Marriage and the nocebo effect

 

Today morning, I opened The Lancet, to see an interesting Statin trial that looked at SAMS (Statin associated muscle symptoms). You can read the trial here


Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase

 

Statins are cholesterol lowering drugs that are sometimes associated with muscle pains. Unlike myopathy or myonecrosis, muscle pains have no objective  biochemical or histological component. The authors had analyzed the statin related adverse effects during the blinded(patient doesn’t know he’s taking statin) and the unblinded(patient knows he’s taking statin) phase of ASCOT trial. When the patients knew they were taking statins, they complained of muscle pains. When they didn’t know what they were taking, they had no symptoms !


In other words, their expectation of what statin might cause (after learning about it from net/other sources) influenced their symptoms. This fascinating phenomenon is called the nocebo effect.It’s the negative cousin of the well known placebo effect. It reflects changes in human psychobiology involving the brain, body, and behaviour rather than drug toxicity.Muscle related adverse effects are often low in randomized trials  compared with observational studies. The strength of this study is that these were the same patients, no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins.


This reminded me of some of the unfortunate posts on marriage I ve been seeing in Facebook and Quora of late. The liberal rants have an unmistakable pattern – they claim that marriage is the worst thing that can happen to a person. There are some sites (such as this one) whose only job appears to “educate” people on the evils of marriage and praise any and every form of decadence. You can see this in present day movies as well – the premise is that if you get married you are screwed. All these sources happen to think the plural of anecdote is data – it’s not.


It’s possible this can have a “nocebo effect” on our youth – for example,some of the fine boys I know appear to have become unusually nervous at the thought of getting married. Such negativity  may even become a self fulfilling doomsday prophecy. At the expense of committing the same sin as the liberals(the plural of anecdotes!), I must say there is nothing to be afraid of about marriage. Sure,occasional mishaps happen – but they are ,thankfully, still not the norm. Of course, our world view is colored by our own atomized experinces. I am also aware that just because,my experience is overwhelmingly positive doesn’t mean everyone’s will be the same. In any case, it’s important to keep an open mind. Negative thoughts are clearly useless.


PS: Here’s a pro tip: Stay away from the leftist/liberal websites that spew constant trash, if you can. You won’t regret it.

How do I know if I have insulin resistance using my glucose curve results?

My answer to How do I know if I have insulin resistance using my glucose curve results?

Answer by Karthik Balachandran:

From the values you have, it appears that you don’t have significant insulin resistance. Several indices can be calculated which look at the relationship between glucose levels and the amount of insulin in your blood. Insulin resistance is said to exist when your body needs to produce more insulin than usual to bring down your blood glucose. By comparing these indices with known normal values, we can tell whether your body has normal insulin sensitivity(a measure of how well your insulin does its job). It is important to note that insulin resistance is not an all or none phenomenon – think of it as a spectrum from good insulin sensitivity to poor insulin sensitivity (aka insulin resistance).

Some important IR indices calculated from your blood glucose and insulin values are

  1. HOMA -1R = 1.96 (less than 2.5 is normal)
  2. Matsuda index – 6.62 ( whole body insulin resistance if less than 2.5)
  3. QUICKI index -0.35
  4. Insulinogenic index – 1.9 ( defect in insulin secretion if less than 0.4)

Several web based calculators are available for calculating these indices and for health professionals downloading the excel file may be useful.

A couple of such online calculators can be accessed at

  1. WEB Calculator for Matsuda Index
  2. calculators (HOMA)

For a more detailed review of how insulin resistance is assessed,( for health care professionals), you can see my presentation below.

Assessing Insulin Resistance

How do I know if I have insulin resistance using my glucose curve results?

virtual journal club–steroid induced osteoporosis

Steroid induced osteoporosis is a common problem which needs to be addressed in patients on long term steroid therapy. The American College of Rheumatology has published guidelines on optimal management of glucocorticoid induced osteoporosis a few days back.

In this edition of the virtual journal club, I will focus on these guidelines. You can get the guidelines (free pdf) here.

Click on the video below to listen to the presentation.

If you don’t have the time, here’s the gist

  • Assess all patients on GC within first 6 months for fracture risk ( clinical

    DXA)

  • Risk stratification is key, adjust FRAX risk for GC use
  • Optimize Calcium (800 to 1000 mg) ,Vitamin D( 600 to 800 IU) and lifestyle
  • Oral bisphosphonates preferred treatment when pharmacological
    management is indicated
  • Follow up every year and reassess fracture risk

You can download the presentation (without author name Smile ) here.

If you like the post/video/presentation, feel free to share with your friends.

Sweet, naturally

Diabetic patients can have a a hard time getting used a life without their favorite sweets. Sweeteners aim to circumvent this perplexing problem by delinking sweet taste from calories. Ironically artificial sweeteners became popular much before the natural ones. The belief was that if the substance can taste sweet and has no calories, it was a godsend. Unfortunately that claim proved too good to be true for many artificial sweeteners.

Just because they didn’t have calories didn’t mean the artificial sweeteners were safe. Paradoxically they have been found to be linked with obesity in some cases. Even though these no calorie sweeteners aren’t metabolised by our body, the gut microbiome can metabolize it and the end products are toxic to the “good bacteria”. This eventually leads to “dysbiosis” (a change in the composition of bacteria in our gut) and defeats the purpose of taking sweeteners.

NATURAL SWEETENERS ARTIFICIAL SWEETENERS
Stevia Saccharin
Monk fruit Acesulfame
Miracle berry Aspartame
Kateme fruit Cyclamate
Licorice root Neohesperidin
HFCS (high fructose corn syrup)

With continuing demand for low colorie/non nutritive sweeteners, the natural ones have become more popular. Some of the main ones are

  1. Stevia
  2. Monk fruit (only extracted active ingredient can be used)
  3. Kateme fruit (probably not available in India)

Stevia

This is the most well known of the natural sweeteners and the best studied. Stevia is a plant native to Paraguay and Brazil and is intensely sweet – 250 times sweeter than sugar. The glcosides – stevioside and rebaudioside are responsible for this sweetness.Unlike other natural sweeteners stevia is easy to cultivate in urban homes and its leaves can be used fresh , without the need for industrial processing. Also because of its low cost, stevia has the potential to be the most popular natural sweetener.

In fact Stevia was featured in a recent TV show. (the video is in Tamil, but the visuals are fairly self explanatory)

The two important questions are

  1. Is this safe?
  2. Is this effective? ( for reducing weight/ reducing blood sugar/reducing cardiovascular risk)

Safety

  • Stevia started off on a bad note, with concerns of carcinogenecity, but the concerns were later found to be baseless. Consequently FDA has given it a GRAS status (Generally recognized as safe). In India, FSSAI has approved the use of stevia in various food products.
  • Like any other plant, stevia has a lot of other ingredients and the safety label given by FDA is for purified rebaudioside.
  • Data on pregnant women and children with type 1 diabetes are scarce – thus caution must be exercised.

Efficacy

  • Stevia has mixed reports of efficacy, but in reality it has not been studied as extensively as prescription drugs or even artificial sweeteners.
  • While the short term studies don’t show great benefit with Stevia in terms of glucose reduction, the longer term studies (>40 weeks) tend to show reduction in weight.

Monk Fruit

monkfruit

Monkfruit(Siraitia grosvenorii) is a subtropical melon grown in South East Asian countries. Legend has it that the fruit derives its moniker by virtue of having been cultivated by Chinese monks more than 800 years ago. Since the fruit is hard to store, it is usually not used in the fresh form. It becomes brown on drying. From the dry fruit, its active ingredient is extracted. These are glycosides – mainly mogrosides.(siamenoside and neomogroside are other glycosides)

Safety :

Rigoroussafety studies have not been carried out – partly because of the difficulty instandardizing the production of monk fruit extract. US FDA has given a GRAS-Generally recognized as safe (3)notice about its safety.

Efficacy

There aren’t any long term studies on the efficacy of monk fruit, perhaps due to the difficulty in cultivation and the expense of import.

Katemfe fruit

thaumatin_katemfe_fruit

This is much less popular than the other two natural sweeteners. Very few long term studies exist. I am not sure if this is even available in India.

The following table compares the common natural sweeteners

STEVIA MONK FRUIT
Availability Better Difficult to obtain
Cost $ $$
Safety GRAS (generally regarded as safe) GRAS
Efficacy Short term : no benefits/ harms Limited data, but not much different from stevia
Long term : weight reduction
Use Fresh leaves can be used Fresh fruit cannot be consumed
Ease of growing Easy Difficult
Other uses Purified stevia extract doesn’t have other uses Purified form doesn’t have other uses

Things to remember

  • Just because something is natural doesn’t mean it is safe (even strychnine is natural). While occasional use of sweetener , for example in a family function , is likely to be safe, usage in pregnant women or children should not be encouraged
  • Taste matters – all natural sweeteners , to varying extent, produce some aftertaste. Ultimately long term use hinges heavily on taste and you can only experiment to see which taste you like
  • Purity and standardization – just like any plant product, it is very hard to standardize purity and manufacturing practices. Since the commercial products are not as well regulated as drugs, you might be getting stevia laced with glucose or other sweeteners too. Read the label, but don’t fully trust it if the company is unknown. You might be better off using the fresh leaves
  • “Side effects” – purified extracts are safe for consumption because they are predictable. But the plants has several other active ingredients which have not been well studied, even though they have been in use for centuries. While the modern reductionist approach is one we are used to, I wouldn’t discount the advantage /disadvantage of consuming the whole leaves/fruit products. Consider this – if you analyze Coke/Pepsi, you will get sugar as the main ingredient, and a variety of others in tiny quantities. Perhaps even the order of adding these ingredients matter, which is why their formula is a closely guarded secret. Just by extracting the main ingredient(sugar), we won’t get Coke/Pepsi. In the same way, the complex interactions between the ingredients in a plant can have unpredictable good /bad effects. Being alert is the prudent option.

Non nutritive sweeteners may never become mainstream. But for the diabetic with a sweet tooth, they may be a godsend. By following common sense, we can avoid the bitter aftertaste, in more ways than one.

Online workflow for writing articles

It has become increasingly common for people to collaborate on writing projects. The tools that enable such collaboration have improved over the years too and currently allow for a completely online workflow. Unfortunately many residents and early career researchers don’t take advantage of the recent developments. In this post, I will outline a completely online workflow for writing articles
This way, you could work with any number of people on the same project and all of you could have access to the same digital library from which you can cite. You might wonder that the functionality of team library has been available for quite some now in popular reference management software like Zotero. However , without going through a few hoops, you can’t get Zotero to work seamlessly with Google docs.
Of late, I am increasingly using Google docs for my document preparation needs. Sure it isn’t MS Word, but few people need the full power of MS Word for their routine documents. The ‘portability’ of a Google docs document is particularly attractive to me since I have computers running different operating systems.
Here’s my completely online workflow. Every component of the workflow is free.(as in free beer).

workflow

The advantages of this online workflow includes

  • No need to install any software
  • You always get the latest and greatest version
  • OS/device independent
  • Collaboration is easy and seamless

The F1000 workspace also has a desktop client and  and you can start working even if you already have a pdf collection. It also has  a word add in, if you prefer to write in MS Word.Try it out for your next article. You will be pleasantly surprised.

Tamilnadu pg counseling–A hard look at the numbers

 

Disclaimer: If you are the type who is easily offended,read no further.

Yesterday the Tamilnadu PG rank list was released. In this post, let’s  look at the numbers – extracted from the government’s rank list.

A little introduction

The Tamilnadu postgraduate ranking has been mired in controversy this year, perhaps more than in any other year in the past. With the new 10-20 –30 rule, the service candidates stood to gain a maximum of 30 % extra marks. 10% of their mark for 1 year , 20 % for 2 years and 30% for 3 or more years in rural, remote or difficult areas.(how this rural/remote/difficult area is defined is another matter altogether)This can cause some service candidates to get a bonus of more than 300 marks ( the total marks –1500). This is an insane increase – So even if you are the best student, it’s like starting a 1500 metre race 300 metres behind the start line!

Needless to say, the non service candidates were annoyed with this arbitrary and huge bonus marks. Many stood to lose their seat. In this heated scenario, the courts after taking sometime gave the verdict that the MCI regulations should be followed and the state promptly called released a ‘rank’ list ! The list can be accessed at tnhealth.org.

The Data

  1. After getting the pdf ,which runs 288 pages, I extracted the data from the pdf with Tabula. (Here’s a previous post on how to do it – Extract data from pdf)
  2. After getting the data – I cleaned it with Excel (the good old Excel always comes in handy).
    1. To remove the rows with specific words, use the sort function and uncheck those words.
    2. Use the If-else construct to replace the blanks in the ‘SERVICE’ columns with NON SERVICE. Confirm that the non service candidates haven’t got any extra marks.
  3. You can download the data (cleaned and in Excel format) here

The Final dataset contains 4294 ranks. The same number can be confirmed with the source pdf.

The Analysis

What is the relative proportion of non service and service candidates in total?

A simple use of pivot table(an Excel feature that is unfortunately not used often by residents) shows that more than half of those in the total are non service candidates

proportions

breakup

Are there more service candidates in the first 1000 ranks?

Yes. 70% of the ranks have gone to service candidates.

top1000

top1000tablet

What about the first 500 ranks?

When we look at the first 500 ranks however, the domination of service candidates is near total. Every doctor( or anyone else for that matter) knows that the ranks are incredibly important in a competitive exam. There is no fun in finishing at the bottom of the heap. The service candidates get the lion’s share of the top 500 ranks. Only around 10 % of the non service candidates get into the top 500 ranks!

top500pie

What’s the big deal. May be the service candidates performed well in the exams. What is the average marks of service and non service candidates?(before 10-20-30)

The average NEET score of the service and non service candidates

avgNEET

As you can see the average mark of the non service candidate is much higher than the service candidate. This difference , predictably is much higher in the first 500 ranks – after all you got to perform really well to break into the top 500 ranks, in spite of starting several hundred metres behind the start line. (may be these are the academic equivalents of Usain Bolt). The difference is a whopping 175marks!

avgtop500tablet

Then how did the service candidates bag the lion’s share of the top500/top1000 ranks?

The bonus marks!! You might wonder – what is the average of all the bonus marks?

incentive

The incentive marks are higher with higher baseline marks. Here’s the same info for the first 500 ranks.

The bump in this graph shows how the average increase has reversed the fortunes.

effect of incentive

May be only a tiny percentage got the 30% in the 10 –20-30. Can you show the break up by benefits?

Wrong. The most common bonus mark was 30 % !!! A whopping 97% people got more than 10% bonus marks.

benefit

I heard there is no difference in the castewise category marks. Is that true?

Well , it depends. Here’s the average marks category wise.

communitywise

This is the overall average mark, broken down by community.

When we restrict the analysis to the top 500 ranks, the difference seems slightly less marked, but still present

top500community

Is there any difference in participation in service between categories?

Yes – look at this chart. There are less general category candidates who take service.

participation

Conclusion

I have just shown a few different perspectives. Of course, no matter how you slice and dice the data, you will see that the non service candidates got a raw deal. This is  not the fault of the service candidates. They didn’t write the judgement or release the rank list.The  10-20-30 rule is possibly  the most unfair way to compensate the service candidates. 

The purpose of this post is not to offend any group of people, but to show how by arbitrary and unfair laws, the lives of medicos can be easily screwed in our country.

 

Lind and the rind

In my last post I had written about BGR 34 and the complete lack of human trials for that ‘vedic’ drug. It sparked a simple question – can we really test concoctions with hundreds of active principles in a scientific manner? What if the ingredients interacted with each other in unpredictable ways?

Today the term ‘randomized controlled trial’ is synonymous with large multicenter studies testing targeted drugs . Many of these last for years and cost millions of dollars. However the answer to this question lies in the distant past – in what many think is the first controlled trial in human history.

The year : March 1747

The setting : HMS Salisbury (a 50-gun ship), somewhere in the English Channel

The British Navy was ravaged by a disease that killed more of its men than the French and the Spanish put together. Thinking mismanagement and the general squalor were to be blamed, the naval scribes sought to downplay the disease. Scurvy was nothing new – it was known since the Hippocratic times. It would rot the gums, cause sores on the body and lead to inexorable death. There was no cure.

A Scottish Naval surgeon named James Lind had a hunch. He speculated that the putrefaction of human tissue can be stopped or even reversed by acids. But what acid? Will it work? No one knew. Indeed vitamin C discovery would happen a 100 years after his death.

He devised an elegant method to test his hypothesis. He divided 12 sick sailors into six pairs, and provided each of them with a different supplement in their diet: cider, vitriolic elixir (diluted sulfuric acid), vinegar, sea water, two oranges and a lemon, or a purgative mixture.1 In modern science, we would call this a factorial design.

Only the sailors who took the oranges and lemons improved. At long last, one of the fearsome scourges of the seas was conquered. It was an astounding achievement by any standards. However there was a twist in the tale. Lind, by his own admission, didn’t realize the nature of the disease. Ironically, he tried to isolate the ‘active principle’ by boiling the lemon juice! Predictably it didn’t work. It took the British Admiralty 42 years to mandate lemon juice in the ships.

You can even read his original account in the James Lind library 2 . The English is a little convoluted and the S is printed like the integral symbol.

There is of course a revisionist version that claims Lind had been baffled by the disease and never really understood it fully 3 . The question is not whether Lind was indeed the hero we make him out to be. He did something remarkable for his times. He controlled the variables of the experiment and compared like with like. All these sailors had similar symptoms, similar living conditions and same food except the supplements. Eventhough the trial seems less rigorous by modern standards, it took just under a month and cost very little.

Lemons and oranges have stuff other than vitamin C – flavonoids, thiamine, potassium to name a few. They aren’t exactly alike. At that time, no one knew about vitamins. Yet the lack of knowledge of pathogenesis, active principle or funds did not stop Lind from experimenting and sharing the details. Compare this with the state of affairs in our country now.

We know more today than we did ever before. Yet there is a reluctance to d0 actual experiments. These simple trials of native drugs don’t need to be costly, but they need to be rigorous. When we commit to solid science, we can improve the credibility of native drugs and ensure that we know more tomorrow than we do today.

Dies Diem Docet.

Further Reading