medical tribune january 2013 sg

7/29/2019 Medical Tribune January 2013 SG

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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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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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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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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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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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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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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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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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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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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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16/57


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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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.


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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


19/57

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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


21/57

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


22/57


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


23/57


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.


24/57


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


25/57


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.


26/57


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-


27/57


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.


28/57


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


29/57


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.


30/57


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


31/57

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.


33/57

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.


34/57


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


35/57


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.


36/57


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

medical tribune january 2013 sg

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