details for their GP, and a consent form was sent by post to the participant for them to complete and return, as well as a pack providing further information about the trial and the supplement. Their GP was also sent a letter at this point, summarising the trial and requesting confirmation of diagnosis. Upon receipt of the confirmation of diagnosis and participant consent forms, participants were randomised to each of the conditions.

Initially participants were sent their first symptom diary pack, which contained detailed instructions on how to complete the diary as well as the first diary itself. The diary required participants to rate the severity of their symptoms (see above) and to specify the times at which they had taken each of their three capsules; to name any medications which they were prescribed, had purchased (including price) and had actually taken (including time taken) that day; and to note any visits to health professionals made that day (including who they visited, reason for visit and advice given).

Participants were contacted by telephone or e-mail a week after this first pack was sent out (week 1), to confirm that they understood how to complete the questionnaires and the diary. Participants were sent their first set of capsules (a "set" comprised four sealed tubs) -all tubs were marked "nutritional supplement, contents 42 capsules (500 mg), two weeks supply", but with A or B clearly marked both on the label and on the cap) one week before they were to need them (week 3), with a letter stating the date on which they should begin taking the capsules. They were contacted by telephone or e-mail a few days after this date (week 5) to ensure that they were taking the capsules at the right dosage (one capsules three times a day, preferably with meals), that they were completing the symptom diary with the required information (time capsules taken, any missed capsules noted), and that they were aware of how to contact the research team if they had concerns about any effect which the capsules may have upon them.

Following this, participants were sent a symptom diary pack every month, their second set of capsules for week 17, a set of questionnaires (described below) at week 13 and week 25. All documentation and capsules were sent one week before they were required to ensure that they arrived in good time. Every letter sent to the participants included contact details for the research team and urged participants to telephone or e-mail with any questions or worries, at any stage of the trial. Participants were sent questionnaire packs at baseline, washout, and end of trial.

Every participant forgot to take at least one capsule across the duration of the trial, but this was usually one capsule only on any given day. There were two exceptions -one participant took capsules erratically over the last six weeks of the experimental condition and after the first five weeks of the placebo condition. This participant had a change of personal circumstances during this time (she underwent a hysterectomy). The other participant took no capsules for 5 days in the last week of the experimental condition as she went away and forgot to take the capsules with her.

Psychological measures

Measures were taken at the beginning of the baseline period, the end of the experimental condition and the end of the placebo condition.

Depression was measured by the CES-D [18] and anxiety was measured by the Stait-Trait Anxiety inventory [19]; a specific measure of health anxiety was provided by the Health Anxiety Questionnaire [20]. General health and happiness were measured by the total of the GHQ-60 [21] and the Affect Balance Scale [22]. The extent to which IBS intrudes into various aspects of everyday life was measured by the 13-item Illness Intrusiveness Rating Scale [23].

Results

The average person with IBS spent approximately £15.00 during the six months trial on medications, supplements, minerals and vitamins and visited the G.P.'s surgery approximately seven times, the majority of the consultation times being for reasons other than IBS.

Symptoms

For symptom recording, three participants had some sequential data missing, i.e. for the first participant this was for seven days in the experimental condition; for the second it was three days in the experimental condition, and for the third, three days during baseline. For each missing data point frequency data were obtained for the particular condition in which the missing data occurred, and the most appropriate (representative) measure of central tendency was inserted.

Analysis of symptoms

Mean ratings for the symptom series for each condition with 95% C.I.'s for the symptoms are represented below (see Figure 2).

A repeated measures ANOVA on each of the symptoms was carried out. Sphericity was not assumed and therefore the Greenhouse-Geisser correction for degrees of freedom was used. The difference between conditions for abdominal pain (F 2,67 = 3.71; Eta 2 = .10), urgency to have a bowel movement (F 2,64 = 3.82; Eta 2 = .10) and a feeling of incomplete evacuation (F = 2,67 = 3.52; Eta 2 = .09) were significant at p < .05. Diarrhoea (F 2,58 = 3.08; Eta 2 = .08), Flatulence (F 2,70 = 2.89; Eta 2 = .07), Bloating (F 2,68 = 2.61; Eta 2 = .07) and Constipation (F 2,49 = .31; Eta 2 = .01) were not statistically significant at p < .05.

The percentage improvement of both placebo and IntestAidIB over baseline is shown below (see Figure 3).

Symptom severity for all symptoms (except constipation) are in the expected direction of baseline>pla-cebo>IntestAidIB.

Psychological measures

Repeated measures ANOVA were carried out on the psychological variables. There were no significant differences between conditions on these measures (p > .05).

It might be expected that due to the benefits of being in a clinical trial, anxiety and depression would decrease over mean symptom severity ratings with 95% C.Is time. We thus tested this by a repeated measures analysis for CES-D and Health Anxiety and Stait-Trait Anxiety comparing measures at baseline, washout and end of trial without considering condition (placebo or experimental). None of these measures were statistically significant (all p > .05)

Discussion

The study has shown that there is a consistent improvement in most of the symptoms of irritable bowel syndrome following nucleotide supplementation with IntestAidIB. There was a very low drop-out rate (18%); none of the participants who completed the study reported any side-effects. A feeling of urgency to have a bowel movement and abdominal pain showed the most improvement over baseline and placebo, and since abdominal pain is the symptom most likely to prompt people to seek medical help, this is a important finding. A feeling of incomplete evacuation after a bowel movement also improved following treatment by the neutroceutical product. However, whilst statistically significant, improvements are modest, and this may be due to several factors. Firstly, people with IBS are not a homogenous group, and show great variability in frequency and severity of symptoms, both from each other, and individually. This makes it difficult to detect effects of interventions. Secondly, the placebo response was strong -Spiller [16] states that it takes approximately 12 weeks for the placebo effect to reduce. Perhaps a longer trial -and with a larger dose -effects might have been stronger. However, this is speculative and further trials need to take these factors into consideration.

Participants were a mixed group of people who have a current diagnosis of IBS, some of whom still attend a gastroenterological clinic, and some of whom do not. They were not obtained from tertiary centres and carried on with their normal life taking their usual medications. Although their symptoms were not perhaps as severe as tertiary patients, their symptoms were bothersome enough for them to enter the clinical trial, and the symptoms were severe enough for the participants to buy a range of products aimed at relieving their symptoms. We expect that the effects found in this simple would be stronger if replicated with participants from tertiary centres.

The benefits over placebo compare favourably with benefits found in some drug trials. For example, Tegaserod (a drug which acts as a selective agonist at 5HT receptors in the gastrointestinal tract) was found to produce 4.7% advantage over placebo in the participants' assessment of global relief of IBS [24]. Although many such drugs are well tolerated, there were no side effects at all reported in the present study, which is a considerable advantage. The percentage improvement varied according to the symp-toms -between 4 and 6%. The symptom improvements shown are unlikely to be the result of a decrease in anxiety or depression which has sometimes been cited as a reason for any improvement in trials, as anxiety and depression in the present study did not decrease significantly as the trial progressed (irrespective of condition). The effect -at least at this dosage -does not seem strong enough to lead to an improvement in psychological state since depression, anxiety, general health and illness intrusiveness did not differ between the conditions. The strong placebo effects found in the present study are similar to those in other IBS-studies [16]. We suggest that the percentage improvement over and above the placebo effect is a physiological effect of the nucleotide supplement on the gut. However, whilst results were consistent and some symptoms were statistically significant, these effects may not be strong enough to be perceived as a great improvement by the participants, who will try to assess the benefits of such a supplement against a background of extremely variable symptoms. The mechanism by which nucleotide supplementation might improve gut function could be via increased mucosal protein, DNA and villus height -as has been found in animal studies [14,25] Evans et al [14] state that rodent models are useful in translational research to identify potential new treatments to increase gut mucosal growth that is potentially relevant to humans with short bowel syndrome (this is not related to IBS). They state "...an increase in the surface area that would correlate with the increased villus height and crypt depth may conceivably correspond to an increase in available nutrient transporters, which may translate into increased nutrient uptake" (Although people with IBS have not been shown to have damage to the gut, nucleotide supplementation may improve gut function nonetheless by such a mechanism. However, this is purely speculative, and the present study set out only to determine whether symptoms of IBS were improved with nucleotide supplementation. Further studies, preferably dose-dependent studies, will need to be carried out to determine the mechanism by which any improvements occur.

Conclusion

A neutroceutical product, IntestAidIB, was found to improve six of the measured seven symptoms of IBS compared to both baseline and placebo. However, only abdominal pain and urgency to have a bowel movement showed statistically significant effects at the p < .05 level. Although the improvements in symptoms were consistent, the effects were not strong, and psychological measures showed no improvement either as a result of the experimental condition, or due to the benefits of taking part of a clinical trial. Further studies need to replicate and

Figure 2
2mean symptom severity ratings with 95% C.Is. bar chart showing percentage change from baseline to placebo and experimental conditions Figure 3 bar chart showing percentage change from baseline to placebo and experimental conditions.
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(page number not for citation purposes) extend these results, seeking to clarify the mechanism by which improvements occur.
This one-year study was funded by Wyreside Products Ltd, who provided us with information relating to the product and nucleotides, and the product itself. Wyreside Products Ltd were not involved in the design, running, analysis or write up of the study.CPD and EA designed the study; KFB was employed as a research assistant and was in charge of the day-to-day running of the trial. All contributed to entering the data, data analyses, and writing the article.Competing interests
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A national survey of 'inactive' physicians in the United States of America: enticements to reentry

Ethan A Jewett
Sarah E Brotherton
Holly Ruch-Ross
A national survey of 'inactive' physicians in the United States of America: enticements to reentry
R E S E A R C H Open Access
Background: Physicians leaving and reentering clinical practice can have significant medical workforce implications. We surveyed inactive physicians younger than typical retirement age to determine their reasons for clinical inactivity and what barriers, real or perceived, there were to reentry into the medical workforce. Methods: A random sample of 4975 inactive physicians aged under 65 years was drawn from the Physician Masterfile of the American Medical Association in 2008. Physicians were mailed a survey about activity in medicine and perceived barriers to reentry. Chi-square statistics were used for significance tests of the association between categorical variables and t-tests were used to test differences between means. Results: Our adjusted response rate was 36.1%. Respondents were fully retired (37.5%), not currently active in medicine (43.0%) or now active (reentered, 19.4%). Nearly half (49.5%) were in or had practiced primary care. Personal health was the top reason for leaving for fully retired physicians (37.8%) or those not currently active in medicine (37.8%) and the second highest reason for physicians who had reentered (28.8%). For reentered (47.8%) and inactive (51.5%) physicians, the primary reason for returning or considering returning to practice was the availability of part-time work or flexible scheduling. Retired and currently inactive physicians used similar strategies to explore reentry, and 83% of both groups thought it would be difficult; among those who had reentered practice, 35.9% reported it was difficult to reenter. Retraining was uncommon for this group (37.5%). Conclusion: Availability of part-time work and flexible scheduling have a strong influence on decisions to leave or reenter clinical practice. Lack of retraining before reentry raises questions about patient safety and the clinical competence of reentered physicians.

Background

Physician reentry first achieved recognition as an important workforce policy issue in 2002, with an article by Mark et al. in which physician reentry was defined as "returning, after an extended absence, to the professional activity/clinical practice for which one has been trained, certified or licensed" [1]. Discussions within the United States of America began among federal policy makers, medical and specialty societies, and educators, leading to the American Academy of Pediatrics (AAP) establishing a multi-organizational Physician Reentry into the Workforce Project (Reentry Project) in 2006. In 2008, the AAP and the American Medical Association (AMA) co-sponsored the Physician Reentry to the Workforce Conference to identify steps for the implementation of a formal physician reentry system. Both the Reentry Project and the AMA have produced a number of resources that examine issues related to physician reentry [2][3][4].

Very little data on physician reentry exist. A state-level study by Rimsza in Arizona and a survey of physicians over age 50 by the Association of American Medical Colleges (AAMC) and several specialty societies have provided some important data [5][6][7]. In addition, Freed et al. conducted studies on clinical inactivity among pediatricians and state medical board licensure policies for active and inactive physicians, reporting that 5% of pediatricians were currently inactive, and 12% had at some point experienced a period of clinical inactivity of 12 months or more [8,9]. Because of numerous data gaps identified by the AAP Reentry Project, a survey was fielded in early 2008 on physician reentry into the workforce.

Methods

A questionnaire (see Additional File 1) was developed using an iterative process with input from members of the AAP Reentry Project Workforce Workgroup and others with expertise in physician workforce issues. Questions were based on those used in the AAMC Survey of Physicians Over 50, conducted in 2006. The Physician Workforce Reentry questionnaire included separate sets of questions for physicians not currently active in medicine and those currently active in medicine. The latter were asked about their experiences leaving and reentering the workforce. Areas of inquiry included reasons for not being active in medicine, planning and experiences related to becoming active again, and several demographic questions.

The questionnaire, with a post-paid return envelope, was mailed to a random sample of 4975 out of 14 113 inactive physicians under the age of 65 years drawn from the Physician Masterfile of the American Medical Association (AMA). The Physician Masterfile is a repository of current and historical information on over 1 million physicians in the United States. The Masterfile is used for AMA membership purposes (although not all physicians in the Masterfile are AMA members) as well as for medical credentials verification, and thus keeping the information current is an ongoing activity. The 'inactive' category in the Masterfile includes individuals who work less than 20 hours per week and report that they are retired, semi-retired, temporarily not in practice or not active for other reasons ('active' physicians are those who report being in direct patient care, or in medical education, research, administration or other medical activities, and work more than 20 hours total per week in those activities). Physicians living outside of the United States were not included in the sample. Respondents were offered a small incentive for prompt return of the questionnaire at each of three rounds (a drawing for gift certificates) in January, February and March 2008.

Data were analyzed using the Statistical Package for the Social Sciences, v. 16. A chi-square statistic was used to test for the significance of the association between categorical variables in contingency tables. T-tests were used to test the significance of differences between means. The Institutional Review Board of the AAP judged this study exempt.

Results

After three mailings, a total of 1576 completed surveys were returned. Another 613 surveys were returned marked "deceased" or with bad addresses. The adjusted response rate was 36.1% (1576/4362). Females (42.2%, vs. 32.8% for males, P < 0.001), those over age 60 (38.4%, vs. 34.6% for under 60, P < 0.01), and those with addresses in the Midwest or West of the United States (40.3% Midwest; 39.8% West; 34.5% South; 30.1% Northeast; P < 0.001) all had somewhat elevated response rates.

Respondents were asked, "Are you currently active in medicine?" and were provided examples of activity in medicine (providing clinical services, conducting medical research, medical teaching, health-care administration, and other professional medical activities). Responses that could be selected were: currently active in medicine; fully retired from medicine; not currently active in medicine; and never active in medicine. Although members of the sample were identified as "inactive" at last entry into the Masterfile, 584 (37.0%) reported they were currently active in medicine at the time of our survey, and of these, 358 reported that they had not taken a leave from medicine of 6 months or more. These latter respondents may have been among those who were coded as "inactive" because they had indicated they were semi-retired, or temporarily not in practice at the time of their last AMA census response but may have been working in, for example, medical education (although fewer than 20 hours per week). We excluded them from the analysis, as, for our purposes, they had never been not active in medicine. We included the remaining 226 currently active respondents who reported that they had at some point taken a leave of six months or more from active medicine, and had then reentered medicine. Nine respondents were excluded because they reported they had never been active in medicine, and 47 were excluded for failing to answer the screening question, "Are you currently active in medicine?" This left a final sample of 1162 physicians, divided into three groups: 436 (37.5%) fully retired, 226 (19.4%) reentered, and 500 (43.0%) not currently active. Table 1 reports characteristics of respondents by status. As expected, the fully retired group was older than both of the other two groups. This group also included the lowest proportion of females. Respondents were predominantly married (77.8%), white (86.2%) and of non-Hispanic ethnicity (95.8%). The reentered group was more likely to report excellent or very good health status (75.6% vs. 58.9%, retired, and 59.3%, inactive). The reentered and fully retired groups reported somewhat better financial health than those not currently active. There were no significant differences between the groups for location of medical school (89.4% United States) or for board certification rate (36.5%) (data not shown). The fully retired group had proportionately more general surgeons and physicians in other surgical specialties, while the reentered group had more internists, and the not currently active group had more pediatricians. Table 2 reflects the current experience and status of respondents not currently in the workforce. Over half of those who are fully retired (59.9%) or currently inactive (62.4%) reported last being active in medicine five or more years previously. More of the not currently active group (27.1%) are currently working in non-medical fields than of the fully retired group (16.9%), but substantial majorities of both groups did not report working in another field. The majority (71.2%) of those who are fully retired reported they have no future plans to become active in medicine; of those not currently active in medicine, 55.3% were "not sure" about plans to return. A large majority of both groups reported retaining at least some medical licenses, although the fully retired respondents were somewhat more likely to report that they had not retained any licensure. Among those with specialty or subspecialty certification, similar majorities reported that their certifications were current. Only a minority had retained any medical liability insurance, and this was almost always tail coverage only. Fully retired respondents were slightly more likely to report retaining tail coverage. Those who have reentered active medicine reported a mean of 40.6 hours worked per week. Among these respondents, the average length of time they had been away from active medicine was 4.3 years (not shown). Table 3 reports the reasons that respondents retired or became inactive. The most frequently cited reason for being fully retired or not currently active in medicine was personal health issues (37.8% for both groups); this reason was frequently cited among those who had reentered active medicine as well (28.8%), second only to the need to care for young children (29.6%). Substantial proportions of both fully retired (27.8%) and not currently active (21.4%) physicians cited rising medical malpractice premiums as a reason for leaving active medicine; this was the reason for a substantially smaller proportion of those who had reentered (13.7%). Fully retired physicians were more likely to cite 'hassle factors' (37.4%) and insufficient reimbursement (20.6%) as reasons for leaving medicine. Those not currently active were more likely than the other physicians to cite the need to care for other family members (15.2%).

Reasons for becoming active again are shown in Table 4. Responses were significantly different between those who were fully retired and those who were not currently active; the leading response among the former   group (34.2%) was that "nothing" would lead them to consider becoming active in medicine again. However, when we exclude those who responded that "nothing" would lead them to consider returning to active medicine, the appeal of many of the remaining reasons to return was very similar for the two groups. The most common response among those not currently active was that availability of part-time work or flexible scheduling (51.1%) would lead them to consider becoming active in medicine again; this was also a common, but less frequent, response among those who were fully retired (42.5%, P < 0.05). The availability of part-time work or flexible scheduling was also, by far, the most commonly cited reason for becoming active again among those who had reentered (47.8%). Nearly a quarter (23.7%) of the fully retired respondents had explored becoming active in medicine again; respondents who were not currently active were twice as likely (50.3%) to report having explored returning to medicine (Table 5). Both groups had used similar strategies to explore reentry, and over 80% of both groups felt that it would be difficult. Of those who had reentered active medicine, slightly more than a third (35.9%) reported that it was difficult to reenter. All three groups were likely to identify limited opportunities for parttime or flexible work schedules as a barrier to reentry. Only 37.5% of the reentered group had retraining before entering practice again. Those who had retraining were, on average, out of the workforce significantly longer than those who did not (6.1 years vs. 2.9 years, F = 28.56, P < 0.001; not shown). Very few of those who reported receiving retraining had been involved in what might be described as formal training for reentry; seven had been in a reentry program, and five were in miniresidencies. Many more used continuing medical education, either online (15.9%) or live (22.1%), as their reentry educational program.

Gender analysis

Additional analyses were performed to examine possible gender differences in family and work responsibilities of our respondents. Table 6 presents the reasons for leaving active medicine for those not currently active and those who have reentered active medicine. Among those not currently active, the most striking differences are the much higher proportions of women who indicate the need to care for young children (35.5% vs. 1.6%, P < 0.001) or for other family members (23.4% vs. 7.2%, P < 0.001) as to why they left active practice. Among those who have reentered active practice, men are more likely to report reasons for leaving related to the structure and practice of medicine ('hassle factor', malpractice premiums, lack of professional satisfaction, insufficient reimbursement, practice not viable) and women to report family needs (care for young children, care for other family members). Overall, characteristics of the practice environment were cited infrequently as a reason for leaving among women who have reentered, especially in comparison to men of either group, but also compared to women who are currently inactive.

Both female and male physicians who are not currently active in medicine report diverse reasons that might lead them to consider becoming active in medicine again (Table 7). Women were significantly more likely than men to report availability of part-time work or flexible scheduling (57.7% vs. 41.6%, P < 0.001) and a change in family or personal circumstances (53.2% vs. 30.0%, P < 0.001) as reasons to consider becoming active again. However, among those who have reentered, missing colleagues is also a reason more likely to be reported by female respondents (28.1% vs. 17.0%, P < 0.05). Men were significantly likely to report reentering to pursue a new challenge (24.1% vs. 9.6%, P < 0.001) or an opportunity with less administrative responsibility (16.1% vs. 5.3%, P < 0.01).

Discussion

Concerns have been raised over the last several years about a current or impending physician workforce shortage within the United States [10][11][12]. The potential of inactive or retired physicians to fill a workforce gap has not yet been adequately explored. The cost of mobilizing this 'shadow workforce' of physicians, either in a long-term capacity or to respond to an acute health emergency (e.g. a bioterrorist attack, pandemic, or natural disaster), is likely to be significantly less than that of expanding medical school class sizes and residency training slots. It would also be more efficient, as the timeframe for a reentry training program (variable from program to program) is substantially shorter than for training new physicians from scratch. Reincorporating these physicians into the active workforce would allow the public to benefit from their clinical knowledge and experience and recuperate its financial investment in the initial training of these physicians.

In this study of inactive physicians younger than age 65, the average length of time away from medicine for reentered physicians was 4.3 years. However, over 60% of the currently inactive and retired physicians had been out of medicine 5 or more years, including a fifth to a quarter for more than 10 years. Less than a quarter of currently inactive physicians had firm plans to reenter. Over two thirds of retired physicians and 80% of inactive physicians kept at least one medical license, although this may be relatively easy to achieve as there are few states that require measures of clinical activity to maintain licensure [9].

Given the amount of time out of practice for some of these physicians, formal training in any reentry pathway, if so chosen, is critical. In the last 10 years, major developments in pharmacology, surgical procedures, medical technology, coding, patient privacy, quality improvement-to name just a few-have dramatically altered practice. Increasing demands from the public for documentation of competence will have to be addressed, particularly considering only 37.5% of reentered physicians reported having any retraining before returning to practice. Freed et al. found that pediatricians who had been clinically inactive were less likely compared to those who had been continuously active to agree that a formal reentry program be required after an absence of 2 years [8]. Although this could be the result of overconfidence in one's ability, this could also reflect the Had retraining before reentering medicine Yes n/a n/a 37.5

Online continuing medical education n/a n/a 15.9

Live continuing medical education n/a n/a 22.1

Other n/a n/a 15.5 (35) a P < 0.001, fully retired vs. not currently active. b positive responses; multiple response permitted. c P < 0.05, fully retired vs. not currently active.

difficulty of finding accessible programs. Formal reentry programs are few, and often present financial and geographical barriers, and may likely account for the low incidence of use among survey respondents. Live and online continuing medical education (CME) will, therefore, need to target the learning needs of inactive and reentering physicians and prepare them to face the challenges of a quickly evolving practice environment. An individualized plan to maintain professional credentials and relationships during inactivity, moreover, may  help physicians who are thinking of leaving the workforce for an extended period to anticipate needs for CME, licensure, board certification, credentialing, networking, and other areas, so that they will be able to return to practice more easily. A common perception among inactive physicians is that reentry to practice would be difficult. The actual experience may not be so, as a majority of respondents who had reentered did not find the process difficult. Easy access to information on how to return to practice, as well as guidance on how to maintain professional credentials during inactivity, may help to dispel the misconceptions of retired and inactive physicians. Freeresponse answers on the survey suggest that some inactive physicians perceive the health care system to be too complicated and inflexible to permit them to reenter.

The influence of family responsibilities on the decision to withdraw from clinical practice was particularly felt by female physicians in our study, as found by others [8]. The ability to work part-time or with a flexible schedule was the reason most often cited for being able to reenter by those women who had, and was the most compelling factor that would lead currently inactive women to reenter. The same is true for male physicians, who more often stated they left clinical practice for personal health reasons. The importance of a reduced or flexible schedule for these physicians cannot be overstated. A full one quarter of inactive physicians is working in fields other than medicine, which may be the result of their dissatisfaction with the structure of the current health care system. The 'hassle factor' of practice, rising malpractice premiums, insufficient reimbursement, and professional dissatisfaction were frequently cited by retired and inactive physicians as reasons they left medicine; many of them are now working in areas that, presumably, do not have these negative characteristics. Fewer reentered physicians cited these characteristics as reasons they had initially left medicine. Physicians who choose to return may not have experienced as intensely the hassles of practice-thus their return-or alternatively, have rationalized their return by 'softening' the negative memories of their past practice experience. These physicians are working, on average, 40.6 hours a week, which for many physicians would be a part-time schedule. Such a practice arrangement may serve to reduce the 'pain' of the perceived 'hassles' of the past, and it is clearly more accommodating for those with conflicting family responsibilities. Addressing these structural issues would likely reduce the number of physicians who choose to become inactive in the first place.

Our response rate of 36.1% was low, yet not surprising. Our population of physicians -'inactives' in the AMA's Physician Masterfile -conjures up a cohort of physicians not highly engaged in medicine, with a matching lack of interest in a survey about their inactivity. In addition, over 20% of initial respondents considered themselves active in medicine and had not taken a leave from medicine longer than 6 months, suggesting that there is room for interpretation as to what an inactive physician actually is. We do not generalize our findings to all inactive physicians, who are most likely a particularly nebulous group. We do hope that we have provided a useful start at describing a group of physicians who could be encouraged to stay active in the workforce.

Conclusions

Looking to the future, stakeholders in a stable and robust physician workforce will need to foster flexibility in the health care system, create incentives for physicians to return to practice, and develop resources to facilitate the reentry into the medical workforce. Survey respondents in all categories identified needed improvements in a number of areas, ranging from regulatory requirements-such as state licensure, insurance companies, and employers-to the cost and availability of retraining opportunities and limited opportunities for part-time work and flexible scheduling. It is tempting to speculate on how many of these physicians would have stayed active if part-time or flexible work hours had been available either in practice or in residency. Strategies to retain physicians will, therefore, need to account for the changing demographics of the physician population and their priority to balance their professional and personal lives. Finally, the development and promotion of better educational resources for physicians, especially those that would allow doctors to maintain their professional credentials and access affordable and relevant CME, would enable more predictable departures and reentry. A coordinated and comprehensive agenda that includes educational, research, regulatory and public policy efforts will thus be required to overcome barriers to physician reentry into the medical workforce and to respond effectively to national workforce needs.

Additional material

Table 1
1Characteristics of fully retired, reentered and not currently active respondentsFully Retired
Reentered
Not currently active
All respondents

(n = 436)
(n = 226)
(n = 500)
(n = 1162)

Age, mean, yrs a
60.1
54.9
55.4
57.1

% (n)
% (n)
% (n)
% (n)

Gender a

Female
31.6 (137)
50.4 (114)
4938 (248)
43.1 (499)

Male
68.4 (296)
49.6 (112)
50.2 (250)
56.9 (658)

Marital status

Married/partnered
80.5 (347)
78.2 (176)
75.2 (373)
77.8 (896)
Divorced/separated
10.2 (44)
12.4 (28)
11.1 (55)
11.0 (127)

Widowed
1.9 (8)
1.8 (4)
3.2 (16)
2.4 (28)

Single
7.4 (32)
7.6 (17)
10.5 (52)
8.8 (101)

Race

White
88.9 (378)
86.8 (191)
87.5 (426)
86.2 (1276)

Asian
4.5 (19)
6.4 (14)
5.1 (25)
5.1 (58)

All others
6.6 (28)
6.8 (15)
7.4 (36)
7.0 (79)

Hispanic origin

Yes
4.5 (19)
3.2 (7)
4.3 (21)
4.2 (47)

Overall health status a

Excellent
35.3 (151)
38.2 (86)
35.6 (177)
36.0 (414)

Very good
23.6 (101)
37.3 (84)
23.7 (118)
26.3 (303)

Good
17.5 (75)
17.3 (39)
20.7 (103)
18.9 (217)

Fair
18.2 (78)
6.2 (14)
13.9 (69)
14.0 (161)

Poor
5.4 (23)
0.9 (2)
6.0 (30)
4.8 (55)

Current financial status a

Excellent
29.8 (127)
29.5 (66)
25.2 (124)
27.7 (317)

Very good
30.3 (129)
28.6 (64)
24.3 (120)
27.4 (313)

Good
25.4 (108)
25.0 (56)
29.0 (143)
26.9 (307)

Fair
13.1 (56)
13.4 (30)
13.2 (65)
13.2 (151)

Poor
1.4 (6)
3.6 (8)
8.3 (41)
4.8 (55)

Primary specialty/subspecialty a

Family medicine
15.0 (57)
17.1 (36)
17.6 (79)
16.5 (172)
Pediatrics
8.7 (33)
7.1 (15)
14.0 (63)
10.7 (111)

Internal medicine
9.5 (36)
20.0 (42)
13.6 (61)
13.4 (139)

Ob-gyn
10.8 (41)
7.6 (16)
8.0 (36)
8.9 (93)

General surgery
7.1 (27)
1.4 (3)
3.1 (14)
4.2 (44)

Other medical specialty
29.5 (112)
36.2 (76)
32.7 (147)
32.2 (335)

Other surgical specialty
19.5 (74)
10.5 (22)
11.1 (50)
14.0 (146)

a

P < 0.001.

Jewett et al. Human Resources for Health 2011, 9:7
http://www.human-resources-health.com/content/9/1/7

Table 2
2Physicians who are fully retired or not currently active in medicine (N = 936) How long since last active in medicine aFully retired (n = 436)
Not currently active (n = 500)

% (n)
% (n)

Table 3
3Reasons not currently active or reason became inactive (before reentry) a .Fully retired (n = 436)
Not currently active (n = 500)
Reentered (n = 226)

Reason not currently active
Reason was inactive b

% (n)
% (n)
% (n)

Table 4
4Reasons to consider becoming active in medicine again or reason reentered aFully
retired
(n = 436)

Not currently
active
(n = 500)

Reentered
(n = 226)

Reasons to consider reentry
Reasons for
Reentry b

%
(n)
%
(n)

Table 5
5Efforts to reenter active medicine, not currently active and reentered physicians (n = 1162)Fully retired
(n = 436)

Not currently active
(n = 500)

Reentered
(n = 226)

%
(n)
%
(n)
%
(n)

Table 6
6Reasons left active medicine for those not currently active and those who have reentered, by gender aNot currently active b
Reentered

Female (n = 248)
Male (n = 250)
Female (n = 114)
Male (n = 112)

%
(n)
%
(n)
%
(n)
%
(n)

Personal health issues/concerns
34.3
(85)
41.2
(103)
26.3
(30)
31.3
(35)
'Hassle factor' (ex: paperwork, compliance issues)
27.8
(69)
28.8
(72)
13.2 d
(15)
30.4
(34)

Rising medical malpractice premiums
19.8
(49)
23.2
(58)
3.5 e
(4)
24.1
(27)

Lack of professional satisfaction
21.8
(54)
22.8
(57)
13.2 d
(15)
26.8
(30)

On-call responsibility
19.4
(48)
16.0
(40)
7.9
(9)
16.1
(18)

Insufficient reimbursement rates
13.7
(34)
16.4
(41)
6.1 e
(7)
23.2
(26)
Pursuing a non-medical career
14.1 c
(35)
21.6
(54)
4.4
(5)
8.9
(10)

Need to care for young children
35.5 e
(88)
1.6
(4)
56.1 e
(64)
2.7
(3)

Practice not economically viable
13.3
(33)
10.4
(26)
4.4 d
(5)
17.0
(19)

Improvement in personal/family finances
9.7
(24)
8.8
(22)
5.3
(6)
8.9
(10)

Need to care for other family member(s)
23.4 e
(58)
7.2
(18)
10.5 c
(12)
2.7
(3)

Hard to keep up with clinical advances
7.7 d
(19)
2.4
(6)
0.9
(1)
0

Inadequate practice volume
0.8
(2)
3.2
(8)
0
0.9
(1)

Other
25.8
(64)
32.4
(81)
25.4 c
(29)
39.3
(44)

a

Positive responses; multiple response permitted.
b Two physicians not currently active in medicine did not report their gender.

c

P < 0.05, female vs. male within activity group.
d P < 0.01, female vs. male within activity group.

e

P < 0.001, female vs. male within activity group.

Table 7
7Reasons to reenter active medicine, by gender a Positive responses; multiple response permitted. b Two physicians not currently active in medicine did not report their gender. P < 0.05, male vs. female, within workforce status. d P < 0.01, male vs. female, within workforce status. P < 0.001, male vs. female, within workforce status.Not Currently Active b
Reentered

Reasons to consider becoming
active in medicine again

Reasons reentered
active medicine

Female
(N = 248)

Male
(N = 250)

Female
(N = 114)

Male
(n = 112)

%
(n)
%
(n)
%
(n)
%
(n)

Jewett et al. Human Resources for Health 2011, 9:7 http://www.human-resources-health.com/content/9/1/7
AcknowledgementsThe study was supported by a grant from the American Medical Association Women Physicians Congress through the Joan F. Giambalvo Memorial Scholarship, to aid in data acquisition, survey printing and mailing, and statistical data analysis. We are also grateful to Holly J. Mulvey, MA and Paul H. Rockey, MD for their careful review of the manuscript, for which they received no compensation.Authors' contributions EAJ was principal investigator and acquired the funding. EAJ and HRR designed the survey. SEB and HRR acquired the data. HRR analyzed the data and all three authors interpreted the data, wrote the manuscript, and approved the final version.Competing interestsThe authors declare that they have no competing interests.
. American Medical Association. N State St.American Medical Association, 515 N State St., Chicago, IL 60654, USA.

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