à votre santé

IFNγ and antibody responses among French nurses during a tuberculosis contact tracing investigation

Without further adieu;

This initial and first French picture provides us with the observation that only 44% of TST-positive HCW were IGRA positive, and the IGRA test allowed the detection of LTBI in two TST negative HCWs.

Source

QFT and CT scan combo wins a guernsey

From the latest issue of the International Journal of Tuberculosis and Lung Disease comes the results of a study conducted by Korean TB authorities in which QuantiFERON®-TB Gold assay was used to confirm TST+ in a contact investigation;

...TST was positive in 388 subjects (37.2%), while QFT-G was positive in 7.6% (30/394).

Importantly they found that the combination of QFT with a CT scan was more effective than the "conventional" method of TST and X-ray.

...Compared to the conventional approach, the additional use of QFT-G in TST-positive subjects and chest CT in subgroups with a high probability of infection was found to be more effective in the differentiation between active TB, latent TB and non-infected subjects in a contact investigation.

Given the relatively small numbers of QFT+ the additional use of a CT scan could provide a modern and cost effective solution to the issue of determining infection status.

Quantiferon is approved in Korea with a reimbursement of 67,000 Won (AU$68.75)

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New Years resolutions fron New Mexico

Pretty standard fare; give up the booze, the fags, dining at the greasy spoon and most importantly, give up the TB skin test

Decrease the number of people unnecessarily started on LTBI treatment due to false positive Tuberculin Skin Testing (TST), by increasing the use of QuantiFERON TB Gold testing in adults age 17 and older, particularly among high-risk populations

Are in vitro diagnostics recession proof?

Kalorama Information's lead diagnostic analyst Shara Rosen tests the assumption that in vitro diagnostics are recession proof and, for the recession busting sum of $2,995.00, you can read what Shara has to say.

Providing silver crosses their palm Bio Portfolio can also bring you up to speed. P&M also want to see the colour of your money as does researchandmarkets.com. Apparently for a small fee you can analyse your way out of a recession

Frost & Sullivan's research analyst Gayathry Ramachandran will tell you for free;

Positive Diagnosis

The European IVD testing market is benefiting from an ageing population and associated diseases. Early diagnosis can save more lives and cut costs, making it a true recession beater

In vitro diagnostics (IVD) tests refer to the tests conducted in a test tube or in a controlled environment outside the living organism. IVD tests are beneficial for the clinical diagnosis of a disease. Their importance and clinical relevance have made them popular amongst physicians and patients, driving market growth.

One of the key trends driving the IVD market is Europe's ageing population. There is an increased incidence of diseases such as respiratory infections and urinary tract infections. The adoption of point-of-care testing (POCT) has increased turnaround times of results and therefore contributed to early diagnosis and treatment. IVD manufacturers are responding to major trends such as consolidation of laboratories by improving pre- and post-analytical automation, which reduces workflow management.

The need for faster detection of infectious agents is forcing laboratories to move away from the routine culture-based microbiological methods towards molecular techniques that provide rapid and accurate results.

Central laboratory testing remains one of the key areas in hospitals, while methods such as glucose testing, cardiac testing and coagulation tests have become decentralised. They therefore find more usage in ICUs, physicians' offices and nursing stations. The growth sectors within the IVD market are molecular assays specifically aimed at cancer testing, cardiac marker testing and blood glucose measurement.

In spite of the challenges posed by regulatory authorities and compulsive CE marking, the IVD market is set to grow further. The introduction of new markers, improvised technologies, high sensitivity and increased specificity of tests will continue to increase the uptake of IVDs. Personalised healthcare, where patients play a major role in the diagnostic process, will drive the market in the future.

Key challenges

Although the IVD market is lucrative, it faces challenges in terms of reimbursement and regulatory hurdles. The complex reimbursement procedure is a challenge faced by the commercial laboratory industry. Labs need to select reimbursement codes from a list that may not include technologically advanced tests. This means that payments made for a particular test may not cover the technological cost involved.

This kind of reimbursement structure affects the commercialisation of developing segments of IVD, like molecular testing. As the cost involved in the development of novel molecular markers increases, manufacturers worry that the coding and payments for molecular tests will prevent them from recovering the R&D expenditure. Proving the clinical significance of a test is a deciding factor for reimbursement. The IVD manufacturer must prove that the test has regulatory approval and is applicable to a large geographical region.

The IVD market is highly competitive and manufacturers must remain technologically advanced to maintain an edge. The dearth in the number of skilled professionals available to perform lab tests is driving laboratories to adopt automated solutions that simplify their workflow at lower costs.

Future focus

Frost & Sullivan believes that infectious disease testing, molecular testing and POCT will be key segments to watch out for by 2014. Sectors such as clinical chemistry, immunoassay, haematology and coagulation will continue to grow at a steady rate with the help of automation, which will enable better adoption rates.

Roche Diagnostics, a leading IVD market participant, is continuing to focus on collateral business segments such as immunohistochemistry with the acquisition of Ventana Medical Systems. This is a key step towards companion diagnostics. The future direction of the industry will be in the development of early disease detection technologies. Merging in-vitro and in-vivo technologies will continue to pave the way for molecular medicine and personalised healthcare.

"Although the IVD market is lucrative, it faces challenges in terms of reimbursement and regulatory hurdles."

This trend has been observed by leading diagnostic manufacturers such as Siemens Medical Solutions, which has gained momentum in the market with the acquisition of DPC, Bayer Diagnostics and Dade Behring. This enables the focus on in-vitro and in-vivo together to provide integrated care for patients. Recent technological advancements are towards areas such as the discovery of new biomarkers, expanding test menus, improving assay sensitivity and better connectivity. The growth potential for this market lies in miniaturisation, information technology, automation and genomics/proteomics.

Offering connectivity solutions and automated solutions have been the technologies that have found broad application in the European IVD industry. Consolidation of workstations has encouraged manufacturers to develop integrated analysers for complete laboratory automation. The adoption rate of these technologies will remain high over the next five years.

End users for diagnostic products, such as central laboratories, decentralised testing centres and self-testing patients, have varying needs in the market. Although customer service and easy-to-use technologies are of prime importance to all these users, features such as miniaturisation are needed at facilities outside core laboratories. Central laboratories, on the other hand, also look for modular instruments with high throughput capabilities.

Personalised research

One of the hot areas of research is biomarker discovery, which will revolutionise the diagnostic industry. However, it currently faces challenges such as the high investment required to prove clinical validity. This challenge can be overcome to some extent with the help of partnerships between pharma companies and diagnostic companies. This is referred to as companion diagnostics.

For instance, tremendous research is taking place in the field of cancer diagnostics. The importance of molecular tests has been elucidated by the success of the human genome project. The identification of mutated genes, which drive oncogenesis, has been the key aim of cancer research. This has allowed rapid proliferation of specific NAT for the detection of tumour markers and holds strong potential for the growth of the market.

The human genome project has opened up space for immense research in the field of cancer diagnostics, especially for early detection and prevention studies. Feedback suggests that biomarker detection and drug discovery processes must happen simultaneously to produce specific drugs for a cancer cure.

Personalised healthcare is essential for cancer treatment. However, major challenges remain for identifying the right biomarker, which will be crucial for the commercial success of the test. To popularise companion diagnostics, access to the tests is very important and therefore the clinical validity of the test must be proved.

As companion diagnostics aid in reducing the time for clinical trials, this will encourage pharmaceutical companies to liaise with the diagnostics companies to develop strategies for biomarker identification. This will also support the diagnostic industry and enable it to become an integral part of healthcare delivery.

Global economic effect

The diagnostics industry is definitely positioning itself on the right track – towards personalised healthcare. However, as with all other industries, it faces the challenge of the global economic downturn.

"The ageing population and the incidence of disease will continue to increase, but companies will have to introduce innovative technologies that will help to save money."

The impact of the slowdown on the diagnostics market appears minimal in the short term. Profit margins of suppliers have been affected, especially in the case of imports of reagents from countries such as the US, due to varying exchange rates. The long-term implications may be more severe. Although the ageing population and the incidence of disease will continue to increase, suggesting that diagnostic tests will still be in demand, companies will have to introduce innovative technologies that will help consumers to save money.

If the recession continues to deepen, this will also affect the cash flows for technology development, which in turn will affect the projects undertaken for diagnostic innovation. Companies that are known for technological developments may well focus on selling what they already have and reduce investment on research.

To handle the global slowdown and make the long-term impact as minimal as possible, IVD manufacturers will be forced to adopt varied business models to remain profitable. A common strategy will be through mergers and acquisitions (M&A). This will happen primarily due to less funding being available from venture capitalists. This reduced funding will have a high impact on smaller companies. M&A between the leading players and new market participants will therefore be a win-win situation, as it will provide innovative intellectual property to larger companies and provide the smaller ones with a better platform on which to launch their products.

A growing preference for refurbished diagnostic instruments can also be expected in the long term as a result of the biting economy. A few laboratories already prefer refurbished instruments due to having a better rapport with the suppliers. This enables them to procure the instruments that best fit their requirements. In the wake of competition from refurbished instrument suppliers, manufacturers are setting up their own refurbished instrument units. This will enable them to gain better profits and help the laboratories to save money in the time of recession.

Anticipating the impact of the downturn, manufacturers will now feel the need to develop early detection technologies, which will help to reduce overall cost. Hospitals will also concentrate on improving existing technologies and liaise with healthcare professionals to create awareness about the importance of the existing panel of tests.

The healthcare industry appreciates the importance of early diagnosis and the role of diagnosis in developing patient-friendly therapy. This will continue to fuel the growth of the IVD market in Europe and other parts of the world. The impact of the global recession will be felt long term in terms of a reduction in the volume of testing. The prescription of special tests will also be delayed due to lack of insurance. But Frost & Sullivan expects the impact to be minimal compared to other industries, due to the indispensable nature of the products.

Pesca inferior

Morgan Stanley take a long look at quantitative easing (QE) by central banks and the desired effect on money supply;

Bottom line: Our survey of money supply measures, interest rate levels and spreads all suggest that active and passive QE is doing what it is supposed to do: increase money supply and improve financing conditions. Importantly, most central banks are not even halfway through with their announced active QE programmes, and the size of these programmes could easily be increased, if needed. Thus, we continue to expect global QE to be an important contributor to a bottoming of the global economy over the summer and to prevent temporary and ‘good’ deflation (deriving from declines in energy and food prices) from turning into lasting and ‘bad’ deflation.

Studying the field from the inside rail

Rob Ferguson, chairman of litigation funder IMF Australia and keen follower of the hayburners talks to Alan Kohler on Inside Business;

ALAN KOHLER: So what do you think is the outlook now for the global economy and Australia's?

ROB FERGUSON: Well, Australia is in better shape but we are part of the world and we can get sucked down like the rest of the world. The rest of the world's in a horrible mess. In particular Europe is in a disastrous situation, Japan's in a very bad situation. In particular the exporters are in a very bad position, Japan, Germany, China, their economies are going down a lot faster than the rest of the world and there is this problem that they don't have domestic demand enough to sustain their economies and I think that that problem is here for a long time. The banking problems seem to be maybe improving and maybe there's progress being made on that front but there's still a lot of damage to be fixed up and as for the stock market, the stock market does anticipate things before they actually turn around and so maybe what we're seeing now is some sort of base in the stock market.

ALAN KOHLER: Are you calling the bottom?

ROB FERGUSON: No, I'm not calling the bottom but the stock market will be going up when everything's still going to hell in a hand basket. That's how stock markets work. It normally goes up with everybody getting used to bad news and maybe that's what we've seen lately.

Death taxes - another nail in the coffin

Daniel Mitchell takes aim at these grave robbers;

The Correct Rate for the Death Tax is Zero

April 24, 2009

I provided the opposing view to USA Today’s pro-death tax editorial today. In my column, I pointed out that the tax was inherently unfair, and also noted that it is a perverse from of double taxation:

If there were a prize for the most destructive tax, the death tax surely would be a prohibitive favorite. Known to policy wonks as the estate tax, this levy is a punitive form of double taxation that penalizes people for trying to create a nest egg for their children. …This matters because every economic theory — even Marxism — agrees that capital formation is the key to growth. Higher living standards are possible only if people invest by setting aside some of today’s income. But a punitive death tax, especially when combined with other forms of double taxation on capital gains and dividends, reduces the incentive to save and invest. Scholars who have examined this issue estimate that the death tax has reduced America’s stock of saving and investment by nearly $850 billion. Moreover, the death tax is a job killer, reducing employment by 1.5 million. Ideally, the death tax should be abolished. Nations as diverse as Russia, Australia and Sweden have killed this unfair levy.

In their pro-death tax editorial, the folks at USA Today offered a rather absurd argument about double taxation, claiming that the dead person is not taxed twice because he or she is dead when the death tax is paid:

Another canard is the double taxation argument, which goes like this: Someone becomes wealthy through hard work and enterprise, all along paying hefty taxes, and then is walloped again at death. This argument has one slight problem: Dead people don’t really pay taxes. Estate taxes are effectively paid by the people who are alive to feel the effect of the tax: the heirs.

Not only is this argument morally dubious, it is economically nonsensical. The death tax is bad for growth because it encourages wealthy people (who are still alive) to be less productive because they want to minimize a future tax. That is the reason America has a huge “estate planning” industry. This industry exists to advise people how to use their money less productively, which is why academics have found the big negative effects I cite in my column.

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TST leads to chronic confusion and befuddlement

Chit chat between various occupational health professionals in the US went along these lines;

- At our EH department we require documentation of MMR, Hepatitis B vaccinations in exposure category 1 and 2, Tb skin test within 30 days of hire, if they are over 50 years old we require a 2 step ppd

- I'm very curious why you only require two step testing on staff over 50. I've never come across that recommendation

- the majority of 2 step testing we do are for those over 50.

- I would advise everyone to follow the 2005 MMWR Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health Care Settings, 2005. See page 29 regarding TST testing and recommendations for two step TSTs.

- Granted the TST is not a great test, but I believe it is the best we have.

- In essence, we are still doing 2-step testing when we accept one from the past 12-months. That is considered #1 and the one done at time of hire is #2.

- While OSHA does not have a TB standard, they did/still have a compliance letter related to TB screening. It references older standards but definitely calls for 2-step testing on all new hires.

- The OSHA TB standard was dropped on Dec 31, 2003 (see page 75 of 2005 MMWR guidelines for more information)...Lack of two step baseline testing could lead to a citation.

- CDC has also stated that Quantiferon Gold Testing can replace all uses of TB skin testing. This would eliminate the need for two step testing and since ok by CDC, should meet any inspectors needs.

Junk Bond King trashes share buy back schemes

Forbes #462 worlds wealthiest Mike Milken has a Eureka moment and sees the light; from the Milken Institute;

..Without stock buybacks, many such companies would have little debt and would have greater flexibility during this period of increased credit constraints. In other words, their current financial problems are self-imposed. Instead of entering the recession with adequate liquidity and less debt with long maturities, they had the wrong capital structure for the time.

The current recession started in real estate, just as in 1974. Back then, many real-estate investment trusts lost as much as 90% of their value in less than a year because they were too highly leveraged and too dependent on commercial paper at a time when interest rates were doubling. This time around it was a combination of excessive leverage in real-estate-related financial instruments, a serious lowering of underwriting standards, and ratings that bore little relationship to reality. The experience of both periods highlights two fallacies that seem to recur in 20-year cycles: that any loan to real estate is a good loan, and that property values always rise. Fact: Over the past 120 years, home prices have declined about 40% of the time.

History isn't a sine wave of endlessly repeated patterns. It's more like a helix that brings similar events around in a different orbit. But what we see today does echo the 1970s, as companies use the capital markets to push out debt maturities and pay off loans. That gives them breathing room and provides hope that history will repeat itself in a strong economic recovery.

Labcorp - market size and share

In their 2007 10-K report Labcorp outline their view of the market

______________________________________

The Clinical Laboratory Testing Industry

Laboratory tests and procedures are used generally by hospitals, physicians and other health care providers and commercial clients to assist in the diagnosis, evaluation, detection, therapy selection, monitoring and treatment of diseases and other medical conditions through the examination of substances in the blood, tissues and other specimens. Clinical laboratory testing is generally categorized as either clinical pathology testing, which is performed on body fluids including blood, or anatomical pathology testing, which is performed on histologic or cytologic samples (e.g., tissue and other samples, including human cells). Clinical and anatomical pathology procedures are frequently ordered as part of regular physician office visits and hospital admissions in connection with the diagnosis and treatment of illnesses. Certain of these tests and procedures are used in the diagnosis and management of a wide variety of medical conditions such as cancer, AIDS, endocrine disorders, cardiac disorders and genetic disease.

The clinical laboratory industry consists primarily of three types of providers: hospital-based laboratories, physician-office laboratories and independent clinical laboratories, such as those owned by the Company. The Company believes that in 2007 the entire United States clinical laboratory testing industry had revenues of approximately $50 billion; approximately 54% of such revenues were attributable to hospital-affiliated laboratories, approximately 41% were attributable to independent clinical laboratories and others, and approximately 5% were attributable to physicians in their offices and laboratories. The Centers for Medicare and Medicaid Services (“CMS”) of the Department of Health and Human Services (“HHS”) has estimated that in 2007 there were approximately 5,350 independent clinical laboratories in the United States.

The clinical laboratory business is intensely competitive. There are presently two major national independent clinical laboratories: the Company and Quest Diagnostics Incorporated (“Quest”), which had approximately $6.7 billion in revenues from clinical laboratory testing in 2007. The remaining estimated $39 billion of testing performed in the United States is performed by hospitals (approximately $27 billion) and regional, specialty, and physicians laboratories (approximately $12 billion).

________________

The Company believes that large scale consolidation has decelerated, but will continue in the clinical laboratory testing business. In addition, the Company believes that it and the other large independent clinical laboratory testing companies will be able to increase their share of the overall clinical laboratory testing market due to a number of external factors including cost efficiencies afforded by large-scale automated testing, reimbursement reductions and the growth of managed health care entities which require cost efficient testing services and large service networks. In addition, legal restrictions on physician referrals and their ownership of laboratories as well as increased regulation of laboratories are expected to contribute to the continuing consolidation of the industry.

Quest Diagnostics - We believe that we have entered the decade of diagnostics

In their annual report, lodged with the U.S. Securities and Exchange Commission, Quest Diagnostics give an overview of the US lab market

________________________

THE UNITED STATES CLINICAL TESTING MARKET

Most clinical tests are performed by one of three types of laboratories: commercial clinical laboratories; hospital-affiliated laboratories; and physician-office laboratories. We believe that hospital-affiliated laboratories account for approximately 60% of the market, commercial clinical laboratories approximately one-third and physician-office laboratories the balance.

Key Trends. There are a number of key trends that we expect to have a significant impact on the clinical testing business in the United States and on our business. These trends present both opportunities and risks. The recent economic slowdown may temporarily reduce industry growth rates. However, because clinical testing is an essential healthcare service and because of the key trends discussed below, we believe that the industry will continue to grow over the long term and that we are well positioned to benefit from the long-term growth expected in the industry.

Demographics. The growing and aging population is increasing the demand for clinical testing.

Increased testing. We believe that we have entered the decade of diagnostics, moving from greater focus on curative care to a greater recognition of the value of detection, prevention and personalized care. Physicians increasingly are relying on testing to help identify risk factors and symptoms of disease, the choice of therapeutic regimen and the evaluation of treatment results. Physicians, consumers and payers increasingly recognize the value of testing as a means to improve health and reduce the overall cost of healthcare through early detection and prevention.

Science and technology advances. Medical advances allow for more accurate and earlier diagnosis and treatment of diseases. Continuing research and development in the area of genomics is expected to yield new, more sophisticated and specialized tests. These advances also are spurring interest in and demand for personalized or tailored medicine, which relies on diagnostic and prognostic testing. In addition, pharmacogenetic testing increasingly is used as a parameter to help speed drug approval processes and to better focus therapy based on patient and tumor-specific genetic markers.

Health information technologies. Demand is growing toward comprehensive care management solutions that serve patients, payers and practitioners by improving access to patient data, increasing patient participation in care management, reducing medical errors and improving clinical outcomes. There is an increasing focus on interconnectivity, the ability to interact with other software and systems, and real time data aggregation. Electronic medical records and patient health records continue to grow.

Customer and payer consolidation. Our customers and payers, including physicians, health insurance plans, employers, pharmaceutical companies and other intermediaries, have been consolidating. We expect that this trend will continue. Consolidation is increasing customer and payer bargaining power, enhancing purchasing sophistication and encouraging internalization of testing.

Highly competitive. The clinical testing industry remains fragmented, is highly competitive and is subject to new competition. Competition is growing from non-traditional competitors. New market entrants with extensive resources may make acquisitions or expand into our traditional areas of operations. We also are expanding into new diagnostic testing areas that are highly competitive.

Regulatory and policy environment. Government oversight of and attention to the healthcare industry in the United States is significant and may increase. There has been extensive discussion of healthcare reform. While it is not possible to predict whether change in U.S. government regulation of healthcare will occur, or the nature or impact of any such change, we believe that any such change should recognize the value and importance of diagnostic testing to patient care.

Globalization. There is a growing demand for healthcare services in emerging market countries. Opportunities are arising to participate in the restructuring or growth of the healthcare systems in these countries. Additionally, our customers are establishing positions outside the United States. Demographic changes globally may also create opportunities.

Point tipped

In his presentation What are the Gamma-Interferon Release Assays Teaching us About Latent TB Infection? presented at the 11th Annual Conference of the IUATLD Dr David M. Lewinsohn noted that "A negative IFN-γ assay may not distinguish remote exposure from no exposure" and asks



In the current edition of the journal Infectious Diseases Dr Lewinson reviews the progress of studies and ensuing data thereby revising his opinion of IGRA

..recent data would suggest that a positive IGRA might predict future progression..

..it is the opinion of the authors that the use of IGRAs, when available, is preferred to TST testing in all situations currently recommended for targeted testing by the CDC.

Significantly this report was the result of work funded by grants made by the NIH.


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Quest tune up HCWs

From Quest Diagnostics transcript of earnings for first quarter 2009

Another test with good potential is the new QuantiFERON test for tuberculosis. This new test replaces the 118-year-old skin test and has significant advantages. It reduces false positives, has higher compliance, and does not require patients to return to the physician for the results. We are educating physicians and public health operatives about the benefits and are starting to see results.

Significant advantages must also include compliance with CDC guidelines!

Not all are singing from the same songsheet

Whilst reading comments made by various Occupational Health professionals in the US I came across this exchange;

_______

Tina: "At our EH department we require documentation of MMR, Hepatitis B vaccinations in exposure category 1 and 2, Tb skin test within 30 days of hire, if they are over 50 years old we require a 2 step ppd..."

Debra: "I'm very curious why you only require two step testing on staff over 50. I've never come across that recommendation..."

Tina: "Our TB prevalence in this area is low. We also require 2 step testing for those foreign born from high prevalence areas, significant past exposure to TB, underlying conditions such as immunosuppression, HIV/AIDS, undergoing corticosteroid therapy. But the majority of 2 step testing we do are for those over 50."

_______

The 2005 CDC guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings advise;

Baseline testing for M. tuberculosis infection is recommended for all newly hired HCWs, regardless of the risk classification of the setting...

...If TST is used for baseline testing, two-step testing is recommended for HCWs whose initial TST results are negative.

....BAMT (eg QuantiFERON) does not require two-step testing and is more specific than skin testing.

It couldn't be made more clear!



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Another Ponzi scheme bites the dust

Warren Buffett has been quoted as saying "when the tide goes out do you discover who's been swimming naked" and for Managed Investment Scheme Timbercorp the tide has well and truly gone out. Curiously named investment advisor "Intelligent Investor" flounders for an explanation as to why they had previously recommended TIM to investors;

We bought this business in the full knowledge that it was selling an unsavoury product...

.. we thought it was making enough money out of the whole charade to justify a substantially higher share price. The lesson here is that it’s impossible to build a sustainable business selling a dud product. And investing in an unsustainable business is almost never a profitable exercise, no matter the apparent value on offer..

Disclosure: The author, Steve Johnson, owns shares in Timbercorp and Timbercorp Convertible Notes, as do other staff members.

All this and more from an operation calling themselves VALUE INVESTING EXPERTS

Clearly "intelligent" is relative term; if they had only listened to instead of misquoting Charlie Munger;

If you mix raisins with turds, they are still turds.

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Performance of commercial blood tests for the diagnosis of latent tuberculosis infection in children and adolescents.

The abstract concludes

Different blood tests for the diagnosis of latent tuberculosis infection in children seem to perform differently, because both QuantiFERON-TB tests were more likely than T-SPOT.TB to give indeterminate results in children

however it is worth reading the full text;

QFT-IT and T-SPOT.TB have both been approved for clinical use by the US Food and Drug Administration, although with some minor modifications in the interpretation of T-SPOT.TB results, compared with the European package insert. This reflects the vast amount of published data available.

Therefore, it is predictable that IGRAs will rapidly become routine in clinical practice. At that point, differences with the standard TST will be particularly relevant. One such difference is the 3-way response of IGRAs (positive, negative, or indeterminate/invalid), compared with the 2-way response of the TST test (positive or negative).

However, the meaning and the impact of indeterminate IGRA results in clinical practice have not been properly evaluated. For now, these results should caution clinicians to be aware of potential false-negative results. In addition, although the difference in the frequency of indeterminate results between the QFTs and T-SPOT.TB in our study was striking, the clinical impact of this difference might be relatively small, because almost all indeterminate QFT results were negative with T-SPOT.TB.

Another interesting finding of our study is the significantly higher concentration of IFN-y produced in QFT-IT compared with QFT-G. Whether this is a consequence of the in-tube format or some other technical factor (such as shaking of tubes), and whether it has an impact on antigen-specific responses, merits additional attention.

It should be noted that this retrospective study of samples taken between January 2004 and July 2007 predates the approval of T-Spot TB in the US and the performance of the T-Spot TB was not evaluated in accordance to limits as set out in the FDA approval.


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Treating INH resistant TB

"IN YOUNG CHILDREN, the risk of progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) is inversely related to age; without specific treatment, approximately one half of infants and one fifth of older children develop active TB up to 2 years after infection. In particular, children 4 years of age fail to contain the spread of intracellular pathogens as a consequence of an impaired T-cell response. Therefore, this age group is considered a priority in the strategies to control TB worldwide." (source)

Using the standard treatment for LTBI does not allow for the existence of drug resistant bacterium; in this article Pediatrics. 2009 Mar;123(3):902-3. practioners call for revised treatment guidelines

CONCLUSION: Because of the high prevalence of isoniazid resistance, rifampin should be considered for children with latent tuberculosis infection originating from countries with >11% isoniazid resistance.

Without monitoring treatment to ensure full eradication of the bacterium the risk of extending drug resistance remains.

QuantiFERON-TB Gold slam dunks the opposition

University of Michigan have updated their admission requirements for foreign students;

You can meet the requirement by providing the following documentation IN ENGLISH, and including your COMPLETE NAME:

• Negative QuantiFERON-TB Gold test done within a year of starting UM classes OR
• Positive QuantiFERON-TB Gold test AND normal chest x-ray (report preferred) OR
• Completed treatment report for active or inactive TB

The following types of documentation are not acceptable:

• TB skin test (PPD)
• Tine test
• QuantiFERON test
• Chest x-ray only
• T-SPOT test

Press release: IGRA successfully used in HIV + TB study

Study to be published in May issue of the International Journal of Tuberculosis and Lung Disease

Source.

Tijuana injection drug users on collision course for HIV and TB

A study by researchers from the University of California, San Diego School of Medicine, in collaboration with Mexican researchers and health officials, shows that as many as 67 percent of injection drug users in Tijuana test positive for tuberculosis (TB) infection. The analysis, which underscores the urgent need for TB screening and treatment for populations that are also at risk for HIV infection, will be published in the May issue of the International Journal of Tuberculosis and Lung Disease (IJTLD).

"While injection drug users are known to be at risk for TB, this is one of the highest infection rates ever reported among this group," said principal investigator Richard Garfein, PhD, MPH, associate professor in the Division of Global Public Health and Department of Medicine at UC San Diego. The analysis is part of a bi-national, community-based study called Proyecto El Cuete that includes more than 1,000 illicit drug injectors residing in Mexico's largest U.S. border city.

What most concerns Garfein is that injection drug users are not only likely to have weakened immune system due to illicit drug use, but are also at high risk for HIV infection. This makes the situation much worse for individuals infected with TB, because HIV further weakens a patient's immune system.

Worldwide, tuberculosis is a leading cause of death among persons with AIDS. Once a person becomes infected from breathing in TB bacteria, the immune system generally encapsulates the bacteria and prevents it from growing. When this happens, the bacteria remain alive in an inactive state called latent TB infection. But the TB bacteria can become active at a later date if the person's immune system is weakened, for example, in those with AIDS.

"Persons with latent TB infection are not sick and are not contagious," said co-investigator Dr. Rafael Laniado-Laborin, MD, chief of Tijuana General Hospital's tuberculosis clinic, adding that, in otherwise healthy individuals, the chance of the latent TB becoming active is about 10 percent over their lifetime. "However, if individuals become infected with HIV, their chance of developing active TB increases to 10 percent per year."

Once active, TB bacteria replicate in the lungs. Symptoms include coughing, which facilitates the airborne spread of bacteria to others.

"Given that two-thirds of Tijuana's injection drug users have latent TB infection, the majority of those who become HIV infected – a risk that is increasing – are also likely to develop active, contagious TB," said Garfein.

TB is endemic in Mexico, where children are routinely vaccinated with the Bacillus Calmett-Guerin (BCG) vaccine, which is not highly effective but can prevent some serious forms of childhood TB. Unfortunately, the vaccine can cause false-positive results with the tuberculin skin test (TST), used for over a century to detect TB infection. For this reason, estimates of TB prevalence using the TST are unreliable in areas of Mexico where the BCG vaccine is given, making it difficult to anticipate future health care needs for at-risk populations.

Instead of TST, participants in this study were given a TB test called interferon-gamma release assay (IGRA) which measures the substance released by sensitized immune cells when they are exposed to TB bacteria. Neither test can differentiate between latent and active TB. However, the IGRA is more sensitive and specific in testing for TB because it doesn't cross-react with the BCG vaccine.

Injection drug users, age 18 years or older, were asked about past TB diagnosis, illness and treatment as well as the presence of TB symptoms such as persistent cough, fever or chills, shortness of breath, fatigue and unexplained weight loss. Participants with TB symptoms were referred to a municipal health clinic for further evaluation.

Of the 1,025 participants who received IGRA results, 681 (67%) tested positive for TB, with 13 individuals reporting symptoms. Injection drug users recruited from two neighborhoods nearest the U.S./Mexico border had 64% higher odds of being IGRA-positive than non-drug users. These odds increased by 20% for every five years of reported injection drug use.

Additional years of residence in Tijuana were also associated with greater prevalence of IGRA-positive results. One explanation is that more time spent among other injection drugs users in Tijuana increased the likelihood of exposure to TB. Only 4% of study participants tested positive for HIV infection. However, if HIV is not controlled and its prevalence increases, the number of injection drug users whose latent TB infection becomes active is destined to increase, according to the researchers.

"This at-risk population urgently needs better screening and treatment for TB,"said Laniado-Laborin. "Treatment reduces the TB reactivation risk by nearly 75%, while cutting the death rate of patients with HIV and TB in half."

###

Additional contributors to the study include principal investigator Steffanie A. Strathdee, Ph.D., Lin Liu, Ph.D., Timothy C. Rodwell, M.D., Ph.D., Robert Deiss, M.D., Antonino Catanzaro, M.D. and Peter G. Chiles, B.A., UC San Diego; Remedios Lozada, M.D. and Jorge Alvelais, M.D., Patronato Pro-COMUSIDA, Tijuana, Baja California, Mexico; and Rafael Laniado-Laborin, M.D., MPH, Universidad Autonoma de Baja California, Tijuana, Baja California, Mexico.

Proyecto El Cuete was funded by a grant from the National Institute on Drug Abuse (NIDA). Dr. Garfein was also funded in part by a grant from the US Agency for International Development (USAID).

Connecticut TB program steps up to the plate

From the CDC;

In 2007.. Connecticut initiated a cross-training program that is helping the TB program nursing supervisor and the TB case managers become certified HIV counselors. The training, which can take several months to complete, is provided by staff of the Connecticut HIV/AIDS prevention program...

..The TB case managers and nursing supervisor also had training in phlebotomy in order to draw blood for QuantiFERON tests (QFTs), which will be performed at the state laboratory. QFTs will be available later in 2008. Protocols will be established on the eligibility requirements for QFTs, but it is expected that the majority of eligible clients will be those seen and managed by the TB staff...

High risk groups in the US

From the 2009 Connecticut Health Disparities Report;

Tuberculosis (TB) trends in Connecticut mirror those of the nation. From 2000 to 2005, the incidence rates of TB among foreign-born persons and racial and ethnic minorities were higher than the incidence among Whites in Connecticut. The Connecticut TB incidence rate for 2000–2005 was highest among Asians (23 times that of Whites).

As reported in the New Haven Independent Dr. Saud Anwar, chair of the Department of Pulmonary and Critical Care Medicine of the Eastern Connecticut Health Network, acknowledges the problem of TB but said it might be overstated simply because TB is a reportable disease and a TB test is required for immigration to the U.S. “

Tuberculosis in their home countries is higher, but there’s also a bias because we are looking for it more — when you look more, you find more,” he said. “In this study some of the sub-groups are very small, so the very high and very low numbers don’t mean much.”

Anwar noted that other subgroups that are not Asian also have a high prevalence of TB and he cautioned against assuming that any group is immune from the disease.

"We have to be careful that we don’t take it for granted that the indigenous [non-immigrant] community is somehow protected from TB,” because it is so infectious. But he said if TB isn’t tested for in less at-risk communities, it won’t be found.

According to Connecticut Health the report

"..can inform how key health decision-makers plan, evaluate, allocate resources, conduct surveillance, and make public policy"

.

Monitoring TB treatment - further update

More information from the Italian study;

All patients who showed a significant decline in IFN-y concentrations and became QFT-G negative after treatment had a complete clinical and microbiological recovery of the TB disease.

Among the 11 patients with persistent positive QFT-G results, 6 patients were considered as ‘responders to treatment’ on the basis of clinical, radiological, microbiological and laboratory findings; the remaining 5 patients, who had persistent culture positive samples after 2 months, did not have a complete resolution of the clinical disease and early relapsed after the 6-month treatment completion

Medical Misdiagnosis -- Best course of action?

Interesting conversation between "yoda634" and "bggrthnjsus" (both are in their early 20's)

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Recently, I was extensively exposed to a sick relative, who eventually turned out to have tuberculosis. I visited him in the hospital most days for a couple hours or more, over the course of 4 months. For the last month or so, after they finally diagnosed it, there was added ventilation in the room, and all visitors were required to wear face masks. However, I still had three months of fairly heavy exposure. After he passed away, the hospital took down the names of frequent visitors -- there were three of us -- and told us to go get a TB test at the county board of health. I'm a fairly busy guy, and I didn't have time to drive over to the facility -- in a neighboring town -- so, after clearing it with someone at the board of health offices, I went to my campus health center for a test.

I was charged $10, and the test was administered -- the initial irritation/redness at the injection spot went away within a few hours as is normal, but over the next few days before it was read, the test site became red, irritated, and extremely tender, with slight hardened swollen area in the center, about the size of a dime. I went back to have it read, and the nurse practitioner/doctor (can't recall which she was at the moment) looked at it for a split second, poked it, and said, "oh, you're fine, it's negative" and signed off on a form saying that there was no induration (medical term for the hardened/palpable swelling at the test site, which is measured to indicate a positive result). I even asked about the definite irritation, but she insisted that was normal and sent me on my way.

The whole thing struck me as odd -- the fact that there was a reaction at all had me worried, and the complete lack of concern over what was, if not technically a positive reaction, definitely a reaction. I did a little research, and was not so sure that my test was read correctly -- I ended up taking a couple of pictures of it, but was not overly worried. As several other relatives who had visited the hospital went over the next few weeks to get theirs done, I compared notes with them -- none had any reaction whatsoever to the test. Also, others had been told to come back in 10 weeks to be retested -- which is apparently SOP for anyone who has had contact with a contagious patient. I had not been told anything along those lines.

Figuring better safe than sorry, I went over to the TB control center at the board of health Monday and got retested. Same reaction as before -- slightly larger (maybe the size of a penny) but otherwise the same as the first test. I went to have it interpreted this morning, and showed it to the nurse at the front desk on arrival. She very obviously instantly recognized it as clearly positive, but did not say anything, just had me sit and wait -- by the time I was called back to see the nurse who was going to do the actual reading, the forms for referring me for a chest X-ray (next step for a positive test -- to determine if the TB is active -- symptomatic and contagious -- or latent -- requiring preventative antibiotic treatment to prevent it from becoming active) were already half filled out, sitting on the desk. The criteria for a positive is a 5mm induration for someone with recent close contact to an active TB case, or a 10mm induration for someone in a lower risk category. Mine measured 15mm, and I was immediately sent for a chest X-ray. As I mentioned, the reaction to the previous test was exactly the same, except a little smaller -- maybe around 10mm.

So, here's the issue -- I believe a very serious mistake was made in the failure to recognize the result of the first test. Left untreated, my understanding is that the latent TB infection would eventually turn into deadly, communicable TB disease. This can be effectively prevented by catching it with the test when it is latent, and the administration of a rigorous course of preventative antibiotic treatment.Had I trusted what I was told at the campus health center, it would have gone untreated and eventually become a potentially fatal, highly contagious illness. I have no interest in suing them, despite the fact that I'm sure doctors have been sued over far less. What I would like is a refund -- of both the $10 I paid for the test and at the very least, the $270 I have paid in mandatory health fees this year, if not the $1100 I have paid in health fees over the past four years. This is my second time seeing a health care professional at this facility -- the first was after I got into a car accident and hit my head on the A-pillar of my car, and was suffering from pretty bad neck and back pain -- after a very brief examination, I was told "you might want to look up some stretches on google and do them."

First, does this seem unreasonable? The way I see it is that I have justifiably lost any faith I may have had in the facility, and at this point have spent a large chunk of money on a service that is essentially worthless to me, and that I have been put at risk by trusting that service.

Second, what would be the best way of going about this? My current thoughts are to write a polite, non-aggressive email to the Vice President of the university that is in charge of of the health center, stating essentially what I have stated here, explaining the situation and laying out my request. If that were met with resistance, my plan would be to work my way up the ladder, with subsequent communications in paper with documentation.

Any other comments or suggestions? I don't think I'm overreacting here, but maybe I'm wrong.
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a comment on tb:

1) latent tb is actually NOT that likely to develop into active TB if your immune system is relatively competent...even if you don't treat it. the reason they treat it anyway is just to prevent it from ever becoming active and therefore spreading it. i wouldn't worry about that one too much. bear in mind that the treatments for tb have a lot of side effects, and can pretty much ruin your liver, and you have to take them for 6 months. since those negatives likely outweigh the odds of you developing active TB anytime soon, i would try to wait on the treatment until absolutely sure you have latent TB (see below)

2) when you went back for the second test, you actually slightly raised your odds of a false positive test because of the previous exposure...which is why you're supposed to wait a long time between skin tests. note that the tb skin test is not very specific; it does not tell you if you actually have the disease (and by that i mean latent or active), only that you have been exposed to it. in addition, if you've had a bcg vaccine in your life (probably only if you were born outside the usa), you stand a higher chance of a false positive.

3) the test is pretty sensitive, but not very specific. so it is very good at being positive when people have been exposed, but at the cost of a lot of false positives. that is further compounded by the expertise of the person interpreting the test.

4) if you really want to be sure, go to a doctor and ask for a quantiferon test, which is a blood test that is both more sensitive as well as more specific...it's altogether a lot more accurate, although a lot more expensive.

so here's what i would do as far as treatment goes: if you really want to know for sure, take the quantiferon test. if it's negative, you save yourself hundreds of dollars in treatment. if it's positive, you kind of get screwed and pay for the test AND the treatment...but i think that is still better than taking the treatment when you don't actually need it.

as far as the legal stuff goes: it depends on what the relative was in the hospital for in the first place...if it was for something unrelated to TB and the TB was just an incidental finding, then there is no way they are going to give you anything for that. if it was for TB like symptoms, then they probably should've had that on their differential diagnosis right away, and there might be some level of liability there. in between that, if they were there for something lung related, and incidentally found TB, i doubt you'll get anything out of it. bear in mind that a lot of diseases are found incidentally...but i'm not really sure of the context here, so i can't really say anything for sure. it's unlucky for sure, but usually that is a perfectly plausible and innocent thing to happen in medicine.

as far as the fees you've listed though, i doubt you would be able to get anything back besides the $10 health fee for the tests. you probably also wouldn't get back anything from the past medical fees, no matter how bad your experience was. the problem is that you don't seem to have suffered any damages or injury as a direct result of negligence.

i think the letter is perfectly reasonable, and will probably make you feel a little better to let them know...but i wouldn't get your hopes up about getting any of your money back.
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Can't afford that test right now, I'm waiting on the results of my chest X-ray to come in Monday and am supposed to make a follow up appointment at that point, and I'll go ahead with whatever treatment gets prescribed to me at the board of health.

The relative was in the hospital for a misdiagnosis of TB symptoms that ultimately were determined to have been TB all along. Long story, but that's wholly unrelated. I'm not dealing with the hospital that treated him at all.
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in your situation as written, i think the hospital that treated him is the only one who has any remote semblance of responsibility for your situation. the people evaluating your TB test did their jobs properly, you probably had something a little under 10mm, which is negative. the second test can't be evaluated with any reliability since you got it so soon after the first one, especially since you had been exposed to active tb. you won't get any money out of the health center.

as for your treatment, bear in mind your treatment is going to cost a lot of money, and if you are actually TB free (which the quantiferon test could reveal), you will not only be wasting a lot of money, you will also be harming your health.

either way its up to you, i'm a big advocate of the blood test since it's so much more effective (it's actually probably going to become the standard in fields that require a yearly test), but the final decision is your prerogative. when you're talking about treatment with a doctor though, make sure you point out the skin test situation, because that might have an effect on what they decide. also remember that if your chest x-ray is negative, it shouldn't be too much of a risk to put off treatment for awhile. i'd try to get the blood test then, because a quantiferon test that is negative will most likely be less costly than taking the medication without a confirmatory test. just make sure the doctor knows the whole story.
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I certainly will discuss the whole situation with the doctor. The issue is -- I'm sure I can get the treatment covered under insurance. A secondary test, maybe not. I'll run that by the doctor I speak with as well, and see what their thoughts are on it.
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yeah if the antibiotics are covered, it might be a tossup. you'll probably take 6 months of an anti-mycobacterial, so it depends what your co-pays are. if it's 6 refills with $20 co-pays, it might be cheaper to just pay for the test (unless it comes up positive, then you'll lose even more money)...but if they give you like a single jar of 6 months worth of drugs then you're probably economically better off just taking the meds. it depends how much you value your liver though, they have some serious side effects. if they give you rifampin, your pee might turn orange, which is pretty cool.
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Yeah, I'll have to see.

I am moderately concerned about the hepatotoxicity of these antibacterials -- I'm a fairly heavy drinker.
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yeah you probably shouldn't be doing any drinking on them at all

Prevalence of drug resistant TB

As published in the New England Journal of Medicine, results of a 3 year study over 1994-97 conducted over 5 continents into anti-tuberculosis drug resistance found

that among patients with no prior treatment, a median of 9.9% of Mycobacterium tuberculosis strains were resistant to at least one drug

leaving them no option but to conclude that

Resistance to antituberculosis drugs was found in all 35 countries and regions surveyed, suggesting that it is a global problem

Importantly these rates were experienced in people with no prior treatment which indicates that a significant quantity of drug resistant TB is being acquired by transmission not by faulty or interrupted TB treatment.

It is logical to assume that the rates for drug resistance in active TB are applicable to latent TB.

Monitoring TB treatment - update

Further on from Pollock (who peremptorily dismissed the use of the QuantiFERON-TB Gold assay to monitor therapy) is this longitudinal study from Italy which found that

nearly one-third of our TB patients were still positive by QFT-G assay despite active TB disease treatment....the present study suggests that the decrease in the M. tuberculosis-specific T cells responses following successful anti-TB therapy may have a clinical value as a supplemental tool for the monitoring of the efficacy of pharmacologic intervention for active TB.

Having a control group strengthens the validity of the study and amongst those who had active TB were those with both pulmonary and non pulmonary TB and with and without prior BCG vaccination.



Following proper analysis of the data the researchers had no option but to challenge the efficacy of current TB treatment and therefore the orthodoxy of specifiers and practitioners of TB treatment;

the antituberculous drugs do not have any direct effect on host immune response

Immunosuppression and IGRA

Also from CHEST, this time the March edition, results of a study into the performance of IGRA against TST in three different groups of immunosuppressed patients. The study group found that the IGRA identified significantly more patients as being infected with M. tuberculosis than did the TST. There represents a subtle shift in thinking in that concordance with TST was not sought.

Telling it as it is

What I like about this study is the clear, unambiguous and unequivocal message- no maybes, could bes or should bes or even the dreaded "need more longitudinal studies" - IGRAs are a more accurate indicator of the presence of LTBI than the TST.

Article published in April issue of CHEST Journal

#####

Comparative Performance of Tuberculin Skin Test, QuantiFERON-TB-Gold In Tube Assay, and T-Spot.TB Test in Contact Investigations for Tuberculosis

Roland Diel, MD, MPHRoland.Diel@uni-duesseldorf.de, Robert Loddenkemper, MD, FCCP, Karen Meywald-Walter, MD, Rene Gottschalk, MD, and Albert Nienhaus, MD, MPH
+Author Affiliations

From the School of Public Health (Dr. Diel), Heinrich Heine University of Düsseldorf, Düsseldorf; German Central Committee Against Tuberculosis (Dr. Loddenkemper), Lungenklinik Heckeshorn, HELIOS, Klinikum Emil von Behring, Berlin; Public Health Department Hamburg-Central (Dr. Meywald-Walter), Hamburg; Institute of Medical Virology (Dr. Gottschalk), University Hospital, Johann Wolfgang Goethe University, Frankfurt am Main; and Institution for Statutory Accident Insurance and Prevention in the Health and Welfare Services (Dr. Nienhaus), Hamburg, Germany.
Abstract

Abstract Rationale
Mycobacterium tuberculosis (MTB)-specific interferon-γ release assays (IGRAs) are an alternative or adjunct to the tuberculin skin test (TST) in identifying recent contacts with latent tuberculosis infection (LTBI), but there are scarce data directly comparing performance of the tests.

Objective
To evaluate the agreement between both IGRAs and to determine which contacts were most likely to represent LTBI, the QuantiFERON-TB-Gold In Tube assay (QFT) and the T-Spot.TB test (T-Spot) were compared in TST-positive persons recently exposed to pulmonary tuberculosis cases.

Methods
Prospectively enrolled close contacts (n = 812) of 123 culture-confirmed tuberculosis source cases underwent IGRA testing using standardized collected data. Factors independently influencing the risk of MTB infection and their interactions with each other were evaluated by multivariate analysis.

Results
Five variables were found to significantly predict a positive IGRA test result (age, source case acid-fast bacilli positive and/or coughing, cumulative exposure time, foreign origin). There was excellent agreement between the two IGRAs (93.9%, κ = 0.85), with QFT finding 30.2% of contacts positive and T-Spot finding 28.7%. Assuming positivity to both IGRAs as true infection, sensitivity of the TST at ≥ 10 mm was 72% and at ≥ 15 mm was 39.7%. The use of either IGRA as a replacement for the TST would decrease the number of LTBI suspects to be investigated by approximately 70%.

Conclusions
IGRAs are a more accurate indicator of the presence of LTBI than the TST. Both QFT and T-Spot appear to be valuable public health tools, showing excellent agreement with each other.

Tipping point - a review

Among the more interesting points is the idea that little causes having big effects, which is related to the idea that once you reach a certain amount of initial buyers of a good with network effects, the success of the product will spread rapidly until it reaches a new equilibrium with a much larger amount of users. Malcolm in his book gives this phenomenon a name: “The Law of the Few.”

From the The National Science Digital Library comes this student review of Malcolm Gladwell’s book, The Tipping Point. The review is reproduced in its entirety below;

#####

Recently in lecture, we’ve been discussing information cascades, network effects, and diffusion through a network. I’ve been catching up on Malcolm Gladwell’s book, The Tipping Point, whose title is related to the critical point that can be seen when modeling the sales of a good with a network effect. Malcolm gives his tipping point three characteristics: “one, contagiousness; two, the fact that little causes can have big effects; and three, that change happens not gradually but at one dramatic moment” (Malcolm 9). The tipping point as described in the context of network effects in class is a point where, once reached, many more users will be inclined to buy the good, leading to its success. On the flip side, if the tipping point is not reached, the good will not succeed because everyone expects that no one will buy the good, and the good’s value is lost without other users.

Among the more interesting points is the idea that little causes having big effects, which is related to the idea that once you reach a certain amount of initial buyers of a good with network effects, the success of the product will spread rapidly until it reaches a new equilibrium with a much larger amount of users. Malcolm in his book gives this phenomenon a name: “The Law of the Few.” He explains that though few people can bring about large change, not everyone is capable of doing so; only those with certain types of influence, whom he refers to as connectors, mavens, and salesmen, can actually cause something to “tip” (Malcolm 30). This is very much related to the idea of diffusion in networks, and how a few initial adopters can cause a cascade to ripple throughout the network. The existence of clusters is what limits the spread of these cascades. Malcom’s connectors are the kind of people who know everyone – they connect the clusters present in networks, and thus facilitate the spread of a cascade from one cluster to another. Mavens are described as “data banks,” or those who provide messages so that connectors can spread it. Mavens are thus what can be seen as the initial adopters of a good; even if the rest of the network is already using a different product, mavens are the ones that can introduce a different, perhaps better product to the rest of the network, which is something they found through large amounts of research and information digging. Without the initial change instigated by the mavens, nothing would change in the network, even with the presence of connectors. Finally, though perhaps less connected to ideas in class, is the idea of salesmen – that is, the people who “persuade us when we are unconvinced of what we are hearing” (Malcolm 70).

In general, Malcom’s Tipping Point is a very interesting book that ties in well with what we are discussing in class, and gives a number of real life examples of how each phenomenon plays into our society today.

Strategic marketing

Those that think that marketing is all about whacking a few ads on TV during the footy should read this;

Word-of-mouth is still the number one driver that results in activations. Therefore, strategizing on ways in which your internal community can be motivated to help you find and attract other new users

a) gets other people to do work for you and
b) results in the best kind of marketing with the highest activation rates.

In the early stages focusing on retention marketing also allows you to best maximize resources by using a tipping point strategy.

In other words it is far more cost effective to service your existing clients, who are potentially your future referees, rather than going all out chasing new customers.


.

Tipping point - a perspective

In his book the TIPPING POINT Malcolm Gledwell attempts to determine exactly what is meant by the term tipping point;

The word "Tipping Point", for example, comes from the world of epidemiology. It's the name given to that moment in an epidemic when a virus reaches critical mass. It's the boiling point. It's the moment on the graph when the line starts to shoot straight upwards. AIDS tipped in 1982, when it went from a rare disease affecting a few gay men to a worldwide epidemic. Crime in New York City tipped in the mid 1990's, when the murder rate suddenly plummeted. When I heard that phrase for the first time I remember thinking--wow. What if everything has a Tipping Point? Wouldn't it be cool to try and look for Tipping Points in business, or in social policy, or in advertising or in any number of other nonmedical areas?

...once you start to understand this pattern you start to see it everywhere. I'm convinced that ideas and behaviors and new products move through a population very much like a disease does. This isn't just a metaphor, in other words. I'm talking about a very literal analogy...

Read on



.

Merky waters

from the Australian;

SCIENTISTS were allegedly recruited by a pharmaceutical giant to put their names on research done by the drug company to promote the safety of its anti-arthritis drug Vioxx.

The Federal Court has heard that Merck & Co "prepared and gathered" doctors and academics to write the company's own research on Vioxx, which was then published in prestigious medical journals as independent studies.

The drug company also allegedly produced an entire journal -- called The Australasian Journal of Bone and Joint Medicine -- and passed it off as an independent peer review publication. These claims were put by lawyers acting for Graeme Peterson, who is suing Merck & Co and its Australian subsidiary Merck, Sharpe and Dohme for compensation.

The 58-year-old -- along with more than 1000 other Australians -- claim Vioxx caused their heart attack or stroke.

The drug was launched in 1999 and at its height of popularity was used by 80 million people worldwide because it did not cause stomach problems, as did traditional anti-inflammatory drugs. It was voluntarily withdrawn from sale in 2004 after concerns were raised that it caused heart attacks and strokes and a clinical trial testing these potential side-effects was aborted for safety reasons.

Merck last year settled thousands of lawsuits in the US over the effects of Vioxx for $US4.85billion ($7.14 billion) but made no admission of guilt.

Counsel acting for Mr Peterson, Julian Burnside, told the court this week the drug company sought out and recruited scientists, academics and doctors to put their name to Merck's own research.

He said medical journal expert George Jelinek would testify that the articles were designed to "reassure the medical profession" about the safety of Vioxx.

The trial, before judge Chris Jessup, continues.

Position vacant..

..for a Medical Technologist at the Department of Veterans Affairs, Palo Alto, California;

This position is primarily responsible for the Quantiferon TB testing program using the Dynex DS2 Elisa analyzer.

According to Dynex the DS2

has all the power and performance of the higher-capacity DSX, but is designed for the needs of demanding near-patient-care settings and lower-throughput labs.

Japan - extended contact study further validates QFT

No reported problems with TST boosting, BCG innoculation and youth and QFT showed excellent predictive value;

none of the 297 students who were QFT-G negative had developed active TB after 3 years of follow-up

According to JATA (Kekkaku October 2004) the new TB law has dropped BCG innoculation of school kids in favour of BCG vaccination at birth;

the new Law will adopt the direct vaccination scheme in which babies will be given the BCG vaccine without tuberculin testing.

Importantly the market for using QFT in contact testing in Japan has now passed the "tipping point", contact tracing in Japan has been described as a "predominant market"

##########

Source

Contact investigation in a primary school using a whole blood interferon-gamma assay.

Higuchi K, Kondo S, Wada M, Hayashi S, Ootsuka G, Sakamoto N, Harada N.
The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose City, Tokyo, Japan.

OBJECTIVES: To evaluate the usefulness of QuantiFERON®-TB Gold (QFT-G) for children.

METHODS: Students in a primary school exposed to a tuberculosis patient were investigated using the tuberculin skin test (TST), chest X-ray examination and sequential QFT-G tests.

RESULTS: The first QFT-G test was conducted one month after the end of exposure for 308 of the 313 children, with 6 (1.9%) positive. TST results were obtained from 306 of the students at 2 months after exposure, and 200 (65.4%) had induration >/=5mm. A second QFT-G test, a further month later, and a third QFT-G test, six months after exposure, found an additional 2 positive and one weakly positive, respectively.

Overall, the rate of QFT-G positivity was 9.8% (4/41) for close contact children (≥90 h exposure), significantly higher than for casual contacts (≥18 h exposure; 1.8%, 5/272; p = 0.020), whereas there was no significant difference in TST positive rates (p = 0.078).

CONCLUSIONS: These data suggest that QFT-G has the same performance characteristics in BCG vaccinated children as it does in adults. The observation that none of the 297 students who were QFT-G negative had developed active TB after 3 years of follow-up suggests that QFT-G has a very high negative predictive value.

Another day another dollar.

Recently published by the AJRCCM (American Journal of Respiratory and Critical Care Medicine) is this study from South Africa into the potential effects of a Mantoux (TST) on interferon-γ-release-assays (IGRAs)

The study group hypothesised that a prior TST could boost subsequent responses and evoke a ‘false positive’ boosted IGRA result. They noted that the tuberculin used, PPD RT-23, contains many antigens, including ESAT-6 and CFP-10. In their FAQ Cellestis advise that when stimulated with TB specific antigens ESAT-6 and CFP-10 T-cells respond by secreting IFN-y. The measurement of IFN-y is time sensitive and if it occurs less than 24 hours after stimulation only effector T-cells are measured (effector T-cells are the ones present at infection). Should the measurement be made at a time greater than 24 hours memory T-cells are also measured (memory T-cells contain a record of the immune response to past infections and require time to convert to effector T-cells). In this way the IGRAs can differentiate between actual infection and past infection.

It should be noted out that the original QuantiFERON (QFT-TB) used PPD but limited the time to less than 24 hours and it should be further noted that there may be an inherent time difference between in vivo (IGRA) and in situ (TST) testing methods.

However by observation the study group found that the potential for IGRA boosting occurred +3 days after the TST was placed and they therefore advised that

IGRAs should ideally be performed at no more than three days after a TST.

This could have serious implications for existing TB guidelines as the TST should be read between 48 and 72 hours after administration which leaves little time to use an IGRA to confirm a +TST.

UK-based National Institute for Clinical Excellence (NICE; (6)) and revised Canadian guidelines (7) recommend a two- step strategy (TST followed by an IGRA up to 6 weeks later in the UK guidelines) for the detection of LTBI. This recommendation is based on a cost-benefit analysis

This could be a problem for policy makers at institutions such as NICE who have already accepted the evidence that IGRA are superior to TST and are on notice to consider further evidence;

Interferon-gamma tests showed little evidence of being affected by prior BCG vaccination, and showed stronger correlation with exposure categories than did TST. This was shown in low prevalence groups, in household contacts, and in outbreak situations. The specificity of interferon-gamma tests seemed better, and there was less potential for false positive results...

...Evidence is emerging on the performance of interferon-gamma tests. If this new evidence is
significant, NICE will consider updating the guideline.

Decreasing the time between TST and IGRA from 6 weeks to maximum 24 hours is going to be a logistical problem making the IGRA only option more feasible and cost effective.

Granny statism

Economist Nancy Folbre from the University of Massachusetts Amherst likens the economics to farming;

Think of the United States economy as a family farm in need of modernization. Energy prices are going up, but all the tractors are gas guzzlers. Some of our fields have accumulated toxic levels of pesticide, and we need to develop new and better technologies of sustainable production. Our grandchildren want to run the farm, but will need good health and a college education to do it well.

Spending money on increased energy efficiency, research and development, health, and education could increase the value of their assets, helping them repay debt.

In other words, the mommy party wants to borrow money to help the kids, not to hurt them. Keynes, history and environmental concerns lend credence, though not certainty, to this plan. So the granddads should lighten up.

An inapt analogy, the economy is not a farm it is what makes the farm viable. Spending money on maintaining the status quo is a foolishly wasting an opportunity to diversify and grow in a competitive world.

Granny should stick with her knitting.

Bailouts, a failure of governance

Professor Leeson from George Mason University writes in the Washington Times;

In a market economy, business deaths are like death itself - an unfortunate but inevitable fact of life. However, recent government bailouts have tried to stop the inevitable by intervening in the market, at least temporarily saving failed firms from the economic grim reaper. Before putting the next failed business on life support, it's worth remembering why it makes sense to let struggling producers expire.

In summary he says that;

• When failing businesses are allowed to fail, resources are released from employments where they don't add value and made available for employments where they do.
• When failing businesses are allowed to fail, producers learn how to combine resources in ways that create wealth.
• When failing businesses are allowed to fail, producers have incentives to combine resources in ways that create wealth.

The Cardona Hypothesis

In the following abstract P J Cardona, from the University of Barcelona's Department of Microbiology, wonders about how a dormant bacilli such as TB can survive for a lifetime

Cardona hypothesises that the bacilli is not in a state of suspension rather it maintains a presence by very slowly growing and replicating (reinfecting), a process which normally will decrease over time, but not a lifetime as previously thought. This can be demonstrated by using T-cell Interferon-Gamma Release Assay (TIGRA), a test which can distinguish between effector T-cells and memory T-cells;

At the present time, this hypothesis can be carefully proved using the new LTBI diagnostic tools. TIGRA techniques support the concept that growing bacilli are constantly present in LTBI, as postulated in the dynamic hypothesis. TIGRAs may detect the IFN-y released by effector lymphocytes (with an approximate half-life of 3 days) after identifying macrophages that present antigens (included in the ESAT-6 complex) produced by growing bacilli

The significance of the presence of effector and/or memory T-cells is explained clearly in the FAQ on the Cellestis website

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Background: It has been traditionally postulated that individuals, once infected by Mycobacterium tuberculosis, will retain throughout their entire lifetime latent bacilli which will remain dormant in old lesions. This bacillus would then be the source of a later reactivation of active tuberculosis (TB), with the aid of resuscitation factors. Unfortunately, the presence of these bacilli can only be predicted by indirect immunological methods, such as the tuberculin skin test (TST) or T cell interferon–gamma release assays. Other evidence shows that a 9-month isoniazid treatment of TST+ individuals converting to TB reduces the incidence of TB by approximately 90%.

Questions: Taking into account this widely accepted framework, I suggest that there are at least three relevant questions to answer:

(1) How can dormant bacilli remain in the lungs for an entire lifetime, taking into account constant cellular turnover and the healing of damaged tissues?

(2) What provides the resuscitation factor to dormant bacilli, assuming that these latent bacilli are indeed present inside old lesions?

(3) Why can a 9-month treatment with isoniazid eliminate dormant bacilli? As isoniazid is active only against growing
bacilli, and thus is only able to destroy them after reactivation of latent bacilli, this treatment should have to be provided for life if the traditionally accepted postulate is correct.

Hypothesis: For a better understanding of latent TB infection. I propose a hypothesis that describes a dynamic scenario of constant endogenous reinfection with M. tuberculosis which explains the efficacy of the current standard of treatment. If this hypothesis is true, new strategies for the management of TB may arise.

Infection 2009
DOI 10.1007/s15010-008-8087-y

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