Post on 03-Apr-2018
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January 2013
www.medicaltribune.com
Worlds rst dissolvable
drug-elung stent
TB in children: We need
to do more
FORUM
Rapid TB test performs
well
CONFERENCE
SINGAPORE FOCUS
IN PRACTICE
Managing COPD in
primary care
New advisory recommends fewer GERD
endoscopies
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2 January 2013
New advisory recommends fewer GERD
endoscopies
Radha Chitale
New recommendations for patients
with gastroesophageal reux disease
(GERD) advise physicians to avoid
unnecessary endoscopies in patients for whom
there is lile benet.
Upper endoscopy is a routine procedure forGERD diagnosis and management, particular-
ly when monitoring for abnormal or cancerous
esophageal tissue, but overuse results in higher
healthcare costs and adverse side eects with-
out improved patient outcomes.
Limited data suggest that clinicians who
care for patients with GERD symptoms oen
do not follow suggested practice, according
to the Clinical Guidelines Commiee of theAmerican College of Physicians.
The Commiee noted that 10-40 percent of
upper endoscopies are not generally indicat-
ed but are performed for patients with GERD
symptoms without additional dysplasia, are
performed too oen, or are performed before
alarm symptoms occur.
The best practice recommendations indicate
upper endoscopy for patients with heartburnand alarm symptoms including dysphagia,
bleeding, anemia, weight loss or recurrent
vomiting. [Ann Intern Med 2012;157:808-816]
Upper endoscopy is also indicated for pa-
tients who persist with GERD symptoms even
aer a 4-8 week course of acid-reducing pro-
ton pump inhibitor therapy, who persist with
severe esophagitis, or who have a history of a
narrowed esophagus.
Persistent GERD can lead to Barres
esophagus, in which the esophageal lining
erodes and is replaced by stomach lining tis-
sue, and both are associated with increased
risk of esophageal adenocarcinoma. Howev-
er, 80 percent of all cancers occur in men, so
screening for cancer or Barres esophagus
via endoscopy is recommended for men over
50 with GERD.If endoscopic screening of patients with
GERD symptoms is to be pursued, men older
than 50 years will provide the highest yield
of both Barres esophagus and early adeno-
carcinoma, the researchers said.
But both men and women with a history
of Barres esophagus may be screened ev-
ery 3-5 years via endoscopy for dysplasia or
cancerous cells.Up to 85 percent of GERD patients have
non-erosive reux disease.
And while upper endoscopy is a relatively
low-risk procedure, it can cause respiratory
failure, hypotension, reactions to anesthet-
ics, and in extreme cases, perforation and
cardiovascular events.
The commiee based their recommenda-
tions on a literature review and comparisonof clinical guidelines from other professional
organizations.
Because of its high prevalence in the gen-
eral population, care of patients with GERD
is largely within the domain of primary care
providers, they said. Upper endoscopy is
not an appropriate rst step in most patients
with GERD symptoms and is indicated only
when empirical PPI therapy for 4-8 weeks is
unsuccessful.
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3 January 2013
Blood protein resistin reduces statin effect
in obese
Rajesh Kumar
Canadian researchers have identied aprotein called resistin, secreted by fattissue, as the cause of elevated low-density
lipoprotein (LDL) in obese people.
Their research, presented at the Canadian
Cardiovascular Congress recently held inToronto, Ontario, Canada, has shown that
resistin increases the production of LDL in
human liver cells and also degrades LDL re-
ceptors in the liver. As a result, the liver is less
able to clear LDL from the body.
Resistin also reduces the ecacy of statins,
so much so that a staggering 40 percent of pa-
tients taking statins cannot lower their blood
LDL, said senior author Dr. Shirya Rashid,assistant professor in the department of med-
icine at McMaster University in Hamilton,
Ontario, Canada.
The bigger implication of our results
is that high blood resistin levels may be
the cause of the inability of statins to lower
patients LDL cholesterol, said Rashid, add-
ing that the discovery could lead to revolu-
tionary new therapeutic drugs, especiallythose that target and inhibit resistin and
thereby increase the eectiveness of statins.
Dr. Goh Ping Ping, medical director of the
Singapore Heart Foundation, termed the re-
search ndings as progressive medical evi-
dence saying they reinforce the importance
of treating cholesterol levels to goal in orderto reduce cardiovascular risk.
[But] this can be challenging in some
high-risk patients whose target cholesterol
level has to be very low. Hence, we wel-
come new developments in medical thera-
py to help patients reach their target levels
safely, said Goh. As physicians, we need
to also continuously motivate patients
to exercise and adhere to a heart healthydiet.
High resistin levels may aenuate the LDL cholesterol-lowering eectsof statins.
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4 January 2013 Forum
TB in children: We need to do more
Excerpted from a presentation by Dr. Anneke Hesseling, director of the Paediatric TB Research
Program at the Desmond Tutu TB Centre at Stellenbosch University in Cape Town, South
Africa, during the 43rd Union World Conference on Lung Health, held recently in Kuala
Lumpur, Malaysia.
showed that only 1.6 percent of 4,821 cases ofchild TB were registered with the NTP there.[BMC Public Health 2011;11:784]
Despite available therapies, children havebeen systematically neglected in a way thathas led to preventable morbidity and mortal-ity.
ProgressThe good news is that for the rst time,
childhood TB is on the public health agenda,with strong leadership from the WHO andother dedicated groups.
Children have been included in guidelinesfor NTPs and these have been updated in thelast several years including reporting prac-tices, dosage revision for young children to
avoid hepatotoxicity, and guidance on man-aging TB/HIV co-infections.
It is estimated that 500,000 children becomeill with tuberculosis (TB) and that 70,000 af-fected children die annually, but these g-
ures still do not reect the true global burden
of TB.Childhood TB is an indication of recenttransmission, as children tend to acquire theinfection in the rst year of life, and as suchis an indication of household dynamics andepidemiology, especially the emergence ofdrug resistance in the community.
Therefore, TB in children is a litmus testindicating how well we are doing with TBcontrol, and clearly we are failing.
Historical approach
The traditional approach to childhood TBhas been the assumption that proper iden-tication and treatment of infectious adultcases will prevent childhood TB.
But children are not the same as smalladults. They have a developing immune sys-tem, which makes them especially suscep-
tible to severe forms of TB such as TB men-ingitis.
And childhood TB is typically a low-priority disease for national tuberculosisprograms (NTP) because it is dicult to di-agnose with a smear test, it is not usually in-fectious, there are limited resources to tackleTB treatment, and there are a lack of record-ing and reporting approaches. Only abouttwo-thirds of cases are actually notied toNTPs.
A cross-sectional study from Indonesia
A childs developing immune system makes them susceptible to forms ofTB.
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5 January 2013 Forum
However, despite good policies, imple-mentation can be an issue, especially givenlooming funding decits, which aect coun-tries with limited resources in particular.
Some methods to combat these barrierswould be to integrate families in childhoodTB care, including pregnant women andthose with HIV infection, in order to con-solidate services. Every clinic visit should bean opportunity to ask about a household TBcontact.
Empowering healthcare workers at all lev-els to get involved in TB care can yield bet-ter disease reporting statistics. A program infour hospitals in Jakarta, Indonesia, showedthat TB diagnosis rates were similar betweennurses, general practitioners and pediatri-cians when they received specic training.
Pragmatic, simple models of care shouldbe implemented where possible.
In one study, directly observed once-weekly treatments for 12 weeks with a com-
bination of rifapentine and isoniazid was
as eective in adults, if not more, as dailyisoniazid-only therapy for 9 months, whichcould be a beer model for treating children.[N Engl J Med 2011;365:2155-2166]
Partnerships and collaborations with in-dustry could also help improve drug avail-ability and make available new pediatricrst-line xed dose combinations. But forthis market research on barriers to treatment,current practice for uptake and accurate esti-mates on childhood TB to quantify the mar-ket are required.
For the global TB community, seing
short- to medium- and long-term goals, andbeing accountable for them, will help us see
where we are going and be honest about as-sessing achievements and failures.
Research
A decade ago, we did not have any newanti-TB drugs. In children, there was limit-ed evidence for rational TB drug use. Therewere few rapid diagnostic tests, especiallyfor smear-negative TB and drug-resistantTB, and there were no TB vaccines in humantrials.
So we really have come a long way, butthere are still considerable gaps in TB re-search.
Drug formulations tend not to be child-friendly they are unpalatable and dicultto give in accurate doses since tablets must
be broken.However, research has shown that indi-
vidualized tailored treatment can dramati-cally improve outcomes, even among thosewith drug-resistant TB more than 80 per-cent of children with multi-drug resistant TB
can achieve favorable outcomes, even in thecontext of HIV positivity. [Clin Infect Dis 2012
Jan 15;54:157-166]However, these regimens are not eas-
ily handled. Requiring injections, they workbeer in older children and some therapiescan cause signicant hearing loss.
More research is required to develop safermulti-drug resistant TB therapy regimes that
are shorter and easier to use. No rigorous ev-idence-based management for drug-resistantTB preventive therapy is available for adults,much less for children.
Trials to evaluate new therapies and re-gimes should include children and adults.
DiagnosticsThe challenges in TB diagnosis, which
tends to be underfunded, have been a big
burden for recognizing TB in the publichealth framework.
Despite available
therapies, children have been
systematically neglected
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6 January 2013 Forum
It does not help that the reference stan-
dard liquid culture is imperfect in chil-
dren and misses a large portion of children
with clinical disease that isnt bacteriologi-
cally proven.Children are usually an aerthought
when new diagnostics get implemented and
evaluated. However, childhood TB naturally
presents with fewer bacterial units.
Sometimes the TB community has been its
own worst enemy by making the situation
more complicated than it is. In fact, children
should be managed on a daily basis to help
demystify diagnosis and make it more acces-
sible.
New technologies that analyze DNA slash
time to diagnosis and are beer at recog-
nizing TB and drug-resistant TB, even in
children.
ConclusionChildhood TB is coming of age and we
are at a unique juncture of increased public
health awareness, advocacy and funding for
clinical and implementation research.
Last year, World TB Day focused on
children, an indication that the eld is mov-
ing forward. More progress will require
working together in a sustained manner,
monitoring progress in order to reach the
nal goal, which is a generation of children
free of TB.
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7 Singapore FocusJanuary 2013
A team of nurses, therapists and doctors simulating the resuscitation of a SARS patient with cardiac arrest at SCI, as President Tony Tan and otherslook on.
New initiatives by Eastern Health Alliance
Singapore President Dr. Tony Tan recently launched the Centre for Innovation (CFI) andChangi Simulation Institute (CSI) two new initiatives by the Eastern Health Alliance tomeet healthcare challenges arising from an ageing population and growth in chronic diseases.
The CFI will provide a platform and resources for generating ideas, prototyping them and
creating partnerships for healthcare innovations, while CSI will provide relevant medical
simulation training for teams of doctors, nurses and allied health professionals.
Located alongside Changi General Hospitals training center, the facilities are open to the
members of the alliance and other healthcare partners and will drive healthcare innovation
and clinical competencies, respectively.The alliance will also join A*STARs ongoing collaboration with the Center for the In-
tegration of Medicine and Innovative Technology (CIMIT) in Boston, Massachuses, US.
This will allow it to benet from CIMITs expertise in developing medical technologies and
solutions, as well as from A*STARs science and engineering research capabilities.
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8 Singapore FocusJanuary 2013
GSK expands manufacturing capabilities
GlaxoSmithKline (GSK) ocials detailed plans to continue expanding in Asian markets,
maintaining their operational headquarters in Singapore, during a recent celebration of 40years of local pharmaceutical manufacturing.
In the last 12 months, we had positive data on 10 new drugs... and were going to le for glob-
al approval for six new major medicines before the end of the year, said GSK CEO Sir Andrew
Wiy. Over the next 3 years we should launch about 15 new medications.
Among the drugs in the pipeline will be therapies for HIV, malaria and muscular dystrophy.
Wiy said Singapore will play a key role in the manufacture of these new drugs, should they
be approved for use.
Singapores Prime Minister Lee Hsien Loong said GSKs strategy was an important indicator
of the value of manufacturing for a large region.
Manufacturing will remain important for [Singapores] economy even as it changes,
he said.
TRAJ/JOURNAL/006-12
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9 Singapore FocusJanuary 2013
From the research bench to your patients bedside JPOG raises the
quality of life of women and children in Asia. Pick up a copy today and
start earning CME points.For further details, visit www.jpog.com today.
JPOG isNOWCME-Accredited...
in Hong Kong, Indonesia,
Malaysia and Singapore
For over 35 years, JPOG has been the only regional,peer-reviewed journal of paediatrics, obstetrics and
gynaecology in Asia. The bimonthly journal is proud to
announce its CME-accreditation in the following Asian
countries: HONG KONG, INDONESIA,
MALAYSIA and SINGAPORE.
HPB takes senior citizens back to
school
To improve health literacy and empower senior citizens to make healthier choices, Singa -pores Health Promotion Board (HPB) has developed and piloted a new program in ChoaChu Kang community.
The Back to School program incorporates classroom workshops, hands-on and experiential
educational activities to help residents and their caregivers understand, for example, the impor-
tance of home safety, good oral health and u vaccination. It also provides senior citizens access
to dental and functional screening services and vaccination for inuenza.
The program, jointly implemented by HPB and Choa Chu Kang Grassroots Organization
and the South View Primary School, will be expanded to more constituencies next year.
Minister for Health and MP for Choa Chu Kang GRC, Gan Kim Yong, said the project is in-
novative and meaningful and will greatly benet Choa Chua Kang residents.
HPBs chief executive ocer, Ang Hak Seng, said there is a low level of u vaccine uptake
among the elderly, with only one in 10 residents aged 50 to 69 vaccinated in 2011. The pro -
gram not only allows them to be healthy, but to receive u vaccine and get routine dental
check under one roof.
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10 Singapore FocusJanuary 2013
Worlds first dissolvable drug-eluting stent
Rajesh Kumar
The worlds rst drug-eluting bioresorb-
able stent promises to revolutionize the
care for patients with coronary artery
disease (CAD).
Absorb (Abbo Vascular) is made from
a naturally dissolvable material called poly-
lactide that is commonly used in dissolving
sutures and is coated with the anti-prolifera-
tive drug everolimus.It works by restoring blood ow in the
blocked coronary artery similar to a metal-
lic drug-eluting stent but then dissolves
into water and carbon dioxide within a few
months, leaving behind a treated vessel that
may resume its natural elasticity and pulsat-
ing movement.
The device is being referred to as scaold
rather than stent to indicate its temporarynature and is creating quite a stir amongst
interventional cardiologists.
There have been three signicant mile-
stones in the treatment of CAD in the last
few decades angioplasty, bare metal stents
and drug-eluting stents. The fourth and lat-
est revolution has been initiated with the in-
troduction of Absorbit has the potential to
transform the way we treat patients, saidDr. Pieter Cornelis Smits, director of inter-
ventional cardiology at Maasstad Zieken-
huis in Roerdam, the Netherlands.
With Absorb, the vessel may return to a
more natural state over time, which could
provide patients with important clinical ben-
ets over the long-term.
A stent is usually not required aer about
6 months of treatment by when the arterygets unblocked and can stay open on its own.
Some patients may require repeat stenting
due to reblockage on either the same or on
dierent sites. As a result, their arterial walls
end up becoming rigid in many places due to
multiple metal stents le behind, explained
Smits.
Absorb leaves behind only two pairs of
tiny metallic markers which help guide its
placement and remain in the artery to enable
physician to subsequently see where the de-
vice was placed.As a result, the vessel can expand and con-
tract as needed to increase the ow of blood
to the heart in response to activities such as
exercise. The need for long-term treatment
with anti-cloing medications may also be
reduced and any subsequent interventions
would be unobstructed, Smits added.
Initial data from multiple ongoing studies
in more than 20 countries around the world,including Singapore, indicate that Absorb
Absorb, a drug-eluting stent made from polylactide, a naturally dissolvable
material.
It has the potential
to transform the way we
treat patients
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11 Singapore FocusJanuary 2013
performs similar to a best-in-class drug-elut-
ing stent across traditional measures such
as major adverse cardiovascular events and
target lesion revascularization, according to
Abbo Vascular.Absorb is now available in Europe, the
Middle East, parts of Asia Pacic including
Hong Kong, Malaysia and New Zealand,
and parts of Latin America. It is not yet regis-
tered in Singapore and is currently available
through special access route, pending regula-tory approval by Health Sciences Authority.
NUS researchers knock down chikungunya
Elvira Manzano
Researchers from the National Univer-sity of Singapores (NUS) Yong Loo LinSchool of Medicine have identied a new
gene silencing approach that can kill the
chikungunya virus quickly, making prophy-
lactic therapy possible for patients with this
condition.
By employing small hairpin RNA (shR-
NA) technology directed against two specicchikungunya virus, E1 and nsP1genes, Ms.
Shirley Lam, a postgraduate student from
NUS and her team, was able to show that the
strategy knocked down the virus and sup-
pressed replication in infected cells within 3
days.
The approach, tested in both human cells
and mice models, was able to protect the cells
for up to 15 days, said Lam who received theSingapore Young Scientist Award at the re-
cent Singapore Health and Biomedical Con-
gress for her work. Our ndings reinforce
the potential usefulness of shRNA technol-
ogy in clinical seings of chikungunya virus
infection.
Chikungunya shares some clinical symp-
toms with dengue. You really need a good
diagnostic lab component to come into aplay, said principal investigator Assistant
Professor Justin Hang-Hann Chu, of the De-
partment of Microbiology, NUS Yong Loo
Lin School of Medicine. A PCR [polymerase
chain reaction] is sensitive enough to tell the
dierence.Patients with chikungunya present with a
sudden onset of fever, chills, headache, nau-
sea and vomiting, joint pain with or without
swelling, rash and low back pain. Currently,
there is no vaccine or specic treatment for
chikungunya infection. Treatment is primar-
ily focused at relieving symptoms which can
drag on for months, or even years.
We have shown that shRNA antiviraltechnology was eective in inhibiting the
Principal investigator Dr. Chu Jang Hann (center), lab executive ChenHuixin (le) and lead researcher Shirley Lam (right) examine an X-ray lmof chikungunya virus protein expression prole.
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12 Singapore FocusJanuary 2013
virus. Its even highly specic for chikungu-
nya, Chu said. Were looking at it as a pos-
sible prophylactic treatment to reduce cases
of infection.
Unlike vaccines which provide long-termprotection, the approach only gives short-
term protection. However, it can be useful
during an outbreak, similar to what Singa-
pore experienced between 2008 and 2010
where we had close to 1,000 chikungunya
cases.
The study was funded by the Agency
for Science, Technology and Researchs(A*STAR) Biomedical Research Council.
Chus team is now working to translate their
study results into clinical applications.
Nine-year-old CKD patient plays scientist
Radha Chitale
Despite having chronic kidney disease(CKD) for the majority of her life,9-year-old Meenakshi Sundaram Losheni
has not felt deterred from laboratories.
On the contrary, science is her favorite
subject and she recently donned a lab coat to
join scientists at Singapores Institute of Bio-engineering and Nanotechnology (IBN) to
participate in their research for a day.
Our researchers are developing next-
generation technologies for organ replace-
ment and regenerative medicine, and volun-
teer opportunities such as this inspire them
by puing a face to the biomedical problems
that they are working on, said Professor
Jackie Y. Ying, IBN Executive Director.People with CKD progressively and ir-
reversibly lose kidney function. As a result,
waste builds up in the kidneys, leading to
fatigue, low appetite, high blood pressure
and nerve and blood vessel damage. Losheni
receives hours of dialysis each night, in addi-
tion to medication every day.
In adults, diabetes and high blood pres-
sure are the primary causes of CKD but chil-
dren may get the disease as a result of a num-
ber of aictions such as obstructive urology
and kidney cysts. Children are commonly af-
fected between ages 2-5.
In patients with CKD, progression to endstage renal disease (ESRD) is inevitable and
kidney transplants are required. About 70
percent of children with CKD will develop
ESRD by age 20; the 10-year survival rate is
80 percent. Death occurs most oen due to
cardiovascular disease and infection.
IBN partnered with the Make-A-Wish
Foundation Singapore to bring Losheni to
their facility in Biopolis.She was able to examine stem cells from
liver, bone and kidney that might be used in
tissue engineering and present her ndings
to the lab group.
Mr. Paul Heng, board chair of the Make-
a-Wish Foundation Singapore, said he hoped
that the experience, aside from fullling
Loshenis intellectual curiosity, would prepare
her for her own kidney transplant.
Volunteer opportunities
such as this inspire
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13 Singapore FocusJanuary 2013
Rajesh Kumar
Skeletal examination before and aer
bariatric surgery and treatment for po-
tential bone loss should form part of pa-
tient care, experts cautioned following review
of several research ndings suggesting bariat-
ric surgery may cause bone loss particularly
in young people.
In most developed countries, Roux-en-Y
gastric bypass surgery is the most invasive and
commonly used method involving removal of
much of the stomach and bypassing of part
of the small bowel, while gastric sleeve and
gastric band are the less radical methods of
obesity surgery. [Obesity Reviews 2012; DOI:
10.1111/j.1467-789X.2012.01050.x]
Even though we dont yet understand all
the mechanisms, we can see that the more
radical the procedure, the greater the bone
loss long-term, said researcher endocrinol-
ogist Dr. Malgorzata Brzozowska of the Gar-
van Institute of Medical Research in Sydney,
Australia.
In many situations signicant weight loss
is associated with bone loss, with or withoutsurgery. The more invasive types of surgery
appear to heighten bone turnover and the as-
sociated bone loss, she said.
This is thought to be caused not only by
rapid weight loss and absorption of fewer
vital nutrients like vitamin D and calcium,
but possibly also by changes in hormones re-
leased by fat and the gut, and their impact on
the central nervous system.Physicians should be aware of surgery-
induced changes in hormones that can aect
the central regulation of appetite and bone
strength. These include the fat-derived hor-
mones leptin and adiponectin; gut-derived
hormones such as peptide YY (PYY), gluca-
gon-like peptide 1 (GLP-1) and ghrelin; and
the hypothalamic regulator of energy balance,
neuropeptide Y (NPY), the review pointed
out.
As the number of bariatric operations in-
creases, Brzozowska said it was imperativeto recognize mechanisms responsible for bar-
iatric surgery-induced bone loss, with careful
monitoring of bone health including long-
term fracture incidence in patients undergo-
ing these procedures.
Associate Professor Jackie Center, also of the
Garvan Institute, said the widely held assump-
tion that obese people were protected against
bone fragility and fracture was true only up toa point.
Bone loss may be an issue after bariatric
surgery
Weight loss is oen linked to bone loss, with or without surgery
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14 Singapore FocusJanuary 2013
Therefore, on all those undergoing invasive
bariatric surgery, bone mineral densitometry
scans can be done and adequate calcium and
vitamin D intake advised. For those patients at
particular risk, additional monitoring may beadvised and protective drugs considered.
Dr. H.G. Baladas of the Raes Surgery Cen-
tre at Raes Hospital, Singapore said surgeons
were well aware of the risks and thats why
bariatric surgery is rarely oered to younger
patients who have not yet reached optimum
bone growth.
Pure bypass operations such as jejunoileal
bypass result in the highest bone loss, but are
no longer being performed, he said, adding
that combined bypass and restriction opera-
tions are associated with a low probability of
clinically signicant bone loss, but patients
with these operations already have their bone
mass monitored and take calcium and vitamin
D supplements.With the purely restrictive operations such
as lap-band and lap sleeve gastrectomy, the
risk of bone loss is almost negligible and pa-
tients need not routinely take calcium and vi-
tamin D supplements, said Baladas.
Studies like these are very important
because the number of bariatric operations
for morbid obesity is increasing in Asia. In
Singapore alone, more than a thousand patients
have undergone bariatric surgery for morbid
obesity, he concluded.
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16 Singapore FocusJanuary 2013
Singapore continues to pour funds into
biomedical research
Radha Chitale
Grants worth over S$100 million have
been awarded to eight biomedical
research programs in Singapore that
target important diseases in the Asia-Pacic
region.
The programs, some new and some ongo-
ing, should help Singapores biomedical sci-
ences sector evolve into a symbiotic web of
laboratory research, clinical care and research
and industry partnership that will support
the countrys bid to turn biomedical sciences
into a key economic contributor.
One of Singapores key dierentiating and
competitive value propositions is our ability
to integrate our research eorts along the in-
novation value chain as well as across mul-
tiple research organizations, said Mr. Lim
Chuan Poh, chairman of the Agency for Sci-
ence, Technology and Research (A*STAR) and
co-chair of the Biomedical Sciences Executive
Commiee.
We have to make sure that Singapore con-
tinually occupies an advantage in this [com-
petitive environment] to make sure to con-stantly create high-value jobs in Singapore.
Supported by the National Medical Re-
search Council of the Ministry of Health, four
Translational and Clinical Research (TCR)
Flagship grants totalling S$68 million were
awarded to research programs in eye disease,
gastric cancer, heart disease and non-small
cell lung cancer.
Each of these research areas have strong,established scientic and clinical capabilities
in Singapore because they are diseases with
high-burden and unique presentation among
Asian populations.
The research program on corneal disease
and glaucoma, led by Professor Donald Tan
of the Singapore National Eye Centre, and the
Singapore Gastric Cancer Consortium, led by
Assistant Professor Khay Guan Yeoh at the
National University Singapore, were each
awarded S$25 million over 5 years.
Two more grants, worth S$9 million over
5 years, were given to researchers at the Na-
tional Heart Centre Singapore and the Na-
tional Cancer Centre Singapore to study heartdisease and non-small-cell lung cancer.
Another S$58.4 million from Singapores
Strategic Positioning Fund were awarded to
projects within A*STAR.
The standout project is the POLARIS (Per-
sonalized OMIC Laice for Advanced Re-
search and Improving Stratication) initia-
tive, which will receive S$20 million over the
next 3 years to improve stratied, or person-alized, medicine by organizing existing local
Over S$100 million in grants have been awarded to eight biomedicalresearch programs in Singapore.
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17 Singapore FocusJanuary 2013
POLARIS initiative hones in on
personalized medicine
Radha Chitale
AS$20 million initiative by Singaporeanresearch institutes and hospitals to linkbiomarker technology and clinical practice
could help get specialized therapies to pa-
tients who need them.The POLARIS initiative will capitalize on
existing genomic and metabolomic research
in Singapore, particularly in diseases which
have a large burden or a dierent presenta-
tion in Asian populations, based on the prin-
ciples of stratied, or personalized, medi-
cine.
We want to transform disease manage-
ment by moving away from a one-size-ts-
all type of approach to targeting specic
biomarker research and clinical assays into a
pipeline to speed diagnostic and treatment
capabilities as well as identify new biomark-
ers for potential therapies.
Its very important that Singapore be seenat the forefront of these developments in
[stratied medicine], said Professor Stephen
Smith, vice president (Research) of Nanyang
Technological University.
Another project seeks to identify larger
trends in disease development through close
examination of rare disease that are oen sin-
gle cases, and will receive S$12.7 million over
three years.
By understanding the rare, you under-
stand the common because you have inroads
into common ailments, said the Genetic Or-
phan Diseases Programme program lead Dr.
Bruno Reversade, senior principal investiga-
tor at A*STARs Institute of Molecular Biology.
Two other projects to analyze circulatingcancer cells and to develop predictive bio-
markers will also each receive S$12.3 million
and S$13.4 million, respectively.
Key performance indicators, including
product development and health outcomes,
will be monitored for these projects.
This initiative is adding signicantly to
Singapores GDP [gross domestic product],
said Sir Richard Sykes, chair of the Biomedi-
cal Sciences International Advisory Council.
There has to be some measure of output.
7/29/2019 Medical Tribune January 2013 SG
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18 Singapore FocusJanuary 2013
therapies to specic patient groups, said
program lead Dr. Patrick Tan, of the Genome
Institute of Singapore at the Agency for Sci-
ence, Technology and Research (A*STAR).
The challenge now lies in how to realizethe clinical value of those initial [biomarker]
discoveries. In order for that to happen, the
technologies that we use to give rise to those
discoveries must then be taken from the re-
search center back into the clinics where
these ndings can be implemented in the
form of certied clinical tests.
Currently, there is no accredited facility to
analyze biomarker assays in Singapore and
patient samples must be sent overseas.
Tan said they hope to set up a local facil-
ity, certied by the College of American Pa-
thologists, to carry out standardized, robust
testing on routine clinical samples that clini-
cians can feel comfortable using to allocate
treatment.
At the end of the day, we want the clini-
cian to take the information and act on it,
he said.
The immediate impact on patients would
be validated biomarker assays that quickly
identify subgroups of patients who will re-
spond to available therapies.
However, a portion of patients do not
respond to existing therapies. The current
model for enrolling such patients in clini-cal trials to receive experimental therapies is
time consuming and costly because assess-
ing their eligibility is decentralized and re-
quires multiple biomarker assays. For exam-
ple a cancer patient at the National Cancer
Centre Singapore must be evaluated several
times to see if they are eligible for one of 40-
50 ongoing clinical trials. During this time,
disease can progress, Tan said.
Unresponsive patients who consent to
participate in POLARIS would be evaluated
once for biomarkers that match existing ex-
perimental therapies in ongoing clinical tri-
als, which reduces the time it takes for themto receive treatment.
Patients who remain unresponsive or who
relapse may be evaluated further by whole
genome sequencing and other types of bio-
marker analysis for novel diagnostic or ther-
apeutic targets, to be tested in clinical trials.
Pharmaceutical industry involvement to
design clinical trials and develop new prod-
ucts will be a key facet of POLARIS.
Its a more orchestrated system to en-
hance discoveries and ndings based upon
patients so that you are capturing the maxi-
mum amount of information from each pa-
tient with the minimum cost and the most
eciency, Tan said.
Four institutes from A*STAR and clini-
cians from Singapore General Hospital, the
National Cancer Centre Singapore, Singa-
pore National Eye Centre and the National
University Health System have partnered to
be part of POLARIS.
At present, POLARIS will focus on lung
and gastric cancers and eye diseases, both
because of the heavy local disease burden
and because of the number of identied bio-
markers. However, the initiative is scalableto other diseases and research groups.
POLARIS is funded by a 3-year S$20 mil-
lion grant from A*STARs Biomedical Re-
search Council and represents the integration
phase of Singapores initiative to grow the
biomedical sciences sector.
*Personalized OMIC Laice for Advanced Research and Improving
Stratication
7/29/2019 Medical Tribune January 2013 SG
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7/29/2019 Medical Tribune January 2013 SG
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20 January 2013 Conference Coverage43rd Union World Conference on Lung Health, 13-17 November, Kuala Lumpur, Malaysia Radha Chitale
reports
New TB therapies offer hope
Two promising new agents under de-
velopment for treating multiple drug-
resistant tuberculosis (MDR-TB) cant
be deployed fast enough, experts say.
The US Food and Drug Administration
(FDA) Anti-Infective Drugs Advisory Com-
miee has approved a request for accelerated
approval of drug-maker Janssens investiga-
tional agent bedaquiline for MDR-TB.
Interim results of a randomized controlled
phase II trial showed that the addition of be-
daquiline to a ve-drug background regimen
(standard second-line drugs) for 24 weeks im-
proved the rate of sputum culture conversion
(shi from positive to negativeMycobacterium
tuberculosis growth) in MDR-TB patients in a
shorter time compared with the background
regimen plus placebo (79 percent vs 58 per-
cent, respectively). The eects of bedaquiline
were durable out to a follow-up assessment
at 72 weeks.
Meanwhile, Otsuka Pharmaceuticals
Group has led for approval of another new
TB agent delamanid with the European
Medicines Agency (EMA).Delamanid has demonstrated increased
sputum culture conversion at 2 months
among patients with MDR-TB compared
with placebo (45.4 percent vs 29.6 percent,
respectively), plus background therapy for
both groups, in a randomized controlled tri-
al. [N Engl J Med 2012;366:2151-2160]
Despite the possibility of approval of these
new agents in the US and Europe, some arefrustrated by the prospect of the lengthy up-
take process required to get new therapies to
where they are really needed.
Geing [drugs] approved in the US where
we only have 130 cases of MDR-TB a year is
really not going to be the place where these
drugs are going to make the biggest dier-
ence, said Mr. Mark Harrington, executive
director of the HIV/AIDS policy think tank
Treatment Action Group.
Countries that have weak regulatory
systems are going to need a lot of political
will and community demand to drive accep-
tance... On the ground youre going to need
regulators, implementers and activists to
work together to speed up not only the de-
mand for the approved drugs but protocol
review for experiments.
Where normal treatment for drug-resis-
tant TB requires a barrage of drugs for up to
2 years or more, novel drug regimens could
shorten treatment courses and improve out-
comes.
But the time required for approval and
implementation of a novel regimen against
MDR-TB, one that would likely include beda-quiline and delamanid together, may prompt
rapid implementation without regulatory go-
ahead.
I think the issue is what to do until we
have beer denitive evidence of a shorter
regimen, said Dr. Mary Edginton of the
University of the Witwatersrand School of
Public Health in Johannesburg, South Africa.
There doesnt seem to me to be any reasonnot to use the short course regimens, under
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21 January 2013 Conference Coverage
research conditions, with informed consent
of patients, and monitored and reported.
Were going to need to pick up the pace,
said Dr. Kenneth Castro, director of the Divi-
sion of TB Elimination at the US Centers forDisease Control and Prevention. The times
of waiting for the best possible evidence to
formulate some early or preliminary recom-
mendations are gone.
Of about 9 million cases of TB globally,
about 630,000 are resistant to treatment, and
440,000 people with MDR-TB die each yearaccording to the WHO Global Tuberculosis
Report 2012.
Intense antibiotic therapy may benefit TB
meningitis patientsAn intensied antibiotic treatment regi-men could improve outcomes in patientswith tubercular (TB) meningitis, according to
an Indonesian study.
We feel that our results challenge the cur-
rent treatment model, said lead researcher
Dr. Rovina Ruslami, of Padjadjaran Univer-
sity in Bandung, West Java, Indonesia.No optimal regimen for TB meningitis ex-
ists. However, as the pathophysiology of TB
meningitis diers from pulmonary tubercu-
losis, Ruslami and colleagues have suggested
that a higher drug dose may garner beer
treatment outcomes.
In their open-label, phase II trial, 60 pa-
tients were randomized to receive a standard
dose (450 mg orally) or high dose (600 mg in-travenously) of rifampicin, aer which they
were divided again into groups to receive
none, 400 mg, or 800 mg of oral moxioxacin
for 2 weeks, aer which patients continued
with standard tuberculosis treatment.
Most patients were young (median age 28
years) and with advanced disease.
Throughout the trial, patients received iso-
niazid and pyrazinamide, which penetrate
well into the cerebrospinal uid (CSF), and
adjunctive corticosteroids.
High-dose rifampicin tripled plasma and
CSF concentrations compared with those seenwith the standard dose (p
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22 January 2013 Conference Coverage
the researchers said.
Ruslami noted that TB meningitis is rare
but can be severe and has high mortality; over
50 percent of patients die even when they
complete treatment.In the current study, half of the patients
died within 6 months, many within the rst
month, mostly due to respiratory failure and
neurological deterioration.
However, the rate of adverse events was no
more than that of standard therapy, Ruslami
said, and the mortality was lower in the high-
dose rifampicin group 34 percent vs 65 per-
cent in the standard therapy group. Moxioxa-
cin did not appear to aect mortality.
Rifampicin is still an appealing drug fortuberculosis, especially in developing coun-
tries since it is cheap, accessible, well toler-
ated, and physicians are aware of it, Ruslami
said, adding that dening the optimum regi-
men from such drugs could help control TB
meningitis in areas of need.
Rapid TB test performs well onsite
Laboratory diagnosis of tuberculosis (TB)improved by 50 percent when a novelrapid DNA test was added to standard spu-
tum smear microscopy.
When used alone, the Xpert MTB/RIF rap-
id DNA test improved diagnosis by 41 per-cent compared with microscopy, according
to data presented by the international group
Medicines Sans Frontieres (MSF).
Culture is the current gold standard for
denitive TB diagnosis, but results can take
up to 6 weeks. However, the Xpert test can
return results within 2 hours.
The rapid assay can also distinguish bacte-
ria resistant to rifampicin, a rst-line TB drug,as well as non-tubercular mycobacteria.
For drug-sensitive TB, based on Xpert,
people can be put on treatment, said Dr. Mar-
tina Casenghi, research advisor with MSFs
Campaign for Access to Essential Medicines.
For drug-resistant TB... in high multiple
drug-resistant TB (MDR-TB) seings, you can
start patients on an optimized regimen and
then send them for a full drug sensitivity test-
ing to tailor the regimen.
MDR-TB diagnosis in low-burden seings
still necessitates a conrmatory culture for ri-
fampicin resistance, she noted.
The Xpert test is a semi-automated DNA
assay in a closed system. A technician pre-
pares a sputum sample with reagents in a car-
A new rapid TB diagnostic test has been rolled out in various locationsaround the world.
Photocredit:WHO
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23 January 2013 Conference Coverage
tridge and loads it into the machine, which is
about the size of a microwave. The machine
costs US$17,000 and each cartridge costs
US$10.
The process limits contamination and re-turns fewer false-positive results as well as
minimizing the skill set required to do diag-
nostic testing.
The Xpert was rolled out in 25 locations
around the world, including one site each in
Vietnam and Myanmar. Some sites were in
high burden MDR-TB locations, some used
Xpert together with sputum culture or mi-
croscopy, some used Xpert alone and some
reported results in children. The total num-
ber of samples was 36,540.
When we added expert to microscopy we
had a relative gain of 50 percent in detection
of TB, said presenter Dr. Elisa Ardizzoni of
the Mycobacteriology Unit of the Institute of
Tropical Medicine in Antwerp, Belgium.
The data included a relatively large numberof inconclusive results from Xpert, almost 7
percent among the whole data set. Howev-
er, these decreased over the 18-month data
gathering period as technicians became more
skilled and new cartridges became available.
Although the benets of the Xpert test do
not exclude the need for beer point of care
tests in peripheral, resource-poor seings,
Casenghi said it is a step in the right direc-
tion to have a simple, fast test that returns
good results in TB endemic countries with-
out requiring extensive infrastructure.
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24 January 2013 Conference Coverage
Interview with the Presidents
8th International Symposium on Respiratory Diseases and American Thoracic Society in China Forum, 8-11
November, Shanghai, China Chuah Su Ping reports
MT: How will the updated Global Initia-
tive for COPD (GOLD) guidelines aect
current clinical practice?
Kra: The main dierence is the criteria for
diagnoses [of COPD]. Theyre quite dierent
from previous versions and we are current-
ly in an adjustment period trying to beerunderstand how to best apply these guide-
lines in practice. The denitions of dierent
severities of COPD have also changed.
MT: How has respiratory clinical practice
today evolved to improve quality of care
for patients, in particular the use of tele-
medicine?
Bai: This year we will be introducing del-egates to what I like to refer to as the Med-
ical Internet of Things, which is basically
a combination of electronic medicine plus
mobile health, or telemedicine. This has
already started being implemented for pa-
tients being treated for sleep apnea [in Chi-
na] and enables a doctor in a clinic or hospi-
tal to monitor a patient who is at home. The
idea is for patients to take home a portable
monitor and the data will be sent directly to
the doctors oce. In some cases, this data
may enable doctors to make a preliminary
diagnosis. Doctors are also able to feedback
directly to patients via the internet upon
receiving the results. This technology will
allow data to be monitored and recorded
while the patient is asleep at home, which isvery useful in the diagnosis and treatment
of sleep apnea.
Kra: I think telemedicine is still an evolv-
ing eld, and I am still skeptical as to how
it will be applied to clinical practice in the
long term. This is an area we still need to
explore in greater detail.
MT: What do you think are the implica-tions of the results from two early-phase
clinical trials [NEJM 2012;366:2443-54,
NEJM 2012;366:2455-65] presented at the
2012 ASCO meeting which provide further
evidence on the role of the immune system
in treating patients with NSCLC?
Bai: I do believe the immune system plays
an important role in lung cancer treatment.
In China, there is ongoing research looking
into the development of a vaccine for [non-
The 8th International Society for Respiratory Disorders (ISRD)
annual meeting marked the inaugural joint scientic session
between the ISRD and the American Thoracic Society (ATS).
Medical Tribune spoke to the leadership of both organizations
- Professor Chunxue Bai, president of the 8th ISRD and ATS in
China Forum, and Dr. Monica Kra, president of the ATS - to
gain their views on key topics in respiratory diseases.
ProfessorChunxue Bai
Dr. Monica Kra
7/29/2019 Medical Tribune January 2013 SG
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25 January 2013 Conference Coverage
small-cell lung cancer (NSCLC)]. However,
at the end of the day, early diagnosis of lung
cancer is key to extending patient survival.
Kra: Lung cancer remains a very challeng-
ing area, but I think weve made some prog-ress in recent years. Its exciting that we have
discovered specic biomarkers and paerns
of gene expression which are associated
with response to specic chemo-therapeutic
agents, as this can help us ensure patients
are receiving the right combination of medi-
cation. In other words we are geing closerto the goal of personalized therapy in lung
cancer.
Towards targeted COPD treatment
Chronic obstructive pulmonary disease(COPD) treatment should be individual-ized based on each patients clinical pheno-
type, says an expert.
To do so, we would need to move away
from the traditional assessment of COPD and
its treatment, said Professor Paul W. Jones,
professor of respiratory medicine and head of
the division of clinical science at St. Georges,
University of London, UK.One of the key updates to the Global Ini-
tiative for COPD (GOLD) guidelines last year
was when we categorized the treatment aims
[for COPD] into two groups symptomatic
benet and risk reduction, said Jones, who is
a member of the GOLD Science Commiee.
Symptomatic benet includes relief of symp-
toms, improvement in exercise tolerance and
health status whereas risk reduction includesprevention of exacerbations and disease pro-
gression, and reduction in mortality. This
was a big step forward as we explicitly started
to recognize that the manifestations of COPD
dier between individual patients.
In the Evaluation of COPD Longitudinally
to Identify Predictive Surrogate Endpoints
(ECLIPSE) study, Hurst JR et al observed, over
a 3-year period, that 71 percent of frequent ex-
acerbators in years 1 and 2 were frequent ex-
acerbators in year 3, whereas, approximately70 percent of patients who had no exacerba-
tions in years 1 and 2 had no exacerbations
in year 3. Thus, they concluded that the sin-
gle best predictor of exacerbations, across all
GOLD stages, was a history of exacerbations.
[N Engl J Med 2010;363:1128-38]
In this years GOLD [2012] update, we
also recognize that hospitalization is a very
important risk factor. If a patient has hadone or more hospitalizations in a year, that
automatically places them in a high-risk
category, said Jones.
In 1997, Jones and Bosh published a study
in which they observed that the patients es-
timate of treatment ecacy correlated with
changes in the St. Georges Respiratory Ques-
tionnaire (SGRQ) score.
If the patients judged their treatmentas ineective, that correlated with a worse
SGRQ score. However, if they judged their
treatment as eective or very eective, the
improvement in SGRQ score was either at
the threshold of clinical signicance or bet-
ter, said Jones. [Am J Respir Crit Care Med
1997;155:1283-1289]
These ndings are signicant as they tell
us that the patients personal feedback should
also be taken into consideration.
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26 January 2013 Conference Coverage
Highlighting a recent study by Mahler DA
et al, Jones noted that when indacaterol was
added to tiotropium, there was a signicantly
greater change in symptoms compared with
patients on tiotropium alone. These resultsare in line with the COPD guideline recom-
mendations to combine bronchodilators with
dierent mechanism of actions, in this case a
long-acting beta agonist and long-acting mus-
carinic antagonist. [Thorax 2012;67:781-788]
In treating COPD, one of the key things
to remember is to treat, to improve the pa-
tients symptoms and reduce exacerbations,Jones said. Physicians can then custom-
ize treatment based on the patients clinical
phenotype.
NIPPV for treating COPD exacerbations
Non-invasive positive pressure venti-lation (NIPPV) is currently the pre-eminent established application in acute
respiratory failure of chronic obstructive
pulmonary disease (COPD) exacerbations,
but experts say skilled application is critical
for patient breathing.
The rationale for selecting NIPPV is to
rst of all reduce the patients breathingworkload, said Dr. Giuseppe A. Marraro,
director of the Anesthesia and Intensive Care
Department at the A.O. Fatebenefratelli and
Ophthalmiatric Hospital in Milan, Italy, and
this procedure can improve gas exchange,
reduce endotracheal intubation, reduce in-
fection rate and increase patient survival.
[Lancet 2009;374:250]
These are all key factors which willeventually determine treatment success in
patients with COPD exacerbations.
But he noted that patient collaboration
and the skill of hospital sta can play a ma-
jor role in how eective NIPPV will be.
Compared with conventional ventila-
tion, NIPPV confers a higher risk of mask
dislodgment and there is a need for higher
ventilator pressure, said Marraro. He high-
lighted that NIPPV is contraindicated in pa-
tients who require more than 50 percent oxy-
gen; with signicant hypotension induced
by conventional ventilator therapy; with
fractured skull base, facial fractures and in-
creased intracranial pressure; and with re-
spiratory arrest.
Marraro cautioned that NIPPV should
be discontinued if there is no improvement
in gas exchange or dyspnea, or if there is aneed for endotracheal intubation to man-
age secretions or protect the airway. Stop
NIPPV immediately if the patient exhibits
coordinative problems, reduced conscious-
ness and increasing levels of carbon diox-
ide coupled with decreasing pH levels, he
stressed.
Patients with COPD who have exacerba-
tions of respiratory failure can benet sig-nicantly from ventilator assistance.
NIPPV has been shown to reduce the se-
verity of breathlessness within the rst four
hours of treatment, decrease the length of
hospital stay and reduce the rates of mortal-
ity and intubation, said Marraro. He noted
that the advantages of NIPPV include the
avoidance of intubation, which is typically
necessary for 16-35 percent of acute COPD
exacerbations and carries its own complica-
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27 January 2013 Conference Coverage
tions.
NIPPV preserves the patients ability to
cough, speak and swallow. It can also be
used away from the ICU, thereby potentially
reducing costs.With NIPPV, physicians have the choice
of selecting either a nasal or facial mask for
their patients. The advantages of the nasal
mask are that it is less claustrophobic and al-
lows the patient to speak, expectorate, vom-
it, and ingest orally. The facial mask on the
other hand, may be more useful for dyspneic
patients who are usually mouth breathers,
said Marraro. NIPPV can be applied in
appropriate non-ICU seings but it is impor-tant to take into consideration the patients
personal feedback as well as the need for
fully trained and experienced hospital sta
and appropriate equipment, monitoring and
support.
OSA linked to glucose dysmetabolism
Accumulating evidence suggests that
obstructive sleep apnea (OSA) is as-
sociated with glucose dysmetabo-
lism, says an expert.
While the link remains controversial,
it is clear that both conditions are related to
obesity, said Professor Mary Ip of the Uni-versity of Hong Kong. OSA may also have
a causal role on increasing insulin resistance,
glucose tolerance and type 2 diabetes mellitus
[T2DM].
There have been many studies examin-
ing the relationship between insulin resis-
tance and OSA, but few studies on the role
of B-cell dysfunction in OSA, noted Ip. One
such study by Punjabi NM et al showed thatsevere OSA is associated with impaired B-
cell dysfunction. [Am J Respir Crit Care Med
2009;179:235-240] This reduces the compen-
satory insulin secretion, leading to the devel-
opment of glucose intolerance or diabetes,
said Ip.
In the Sleep Heart Health Study, Seicean S
et al found that OSA may be independently
associated with various states of glucose me-
tabolism including impaired fasting glucose,
impaired glucose tolerance and occult diabe-
tes. [Diabetes Care 2008;31:1001-1007]
CPAP has been shown to improve insulin sensitivity in non-diabeticpatients.
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28 January 2013 Conference Coverage
Similarly, a study in Hong Kong showed
that OSA was independently associated
with metabolic syndrome, hypertension and
[increased] waist circumference, said Ip.
[Respir Med 2006;100:980-987]More recent studies in Japan and China
have also shown that patients with severe OSA
had a higher prevalence of hypertension, dys-
lipidemia, glucose intolerance and metabolic
abnormalities. [Respirology 2010;15:1122-1126,
Sleep Breath 2012;16:571-578]
Continuous positive airway pressure
(CPAP) treatment for OSA has been shown
to improve insulin sensitivity in non-diabetic
patients with BMI less than 30 kg/m2. [Am J
Respir Crit Care Med 2004;169:152-62] However,
the eects of CPAP treatment in patients with
T2DM remains controversial, Ip said.
Many studies have been carried out to ex-
amine the eect of CPAP treatment of OSA in
patients with T2DM, however, most did not
report any signicant dierence on glycemic
control [post-treatment], she said. Compli-ance to CPAP may also play an important
role in improving insulin resistance in OSA
patients. The use of CPAP to improve insu-
lin sensitivity in OSA patients remains to be
validated.
While convincing data demonstrate a link
between OSA and B-cell dysfunction, insulin
resistance, metabolic syndrome and increas-
ing HbA1c levels, lile is known about the
long-term outcomes of OSA treatment for
T2DM, which Ip said would be a key area for
future research.
CPAP may improve cognitive function inOSA patients
Continuous positive airway pressure(CPAP) treatment for obstructive sleepapnea (OSA) may improve neurocognitive
function, show the latest results from the
Apnea Positive Pressure Long-Term Ecacy
Study (APPLES).Up till recently, there have been studies
examining the eect of sleep apnea on neu-
rocognitive function said Professor Clete A.
Kushida of Stanford University Medical Cen-
ter in Stanford, California, US.
Previous studies, however, have been lim-
ited by relatively small sample sizes, noncom-
prehensive test baeries and inadequate con-
trol groups. [J Clin Sleep Med 2006;2:288-300]
In APPLES, Kushida and his team random-
ized 1,100 OSA patients to receive either active
CPAP or its sham version to test the hypoth-
eses that hypoxemia and/or sleepiness in OSA
is responsible for neurocognitive decline.
The main aims of the study were to identi-
fy specic decits in neurocognitive functionin a large heterogenous population of OSA
patients and to assess the long-term eec-
tiveness of CPAP therapy on neurocognition,
mood, sleepiness and quality of life. It also
sought to evaluate which decits are revers-
ible and most sensitive to the eects of CPAP.
[J Clin Sleep Med 2006;2:288-300]
The primary outcomes examined were
aention and psychomotor function; learn-
ing and memory (L/M); and executive and
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29 January 2013 Conference Coverage
READ JPOG ANYTIME, ANYWHERE.Download the digital edition today at www.jpog.com
frontal-lobe function (E/F). These were ex-
amined via the Pathnder Number (PN) Test,
the Buschke Selective Reminding Test (BSRT),
and the Sustained Working Memory Test
(SWMT), respectively, said Kushida, who isalso president of the World Sleep Federation.
While covariate-adjusted analyses re-
vealed no signicant dierences in the PN
and BSRT test results between the active
CPAP and sham group, we did nd signi-
cantly beer SWMT results, which examined
E/F, in the active CPAP group, he said. Low-
er levels of oxygen saturation and increased
sleepiness also produced signicant eects on
the E/F test.
However, these eects were only de-
tected at 2 months and were minor com-
pared with the eects of caeine and
diphenhydramine for this measure in other
studies, he noted.
Interestingly, the study also reported that
adherence to CPAP was signicantly lower in
the sham group, and this, said Kushida, was a
major limitation in APPLES.
Interpreting APPLES
The detection of CPAP eects in the pri-
mary E/F variable suggests that the SWMT
test - in which a cognitive task is combined
with simultaneous electroencephalographicmeasures of brain function - is a more sen-
sitive measure for subtle neurocognitive
changes, said Kushida.
The mixed results from prior studies, as
well as the limited eect on CPAP on neuro-
cognition in APPLES, suggest the existence
of a complex OSA-neurocognitive relation-
ship. Clinicians should consider disease
severity, sleepiness, individual dierences
(variability in neurocognitive function and
brain reserve) and treatment adherence
in managing OSA patients with CPAP, he
opined.
Lastly, we need more large-scale sleep
studies to further examine the ecacy or in-
ecacy of CPAP therapy on this very preva-
lent sleep-related breathing disorder.
The results of APPLES are expected to be
published in December 2013.
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30 January 2013 Conference Coverage
Personal Perspectives
In developing the new GOLD guidelines, we set clear treatmentobjectives based on improving symptoms; and for the rst time in
COPD, identifying that risk reduction is a key component in treatment,
particularly in terms of reducing the risk of exacerbations.
Paul W. Jones, University of London, UK
One of the things we need to do is to strengthen the bridge betweenEastern and Western science. Meetings like these not only showcase the
science being done here in China but also facilitate the exchange of ideas
to advance the state of the science globally. As an economist, my interest
lies mainly in the cost-of-care issues of access and delivery systems.
Stephen Crane, Executive Director, American Thoracic Society
The topics of any conference should rst of all reect the prevalenceof the disorders in the [host] country. Sleep apnea, lung cancer and
COPD are all prevalent in China. Second, it should also reect the
emerging science which will aect treatment and diagnosis. Third, it
should support ongoing research within the country. Lastly, it should
also dene what the young physicians will be facing in the future. In
my opinion, the ISRD 2012 has done an excellent job in bringing all that
together.
Teolo Lee-Chiong, University of Colorado, US
Being an international conference with delegates aending from all over
the world, there should be more English speaking sta on hand. Every
time we need any help, we have to go the secretariat oce. Other than
that, everything else was great.
Maulik Sanghvi, India
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31 January 2013 Gastroesophageal Reflux Disease
Rajesh Kumar
Obese individuals can reduce theirrisk of developing gastroesophagealreux disease (GERD) by exercis-
ing even if only once-a-week, according to aSwedish study.
However, no such benet from occasional
physical activity was seen in patients with nor-mal body mass index (BMI). [World J Gastroen-terol 2012;28:3710-3714]
Researchers randomly selected 4,910 peo-ple aged between 40 and 79 years from theSwedish registry of the total population fora cross-sectional survey. Data on their physi-cal activity, GERD, BMI and the covariatesage, gender, comorbidity, education, sleep-ing problems, and tobacco smoking were ob-tained using validated questionnaires.
GERD was self-reported and denedas heartburn or regurgitation at least onceweekly, and the presence of at least moderateproblems from such symptoms. Frequency ofphysical activity was categorized into high(several times/week), intermediate (approxi-mately once weekly) and low (1-3 times amonth or less).
Analyses were stratied for participantswith normal weight (BMI < 25 kg/m2), over-weight (BMI 25 to 30 kg/m2) and obese (BMI> 30 kg/m2). Obese participants were on aver-age slightly older, had fewer years of educa-tion, more comorbidity, slightly more sleepingproblems, lower frequency of physical activity,and higher occurrence of GERD.
In 680 obese individuals, intermediate fre-quency of physical activity was associatedwith a decreased occurrence of GERD com-
pared with low physical activity (adjustedhazard ratio [HR] 0.41). Among the 2,146normal-weight participants, a decreased riskof GERD was seen with higher physical ac-tivity (HR 0.59), but the benet was negatedaer adjusting for potential cofounders suchas sleeping problems and high comorbidity.A similar trend was seen in 1,859 overweight
participants.The studys limitations include an inherent
uncertainty about the accuracy of self-report-ed data and lack of validation of the assess-ment of frequency of physical activity, BMIand possible previous surgical interventionsfor GERD, said the study authors.
Because it is a cross-sectional study, it isnot possible to know if the participants witha self-detected association between reux andphysical exercise may have changed their
behavior, resulting in reverse causality, theysaid.
The current ndings conrm the previouspopulation-based studies assessing an asso-ciation between physical activity and GERDwithin the general population.
However, none of the previous studiesstratied analyses for BMI categories; mean-
ing that the decreased risk of GERD limited toobese individuals is a rst time observation,said authors Dr. Therese Djrv and colleaguesat the department of molecular medicine andsurgery, Karolinska Institutet in Stockholm,Sweden.
Should the present results be conrmed infuture research, the ndings from this studymight be important for the prevention andtreatment of GERD and its complications,they concluded.
Once weekly exercise enough to reduce
GERD risk in obese
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32 January 2013 Gastroesophageal Reflux Disease
Alexandra Kirsten
Aretrospective study has shown thatpatients with type 2 diabetes havetwice the risk of Barres esopha-
gus, a condition where the esophageal lin-ing becomes abnormal, whether or not otherrisk factors such as smoking or obesity were
present.The ndings were presented during the
American College of Gastroenterologys 77thAnnual Scientic Meeting, held recently inLas Vegas, Nevada, US. [Abstract 49]
To determine whether there is an asso-ciation between type 2 diabetes and Barresesophagus, Dr. Prasad Iyer, associate profes-sor of gastroenterology and hepatology at the
Mayo Clinic College of Medicine in Roches-ter, Minnesota, US, and his fellow researchersconducted a population-based, case-controlstudy.
They identied 14,245 patients with Bar-res esophagus and 70,361 control subjectswho were matched for age, sex, enrolmentdate, duration of follow-up, and practice re-gion using the United Kingdoms GeneralPractice Research Database, a primary care
database that includes over 8 million patients.The data showed that patients with Bar-
res esophagus were more likely to havesmoked and consumed alcohol, had a higher
body mass index, and a higher prevalence oftype 2 diabetes than control subjects.
Multivariate analysis showed a 49 per-cent increased risk for Barres esophagus inpatients with type 2 diabetes. The link was
stronger in men (OR, 2.03; 95% CI, 1.01 - 4.04)than in women (OR, 1.37; 95% CI, 0.63 - 2.97).
Interestingly, we found that among thestudy cohort, if you had diabetes there wasa twofold increase in your risk for Barresesophagus, Iyer said. When we stratied
the results by gender, the association of type2 diabetes with Barres esophagus was stron-ger in males compared to females, which mayreect the dierent fat distributions in menand women.
There is some evidence that central obe-sity is a risk factor for Barres esophagusand esophageal cancer through mechanicalor metabolic mechanisms, such as hyperin-sulinemia. The researchers suggested fat in
the abdomen could be a reux-independentmechanism leading to Barres esophaguswhich is known to be a precursor of esopha-geal adenocarcinoma.
If we nd the precursor early enough, wecould put these patients under surveillanceor treat the precursor and reduce the risk,Iyer said. He added that further prospectivestudies are needed to beer understand the
link between Barres esophagus and type 2diabetes.
Barretts esophagus linked to type 2
diabetes
Patients with Barres esophagus were also more likely to have smoked orconsumed alcohol, and had a higher mean BMI than controls.
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33 January 2013 News
Alexandra Kirsten
Toxic smoke and soot from open-
re cooking causes nearly 2 million
deaths each year, primarily among
women and children who spend the most
time at reside, according to the World
Health Organization.
To examine the link between the atmo-
sphere and human health, the US National
Center for Atmospheric Research (NCAR) in
Boulder, Colorado, US, is launching a large-
scale study into the impact of open-re cook-
ing on regional air quality and disease.
Pollutants and particles spewed by open
res are a proven health risk to individuals, to
villages and entire regions, explained NCAR
lead scientist Dr. Christine Wiedinmyer. The
3-year study will be the rst to discuss broad-
scale solutions to disease and pollution from
open-re cooking
The use of wood, animal and agricultural
waste for cooking and warming homes in
developing countries is a principal source
of carbon monoxide, particulates and smog.
These can cause a variety of symptoms, rang-ing from headaches and nausea to conditions
like cardiovascular and respiratory diseases.
The international team of pollution, cli-
mate, and health experts from NCAR, the
University of Colorado Boulder, the Universi-
ty of Ghana School of Public Health and Gha-
na Health Services, will analyze the eects of
smoke from traditional cooking methods on
households, villages, and entire regions.
Given that an estimated 3 billion people
worldwide are cooking over re and smoke,
we need to beer understand how these pol-
lutants are aecting public health as well as
regional air quality and even the climate,
said Wiedinmyer.
The research group will focus on deter-
mining the inuence of traditional cooking
methods on human health using air quality
sensors and computer and statistical models.
They will also evaluate the disease reduc-
tion capacity of low-emission cook stoves and
if these newer, more ecient stoves positively
aect regional air quality. Surveys among vil-lagers on their understanding of the connec-
tion between open-re cooking and disease
will also help gauge their interest in changing
their cooking habits.
The results of the study could point to the
best means for a transition to cleaner cook-
ing methods and show how the open-re
emissions are aecting weather paerns that
contribute to global warming.
Health impact of open-fire cooking to be
studied
The large-scale study will also assess the potential of low-emission cookstoves to reduce disease.
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34 January 2013 News
Rajesh Kumar
Elderly hypertensive patients may be at
higher risk of hip fractures in the rst
45 days aer starting antihypertensive
drug therapy, according to research.
Canadian researchers linked a cohort of
301,591 newly treated hypertensive rest home
residents (mean age, 81 years) to the records
of 1,463 hip fractures between 1 April 2000 to
31 March 2009. They analyzed the risk dur-
ing the rst 45 days following therapy initia-
tion, with equal control periods before and
aer that and a total of 450-day observation
period. [Arch Intern Med2012; doi:10.1001/2013.
jamainternmed.469]
The outcome was the rst occurrence of a
proximal femoral fracture during the risk pe-riod. The researchers found a 43 percent in-
creased risk of having a hip fracture during the
risk period compared with the control periods
(incidence rate ratio [IRR], 1.43; 95% con-
dence interval [CI], 1.19 to 1.72).
Initiating antihypertensive drugs such as
thiazide diuretics, angiotensin II converting
enzyme (ACE) inhibitors, angiotensin II re-
ceptor blockers (ARBs) or calcium channelblockers in the elderly is already associated
with an immediate increased risk of falls. The
study sought to nd out the immediate risk of
hip fracture.
Adjusting for age and use of other medica-
tions implicated in falls, such as psychotropic
drugs, did not change the risk. The relation-
ship was generally consistent for all classes of
antihypertensive drugs (IRRs, 1.30 to 1.58), al-though it reached statistical signicance only
for ACE inhibitors (IRR, 1.53, 95% CI, 1.12 to
2.10) and -blockers (IRR, 1.58, 95% CI, 1.01
to 2.48).
Dr. Kenneth Ng Kwan Chung, cardiolo-
gist at Novena Heart Centre in Singapore,
said physicians know that ACE inhibitors can
cause rst dose hypotension, especially in pa-
tients who are already on diuretics. But it is not
clear why -blockers were also implicated in
the study.
Elderly patients are more likely to have
sick sinus syndrome and -blockers may
cause severe bradycardia and then fainting
and falls [leading to fracture], explained Ng.
Asian patients are usually frailer and
smaller sized than their Western counter-
parts, which might make the eect of anti-
hypertensive medications more marked inthem, he said, adding that physicians should
start with the lowest possible dose of one
medication and rst check for postural hy-
potension, particularly when starting ACE
inhibitors and -blockers in elderly patients.
Check the heart rate before starting
-blockersand educate the patient to get
up slowly out of the bed or chair. Wait for
any giddiness or instability to subside beforetaking the next few steps to walking. Ask a
family member to watch over them when
they get up in the middle of the night, said
Ng.
Patients could also monitor their blood
pressure at home and send the readings to
their family doctor, who can then advise them
on the dose reduction or discontinuation of
the medication if the blood pressure goes toolow, he concluded.
Elderly face higher hip fracture risk after
starting BP drugs
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35 January 2013 News
Rajesh Kumar
In patients with multivessel coronary ar-tery disease, coronary artery bypass gra(CABG) surgery was more eective in an
older cohort, while percutaneous coronaryintervention (PCI) was favored in a relativelyyounger one in a large analysis.
Researchers pooled individual data from7,812 patients who were randomized in 10clinical trials of CABG or PCI to assess whetherpatient age modies the comparative eective-ness of those interventions. [J Am Coll Cardiol2012; 60:2150-2157]
They analyzed age as a continuous vari-able in the primary analysis and divided it intothree groups of 56.2 years, 56.3 to 65.1 years
and 65.2 years for descriptive purposes. Theoutcomes assessed were death, myocardialinfarction and repeat revascularization overcomplete follow-up and angina at 1 year. Old-er patients were more likely to have hyperten-sion, diabetes, and 3-vessel disease comparedwith younger patients (p=0.001 for trend).
Over a median follow-up of 5.9 years, theeect of CABG versus PCI on mortality var-ied according to age (interaction p=0.01), with
adjusted CABG/PCI hazard ratios and 95 per-cent condence intervals of 1.23 (95% CI 0.95 to1.59) in the youngest group; 0.89 (95% CI 0.73to 1.10) in the middle group; and 0.79 (95% CI0.67 to 0.94) in the oldest group.
The CABG/PCI hazard ratio was less than 1for patients 59 years. A similar interaction ofage with treatment was present for the compos-ite outcome of death or myocardial infarction.
In contrast, patient age did not alter the com-parative eectiveness of CABG and PCI on theoutcomes of repeat revascularization or angina.
Dr. Kenneth Ng Kwan Chung, cardiologistat Novena Heart Centre in Singapore, said in-creasing age is known to be a risk factor formortality and complications resulting fromCABG.
Therefore in patients who are elderly, we
sometimes aempt to perform PCI on the ste-notic lesions rather than send them for surgery.However, this study points out that the olderpatients actually benet more from CABGthan PCI. It could be that older patients havemore diuse disease than younger patients.
Ng said the ndings are relevant for Asians aswe have a higher proportion of patients who arediabetic, compared with Caucasians, and havea rapidly aging population in which ischemic
heart disease is the biggest cause of morbidity.The take home message for us is to explain
to the patients aged >59 years that CABG couldbe a beer option than PCI if they have triplevessel disease and diabetes. This is becauseof a 21 percent lower risk of cardiovascularmortality in the >65 years age group in thestudy, he said.
Also, there was no dierence in compli-
cations between the PCI and CABG groupsin terms of death from the procedure andstroke.
CABG more effective than PCI in older
CAD patients
Researchers analyzed pooled data from 10 clinical trials involving patientswho had undergone CABG or PCI.
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36 January 2013 News
Bleeding rates with warfarin much higher
in reality?
Elvira Manzano
The rates of major bleeding with warfa-
rin use in atrial brillation (AF) may be
higher than reported in clinical trials
and are oen fatal, new research suggests.
A population-based study conducted in
Canada involving 125,195 patients who start-
ed warfarin therapy aer a diagnosis of AFshowed an overall rate of hemorrhage of 3.8
percent per person-year over a study period
of 13 years. The risk of major hemorrhage (de-
ned as a visit to an emergency department
or admission to hospital) was highest during
the rst 30 days of treatment (11.8 percent
per person-year). [CMAJ 2012;doi:10.1503/
cmaj.121218]
The results were important as they re-ect the bleeding rates with warfarin in the
real world, said lead study author Assistant
Professor Tara Gomes, of the University of
Toronto in Ontario. These rates are consid-
erably higher than the rates of 1 to 3 percent
per person-year reported in randomized con-
trolled trials of warfarin therapy.
The dierence, she said, may be due to the
strict inclusion criteria and close monitoringof patients in clinical trials and the average
age of participants in their study being older.
Warfarin helps prevent stroke and blood
clots in AF patients. However, it has a nar-
row therapeutic window (international nor-
malized ratio [INR] 3-4) and requires regular
monitoring to minimize the risk of hemor-
rhage. Currently, there are no large trials of-
fering real-world, population based-estimatesof bleeding rates among patients on warfarin.
This prompted Gomes and colleagues
to study the medical records of AF patients
(aged 66 years or older) who started warfarin
therapy between April 1997 and March 2008.
The cumulative incidence of hemorrhage
was 4.1 percent at 1 year and 8.7 percent at5 years. In total, 1,963 patients (18.1 percent)
died in the hospital or a week aer discharge.
Although the rate of intracranial hemorrhage
was low in the study, it was associated with
a high mortality rate (42 percent). As expect-
ed, bleeding rates were higher in those with
a CHADS2 score of 4 or higher (16.7 percent
per person-year) and in patients older than 75
years (4.6 percent per person-year).Our study provides timely estimates of
warfarin-related adverse events that may be
useful to clinicians, patients and policymak-
ers as new options for treatment become
available, Gomes said.
Doctors should know the potential for
bleeding in patients whe