Gut, 1988, 29, 1035-1041
`
`Measurement of gastrointestinal pH profiles in normal
`ambulant human subjects
`
`D F EVANS, G PYE, R BRAMLEY, A G CLARK, T J DYSON,
`AND J D HARDCASTLE
`
`From University Hospital, Queen's Medical Centre, Nottingham
`
`SUMMARY Gastrointestinal (GI) pH has been measured in 66 normal subjects using a pH sensitive
`radiotelemetry capsule passing freely through the gastrointestinal tract. Signals were recorded with
`a portable solid state receiver and recording system, enabling unconstrained measurements with
`normal ambulatory activities for up to 48 h during normal GI transit. Capsule position in the gut was
`monitored by surface location using a directional detector. Gastric pH was highly acidic (range
`l ·0-2· 5) in all subjects. The mean pH in the proximal small intestine was 6·6 (0· 5) for the first hour of
`intestinal recording. By comparison the mean pH in the terminal ileum was 7·5 (0·4) (p<0·OOl). In
`all subjects there was a sharp fall in pH to a mean of 6·4 (0·4) (p<0·OOl) as the capsule passed into the
`caecum. Values are means (SD). pH then rose progressively from the right to the left colon with a
`final mean value of 7·0 (0·7) (p<0·OOl).
`
`portable receiving apparatus1 it is also possible to
`measure GI pH whilst patients are carrying out
`normal daily activities, this being desirable to ensure
`that measurements are recorded under physiological
`conditions in ambulant subjects.
`The aim of our present study was to investigate the
`range of GI pH profiles in a representative group of
`normal subjects in order to establish a base line for
`future reference.
`
`Methods
`
`In recent years there has been increasing interest in
`the pH of the contents of the gastrointestinal tract.
`Previous measurements using aspiration or discrete
`sampling from the stomach or the rectum 1 2 are
`unsatisfactory because of the problems of pooled
`measurements and also of the relative inaccessibility
`of other parts of the gastrointestinal tract.
`Previous workers have attempted to identify
`gastrointestinal pH profiles using a pH sensitive
`radiotelemetry capsule. Bown et a/3 and Meldrum et
`al' used a pH telemetry capsule to plot pH profiles in
`the GI tract. At the time, however, capsules were
`relatively unreliable, suffering from severe drift
`problems and a short life span. 5 Although this work is
`of interest as a guide line to the present study, the
`results must be viewed with some caution because of
`the doubt about the accuracy of the radiocapsules
`which were used.
`With the advent of a new stable, reliable, pH
`sensitive capsule with a longer usable life6 it is now
`possible to monitor pH in the gastrointestinal tract
`with a greater degree of accuracy than was previously
`possible. Additionally, with the introduction of
`
`Address for correspondence: Dr D F Evans. Dept of Surgery. University
`Hospital, Queen's Medical Centre. Nottingham NG7 2UH.
`Received for publication I 9 February I 988.
`
`SUBJECTS
`A total of 72 subjects (51 men) median age 26 years,
`range 20-83 years, with no previous or current
`gastrointestinal disease were recruited for the study
`over an 18 month period. The project was approved
`by the Nottingham Medical School Ethical Com(cid:173)
`mittee and all subjects gave written, informed
`consent before the study.
`Subjects were not restricted to any dietary control
`either before or during the study. This was inten(cid:173)
`tional in order to establish a base line from a mixed
`group of normal individuals with a wide age range
`and a mixed European diet. All subjects ~ere
`interviewed before the study and questioned regard-
`ing dietary habits. Any subject found to have unusual
`CELGENE 2015
`1035
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`1036
`
`Evans, Pye. Bramley. Clark, Dyson, and Hardcastle
`
`Before swallowing, the RTC was calibrated in
`buffers pH 4 and pH 9·2 at 37°C. Transit of solids
`through the GI tract varies widely between indi(cid:173)
`viduals but in most cases the 48 hour recording time
`was sufficient to record pH from the stomach to the
`rectum. At the end of the study the RTC was
`collected in the faeces using a specially designed
`frame . The RTCs were cleaned and resterilised after
`performing a check for pH drift in the calibration
`buffers.
`Data were replayed on a dedicated microprocessor
`controlled replay unit to give a hard copy of pH
`against time. Tbe data were also transferred to an
`ICL2900 mainframe computer via a BBC B micro(cid:173)
`computer and 13-3 cm floppy discs. Group analysis of
`the data could then be done automatically using
`standard programming packages.
`The data transfe.r via a British Telecom land line
`was facilitated using Decce and Kermit software.'""
`this enabling a continuous accurate flow of data to a
`large database without line errors. As each recording
`used approximately 70 kbytes of computer memory.
`mainframe storage was essential in order to compare
`data from a large group of subjects.
`
`LOCALISATION OF RT C
`The capsule was localised in the GI tract utilising two
`distinctive changes during transit.
`First, in order to identify the transition of the
`capsule from the stomach to the small intestine the
`sharp rise in pH signified by the capsule leaving the
`highly acidic environment of the stomach into the
`relatively alkaline environment of the duodenum was
`used as a marker.
`Second, in order to locate the transit of the RTC
`into the caecum and its subsequent passage distally,
`the following method was used.
`The surface position of the RTC was located over
`the abdomen using a highly directional aerial probe
`connected to a portable radiotelemetry receiver
`tuned to the capsule frequency (Remote Control
`Systems, London). The position of the capsule was
`assessed to be where the maximum signal strength of
`transmission was received by the probe. This position
`was recorded on a body map divided into nine
`sections over the abdomen at two to four hourly
`intervals, by the subjects during the study period
`(Fig. 2). The position of the capsule on arrival in the
`caecum was always found to be in the right iliac fossa .
`The capsule then moved round the abdomen from
`the right to the left side during its passage through the
`colon .
`This method has been validated by us using radio
`isotopically labelled capsules and a gamma scinti(cid:173)
`graphy technique. The GI tract was outlined in six
`volunteers with JOO ml water labelled with 10 MBq
`
`Fig. I The [>H sensitive radiopill (inset) and portable solid
`state recording equivmem. The aerial array is worn around
`the abdomen inside a cloth band.
`
`eating patterns - for example. vegetarian or ethnic
`diets - was excluded from the study.
`Gastrointestinal pH was measured using a freely
`moving pH sensitive radiotelemetry capsule (RTC),
`(Remote Control Systems). The capsule consists of
`a glass electrode with integral reference cap and
`battery which has already been widely evaluated in
`measurements in the oesophagus"' (Fig. 1). This
`device enables continuous measurement of pH as the
`RTC passes through the GI tract, it is cable free and
`non-invasive. Signals from the capsule are detected
`by an aerial band worn around the abdomen record(cid:173)
`ing on tO a portable solid state receiver (John Caunt
`Scientific. Oxon). (Fig. I). The recorder samples the
`pH from the capsule ;it 12 sec intervals thus enabling
`continuous totally ambulant monitoring for up to 48
`hours.
`
`

`

`Gastrointestinal pH in man
`
`Surface map - Gastrointestinal pH studies
`
`Name .... J:: <:;..\---\.,,\-;\ ..................................................... ...
`Date ••. 'b).:::.'J: .. :.~ .......... Study No .•.•• 9..~ ............... .
`Sex ...• n ....... Age .. ~'..! ...... Study group •. N9.W..f.'!".h ...
`
`Please record surface position every 2 hours during the daytime.
`You should record the date and time in the first two columns
`and the recorder reading in column 3 with the anatomical zpne
`(see diagram) in the last column.
`
`Left hand side
`
`Date
`
`Time
`
`2J -',-~6 09 ·00
`
`\\
`
`\I
`
`\\
`
`\ I
`
`\\ ·05
`
`\~ · \ 2....
`
`1s-oo
`
`,r:i-- 0~
`
`·pH value
`, -s
`
`b·S
`
`"f-4-
`"7 9
`
`b· 2..
`
`Zone
`
`'C)
`u
`\-\
`
`\--\
`Ei
`
`Fig. 2 Body map used to aid localisation of the RTC as it
`passes through the GI tract.
`
`1037
`
`SIGNAL LOSS
`Periods of signal loss are not uncommon from
`radiocapsules because the rf emission from this type
`of transmitter is highly directional. Studies involving
`free transit through the GI tract are therefore more
`likely to incur greater signal loss than in studies using
`tethered capsules, 12 which have been reported at 10%
`or less. Improvements in aerial design and electronic
`aerial switching units 13 1
`' have been incorporated into
`the solid state recorder and thus signal loss has been
`reduced to an acceptable level for GI transit studies.
`In these studies periods of signal loss of greater than
`75% of the total recording were excluded from the
`analysis.
`
`STUDY PROTOCOL
`At 8 30 am on the morning of the study after an
`overnight fast subjects swallowed the RTC with a
`small quantity of water. The recording equipment
`was applied and the recordings started immediately.
`Subjects were required to remain in the laboratory
`until the RTC had left the stomach, this being
`indicated by a rapid rise in pH from approximately
`pH l ·5 to a pH sustained at greater than 5. After
`gastric transit subjects were allowed to eat and drink
`normally. Subjects were fasted before the study in
`order to prevent delay of transit of the capsule from
`the stomach as it is known that large particles are
`retained in the stomach when associated with a
`meal. i;
`During its passage through the GI tract the
`RTC was localised using the method previously
`described. Subjects were required
`to do
`this
`at approximately two hourly intervals to give an
`accurate location of the capsule. Normal food and
`drink were allowed throughout the study and the
`subjects were permitted to leave the laboratory for
`the remainder of this period. At night subjects
`removed the recording equipment but continued to
`wear the aerial around the abdomen to facilitate
`continuous recording without interrupting sleep. At
`the end of the study period recordings were replayed
`on to the Oxford replay unit to give a hard copy of the
`results and also transferred to the mainframe com(cid:173)
`puter as previously described.
`
`technicium 99m and the RTC labelled with indium"'.
`pH and surface position were continuously moni(cid:173)
`tored during the passage of the RTC through the
`small intestine. In all cases the RTC was seen to enter
`the caecum as outlined by the marker at the same
`time as localisation in the right iliac fossa. Character(cid:173)
`istic pH changes were also noted and subsequently
`used in .the identification of the important ileocaecal
`transition.
`
`ANALYSIS
`pH was sampled at 12 second intervals for the total
`recording period of up to 48 hours during the passage
`of the RTC through the gastrointestinal tract. Thus a
`total of 14 400 data points were possible from each
`subject. In order to analyse data from specific parts of
`the gut the real time clock incorporated in the
`recorder was utilised to define the time periods when
`the RTC was passing through these areas.
`Six specific periods were assessed.
`
`

`

`1038
`
`11
`
`9
`
`Sn-all bowel
`
`Large bowel
`
`I
`I
`
`3
`
`I
`I
`I
`I
`
`.
`
`l Mid colon
`
`I
`I
`I
`I
`I
`
`I
`I
`I
`I
`
`7
`pH
`I
`5 -,
`I
`~:
`I
`: Right
`n, : colon
`.8: l
`_,
`3:
`-, .8
`0
`C,,
`.D
`E'
`Vl: 0
`_,
`0
`E I
`o, E
`~.
`Vl -,
`~·
`Vl
`I
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`I
`·-•
`5, :Q
`.£2,
`0.. I ~ o•
`19
`21
`17
`15
`13
`11
`7
`9
`3
`5
`Time after ingestion of radiotelemetry capsule ( h)
`
`I
`I
`I
`I
`
`, Left
`l colon:
`I
`I
`I
`I
`
`t
`
`RTC
`passed
`
`23
`
`Fig. 3 Gastrointestinal pH profile from a normal subject.
`The position of the capsule in specific areas is labelled
`accordingly.
`
`I Proximal small bowel
`The first hour of recording after the RTC had left the
`acidic environment of the stomach.
`
`2 Distal small bowel
`The last hour of the recording before the RTC was
`assessed to be in the caecum. Ileocaecal transition
`was associated with a sharp fall in pH from a
`relatively high stable ilea! level (Fig. 3), together with
`a simultaneous surface location over the right iliac
`fossa.
`
`3 Mid small bowel
`The time period between 1 and 2 above.
`
`4 Right colon
`The four hour period after transition of the RTC into
`the caecum.
`
`5 Leftco/on
`The four hour period immediately preceding passage
`of the RTC from the rectum, or the last four hours of
`the study period providing the RTC was located in
`the left iliac fossa.
`
`6 Mid colon
`The period between 4 and 5 above.
`A Fortran 77 program has been developed to
`calculate the mean pH from the six epochs. The use
`of mean values was justified as there was a minimum
`of 300 data points for each epoch for each subject.
`A normal distribution was confirmed by an initial test
`
`Evans, Pye, Bramley, Clark, Dyson, and Hardcastle
`
`of skewness (gl <0-05 in all cases). The means
`were grouped. from all the subjects and compared
`statistically using the Student's t test for unpaired
`data.
`
`Results
`
`All subjects completed the study without difficulty or
`complications and were not aware of the capsule
`within the GI tract. Four tests failed because of
`excessive pill drift > l ·0 pH and two tests failed
`because of excessive signal loss leaving a total of 66
`studies suitable for analysis.
`
`SIGNAL LOSS
`Small bowel signal loss accounted for the majority of
`the losses and was greater than 75% in 14 studies.
`These values were not included in the final analysis.
`Median signal loss due to the movement of the
`capsule was 20·4% (range 6-9-64·1%). In these
`studies where multiple measurements were made in
`each bowel segment these signal losses were con(cid:173)
`sidered acceptable.
`
`PILL DRIFT
`A post calibration check for pill drift was only
`possible in 38 of the 72 studies carried out where the
`RTCs were retrieved at the end of the recording
`period. In the remaining studies the RTC remained
`in the colon or rectum beyond the 48 hour study
`period and a post calibration was not considered
`feasible when the capsules were finally retrieved.
`After superficial cleaning in running water the
`RTCs were recalibrated in the two standard buffer
`solutions. The measured values after the tests can be
`seen in Table 1.
`The RTC passed through the small bowel and
`entered the caecum in all 66 subjects but in 16 the
`capsule failed to reach the left side of the colon within
`the 48 hour recording period and so no left sided
`recordings were obtained for these subjects.
`Figure 3 shows a typical pH profile of the GI tract
`in a normal subject. The transition from the acid to
`alkaline environment is clearly seen as the capsule
`passes from the stomach to the small intestine;
`another distinct change can be seen as the RTC
`moves from ileum to caecum.
`
`Table I pH drift as measured by a post test calibration
`
`Initial buffer
`pH(n=38)
`
`Median post calibration p H
`
`Median drift in pH
`
`4·0
`9·2
`
`4-()() (3 ·6-4·8)
`9·40 (9•0 - !0·2)
`
`0·2 (0- 0·6)
`0·3 (0- 1 ·0)
`
`

`

`Gastrointestinal pH in man
`
`1039
`
`1 Proximal small bowel
`The RTC's passage from the stomach to the duo(cid:173)
`denum was associated with a rapid rise in pH to a near
`neutral level. The mean pH in the proximal small
`intestine for the first hour of transit was pH 6·6 (0·5)
`for the whole group (Table 2).
`
`2 Distal small bowel
`The RTC spent a variable period in the right iliac
`fossa before transit into the caecum, typically in zone
`H (Fig. 2). This period was always associated with a
`relatively high value and with little overall fluctuation
`from a stable level (Fig. 3). The mean pH in this area
`was pH 7·5 (0·5). This was significantly higher than
`the proximal small intestine (p<0·OOl) and was
`typical for all subjects studied (Table 2).
`
`3 Mid small bowel
`The period analysed for this segment was necessarily
`of variable duration as it was derived by subtraction
`of the start and end time of periods of 1 and 2 above.
`Thus the period of analysis for each individual varied
`by the total transit of the RTC through the whole
`small bowel (that is, small bowel transit - two hours).
`The mean pH in the mid small bowel was pH 7·4
`(0·4). This was significantly higher than pH in the
`proximal small bowel (p<0-001) but was not differ(cid:173)
`ent from the distal recording.
`
`4 Right colon
`pH in the right colon was measured as the mean of the
`first four hours of colonic recording defined by the
`crieria of surface mapping and pH profile.
`The pH in the right colon showed more coarse
`fluctuations with a significantly lower value than that
`measured in the ileum. The mean pH in the right
`colon was 6·4 (0·6) for the group, this was signifi(cid:173)
`cantly lower than the distal small bowel (p<O·OOl)
`(Table 2).
`
`Table2 Results and statistics of pH measurements in
`normal subjects
`
`Site
`
`Jejenum
`MidSB
`Ileum
`
`Right colon
`Mid colon
`Left colon
`
`Whole SB
`Whole colon
`
`n
`
`55
`52
`58
`
`66
`51
`50
`
`51
`48
`
`Statistical analysis (Student's t test)
`Group
`Group
`
`Jejenum
`MidSB
`Ileum
`Right colon
`Midcolon
`
`Right colon
`Whole SB
`
`MidSB
`Ileum
`Right colon
`Mid colon
`Left colon
`
`Left colon
`Whole colon
`
`MeanpH
`
`Stddev
`
`6·63
`7-41
`7.49
`
`6·37
`6·61
`7.04
`
`7·30
`6·63
`
`df
`
`105
`105
`122
`115
`99
`
`114
`97
`
`0-53
`0-36
`0·46
`
`0-58
`0·83
`0·67
`
`0·34
`0·67
`
`p<
`
`0·001
`nsd
`0·001
`nsd
`0-01
`
`0 ·001
`0 ·001
`
`8·9
`1·0
`11 ·8
`1 ·8
`2·8
`
`5· 1
`6·3
`
`value of 6·6 (0·8). This was significantly higher than
`the left colonic value (p<0·Ol), but similar to the pH
`in the right colon.
`
`TRANSIT TIME
`The mean RTC transit through the small intestine
`was 5·7 hours (2·04) hours. This compares well with
`other methods of small bowel transit methods' 5 and
`confirms the validity of the ileo-caecal transition.
`Whole gut transit of the RTC was calculated in the
`32 subjects where the capsule was passed before the
`study end. The mean whole gut transit for the capsule
`was 23· 3 hours (8· 16).
`
`Discussion
`
`5 Leftcolon
`Left colonic pH was calculated from the 50 subjects
`where the RTC had migrated into the distal colon
`before the end of the recording. In 32 of the subjects
`the RTC was passed per rectum by the end of the
`recording period. In the remainder, the RTC was
`surface located in zone J (Fig. 2), this denoting
`sigmoid colon or rectal positioning. In both groups
`therefore pH could be calculated from the final four
`hours of the recording period.
`The mean pH in the left colon was 7 ·0 (0· 7) for the
`50 subjects. This value was significantly higher than
`in the right colon (p<0·00l) (Table 2).
`
`6 Midcolon
`Mid colonic pH, calculated as described had a mean
`
`This study has evaluated a new method of measure(cid:173)
`ment of pH in the gastrointestinal tract in ambulant
`subjects using an improved pH sensitive radio(cid:173)
`telemetry capsule and portable receiving system. pH
`profiles were measured in a group of normal subjects
`in order to establish base lines for comparative
`studies. All studies were completed without diffi(cid:173)
`culty, the majority being available for analysis. In
`some cases the pH pill was retained in the right colon
`until the end of the study period, thus demonstrating
`the wide variety of transit in normal, asymptomatic
`subjects. All capsules were eventually passed without
`complications.
`The pH measured by the RTC is that of the
`intraluminal contents in direct contact with the
`electrode. It is not the mucosa! pH which is being
`
`

`

`1040
`
`Evans, Pye, Bramley, Clark, Dyson, and Hardcastle
`
`measured but that of the luminal contents which is in
`direct contact with the mucosa. In the fluid or
`semi fluid of the small bowel the pH profile will reflect
`the homogeneity of the environment. This is similarly
`the case even in the solid or semisolid of the distal
`colon where there was considerable local variation in
`measured pH. If the electrode were to become
`embedded in solid matter in the distal colon then the
`pH recording would become static which was a
`phenomenon not seen in our studies.
`Meldrum et al' carried out similar studies in only
`two normal controls and seven patients with miscel(cid:173)
`laneous GI disorders. pH profiles were similar to
`those found in our study although some of the
`extreme values of their measurements were outside
`those found by us. This may be due either to their
`capsule instability or the population sampled .
`A major problem in the methodology in this type
`of study has been the difficulty of location of the RTC
`in the bowel lumen, especially in the less well
`definable loops of the small intestine. We found that
`by classifying the gut into zones which were positively
`identifiable and with the added evidence from surface
`location and pH, measurements could be relied upon
`as accurate.
`The significance of gastrointestinal pH levels is as
`yet not clear. Intraluminal contents of the GI tract
`may well influence the development of diseases such
`as inflammatory bowel diseases or tumour formation .
`Thornton10 postulated that intraluminal colonic pH
`might be important in the development of colonic
`neoplasia. Epidemiological evidence1' and labora(cid:173)
`
`tory studies1"-2" suggest that degradation of meta(cid:173)
`bolites of digestion may be carcinogenic. As these
`reactions are enzymic and pH dependent then pH
`in the colon may be an important factor in neoplastic
`development.
`Further evidence of the association between
`cancer incidence and colonic effluent has come from
`faecal pH measurements in low and high risk popula(cid:173)
`tions'1 although faecal pH measurements may not be
`the most accurate means of assessment of colon pH.
`Furthermore the measurement of faecal pH gives no
`information about pH in the right side of the colon.
`As colorectal neoplasia is found in 90% of cases in the
`distal left colon'' then differences from right to left
`may be important. Obviously a free moving radiopill
`would give this information and studies are under(cid:173)
`way23 to assess differences in right and left sided pH in
`patients with colorectal neoplasia, different dietary
`groups and low and high risk populations.
`If GI pH be a dynamic measurement influenced by
`diet and lifestyle then one might expect not only
`differences between individual dietary groups but
`also changes during dietary fibre manipulation.
`Bown et al' investigated the effects of lactulose, an
`
`undigestible disaccharide, on colon pH in volunteers.
`They used an early version of the pH capsule similar
`to Meldrum, but in non-ambulant subjects. The
`results from their studies showed similar trends to our
`own in control studies and a significant acidification
`in the right colon between lactulose and controls, but
`less so on the left side.
`In a recent study in our departmene a similar
`effect was demonstrated using Fybogel (Reckitt and
`Colman), a colonic bulking agent. In this study,
`however, pH was altered significantly
`in both
`proximal and distal colon . If, therefore, it is easily
`possible to alter pH in the large bowel and bowel pH
`is subsequently shown to be important as a protection
`against neoplasia then it would be highly desirable to
`know which substances are most efficient in altering
`pH in the colon .
`There is increasing interest in the development of
`enteric coatings of drugs'''" in order to deliver topic(cid:173)
`ally acting substances to the distal gut to improve
`efficiency and efficacy. Many of these coatings have a
`pH dependent dissolution, thus it becomes important
`to know not only the pH profile along the GI tract,
`but also whether there are any differences in disease
`states, such as inflammatory conditions, in order to
`target the drugs correctly.
`There is also some evidence to suggest that there
`are substantial changes in GI pH associated with
`malabsorption in cystic fibrosis ." Such changes may
`therefore exist in other chronic bowel disorders such
`as ulcerative colitis and Crohn's disease. These
`questions as well as many others concerning the
`influence of gut pH remain unanswered. The
`methodology described in this paper may be helpful
`in the search for such information.
`
`References
`
`Reynolds JR, Walt RP, Hardcastle JD, Clark AG ,
`Smart HL, Langman M. 24 hour intragastric pH:
`Continuous monitoring or nasogastric aspiration?
`Digestion 1986; 33: 219- 44.
`2 Pietrousti A, Caprilli R, Guilano M , Serrano S, Vita S.
`Faecal pH in co!orectal cancer. Ital J Gastroenterol 1985 ;
`17: 88-91.
`3 Bown BL, Gibson JA, Sladen GE, Hicks B, Dawson
`AM. Effect of Lactulose and other laxatives on ileal and
`colonic pH as measured by a radiotelemetry device. Gut
`1974; 15:999- 1004.
`4 Meldrum SJ , Watson BW , Riddle HC, Brown RL,
`Sladen GE. pH profile of the gut as measured by a
`radiotelemetry capsule. Br Med J 1972; 2: 104- 6.
`5 Colson RH, Watson BW . Improved techniques in the
`construction of pH sensitive radiopills. In: Amlander
`CJ , Macdonald DW, eds . A handbook of biotelemetry
`and radio/racking. Oxford: Pergammon Press, 1979:
`209-12 .
`
`

`

`Gastrointestinal pH in man
`
`1041
`
`6 Colson RH, Watson BW, Fairclough PD, et al. An
`accurate, long term pH sensitive radiopill for ingestion
`and implantation. Biotelemetry Patient Monitg 1981; 4:
`213-27.
`7 Evans OF, Jones JA, Hardcastle JD. Ambulatory
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