CT

colonography

optimisation

diagnostic

performance

and

patient

acceptability

of

reduced-laxative

regimens

using

barium-based

faecal

tagging

To

establish

the

optimum

barium-based

reduced-laxative

tagging

regimen

prior

to

CT

colonography

-LRB-

CTC

-RRB-

Ninety-five

subjects

underwent

reduced-laxative

-LRB-

g

g

magnesium

citrate

-RRB-

CTC

prior

to

same-day

colonoscopy

and

were

randomised

to

one

of

four

tagging

regimens

using

ml

w/v

barium

sulphate

regimen

A

four

doses

B

three

doses

C

three

doses

plus

ml

barium

sulphate

or

D

three

doses

plus

ml

diatriazoate

megluamine

Patient

experience

was

assessed

immediately

after

CTC

and

week

later

Two

radiologists

graded

residual

stool

-LRB-

none/scattered

to

circumference

-RRB-

and

tagging

efficacy

for

stool

-LRB-

untagged

to

tagged

-RRB-

and

fluid

-LRB-

untagged

layered

tagged

-RRB-

noting

the

HU

of

tagged

fluid

Preparation

was

good

-LRB-

segments

graded

-RRB-

although

best

for

regimen

D

-LRB-

P

-RRB-

Across

all

regimens

stool

tagging

quality

was

high

-LRB-

mean

-RRB-

and

not

significantly

different

among

regimens

The

HU

of

layered

tagged

fluid

was

higher

for

regimens

C/D

than

A/B

-LRB-

P

-RRB-

Detection

of

cancer

-LRB-

n

-RRB-

polyps

mm

-LRB-

n

-RRB-

and

mm

-LRB-

n

-RRB-

was

and

respectively

with

only

four

false

positives

mm

Reduced

preparation

was

tolerated

better

than

full

endoscopic

preparation

by

Reduced-laxative

CTC

with

three

doses

of

ml

barium

sulphate

is

as

effective

as

more

complex

regimens

retaining

adequate

diagnostic

accuracy

Introduction

Full

bowel

purgation

remains

a

major

cause

of

discomfort

prior

to

any

colonic

investigation

-LSB-

-RSB-

Furthermore

fluid

and

electrolyte

imbalance

may

occur

following

aggressive

cleansing

-LSB-

-RSB-

A

potential

advantage

of

computed

tomography

colonography

-LRB-

CTC

-RRB-

over

colonoscopy

is

the

ability

to

reduce

laxative

requirements

while

maintaining

diagnostic

accuracy

-LSB-

-RSB-

Reduced

laxative

regimens

often

incorporate

orally

ingested

contrast

agents

to

tag

or

label

residual

fluid

and

faecal

residue

The

ideal

tagging

regimen

remains

controversial

but

must

be

safe

effective

simple

and

well

tolerated

In

many

respects

barium

is

an

ideal

tagging

agent

it

has

an

established

safety

profile

is

relatively

palatable

produces

minimal

side

effects

and

is

effective

for

tagging

solid

residue

-LSB-

-RSB-

Previous

work

has

shown

adequate

tagging

may

be

achieved

using

low

volumes

of

w/v

barium

although

the

ideal

volume

and

dosing

regimen

has

not

been

fully

established

-LSB-

-RSB-

Furthermore

efficacy

for

fluid

tagging

has

been

questioned

-LSB-

-RSB-

with

some

investigators

preferring

iodine-based

contrast

either

alone

or

in

combination

claiming

a

more

homogeneous

fluid

opacification

better

suited

to

digital

subtraction

-LSB-

-RSB-

We

aimed

to

establish

the

optimum

barium-based

reduced-laxative

faecal

and

fluid-tagging

regimen

to

assess

patient

acceptability

and

to

document

diagnostic

accuracy

compared

to

an

enhanced

colonoscopic

reference

standard

Materials

and

methods

Full

ethical

committee

approval

was

obtained

and

all

subjects

gave

written

informed

consent

Consecutive

patients

were

recruited

from

those

scheduled

to

undergo

afternoon

diagnostic

colonoscopy

for

symptoms

suggestive

of

colorectal

neoplasia

-LRB-

change

in

bowel

habit

rectal

bleeding

unexplained

weight

loss

or

palpable

abdominal

mass

-RRB-

from

one

of

three

institutions

Patients

were

excluded

if

below

age

or

if

they

had

a

known

diagnosis

of

inflammatory

bowel

disease

Eligible

patients

were

invited

to

undergo

CTC

at

am

prior

to

same

day

colonoscopy

and

were

randomised

via

a

computer

random

number

generator

to

one

of

four

reduced-laxative

regimens

using

barium-based

faecal

tagging

-LSB-

ml

w/v

barium

sulphate

suspension

-LRB-

Tagitol

V

EZEM

Lake

Success

NY

-RRB-

-RSB-

-LRB-

Fig.

-RRB-

For

each

of

the

regimens

patients

followed

a

low-residue

diet

days

before

the

CTC

-LRB-

avoiding

fatty

food

milk

and

vegetables

-RRB-

The

day

prior

to

CTC

all

patients

were

allowed

a

low-residue

meal

kit

-LRB-

Nutraprep

EZEM

-RRB-

and

ingested

the

same

reduced-laxative

protocol

-LSB-

g

sachet

of

senna

granules

-LRB-

Reckitt

Benckiser

Healthcare

Hull

UK

-RRB-

at

am

and

g

magnesium

citrate

-LRB-

Lo-So

prep

EZEM

-RRB-

at

pm

-RSB-

This

laxative

regimen

was

defined

as

reduced

given

the

normal

laxative

preparation

prior

to

colonoscopy

at

the

recruiting

institutions

includes

an

additional

g

of

magnesium

citrate

-LRB-

see

below

-RRB-

Overall

fluid

intake

was

restricted

to

l

the

day

prior

to

CTC

for

all

four

regimens

Fig.

of

reduced-laxative

tagging

regimens

Taken

with

meals

from

low

residue

meal

kit

-LRB-

single

star

-RRB-

Diluted

in

mls

of

water

-LRB-

double

stars

-RRB-

In

an

attempt

to

improve

fluid

tagging

two

regimens

-LRB-

C

and

D

-RRB-

included

either

an

additional

ml

w/v

barium

sulphate

-LRB-

Readi-Cat

Banana

Smoothie

EZEM

-RRB-

or

ml

meglumine

amidotrizoate

-LRB-

g

sodium

g

meglumine

amidotrizoate

per

ml

Gastrograffin

Schering

-RRB-

diluted

in

ml

of

water

taken

h

prior

to

CTC

-LSB-

-RSB-

Patients

otherwise

took

nothing

by

mouth

the

day

of

the

CTC

Study

power

The

study

was

powered

to

detect

a

difference

in

tagging

quality

-LRB-

see

below

-RRB-

across

the

four

regimens

Based

on

pilot

data

the

interclass

correlation

coefficient

between

colonic

segments

was

calculated

to

be

and

it

was

calculated

that

a

sample

size

of

per

group

was

required

-LRB-

alpha

at

power

-RRB-

CT

colonography

Prone

and

supine

CTC

was

performed

with

automated

insufflation

-LRB-

Protocol

pump

EZEM

-RRB-

-LSB-

-RSB-

using

either

a

-LRB-

GE

Lightspeed

Plus

GE

Milwaukee

WI

USA

kV

mA

mm

collimation

slice

reconstruction

mm

pitch

n

patients

-RRB-

or

scanner

-LRB-

Siemens

Somatom

Sensation

SEMS

Germany

kV

mA

mm

collimation

pitch

n

patients

-RRB-

One

of

three

experienced

radiologists

-LRB-

each

with

experience

of

at

least

CTC

cases

with

endoscopic

validation

-RRB-

evaluated

the

datasets

immediately

after

the

examination

using

a

dedicated

workstation

with

proprietary

software

-LRB-

Vitrea

Vital

Images

Minnetonka

MN

USA

-RRB-

and

noted

the

segmental

location

of

any

polyps

or

cancers

on

a

study

report

sheet

together

with

lesion

size

measured

using

electronic

callipers

applied

to

the

MPR

best

showing

the

maximum

diameter

The

choice

of

reporting

radiologist

for

each

patient

was

dependent

upon

the

particular

recruiting

institution

and

availability

on

the

day

of

the

scan

All

three

radiologists

used

a

primary

approach

with

reserved

for

problem

solving

Colonoscopy

Immediately

following

CTC

patients

ingested

a

further

g

of

magnesium

citrate

in

order

to

complete

the

normal

endoscopic

cleansing

regimen

prior

to

afternoon

colonoscopy

Colonoscopy

was

performed

as

per

usual

practice

by

one

of

five

experienced

endoscopists

on

average

h

-LRB-

range

h

-RRB-

after

the

CTC

scan

Segmental

unblinding

was

used

as

described

previously

-LSB-

-RSB-

using

the

sealed

CTC

report

In

brief

the

CTC

report

was

handed

to

the

endoscopy

nurse

accompanying

the

patient

CTC

findings

were

revealed

to

the

colonoscopist

by

the

nurse

on

a

segmental

basis

-LRB-

caecum

to

rectum

-RRB-

once

examination

of

each

colonic

segment

was

deemed

complete

during

extubation

of

the

colon

If

CTC

suggested

a

lesion

had

been

missed

the

segment

was

re-intubated

and

a

second

segmental

examination

performed

There

was

no

time

limit

imposed

on

the

colonoscopist

for

this

second

look

All

polyps

were

photographed

their

sizes

estimated

by

direct

comparison

to

adjacent

open

biopsy

forceps

and

then

excised

for

histology

where

possible

Polyp

correlation

Polyps

found

at

CTC

were

deemed

true

positive

if

a

corresponding

polyp

was

found

in

the

same

or

adjacent

segment

at

endoscopy

and

if

the

estimated

size

of

the

polyp

was

within

of

the

endoscopic

measurement

Patient

experience

Immediately

following

CTC

a

questionnaire

was

administered

-LSB-

-RSB-

investigating

patient

experience

of

the

reduced-laxative

tagging

regimen

-LRB-

Table

-RRB-

Patient

responses

were

compared

to

a

historical

cohort

of

symptomatic

patients

recruited

from

the

same

endoscopy

lists

during

a

prior

study

comparing

CTC

to

colonoscopy

-LSB-

-RSB-

As

part

of

this

prior

study

patients

had

undergone

full

bowel

preparation

-LSB-

g

senna

granules

and

two

doses

of

g

magnesium

citrate

-LRB-

total

g

-RRB-

prior

to

CTC

-RSB-

and

had

completed

the

same

questionnaire

under

similar

circumstances

Table

questionnaire

questions

and

responses

in

comparison

to

historical

controls

undergoing

full

bowel

preparationVariableResponseReduced

preparationa

n

-LRB-

-RRB-

Historical

controls

-LSB-

full

preparation

-RSB-

b

n

-LRB-

-RRB-

P

valueHow

did

you

find

understanding

prep

-LRB-

-RRB-

-LRB-

-RRB-

Fairly

-LRB-

-RRB-

-LRB-

-RRB-

How

did

you

find

swallowing

-LRB-

-RRB-

-LRB-

-RRB-

Fairly

-LRB-

-RRB-

-LRB-

-RRB-

Quite

-LRB-

-RRB-

-LRB-

-RRB-

How

did

you

find

coping

with

special

diet?No

-LRB-

-RRB-

-LRB-

-RRB-

Bit

-LRB-

-RRB-

-LRB-

-RRB-

Very

-LRB-

-RRB-

-LRB-

-RRB-

How

did

you

feel

after

-LRB-

-RRB-

-LRB-

-RRB-

Unwell/very

-LRB-

-RRB-

-LRB-

-RRB-

Did

you

have

any

abdominal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Did

you

have

any

nausea/vomiting

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Did

you

experience

any

faintness

or

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Did

you

experience

any

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Did

you

experience

any

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Did

you

experience

any

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Did

you

experience

any

sleep

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

How

many

times

did

you

open

your

bowel

after

starting

the

preparation

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Not

applicable

-LRB-

not

asked

-RRB-

g

senna

plus

g

magnesium

g

senna

plus

g

magnesium

citrate

One

week

later

a

follow-up

questionnaire

-LRB-

Table

-RRB-

was

mailed

to

the

current

study

cohort

investigating

tolerance

of

the

preparation

prior

to

CT

and

preference

if

any

over

the

full

preparation

required

for

subsequent

colonoscopy

Table

and

responses

to

follow-up

questionnaire

pertaining

to

patient

tolerance

and

preferencesVariableResponsePatient

number

-LRB-

-RRB-

How

did

you

find

taking

the

low-residue

diet?No

-LRB-

-RRB-

Moderately

-LRB-

-RRB-

Very

-LRB-

-RRB-

How

did

you

find

drinking

the

tagging

liquid?No

-LRB-

-RRB-

Moderately

-LRB-

-RRB-

Very

-LRB-

-RRB-

How

did

you

tolerate

the

preparation

before

-LRB-

-RRB-

Fairly

-LRB-

-RRB-

-LRB-

-RRB-

How

did

you

tolerate

the

additional

preparation

prior

to

colonoscopy

compared

to

that

before

the

CT?No

-LRB-

-RRB-

More

-LRB-

-RRB-

Much

-LRB-

-RRB-

How

did

you

find

the

preparation

before

CTC

compared

to

the

full

colonoscopy

preparation?Much

-LRB-

-RRB-

-LRB-

-RRB-

No

-LRB-

-RRB-

Grading

of

bowel

preparation

Two

experienced

radiologists

-LRB-

both

with

experience

of

over

validated

CTC

cases

-RRB-

in

consensus

retrospectively

reviewed

all

CTC

examinations

grading

the

quality

of

preparation

and

success

of

tagging

Observers

were

unaware

of

the

tagging

regimen

used

and

divided

the

colon

into

six

segments

-LRB-

rectum

to

caecum

-RRB-

for

analysis

-LSB-

-RSB-

Grading

of

residual

stool

-LRB-

irrespective

of

tagging

status

-RRB-

was

based

on

the

percentage

of

total

mucosal

circumference

coated

on

an

axial

image

For

each

colonic

segment

the

slice

with

the

most

residual

stool

was

used

to

assign

the

score

Scores

were

as

follows

no

residue

or

scattered

residue

coating

of

or

thin

circumferential

film

less

than

mm

in

depth

coating

of

to

coating

Grading

of

residual

fluid

-LRB-

irrespective

of

tagging

status

-RRB-

was

based

on

the

maximum

anteroposterior

-LRB-

AP

-RRB-

diameter

of

the

colonic

lumen

submerged

For

each

colonic

segment

the

slice

with

the

most

residual

fluid

was

used

to

assign

the

score

Scores

were

as

follows

no

fluid

AP

diameter

to

AP

diameter

AP

diameter

The

quality

of

tagging

for

solid

residue

and

fluid

was

scored

using

a

system

adapted

from

Lefere

at

al.

-LSB-

-RSB-

and

assigned

for

supine

and

prone

positions

combined

for

each

colonic

segment

Residual

stool

was

divided

into

that

measuring

mm

and

mm

-LRB-

based

on

measurement

using

electronic

calipers

-RRB-

and

the

number

of

stool

balls

mm

was

counted

for

each

patient

Readers

assessed

the

percentage

of

total

residual

stool

volume

-LRB-

for

each

size

category

-RRB-

that

had

been

tagged

for

each

colonic

segment

Scores

were

assigned

as

follows

all

residual

stool

untagged

to

tagged

to

tagged

to

tagged

to

tagged

Tagging

of

residual

fluid

was

scored

as

follows

fluid

untagged

layered

tagging

-LRB-

a

mix

of

tagging

densities

in

one

fluid

level

with

a

denser

dependent

layer

and

visibly

less

dense

non-dependent

layer

-LRB-

Fig.

-RRB-

fluid

homogeneously

tagged

-LRB-

single

tagging

density

-RRB-

The

density

of

tagged

fluid

-LRB-

in

HU

-RRB-

was

also

recorded

by

taking

the

average

of

three

regions

of

interest

drawn

in

the

deepest

fluid

pool

for

each

colonic

segment

If

fluid

was

layered

-LRB-

Fig.

-RRB-

the

minimum

and

maximum

HU

was

recorded

Finally

observers

recorded

their

confidence

using

a

percentage

score

that

based

on

the

bowel

preparation

they

would

be

able

to

exclude

a

polyp

mm

in

day-to-day

clinical

practice

for

each

colonic

segment

Fig.

female

with

change

in

bowel

habit

Axial

CT

colonographic

image

demonstrating

layering

of

contrast

-LRB-

arrow

-RRB-

within

tagged

fluid

Statistical

analysis

Preliminary

data

analysis

revealed

skewed

data

for

most

bowel

preparation

and

tagging

variables

and

thus

scores

were

combined

for

subsequent

analysis

For

residue

scores

were

grouped

into

either

a

score

of

or

a

score

of

or

more

For

residual

fluid

scores

were

grouped

into

scores

of

or

scores

of

Scores

for

solid

residue

tagging

were

grouped

into

those

of

or

Fluid

tagging

scores

were

grouped

into

scores

of

or

score

of

Logistic

regression

was

then

applied

adjusting

for

colonic

segment

to

compare

the

four

regimens

overall

and

to

compare

the

distal

-LRB-

rectum

sigmoid

descending

-RRB-

and

proximal

colon

-LRB-

transverse

ascending

and

caecum

-RRB-

In

addition

the

prevalence

of

layering

within

tagged

fluid

was

compared

on

a

per-patient

basis

using

the

chi-squared

test

Tagged

fluid

attenuation

was

compared

using

linear

regression

following

log

transformation

of

the

data

Confidence

scores

for

excluding

a

polyp

mm

were

grouped

as

either

or

and

compared

using

logistic

regression

For

all

regression

analyses

robust

standard

errors

were

employed

to

account

for

interdependency

between

colonic

segments

and

scan

position

-LRB-

supine/prone

-RRB-

in

the

same

patient

Results

were

expressed

as

the

odds

of

the

outcome

under

consideration

compared

to

regimen

A.

Questionnaire

responses

were

compared

using

Fischer

's

exact

test

Overall

categorical

per-polyp

and

per-patient

data

are

presented

using

descriptive

statistics

Given

the

relatively

low

polyp

incidence

-LRB-

and

thus

low

statistical

power

-RRB-

comparative

statistics

for

polyp

detection

were

not

performed

across

regimens

False-positive

numbers

were

compared

using

one-way

ANOVA

Results

A

total

of

patients

were

recruited

-LRB-

female

mean

age

years

range

years

-RRB-

with

and

randomised

to

regimens

A

to

D

respectively

Seventy-seven

and

patients

were

recruited

from

institutions

and

respectively

Overall

-LRB-

-RRB-

had

a

change

in

bowel

habit

-LRB-

-RRB-

had

rectal

bleeding

-LRB-

-RRB-

had

non-specific

weight

loss

and

-LRB-

-RRB-

had

a

clinically

palpable

abdominal

mass

Bowel

preparation

The

percentage

of

segments

-LRB-

supine

and

prone

combined

-RRB-

assigned

a

score

of

for

residual

solid

residue

-LRB-

i.e.

no

residue

or

scattered

-RRB-

was

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

for

regimens

A

to

D

respectively

and

on

average

there

were

and

stool

balls

mm

per

patient

The

improved

quality

of

preparation

in

regimen

D

reached

statistical

significance

-LSB-

odds

of

score

-LRB-

CI

-RRB-

P

-RSB-

Across

all

regimens

the

distal

colon

was

significantly

better

prepared

then

the

proximal

colon

-LRB-

P

-RRB-

For

example

the

number

of

segments

assigned

at

least

a

score

of

for

solid

residue

in

the

caecum

was

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

for

regimens

A

to

D

respectively

compared

to

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

for

the

rectum

The

percentage

of

segments

-LRB-

supine

and

prone

in

total

-RRB-

assigned

a

score

of

or

for

residual

fluid

was

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

for

regimens

A

to

D

respectively

There

was

no

significance

difference

between

groups

either

overall

or

between

the

proximal

and

distal

colon

-LRB-

P

-RRB-

Tagging

quality

Tagging

quality

was

generally

good

-LRB-

mean

tagging

score

-RRB-

-LRB-

Fig.

-RRB-

While

there

was

weak

evidence

of

improved

proximal

colonic

tagging

for

residue

mm

for

regimens

C

and

D

-LRB-

P

-RRB-

overall

there

was

no

difference

in

the

efficacy

of

solid

residue

tagging

across

regimens

-LRB-

Table

-RRB-

Fig.

male

with

unexplained

rectal

bleeding

Axial

CT

colonographic

image

showing

homogeneous

tagging

of

stool

mm

-LRB-

arrow

-RRB-

and

mm

-LRB-

arrowhead

-RRB-

in

sizeTable

of

tagging

of

solid

residue

according

to

size

and

regimenSolid

residue

sizeColon

segmentsRegimenMean

tagging

score

-LRB-

SD

-RRB-

Odds

ratio

-LRB-

CI

-RRB-

aP

value

mmAll

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Distal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Proximal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

mmAll

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Distal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Proximal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

SD

Standard

deviationaOdds

of

tagging

score

of

-LRB-

best

-RRB-

compared

to

regimen

AbRectum

sigmoid

and

descending

colon

combinedcTransverse

ascending

colon

and

caecum

combined

The

average

per-segment

fluid

tagging

score

was

-LRB-

SD

-RRB-

-LRB-

SD

-RRB-

-LRB-

SD

-RRB-

and

-LRB-

SD

-RRB-

for

regimens

A

to

D

respectively

The

odds

of

homogeneous

tagging

-LRB-

i.e

score

-RRB-

did

not

differ

across

the

four

regimens

either

overall

or

between

the

proximal

and

distal

colon

-LRB-

P

-RRB-

In

total

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

of

segments

respectively

contained

non-tagged

fluid

-LRB-

score

-RRB-

-LRB-

Fig.

-RRB-

Fig.

female

with

change

in

bowel

habit

Axial

CT

colonographic

image

showing

failure

of

fluid

tagging

-LRB-

arrow

-RRB-

-LRB-

grade

-RRB-

Overall

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

of

patients

receiving

regimens

A

to

D

respectively

had

at

least

one

segment

with

layering

of

tagged

fluid

-LRB-

P

-RRB-

-LRB-

Fig.

-RRB-

Fluid

tagging

density

In

terms

of

mean

HU

of

the

tagged

fluid

-LRB-

excluding

the

least

tagged

layer

if

tagging

was

layered

-RRB-

there

was

no

significant

difference

among

the

four

regimens

either

overall

or

between

the

proximal/distal

colon

-LRB-

P

-RRB-

The

mean

HU

of

tagged

fluid

was

-LRB-

SD

-RRB-

-LRB-

SD

-RRB-

-LRB-

SD

-RRB-

and

-LRB-

SD

-RRB-

for

regimens

A

to

D

respectively

However

in

those

segments

with

layering

of

contrast

the

maximum

attenuation

-LRB-

HU

-RRB-

of

the

least

tagged

layer

was

significantly

higher

for

regimens

C

and

D

than

for

regimens

A

and

B

-LRB-

P

-RRB-

-LSB-

-LRB-

SD

-RRB-

-LRB-

SD

-RRB-

-LRB-

SD

-RRB-

and

-LRB-

SD

-RRB-

for

regimens

A

to

D

respectively

-RSB-

Patient

experience

A

total

of

of

-LRB-

-RRB-

patients

completed

the

questionnaire

-LRB-

Table

-RRB-

although

responses

were

incomplete

in

Demographic

data

for

the

present

study

cohort

-LRB-

female

mean

age

years

range

years

-RRB-

were

not

significantly

different

from

the

historical

controls

-LRB-

female

mean

years

range

years

-RRB-

-LSB-

-RSB-

Other

than

sleep

disturbance

-LRB-

worse

after

reduced

preparation

-RRB-

-LRB-

P

-RRB-

there

was

no

significant

difference

in

reported

tolerance

of

the

reduced

and

full

bowel

preparation

regimens

for

any

of

the

factors

tested

Follow-up

questionnaire

Sixty-nine

-LRB-

-RRB-

patients

returned

the

follow-up

questionnaire

-LRB-

Table

-RRB-

Overall

tolerated

the

reduced

preparation

regimen

well

or

fairly

well

and

most

-LRB-

-RRB-

found

drinking

the

tagging

agents

acceptable

Although

most

-LSB-

-LRB-

-RRB-

-RSB-

found

the

additional

preparation

required

for

colonoscopy

no

problem

a

majority

-LRB-

-RRB-

found

the

reduced

preparation

regimen

better

or

much

better

than

the

full

preparation

required

for

colonoscopy

Diagnostic

performance

Five

patients

-LRB-

one

each

from

regimens

A

B

and

C

and

two

from

regimen

D

-RRB-

were

excluded

from

the

performance

analysis

due

to

a

new

diagnosis

of

inflammatory

bowel

disease

-LRB-

all

presenting

with

rectal

bleeding

-RRB-

A

further

patient

-LRB-

from

regimen

B

-RRB-

was

excluded

after

refusing

colonoscopy

Of

the

remaining

patients

had

either

normal

colonoscopy

or

diminutive

polyps

-LRB-

mm

-RRB-

only

and

had

at

least

one

polyp

mm

or

cancer

Colonoscopy

was

incomplete

in

-LRB-

-RRB-

reaching

the

transverse

colon

in

sigmoid

in

and

hepatic

flexure

in

Reasons

for

failure

were

obstructing

stricture

-LRB-

-RRB-

severe

diverticulosis

-LRB-

-RRB-

tortuous

colon

-LRB-

-RRB-

and

pain

-LRB-

-RRB-

Only

those

segments

visualised

at

colonoscopy

were

included

in

the

assessment

of

diagnostic

performance

Per

polyp

analysis

In

total

there

were

polyps

mm

-LRB-

all

adenomatous

-RRB-

polyps

mm

-LRB-

adenomatous

hyperplastic

-RRB-

and

polyps

mm

-LRB-

were

recovered

for

histology

of

which

were

adenomatous

hyperplastic

and

normal

mucosa

-RRB-

One

polyp

and

two

polyps

were

found

only

on

re-look

endoscopy

after

segmental

unblinding

of

the

CTC

report

No

CTC-detected

polyps

were

classified

as

false

positives

due

to

segmental

or

size

mismatching

with

colonoscopy

Summed

across

regimens

A

D

detection

of

cancer

polyps

mm

mm

and

mm

was

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

respectively

-LRB-

Fig.

-RRB-

-LRB-

Table

-RRB-

In

total

there

were

only

four

false

positives

mm

-LRB-

Figs.

and

-RRB-

with

no

significant

difference

between

regimens

-LRB-

P

-RRB-

Fig.

male

with

rectal

bleeding

Axial

CT

colonographic

image

demonstrating

a

rectal

cancer

-LRB-

arrow

-RRB-

Note

the

adjacent

well-tagged

residue

-LRB-

arrowheads

-RRB-

Table

detection

overall

and

according

to

tagging

regimenRegimenPatient

numberDetection

cancer

n

-LRB-

-RRB-

Detection

mm

n

-LRB-

-RRB-

Detection

mm

n

-LRB-

-RRB-

Detection

mm

n

-LRB-

-RRB-

False

positive

mm

nFalse

positive

mm

nFalse

positive

mm

nP

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Not

applicableaComparison

of

false

positives

across

regimens

using

one-way

ANOVAbIn

patient

with

confirmed

polypcIn

patient

with

confirmed

polypFig

male

with

change

in

bowel

habit

Axial

CT

colonographic

image

of

a

filling

defect

in

the

rectum

reported

as

a

polyp

No

lesion

was

found

at

colonoscopy

with

segmental

unblinding

suggesting

the

lesion

was

untagged

faecal

residueFig

number

of

false

positives

according

to

size

and

regimen

-LRB-

n

-RRB-

Per

patient

analysis

Across

all

regimens

sensitivity

specificity

positive

and

negative

predictive

values

for

detection

of

patients

with

any

lesion

mm

were

and

respectively

-LRB-

Table

-RRB-

Table

performance

overall

and

according

to

tagging

regimenRegimenPatient

numberPolyp

mm

incl

cancer

n

-LRB-

-RRB-

-LSB-

confidence

limits

-RSB-

Polyp

mm

incl

cancer

n

-LRB-

-RRB-

-LSB-

confidence

limits

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

NPV

Negative

predictive

value

PPV

positive

predictive

valueaPrevalence

of

abnormality

bPrevalence

of

abnormality

Reader

confidence

The

mean

segmental

observer

confidence

for

excluding

a

polyp

mm

was

and

for

regimens

A

to

D

respectively

There

was

no

significant

difference

among

the

regimens

either

overall

or

in

the

proximal/distal

colon

-LRB-

P

-RRB-

Discussion

In

accordance

with

previous

studies

-LSB-

-RSB-

we

found

patients

in

general

preferred

reduced

preparation

to

the

full

purgation

required

for

colonoscopy

although

this

preference

was

much

less

than

expected

-LRB-

only

preferred

the

reduced

preparation

-RRB-

We

defined

the

laxation

used

as

reduced

in

comparison

to

the

endoscopic

preparation

used

at

our

institutions

which

includes

an

additional

g

of

magnesium

citrate

We

also

used

senna

rather

than

bisacodyl

as

used

by

Lefere

et

al.

-LSB-

-RSB-

Both

are

stimulant

laxatives

with

a

similar

mode

of

action

and

effect

at

the

doses

administrated

although

senna

was

preferred

as

it

is

widely

used

at

our

institutions

However

a

combination

of

g

of

senna

and

g

magnesium

citrate

clearly

produces

relatively

strong

purgation

reflected

in

the

induced

symptoms

-LRB-

of

patients

opened

their

bowels

over

five

times

-RRB-

and

marginal

patient

preference

It

would

therefore

seem

reasonable

to

study

reduced

laxation

further

perhaps

omitting

the

senna

and/or

reducing

the

dose

of

magnesium

citrate

It

is

however

important

to

realise

that

whereas

normally

patients

took

no

solids

by

mouth

for

h

prior

to

colonoscopy

in

the

present

study

they

were

permitted

to

eat

from

a

low-residue

diet

kit

an

issue

we

did

not

specifically

address

with

our

questionnaires

thereby

potentially

underestimating

this

benefit

Recent

data

have

questioned

whether

CTC

is

actually

better

tolerated

than

conventional

colonoscopy

-LSB-

-RSB-

but

because

full

bowel

purgation

is

often

cited

by

patients

as

the

worst

part

of

any

colonic

examination

-LSB-

-RSB-

it

is

assumed

that

reduced

laxative

CTC

will

improve

patient

compliance

-LRB-

notably

in

a

screening

setting

-RRB-

However

this

assumption

has

not

been

proven

in

prospective

trials

and

we

can

not

extrapolate

the

preferences

we

found

into

increased

compliance

with

CTC

Indeed

it

could

be

argued

the

laxative

regimen

we

used

would

have

relative

little

impact

on

compliance

in

a

screening

setting

given

the

side-effect

profile

The

overall

quality

of

bowel

preparation

was

good

with

all

four

regimens

producing

at

least

of

segments

with

either

no

or

scattered

residue

only

This

is

similar

to

data

reported

by

Lefere

et

al.

-LSB-

-RSB-

who

combined

g

of

magnesium

citrate

with

biscodyl

tablets

and

suppository

Interestingly

regimen

D

which

included

ml

meglumine

amidotrizoate

resulted

in

significantly

better

preparation

than

the

other

regimens

possibility

due

to

a

washing

effect

of

the

iodine-based

contrast

incorporating

solid

residue

into

a

more

fluid

solution

-LSB-

-RSB-

Although

we

used

a

small

dose

meglumine

amidotrizoate

is

also

known

to

have

a

laxative

effect

that

may

also

have

added

to

the

superior

cleansing

Tagging

of

solid

residue

was

in

general

good

with

no

significant

difference

between

the

regimens

tested

This

suggests

barium-based

tagging

can

be

simplified

to

a

regimen

only

when

combined

with

reduced

cathartic

preparation

Similarly

all

regimens

produced

an

average

tagged

fluid

density

of

around

HU

Recent

phantom

data

suggest

that

although

submerged

polyp

conspicuity

is

optimised

at

HU

it

remains

good

at

HU

-LSB-

-RSB-

We

did

however

demonstrate

that

fluid

tagging

could

be

manipulated

by

additional

oral

agents

on

the

morning

of

CTC

As

it

is

non-miscible

with

water

barium

often

produces

a

layering

effect

with

lower

attenuation

fluid

sitting

above

denser

barium

Although

there

was

no

significant

difference

in

layering

among

the

regimens

the

addition

of

morning

barium

sulphate

or

meglumine

amidotrizoate

significantly

increased

the

attenuation

of

the

non-dependent

fluid

layer

It

is

arguable

whether

this

will

have

significant

impact

clinically

not

least

because

fluid

moves

between

supine

and

prone

positions

but

it

may

have

implications

for

subtraction

software

Zalis

et

al.

have

recently

demonstrated

suboptimal

subtraction

when

high-density

barium

is

used

as

the

sole

tagging

agent

-LSB-

-RSB-

It

is

interesting

to

speculate

whether

manipulation

of

fluid

tagging

could

optimise

subtraction

It

should

also

be

noted

our

regimen

mildly

restricted

fluid

intake

the

day

prior

to

CTC

which

may

have

influenced

our

fluid

tagging

results

One

major

advantage

of

barium

as

a

tagging

agent

is

its

inert

nature

and

safety

Although

iodinated

contrast

medium

produces

more

homogeneous

fluid

tagging

this

is

mainly

of

clinical

importance

if

subtraction

software

is

being

used

While

the

risks

of

allergy

to

oral

iodinated

contrast

are

minimal

adverse

events

do

occur

-LSB-

-RSB-

Our

data

suggest

good

results

can

be

achieved

using

only

barium

Ultimately

diagnostic

performance

is

the

best

measure

of

the

success

of

any

reduced-laxative

protocol

Reassuringly

overall

we

prospectively

found

high

diagnostic

performance

when

compared

to

colonoscopy

Our

data

confirm

again

that

full

bowel

preparation

is

not

required

to

maintain

diagnostic

accuracy

for

CTC

assuming

adequate

reader

training

-LSB-

-RSB-

Importantly

there

were

only

four

false

positive

polyps

over

mm

and

across

all

regimens

the

positive

predictive

value

for

patients

with

any

lesion

mm

and

mm

was

and

respectively

-LRB-

Table

-RRB-

Our

study

does

have

weaknesses

It

could

be

argued

that

we

used

a

relatively

harsh

laxative

regime

given

that

good

results

have

been

reported

without

any

laxative

at

all

-LSB-

-RSB-

However

the

vast

majority

of

CTC

worldwide

is

still

performed

using

full

bowel

preparation

and

in

the

authors

opinion

significant

changes

in

practice

are

most

likely

to

follow

gradual

reduction

of

purgation

which

allows

radiologists

to

become

comfortable

with

this

approach

However

we

acknowledge

that

if

there

was

good

evidence

of

acceptable

performance

data

using

CTC

without

prior

laxation

this

may

well

rapidly

become

widely

implemented

by

the

CTC

community

We

compared

patient

symptomatology

with

a

historical

cohort

and

although

well-matched

in

demographic

terms

we

can

not

exclude

bias

completely

We

did

not

instruct

colonoscopists

to

grade

the

quality

of

bowel

preparation

and

in

particular

the

influence

of

retained

barium

on

mucosal

visibility

although

no

endoscopy

failed

due

to

incomplete

bowel

preparation

It

could

be

argued

that

reduced

preparation

regimens

are

best

suited

to

increase

compliance

in

asymptomatic

screening

populations

-LSB-

-RSB-

However

for

pragmatic

reasons

we

used

symptomatic

patients

as

we

do

not

have

access

to

a

large

screening

population

Finally

although

we

were

able

to

show

high

diagnostic

performance

for

reduced-preparation

CTC

overall

given

the

relatively

low

number

of

polyps

we

were

unable

to

meaningfully

compare

across

regimens

In

conclusion

a

combination

of

reduced

laxatives

and

a

simple

tagging

regimen

based

on

barium

sulphate

the

day

prior

to

CTC

maintains

acceptable

diagnostic

accuracy

Three

doses

of

ml

w/v

barium

sulphate

are

as

effective

as

more

complex

regimens

but

fluid

tagging

can

be

manipulated

by

addition

of

dilute

barium

or

meglumine

amidotrizoate

on

the

morning

of

CTC

the

latter

also

reducing

the

volume

of

residual

stool

O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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