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BMJ

Scrooge

and

intellectual

property

rights

A

medical

prize

fund

could

improve

the

financing

of

drug

innovations

t

Christmas

we

traditionally

retell

Dickens

's

story

of

Scrooge

who

cared

more

for

money

than

for

his

fellow

human

beings

What

would

we

think

of

a

Scrooge

who

could

cure

diseases

that

blighted

thousands

of

people

's

lives

but

did

not

do

so

Clearly

we

would

be

horrified

But

this

has

increasingly

been

happening

in

the

name

of

economics

under

the

innocent

sounding

guise

of

intellectual

property

rights

Intellectual

property

differs

from

other

property

restricting

its

use

is

inefficient

as

it

costs

nothing

for

another

person

to

use

it

Thomas

Jefferson

America

's

third

president

put

it

more

poetically

than

modern

economists

-LRB-

who

refer

to

zero

marginal

costs

and

non-rivalrous

consumption

-RRB-

when

he

said

that

knowledge

is

like

a

candle

when

one

candle

lights

another

it

does

not

diminish

from

the

light

of

the

first

Using

knowledge

to

help

someone

does

not

prevent

that

knowledge

from

helping

others

Intellectual

property

rights

however

enable

one

person

or

company

to

have

exclusive

control

of

the

use

of

a

particular

piece

of

knowledge

thereby

creating

monopoly

power

Monopolies

distort

the

economy

Restricting

the

use

of

medical

knowledge

not

only

affects

economic

efficiency

but

also

life

itself

We

tolerate

such

restrictions

in

the

belief

that

they

might

spur

innovation

balancing

costs

against

benefits

But

the

costs

of

restrictions

can

outweigh

the

benefits

It

is

hard

to

see

how

the

patent

issued

by

the

US

government

for

the

healing

properties

of

turmeric

which

had

been

known

for

hundreds

of

years

stimulated

research

Had

the

patent

been

enforced

in

India

poor

people

who

wanted

to

use

this

compound

would

have

had

to

pay

royalties

to

the

United

States

In

the

Uruguay

round

trade

negotiations

concluded

in

the

establishment

of

the

World

Trade

Organization

which

imposed

US

style

intellectual

property

rights

around

the

world

These

rights

were

intended

to

reduce

access

to

generic

medicines

and

they

succeeded

As

generic

medicines

cost

a

fraction

of

their

brand

name

counterparts

billions

could

no

longer

afford

the

drugs

they

needed

For

example

a

year

's

treatment

with

a

generic

cocktail

of

AIDS

drugs

might

cost

-LRB-

-RRB-

compared

with

for

the

brand

name

version

Billions

of

people

living

on

a

day

can

not

afford

though

they

might

be

able

to

scrape

together

enough

for

the

generic

drugs

And

matters

are

getting

worse

New

drug

regimens

recommended

by

the

World

Health

Organization

and

second

line

defences

that

need

to

be

used

as

resistance

to

standard

treatments

develops

can

cost

much

more

Developing

countries

paid

a

high

price

for

this

agreement

But

what

have

they

received

in

return

Drug

companies

spend

more

on

advertising

and

marketing

than

on

research

more

on

research

on

lifestyle

drugs

than

on

life

saving

drugs

and

almost

nothing

on

diseases

that

affect

developing

countries

only

This

is

not

surprising

Poor

people

can

not

afford

drugs

and

drug

companies

make

investments

that

yield

the

highest

returns

The

chief

executive

of

Novartis

a

drug

company

with

a

history

of

social

responsibility

said

We

have

no

model

which

would

-LSB-

meet

-RSB-

the

need

for

new

drugs

in

a

sustainable

way

You

ca

n't

expect

for-profit

organizations

to

do

this

on

a

large

scale

Research

needs

money

but

the

current

system

results

in

limited

funds

being

spent

in

the

wrong

way

For

instance

the

human

genome

project

decoded

the

human

genome

within

the

target

timeframe

but

a

few

scientists

managed

to

beat

the

project

so

they

could

patent

genes

related

to

breast

cancer

The

social

value

of

gaining

this

knowledge

slightly

earlier

was

small

but

the

cost

was

enormous

Consequently

the

cost

of

testing

for

breast

cancer

vulnerability

genes

is

high

In

countries

with

no

national

health

service

many

women

with

these

genes

will

fail

to

be

tested

In

countries

where

governments

will

pay

for

these

tests

less

money

will

be

available

for

other

public

health

needs

A

medical

prize

fund

provides

an

alternative

Such

a

fund

would

give

large

rewards

for

cures

or

vaccines

for

diseases

like

malaria

that

affect

millions

and

smaller

rewards

for

drugs

that

are

similar

to

existing

ones

with

perhaps

slightly

different

side

effects

The

intellectual

property

would

be

available

to

generic

drug

companies

The

power

of

competitive

markets

would

ensure

a

wide

distribution

at

the

lowest

possible

price

unlike

the

current

system

which

uses

monopoly

power

with

its

high

prices

and

limited

usage

The

prizes

could

be

funded

by

governments

in

advanced

industrial

countries

For

diseases

that

affect

the

developed

world

governments

are

already

paying

as

part

of

the

health

care

they

provide

for

their

citizens

For

diseases

that

affect

developing

countries

the

funding

could

be

part

of

development

assistance

Money

spent

in

this

way

might

do

as

much

to

improve

the

wellbeing

of

people

in

the

developing

world

and

even

their

productivity

as

any

other

that

they

are

given

A

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Editorials

The

medical

prize

fund

could

be

one

of

several

ways

to

promote

innovation

in

crucial

diseases

The

most

important

ideas

that

emerge

from

basic

science

have

never

been

protected

by

patents

and

never

should

be

Most

researchers

are

motivated

by

the

desire

to

enhance

understanding

and

help

humankind

Of

course

money

is

needed

and

governments

must

continue

to

provide

money

through

research

grants

along

with

support

for

government

research

laboratories

and

research

universities

The

patent

system

would

continue

to

play

a

part

for

applications

for

which

no

one

offers

a

prize

The

prize

fund

should

complement

these

other

methods

of

funding

it

at

least

holds

the

promise

that

in

the

future

more

money

will

be

spent

on

research

than

on

advertising

and

marketing

of

drugs

and

that

research

concentrates

on

diseases

that

matter

Importantly

the

medical

prize

fund

would

ensure

that

we

make

the

best

possible

use

of

whatever

knowledge

we

acquire

rather

than

hoarding

it

and

limiting

usage

to

those

who

can

afford

it

as

Scrooge

might

have

done

It

is

a

thought

we

should

keep

in

mind

this

Christmas

Joseph

E

Stiglitz

professor

-LRB-

-RRB-

Columbia

University

New

York

NY

USA

Competing

interests

JES

was

chief

economist

of

the

World

Bank

from

to

and

a

member

and

then

chairman

of

President

Clinton

's

Council

of

Economic

Advisers

from

to

He

won

the

Nobel

Prize

for

economics

in

M

decins

Sans

Fronti

res

People

not

getting

the

treatment

they

need

to

stay

alive

Newer

AIDS

drugs

unaffordable

and

unavailable

Geneva

MSF

November

Andrew

J.

Novartis

chief

in

warning

on

cheap

drugs

Financial

Times

September

Stiglitz

JE

Making

globalization

work

New

York

WW

Norton

Hollis

A.

Optional

rewards

for

new

drugs

for

developing

countries

Geneva

World

Health

Organization

April

Pogge

T.

Human

rights

and

global

health

a

research

program

Metaphilosophy

-LRB-

-RRB-

Love

J.

Submission

of

CPTech

to

IGWG

November

doi

bmj

Shooting

down

the

NHS

reform

track

Why

ministers

can

not

pull

the

brake

even

if

they

want

to

nyone

who

wants

to

understand

the

process

of

change

in

England

's

National

Health

Service

could

do

worse

than

to

summon

up

memories

of

watching

the

bobsleigh

events

in

the

winter

Olympics

The

bobsleigh

riders

hurtle

down

the

icy

track

at

great

speed

There

is

nothing

they

can

do

to

change

direction

Their

course

and

goal

is

determined

for

them

and

there

is

little

they

can

do

apart

from

keeping

their

balance

and

their

nerve

as

they

round

the

terrifying

bends

If

they

were

to

brake

suddenly

regretting

that

they

had

ever

got

themselves

involved

in

such

a

high

risk

sport

disaster

would

strike

The

policy

makers

engaged

in

transforming

the

NHS

are

in

a

similar

position

to

those

bobsleigh

riders

Once

the

government

had

decided

on

the

new

three

part

model

for

the

NHS

the

course

was

set

In

turn

the

logic

of

the

model

competing

providers

active

purchasers

and

money

following

the

patient

drives

policy

and

allows

for

no

deviation

or

delay

Moreover

just

like

the

bobsleigh

riders

ministers

are

racing

against

the

clock

For

the

time

being

extra

billions

are

flowing

into

the

NHS

at

an

unprecedented

rate

But

the

government

's

commitment

to

this

increased

rate

of

spending

ends

in

Thereafter

the

annual

increment

in

expenditure

may

be

less

generous

especially

if

the

extra

investment

does

not

produce

commensurate

improvements

So

in

effect

a

deadline

exists

for

the

new

model

to

show

that

it

is

working

that

ministerial

rhetoric

about

greater

efficiency

improved

responsiveness

and

rising

quality

is

being

turned

into

reality

and

for

the

NHS

to

turn

into

a

political

asset

not

a

political

liability

for

the

government

The

government

may

well

have

stumbled

into

devising

the

new

model

incrementally

But

once

adopted

the

model

drives

the

adopters

Success

for

the

government

depends

on

combining

the

elements

of

competition

purchasing

and

payment

by

results

delay

in

introducing

any

element

puts

the

whole

model

at

risk

This

interdependence

of

the

various

strands

of

policy

explains

the

relentless

pace

of

change

with

ministers

deaf

to

all

pleas

for

adopting

a

less

hectic

pace

for

fear

of

derailing

the

whole

exercise

If

competition

is

to

exist

private

providers

must

be

tempted

to

enter

the

market

even

if

they

have

to

be

paid

over

the

odds

For

active

purchasing

to

occur

primary

care

trusts

must

be

strengthened

through

amalgamation

even

if

this

means

adding

to

organisational

disruption

in

the

NHS

If

payment

by

results

is

to

provide

the

dynamic

for

greater

efficiency

and

responsiveness

providers

and

purchaser

trusts

must

balance

their

books

even

if

this

leads

to

staffing

cuts

and

painful

service

reconfigurations

The

point

about

fiscal

balance

helps

to

explain

the

past

and

has

implications

for

the

future

The

NHS

has

always

been

the

envy

of

the

world

for

its

ability

to

contain

spending

within

the

annual

budgetary

limits

set

by

the

Treasury

But

collective

discipline

went

hand

in

hand

with

individual

indulgence

An

opaque

system

of

loans

and

brokerage

allowed

some

trusts

to

accumulate

large

year-on-year

deficits

so

smoothing

out

turbulence

and

avoiding

the

political

embarrassment

of

painful

cutbacks

However

this

system

is

incompatible

with

the

new

model

If

trusts

are

not

required

to

stay

within

budget

if

they

can

be

rescued

when

needed

where

is

the

incentive

to

be

efficient

and

responsive

Which

is

why

a

minor

financial

blip

in

which

turned

out

to

be

a

deficit

of

-LRB-

-RRB-

the

loose

change

in

a

budget

produced

disproportionate

shock

waves

and

pain

in

the

NHS

as

ministers

cranked

up

the

pressure

on

trusts

to

balance

their

books

Moreover

this

will

be

the

story

of

the

NHS

in

even

though

its

budget

is

rising

to

the

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Editorials

paradoxical

spectacle

of

famine

amid

financial

plenty

will

continue

In

dealing

with

this

situation

ministers

have

as

argued

little

room

for

manoeuvre

if

they

are

not

to

subvert

their

own

policy

goals

They

might

well

wish

to

avoid

the

political

costs

of

an

epidemic

of

reconfiguration

widely

perceived

-LRB-

sometimes

accurately

so

-RRB-

as

a

euphemism

for

service

cuts

But

because

the

new

model

is

designed

to

produce

a

slimmer

fitter

NHS

able

to

cope

with

a

more

rigorous

financial

environment

after

they

have

to

accept

and

justify

such

an

especially

as

the

new

model

will

like

all

policy

experiments

generate

a

new

set

of

problems

while

dealing

with

old

ones

Most

conspicuously

in

terms

of

public

visibility

it

will

give

a

new

edge

to

the

question

of

how

best

to

contain

-LRB-

ration

-RRB-

demands

within

existing

and

foreseeable

future

financial

constraints

In

the

emerging

NHS

provider

trusts

have

for

the

first

time

an

incentive

to

maximise

activity

to

attract

more

patients

to

encourage

hospital

admissions

and

to

increase

the

number

of

procedures

This

is

what

payment

by

results

means

In

theory

strong

primary

care

trusts

will

offer

a

countervailing

power

to

aggressive

providers

But

they

lack

political

legitimacy

when

it

comes

to

taking

tough

rationing

decisions

Perversely

the

government

introduced

an

element

of

public

representation

into

foundation

trusts

but

resisted

the

stronger

argument

for

giving

primary

care

trusts

a

democratic

dimension

And

just

how

are

primary

care

trusts

to

restrain

demand

As

waiting

lists

fall

so

this

traditional

method

of

discouraging

demands

loses

much

of

its

potency

As

patient

choice

takes

hold

so

the

ability

of

primary

care

trusts

to

control

the

direction

of

demand

will

weaken

Enter

practice

based

budgets

fundholding

resurrected

which

are

meant

to

create

a

framework

in

which

general

practitioners

will

take

resource

constraints

into

account

in

their

clinical

decisions

when

managing

patients

Enter

also

referral

assessment

centres

wherein

general

practitioners

are

responsible

for

reviewing

the

referral

decisions

of

their

colleagues

To

a

non-medical

observer

of

the

NHS

this

last

development

which

has

attracted

surprisingly

little

attention

carries

one

step

further

a

process

that

has

gradually

transformed

relations

between

the

government

and

the

medical

profession

over

the

past

decade

or

so

Increasingly

the

government

has

relied

upon

the

medical

profession

collectively

to

hold

individual

members

to

account

In

effect

collective

autonomy

has

been

maintained

and

collective

responsibility

has

grown

while

individual

autonomy

has

been

increasingly

circumscribed

And

here

we

come

to

a

paradox

The

government

's

dependence

on

the

medical

profession

collectively

will

increase

as

the

new

model

NHS

emerges

as

the

success

of

the

model

depends

largely

on

the

profession

's

active

commitment

to

managing

resources

and

introducing

new

patterns

of

service

delivery

Yet

at

the

same

time

the

government

seems

set

to

challenge

the

notion

of

collective

autonomy

by

implementing

Donaldson

's

proposals

for

substituting

appointed

members

for

those

at

present

elected

to

the

General

Medical

Council

by

the

profession

and

for

hiving

off

the

educational

role

of

the

GMC

to

a

separate

body

This

would

greatly

dilute

the

notion

of

professional

self

regulation

not

a

strategy

calculated

to

generate

enthusiastic

cooperation

The

way

in

which

this

paradox

is

resolved

whether

policy

makers

come

to

see

doctors

as

the

solution

to

or

the

cause

of

the

NHS

's

problems

may

well

decide

how

the

perilous

run

down

the

icy

track

ends

Rudolf

Klein

visiting

professor

-LRB-

-RRB-

London

School

of

Economics

London

Competing

interests

declared

Klein

R

The

new

politics

of

the

NHS

ed

Oxford

Radcliffe

Publishing

Carvel

J.

Hewitt

vows

to

quit

if

NHS

fails

to

stay

within

budget

Guardian

November

Chief

Medical

Officer

Good

doctors

safer

patients

London

Department

of

Health

Publications/PublicationsPolicyAndGuidance/PublicationsPolicyAnd

GuidanceArticle/fs/en

chk

doi

bmj

BE

What

stays

constant

at

the

heart

of

medicine

There

is

no

one

division

of

medicine

by

which

we

know

and

another

by

which

we

act

he

expression

the

science

and

art

of

medicine

is

much

misunderstood

Too

often

the

parts

of

medicine

termed

as

its

art

seem

to

amount

to

no

more

than

good

communication

skills

or

to

what

was

once

called

a

good

bedside

manner

No

doubt

patients

feel

better

and

perhaps

even

do

better

when

they

think

their

doctor

cares

about

them

But

stories

also

abound

of

well

dressed

doctors

with

smooth

manners

but

little

knowledge

who

have

gained

and

sometimes

abused

the

trust

of

their

patients

While

the

historical

record

is

replete

with

such

examples

and

almost

every

practitioner

will

be

able

to

call

others

to

mind

it

is

the

fictional

creations

of

writers

such

as

Moli

re

Shaw

and

Cronin

that

have

most

amused

and

scandalised

us

To

provide

a

counterweight

to

such

social

frauds

all

kinds

of

programmes

and

regulations

have

been

introduced

to

make

competence

and

knowledge

more

important

to

professional

advancement

than

manners

social

graces

and

public

regard

But

to

identify

the

art

of

medicine

with

artfulness

is

to

fall

into

a

set

of

modern

confusions

It

is

now

common

to

think

of

art

as

something

done

by

artists

and

the

arts

as

a

different

field

of

activity

than

science

sometimes

even

a

field

of

activity

opposed

to

science

But

in

the

older

uses

of

the

English

language

art

meant

something

else

The

first

entry

for

the

word

in

the

Oxford

English

Dictionary

defines

it

as

skill

in

doing

anything

as

the

result

of

knowledge

and

practice

citing

uses

from

the

medieval

period

to

the

T

BMJ

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century

In

other

words

the

art

of

medicine

is

not

about

appearance

at

the

expense

of

substance

but

rather

the

way

in

which

knowledge

is

related

to

advice

and

treatment

It

was

in

this

sense

that

art

was

used

in

book

titles

of

the

and

centuries

for

example

The

Art

of

Curing

Diseases

-LRB-

Gideon

Harvey

-RRB-

and

A

Plain

Introduction

to

the

Art

of

Physick

-LRB-

John

Peachey

-RRB-

Such

titles

indicate

that

when

dealing

with

patients

doctors

do

not

simply

apply

knowledge

but

also

engage

the

art

of

medicine

The

problem

might

be

reformulated

in

this

way

medicine

requires

knowledge

of

universals

and

of

the

application

of

them

to

particular

instances

as

embodied

in

individual

patients

Or

as

it

was

put

a

millennium

ago

by

the

famed

Avicenna

When

we

say

that

practice

proceeds

from

theory

we

do

not

mean

that

there

is

one

division

of

medicine

by

which

we

know

and

another

distinct

there

from

by

which

we

act

as

many

examining

this

problem

suppose

We

mean

instead

that

these

two

aspects

are

both

sciences

but

one

dealing

with

the

basic

problems

of

knowledge

the

other

with

the

mode

of

operation

of

these

principles

The

first

aspect

was

called

science

proper

the

second

art.

Medical

art

may

be

a

form

of

knowledge

that

is

more

probabilistic

than

the

demonstrative

certainty

of

science

but

it

is

crucially

important

knowledge

nevertheless

Moreover

all

commentators

on

this

art

emphasise

that

its

exercise

requires

not

only

knowledge

of

content

but

something

called

judgment

Philosophically

speaking

the

importance

of

judgment

is

today

highlighted

in

phenomenology

aesthetics

virtue

ethics

and

emotional

intelligence

Judgment

is

downplayed

in

instrumentalist

and

functionalist

reasoning

where

pride

of

place

is

given

to

the

rationality

of

calculation

impartiality

and

disinterestedness

On

their

own

attributes

of

disinterestedness

can

lead

to

coldly

experimenting

with

cases

clinical

judgment

on

the

other

hand

requires

attending

to

a

patient

While

the

science

of

medicine

continues

to

be

advanced

by

laboratory

research

and

the

statistical

investigations

of

evidence

based

medicine

the

parts

of

it

termed

the

art

are

developing

too

and

remain

a

source

of

resistance

to

bureaucratic

assessment

and

benchmarking

For

thousands

of

years

the

question

of

how

best

to

associate

the

universal

and

the

particular

has

always

been

the

real

doctor

's

dilemma

No

formulae

however

good

can

ever

obscure

the

second

part

of

medical

knowledge

which

comes

from

the

exercise

of

clinical

judgment

Harold

J

Cook

professor

and

director

-LRB-

h.cook@ucl.ac.uk

-RRB-

Wellcome

Trust

Centre

for

the

History

of

Medicine

at

UCL

London

Competing

interests

declared

Grant

E

ed

Avicenna

's

canon

In

A

source

book

in

medieval

science

Cambridge

MA

Harvard

University

Press

doi

bmj

Mistletoe

as

a

treatment

for

cancer

Has

no

proved

benefit

and

can

cause

harm

ost

doctors

in

the

United

Kingdom

will

be

surprised

to

learn

from

a

case

reported

in

this

week

's

BMJ

of

a

use

for

mistletoe

-LRB-

Viscum

album

-RRB-

that

has

nothing

to

do

with

Christmas

Some

patients

with

cancer

inject

themselves

with

extract

of

mistletoe

in

the

hope

of

improving

their

condition

In

continental

Europe

at

least

different

mistletoe

preparations

are

available

In

Europe

most

cancer

patients

use

such

extracts

at

a

total

expense

of

about

-LRB-

-RRB-

each

year

and

in

Germany

the

insurance

system

pays

for

this

treatment

A

Google

search

-LRB-

November

-RRB-

showed

that

websites

promote

or

mention

mistletoe

as

a

treatment

for

cancer

This

much

publicity

may

mean

that

many

cancer

patients

in

the

UK

will

try

mistletoe

in

the

future

or

ask

their

doctor

about

it

It

is

therefore

timely

to

discuss

the

value

of

mistletoe

as

an

anticancer

drug

A

century

ago

Rudolf

Steiner

developed

anthroposophy

a

school

of

thought

that

led

to

innovations

such

as

the

Waldorf

schools

biodynamic

farming

and

anthroposophic

medicine

This

approach

to

healthcare

is

based

on

intuitive

thinking

about

assumed

associations

between

four

postulated

dimensions

of

the

human

body

-LRB-

physical

body

etheric

body

astral

body

and

ego

-RRB-

plants

minerals

and

the

cosmos

Anthroposophic

medicine

includes

drugs

art

therapy

rhythmic

massages

special

exercises

external

applications

counselling

and

anthroposophic

nursing

These

treatments

are

used

partly

as

adjuncts

to

and

partly

as

substitutes

for

conventional

medicine

Anthroposophic

drugs

are

based

on

ancient

alchemistic

and

homeopathic

notions

far

removed

from

the

concepts

of

pharmacology

Many

of

these

drugs

are

produced

in

unusual

ways

some

mistletoe

preparations

are

fermented

while

other

anthroposophic

drugs

are

highly

diluted

according

to

homoeopathic

principles

Steiner

's

intuition

that

mistletoe

might

help

treat

cancer

is

based

on

the

fact

that

like

cancer

mistletoe

is

a

parasitic

growth

that

eventually

kills

its

host

Inspired

by

Hahnemann

's

like

cures

like

principle

he

believed

that

an

extract

of

mistletoe

would

cure

cancer

Despite

the

implausibility

of

this

idea

about

in

vitro

studies

have

shown

that

mistletoe

or

its

main

constituents

-LRB-

alkaloids

lectins

and

viscotoxins

-RRB-

do

have

anticancer

activity

However

many

plants

have

some

sort

of

anticancer

activity

Occasionally

this

is

useful

therapeutically

vinblastine

and

vincristine

are

derived

from

the

common

periwinkle

and

Taxol

comes

from

the

yew

tree

In

most

cases

though

toxicity

or

lack

of

bioavailability

prohibit

the

use

of

these

compounds

Proponents

of

anthroposophic

medicine

make

two

claims

about

mistletoe

Firstly

they

claim

that

regular

injections

of

mistletoe

extract

improve

the

natural

course

of

cancer

by

slowing

down

or

stopping

tumour

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growth

Secondly

they

say

that

such

extracts

improve

the

quality

of

life

in

patients

with

cancer

Many

clinical

studies

of

mistletoe

exist

but

their

findings

are

inconsistent

Most

of

them

are

methodologically

weak

and

the

less

rigorous

they

are

the

greater

the

likelihood

of

a

positive

result

The

conclusions

of

systematic

reviews

are

therefore

contradictory

Anthroposophical

doctors

who

tend

to

include

unreliable

primary

studies

arrive

at

positive

conclusions

In

contrast

independent

reviewers

tend

to

focus

on

the

most

reliable

evidence

and

regularly

find

that

neither

of

the

above

two

claims

is

supported

by

good

evidence

In

this

week

's

BMJ

Finall

and

colleagues

report

a

case

of

subcutaneous

inflammation

mimicking

metastatic

malignancy

induced

by

injection

of

mistletoe

So

how

safe

is

this

treatment

A

wide

range

of

serious

adverse

reactions

have

been

noted

such

as

local

reactions

at

the

site

of

injection

anaphylaxis

dyspnoea

haemorrhagic

colitis

herpes

simplex

herpes

zoster

joint

pain

kidney

failure

lymphangiitis

paraesthesias

sarcoidosis

ulceration

and

vertigo

-LRB-

Saller

R.

Zu

den

unerwuenschten

Nebenwirkungen

von

Mistelpraeparaten

Drittens

Mistelsymposium

Otzenhausen

November

-RRB-

Findings

from

in

vitro

studies

suggest

that

mistletoe

extract

may

enhance

the

proliferation

of

some

cancers

In

addition

some

patients

with

cancer

may

use

mistletoe

as

an

alternative

to

conventional

treatments

for

cancer

rather

than

as

just

a

complementary

treatment

The

claim

frequently

voiced

by

proponents

of

anthroposophic

medicine

that

mistletoe

injections

have

no

serious

is

therefore

misleading

Thus

mistletoe

has

been

tested

extensively

as

a

treatment

for

cancer

but

the

most

reliable

randomised

controlled

trials

fail

to

show

benefit

and

some

reports

show

considerable

potential

for

harm

The

costs

of

regular

mistletoe

injections

are

high

I

therefore

recommend

mistletoe

as

a

Christmas

decoration

and

for

kissing

under

but

not

as

an

anticancer

drug

At

the

risk

of

upsetting

many

proponents

of

alternative

medicine

I

also

contend

that

intuition

is

no

substitute

for

evidence

Edzard

Ernst

professor

of

complementary

medicine

-LRB-

Edzard.Ernst@pms.ac.uk

-RRB-

Department

of

Complementary

Medicine

Peninsula

Medical

School

Universities

of

Exeter

and

Plymouth

Exeter

Competing

interests

declared

Finall

AI

McIntosh

SA

Thompson

WD

Subcutaneous

inflammation

mimicking

metastatic

malignancy

induced

by

injection

of

mistletoe

extract

BMJ

doi

bmj

BE

Steuer-Vogt

MK

Bonkowsky

V

Scholz

M

Arnold

W.

Plattenepithelkarzinome

des

Kopf-Hals-Bereichs

Viscumtherapie

Deutsches

Arzteblatt

Ernst

E.

Anthroposophische

Medizin

Geheimwissenschaft

oder

Heilmethode

Perfusion

Kienle

GS

Kiene

H

Albonico

HU

Anthroposophische

Medizin

Health

Technology

Assessment

Bericht-Kurzfassung

Forsch

Komplementarmed

-LRB-

suppl

-RRB-

Mansky

PJ

Mistletoe

and

cancer

controversies

and

perspectives

Semin

Oncol

Kintzios

SE

Barberaki

MG

Plants

that

fight

cancer

Boca

Raton

FL

CRC

Press

Kleijnen

J

Knipschild

P.

Mistletoe

treatment

for

cancer

review

of

controlled

trials

in

humans

Phytomedicine

Stauder

H

Kreuser

E-D

Mistletoe

extracts

standardised

in

terms

of

mistletoe

lectins

-LRB-

ML

I

-RRB-

in

oncology

current

state

of

clinical

research

Onkologie

Ernst

E

Schmidt

K

Steuer-Vogt

MK

Mistletoe

for

cancer

A

systematic

review

of

randomised

controlled

trials

Int

J

Cancer

Huber

R

Klein

R

Berg

PA

Luedtke

R

Werner

M.

Effects

of

a

lectin

and

a

viscotoxin-rich

mistletoe

preparation

on

clinical

and

hematologic

parameters

a

placebo-controlled

evaluation

in

healthy

subjects

J

Altern

Complement

Med

Gabius

S

Gabius

H-J

Lektinbezogene

Mistelanwendung

experimentelle

Therapieform

mit

praeklinisch

belegtem

Risikopotenzial

Dtsch

Med

Wochenschr

doi

bmj

How

Web

is

changing

medicine

Is

a

medical

wikipedia

the

next

step

ew

concepts

in

information

technology

create

more

confusion

than

Web

The

truth

is

that

Web

is

a

difficult

term

to

define

even

for

web

experts

Nebulous

phrases

like

the

web

as

platform

and

architecture

of

participation

are

often

used

to

describe

Web

Medical

librarians

suggest

that

rather

than

intrinsic

benefits

of

the

platform

itself

it

's

the

spirit

of

open

sharing

and

collaboration

that

is

paramount

The

more

we

use

share

and

exchange

information

on

the

web

in

a

continual

loop

of

analysis

and

refinement

the

more

open

and

creative

the

platform

becomes

hence

the

more

useful

it

is

in

our

work

What

seems

clear

is

that

Web

brings

people

together

in

a

more

dynamic

interactive

space

This

new

generation

of

internet

services

and

devices

often

referred

to

as

social

software

can

be

leveraged

to

enrich

our

web

experience

as

information

is

continually

requested

consumed

and

reinterpreted

The

new

environment

features

a

highly

connected

digital

network

of

practitioners

-LRB-

medical

or

otherwise

-RRB-

where

knowledge

exchange

is

not

limited

or

controlled

by

private

interests

For

me

the

promise

of

open

access

in

Web

freed

of

publishing

barriers

and

multinational

interests

is

especially

compelling

Web

is

primarily

about

the

benefits

of

easy

to

use

and

free

internet

software

For

example

blogs

and

wikis

facilitate

participation

and

conversations

across

a

vast

geographical

expanse

Information

pushing

devices

like

RSS

feeds

permit

continuous

instant

alerting

to

the

latest

ideas

in

medicine

Helpful

but

lesser

known

website

tagging

and

organising

tools

such

as

Connotea

and

Del.icio.us

are

proving

useful

-LRB-

table

-RRB-

Multimedia

tools

like

podcasts

and

videocasts

are

increasingly

popular

in

medical

schools

and

medical

journals

-LRB-

This

bird

's

eye

view

of

social

software

can

be

fully

explored

with

your

favourite

medical

librarian

after

the

holidays

-RRB-

For

now

let

's

examine

the

notion

of

a

blog

which

was

the

first

of

the

social

software

tools

Blogs

are

interactive

websites

that

consist

of

regular

diary-like

entries

Unlike

static

web

pages

-LRB-

a

feature

of

Web

-RRB-

blogs

are

F

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useful

tool

if

you

know

what

to

search

for

Doctors

can

retrieve

lots

of

evidence

and

open

access

material

via

search

tools

and

they

need

to

learn

how

to

use

these

tools

responsibly

With

its

many

multilingual

editions

Google

is

a

boon

for

developing

countries

with

few

information

retrieval

alternatives

This

tour

through

Web

ultimately

returns

to

the

idea

of

using

software

to

create

optimal

knowledge

building

opportunities

for

doctors

The

rise

of

wikis

as

a

publishing

medium

especially

Wikipedia

holds

some

unexamined

pearls

for

the

advancement

of

medicine

The

notion

of

a

medical

wikipedia

freely

accessible

and

continually

updated

by

doctors

is

worthy

of

further

exploration

Could

wikis

be

used

for

example

as

a

low

cost

alternative

to

commercial

point

of

care

tools

like

UpToDate

To

a

certain

extent

this

is

happening

now

as

the

search

portal

Trip

already

indexes

Ganfyd

one

of

a

handful

of

medical

wikis

being

developed

Web

's

push

for

openness

has

resulted

in

the

expectation

of

equal

amounts

of

transparency

and

openness

in

medical

publishing

The

collapse

of

CMAJ

the

journal

of

the

Canadian

Medical

Association

this

past

was

in

a

sense

due

to

the

opposing

tensions

of

openness

exemplified

by

Web

and

the

monolithic

lack

of

openness

in

old

forms

of

media

like

CMAJ

The

web

is

a

reflection

of

who

we

are

as

human

beings

but

it

also

reflects

who

we

aspire

to

be

In

that

sense

Web

may

be

one

of

the

most

influential

technologies

in

the

history

of

publishing

as

old

proprietary

notions

of

control

and

ownership

fall

away

An

expert

-LRB-

that

is

doctor

-RRB-

moderated

repository

of

the

knowledge

base

in

the

form

of

a

medical

wiki

may

be

the

answer

to

the

world

's

inequities

of

information

access

in

medicine

if

we

have

the

will

to

create

one

Dean

Giustini

UBC

biomedical

branch

librarian

-LRB-

dean.giustini@ubc.ca

-RRB-

University

of

British

Columbia

Biomedical

Branch

Library

Diamond

Health

Care

Centre

and

Vancouver

Hospital

BC

Canada

Web

examples

in

medicine

Application

Bloglines

Citizendium

Connotea

Del.icio.us

Flickr

Ganfyd

Google

blogsearch

Google

health

MedWorm

SlideShare

Wikipedia

YouTube

Website

Purpose

RSS

reader

Expert

wiki

Online

reference

organiser

Website

tagging

Photo

sharing

Medical

wiki

Blog

searches

Create

your

own

search

tool

RSS

aggregator

Slide

sharing

All

purpose

wiki

Video

snippets

more

dynamic

and

permit

bloggers

to

write

articles

and

engage

in

one

to

many

conversations

with

readers

Political

bloggers

are

said

even

to

have

influenced

the

outcome

of

elections

One

of

the

best

blogs

in

medicine

is

Ves

Dimov

's

Clinical

Cases

and

Images

It

contains

a

rich

collection

of

presurfed

material

for

busy

clinicians

and

features

interactivity

and

timely

discussion

Dimov

is

also

a

supporter

of

medical

librarian

bloggers

Why

waste

time

fumbling

with

search

engines

when

you

can

consult

this

blog

for

timely

updates

As

well

as

case

discussions

Ves

provides

links

to

today

's

medical

headlines

from

Reuters

and

clinical

images

via

a

dynamic

free

photo

sharing

tool

called

Flickr

One

of

his

slide

presentations

Web

in

medicine

is

available

on

Slideshare

-LRB-

itself

a

fantastic

new

tool

-RRB-

Clinical

Cases

and

Images

is

a

virtual

laboratory

for

doctors

and

medical

librarians

interested

in

Web

In

the

past

year

several

doctors

and

medical

librarians

have

put

Web

in

the

one

excellent

article

even

discusses

its

impact

in

clinical

practice

What

is

obvious

is

that

doctors

are

seeking

new

methods

of

information

discovery

because

of

the

limitations

of

search

engines

Even

Medline

for

all

its

benefits

is

no

longer

a

sufficiently

detailed

map

of

the

medical

literature

Busy

but

organised

doctors

need

a

variety

of

evidence

sent

to

them

in

a

single

organising

interface

easily

accomplished

using

an

RSS

reader

-LRB-

ask

your

favourite

medical

librarian

to

show

you

how

to

use

aggregators

like

Bloglines

and

MedWorm

-RRB-

RSS

may

be

a

useful

way

to

fight

information

overload

RSS

feeds

help

to

organise

new

web

content

sent

to

you

in

real

time

by

the

best

medical

blogs

evidence

based

sites

like

the

Cochrane

Library

and

newly

published

video

and

audio

from

major

medical

journals

In

fact

technology

savvy

doctors

are

keen

to

use

RSS

feeds

on

mobile

devices

iPods

and

Blackberries

and

scan

research

on

their

way

to

ward

rounds

For

those

who

prefer

to

play

in

the

digital

sandbox

while

on-call

try

photo

sharing

software

like

Flickr

and

medical

video

sharing

at

YouTube

two

of

the

more

popular

multimedia

sites

By

searching

YouTube

-LRB-

bought

by

Google

for

-LRB-

bn

bn

-RRB-

in

-RRB-

you

can

dazzle

your

family

during

the

holidays

Over

the

past

year

as

a

medical

librarian

I

have

watched

the

impact

of

Web

tools

on

access

to

information

A

highlight

for

me

was

a

recent

BMJ

article

which

concluded

that

Google

the

quintessential

Web

company

is

a

useful

diagnostic

aid

Google

is

a

Competing

interests

declared

O'Reilly

T

What

is

Web

Design

patterns

and

business

models

for

the

next

generation

of

software

O'Reilly

Media

Barsky

E.

Introducing

Web

weblogs

and

podcasting

for

health

librarians

J

Can

Health

Libr

Assoc

Giustini

D.

Top

RSS

feeds

in

medicine

UBC

Academic

Search

Google

Scholar

Blog

May

Giustini

D.

Top

five

-LRB-

-RRB-

podcasts

in

medicine

UBC

Academic

Search

Google

Scholar

Blog

March

Kiely

K.

Freewheeling

bloggers

are

rewriting

the

rules

of

journalism

USA

Today

December

Dimov

V.

Physician

bloggers

talk

to

a

medical

librarian

Clinical

Cases

and

Images

Blog

May

physician-bloggers-talk-to-medical.html

Dimov

V

How

to

use

Web

in

medicine

Clinical

Cases

and

Images

Blog

May

Abbasi

K.

Journals

join

the

podcast

revolution

J

R

Soc

Med

Boulos

MNK

Maramba

I

Wheeler

S.

Wikis

blogs

and

podcasts

a

new

generation

of

web-based

tools

for

virtual

collaborative

clinical

practice

and

education

BMC

Med

Educ

YouTube

AskDrWiki

Coronary

dissection

November

Tan

H

Ng

JHK

Googling

for

a

diagnosis

use

of

Google

as

a

diagnostic

aid

internet

based

study

BMJ

Shuchman

M

Redelmeier

DA

Politics

and

independence

the

collapse

of

the

Canadian

Medical

Association

Journal

N

Engl

J

Med

doi

bmj

Editorial

picture

credits

Cameron

Collection

Jane

Hamlin

Peter

Sant/AP

Wellcome

Library

London

MEPL

BMJ

VOLUME

DECEMBER

bmj.com

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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