The Metabolic Syndrome

Metabolic disorder is a bunch of medical problems - expanded pulse, high glucose, overabundance muscle to fat ratio around the midsection, high triglyceride (awful cholesterol) levels and low HDL (great cholesterol). At the point when even three of these conditions happen together, the individual is at high hazard for coronary illness, stroke and diabetes.

This sort of out and out metabolic issue can't be viewed as uncommon either. Around 35% of grown-ups in the United States have metabolic disorder and 1 in each 4 individuals are in danger of creating it.

Our way of life is to a great extent to fault for this sort of broken digestion that can turn hazardous. In fact, it is the blend of unfortunate nourishment propensities, a stationary way of life, exorbitant pressure and reliance on comfort sustenances that play ruin with the framework and drive it out of apparatus.

Presently there are metabolic disorder eat less carbs alternatives and individuals are to a great extent mindful of what they have to do to recover their body on track. Getting in shape is unquestionably basic. Eating the correct nourishments, being more dynamic and dealing with the feelings of anxiety is similarly fundamental for dealing with the metabolic disorder and furthermore keeping such conditions under control.

In any case, what number of individuals really roll out the required improvements in their way of life and stick to more beneficial choices is another inquiry out and out. For example, the admission of prepared sustenances, manufactured sweeteners, liquor, sugar, refined starches and trans-unsaturated fats should be entirely directed. Alongside moving to a plant-based eating regimen, customary exercise and wellness is additionally critical.

What to do?

Realizing what to do and really doing it are not synonymous. This is the place a confirmed wellbeing mentor can enable you to turn around the side effects of metabolic disorder.

Wellbeing mentors don't instruct you to simply take after a metabolic disorder consume less calories, get thinner or exercise consistently. They focus on building a profound attention to the more beneficial propensities and how they can help you. You will be educated on the particular sorts regarding practices that enhance blood glucose affectability and lessen lifted insulin levels. You end up aware of the sorts of sustenance things that enhance your cholesterol capacity and how to join them in your day by day life. Aside from the unique dinner designs, you additionally figure out how to shop right and monitor the enticements.

Rather than emotional changes, wellbeing mentors set little objectives that are more practical and achievable. Indeed, even the little advances help support the digestion and minor changes in weight, sugar levels and triglyceride begin appearing. The mentor keeps you persuaded and light all through with energy talks and productive supportive gestures. You end up mindful of the undue feelings of anxiety and how to make the triggers more sensible. The way of life changes gradually and it is reasonable too.

In this way, a wellbeing mentor makes is conceivable to roll out the positive improvements for overseeing metabolic disorder and to assemble long haul wellbeing.

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Turmeric And Its Health Benefits

One flavor you will need to begin pondering incorporating into your cooking at whatever point conceivable is turmeric. Numerous individuals turn their nose up at it as they are not an aficionado of curry-based dishes, but rather remember turmeric does not need to dependably be as curry. You can add turmeric to numerous regular dinners you might make at the present time. Furthermore, you should. There are a considerable number advantages to utilizing turmeric - benefits that ought not be neglected.

Give us a chance to take a gander at a couple of these advantages at this moment...

1. A Reduced Risk of Cancer. The main advantage turmeric can offer is a diminished general hazard factor for tumor. The individuals who use turmeric may have a lower general rate of carcinogenic cell development, and in this way, it can help leave tumor speechless.

While it may not cure malignancy on the off chance that you as of now have it, by utilizing it routinely as a precaution treatment, you may discover you decrease your odds of falling sick.

2. An Anti-Depressant. Another incredible thing is a compound in turmeric may profit those with misery. Stimulant medicines, sadly, accompany some undesirable reactions, for example, weight pick up and loss of charisma.

With turmeric, since it is all characteristic, you don't have the danger of building up any undesirable symptoms. This could be a vastly improved approach to fend off gloom.

Address your specialist about how turmeric can help you on the off chance that you are experiencing nervousness or sorrow before you utilize any upper drugs: it might be useful. It is dependably a smart thought to adopt the common strategy at whatever point conceivable.

3. Mitigating. Aggravation is one of the main sources of infection today, and unfortunately, huge numbers of us are incessantly influenced. The uplifting news, in any case, is turmeric can help. This zest can bring down the general level of aggravation occurring in your body, helping you with avoiding issues, for example, coronary illness, stroke, hypertension, and even joint inflammation.

The individuals who are now experiencing joint inflammation will regularly discover alleviation of their indications once they begin utilizing turmeric. Ensure you try this zest out.

4. Fat Loss Benefits. One other advantage to note about turmeric is it gives astounding fat misfortune benefits. Turmeric may diminish the aggregate weight pick up and also lipolysis that happens when nourished a high-fat eating regimen, so think of it as a guide in your mission to a less fatty body.

While it won't work marvels, it can give you an edge.

There you have only a couple of the basic advantages turmeric may give. Is it accurate to say that it isn't time you incorporated this flavor some place in your dinner design?

Despite the fact that dealing with your sickness can be exceptionally testing, Type 2 diabetes isn't a condition you should simply live with. You can roll out basic improvements to your every day routine and lower both your weight and your glucose levels. Keep it together, the more you do it, the less demanding it gets.

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Check Out The Health Benefits Of Moringa Seed

Local to Africa and Asia, the Moringa Tree, or Moringa Oleifera (plant name) is a standout amongst the most supplements rich plants on the planet.

As Moringa Powder is a characteristic wellspring of these supplements, it is exceedingly bioavailable, so the human body can retain the supplements more effortlessly than by taking simulated or manufactured supplements.

Presently we should go in a visit through the ten advantages of moringa.

MORINGA BENEFITS: TOP 10 HEALTH and BEAUTY BENEFITS

1. Diminishment OF TIREDNESS and FATIGUE

In many days, 1 of every 5 individuals feel uncommonly worn out, and 1 of every 10 have drawn out exhaustion, as indicated by the Royal College of Psychiatrists in the UK.

Moringa battles against these uniform and tiredness by giving iron and vitamin A to the human body.

Press is exceptionally valuable for the anticipation of weakness in our body and vitamin A paces up the substance response of iron, in this way expanding digestion. Moringa ought to be modestly added to our every day schedules to adequately control and avert weakness and bizarre tiredness.

The rich iron substance of moringa powder additionally makes it perfect for veggie lover, vegans and those torment from sickliness.

2. SKIN

Moringa additionally keeps up skin and anticipate maturing and blurring without end.

It is additionally comprised of skin vitamins like Vitamin An and vitamin E.

Vitamin An is fundamental for sound, brilliant skin and vitamin E shields cells from oxidative pressure helping battle the indications of maturing and enable you to look young.

Moringa likewise has one of the most elevated cancer prevention agent substance of any nourishment. With an ORAC estimation of 157,000, it has 6x the cancer prevention agents of goji berries and similar levels to the cell reinforcement powerhouse matcha.

Cancer prevention agents are fundamental for securing, repairing and counteracting cell harm, limiting the maturing procedure of the skin in the long haul. They help balance oxidative pressure and the impacts of free radicals. Free radicals are precarious atoms that harm collagen causing skin dryness, scarcely discernible differences, wrinkles and untimely maturing.

3. Insusceptibility

Extraordinary compared to other moringa benefits is its super invulnerable boosting powers that enables your body cells to remain deft and battle germs. Keeping up a sound invulnerable framework is fundamental for helping our bodies keep off destructive diseases and ailments. Moringa Oleifera leaves are a to a great degree rich wellspring of:

Press: 32.2% of NRV

Vitamin A: 18.9% of NRV

Both of which are basic for the ordinary and legitimate capacity of the human insusceptible framework.

Researchers have done looks into over moringa as a cure for tumor or to counteract disease. Moringa leaves have been appeared to have valuable properties in the battle against both bosom and colon tumor cells and research is continuous.

4. MUSCLE GROWTH

Moringa oleifera leaves are just about 25% protein, which is bizarrely high for a plant. The high protein substance of moringa makes it especially advantageous for veggie lovers and vegans who can battle to get an adequate protein supply.

Take a stab at shaking it into a smoothie for a post/pre exercise help, or basically sprinkling some on your simmered vegetables for a simple method to build your protein consumption!

5. Against STRESS

A recent report in the Research Journal of Pharmacology and Pharmacodynamics affirmed that the leaves of the moringa tree are an effective, normal adaptogen.

WHAT ARE ADAPTOGENS???

Adaptogens are herbs or plants that shield the body from the lethal impacts of pressure. They help to enhance continuance even with exhaustion.

Studies demonstrate that adaptogens not just help the body to adapt to pressure, however can upgrade general wellbeing and execution.

For what reason not swap your morning espresso for a nutritious Moringa Latte and make proper acquaintance with a tranquil day!

6. Absorption

Moringa powder is a rich wellspring of calcium (24.7% NRV) which adds to the typical capacity of stomach related compounds.

It additionally contains 24% fiber which can help bolster a solid stomach related framework and inside normality. Fiber can likewise be useful for weight administration as it encourages you feel more full for more and backings a sound digestion.

7. Vitality RELEASE

Moringa is a rich wellspring of iron (32.2% NRV)

what's more, calcium (24.7% NRV), both of which bolster vitality yielding digestion. Begin your day with moringa and look empowering for whatever is left of the day.

8. VISION

Having sound eyes and ordinary vision is something that can regularly be underestimated yet requires the correct sustenance on request to keep up typical capacity. Moringa is a wellspring of vitamin A (18.9% NRV per serving) which adds to ordinary vision.

9. Against DIABETIC

Normally utilized as a part of customary solutions, late logical examinations have affirmed that moringa is in truth an effective method to treat diabetes, and is demonstrated to diminish blood glucose level.

Also, additionally inquire about has demonstrated that those eating an eating regimen rich in plant proteins can diminish their danger of sort 2 diabetes (T2D). A 19 year examine by the University of Eastern Finland has discovered that supplanting only 5 grams of meat-based protein utilization daily with a plant-based source, could diminish danger of T2D beginning by as much as 18% - moringa contains 25% plant protein.

10. BONES

Keeping up solid and sound bones is an imperative part of general wellbeing. Moringa oleifera leaves are a rich wellspring of vitamin K (158.7% NRV), protein (25%) and calcium (24.7% NRV) all of which bolster ordinary bones.

WHAT DOES MORINGA TASTE LIKE?

Moringa has a green, hearty taste - like spinach or matcha green tea. It is delectable blended into sustenance or beverages for a supplement help.

Step by step instructions to CHOOSE THE RIGHT MORINGA

Moringa is winding up progressively accessible around the globe as individuals find its various medical advantages - nonetheless, not all moringa is made equivalent. Moringa is generally developed in creating nations where framework can be poor. Gathered moringa leaves are frequently washed with unpure water which can contain microscopic organisms and different microorganisms. It is essential to utilize a natural affirmed moringa brand to guarantee the powder is free from any unsafe substances.

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Health Benefits Of Coconut Oil

Coconut Oil is for the most part utilized for cooking purposes however it has a wide range of uses which incorporate some mending capacities. Regardless of whether you utilize it all alone or as a key fixing, there are numerous approaches to fuse it in your life.

Coconut Oil can be utilized as the accompanying cures:

• It can decrease the appearance scars and extend marks. Rub it on the region every day to profit by this.

• If you have hard broken foot sole areas, you can utilize coconut oil to relax your rear areas.

• Head lice can be an issue with generally kids. Utilize coconut oil to treat for lice.

• You can utilize it to treat certain parasitic contaminations.

• It can be utilized to enhance Parkinson's infection and to diminish the impacts of Dementia.

• Use it to enhance Osteoporosis and in addition to enhance your memory.

• For babies that experience the ill effects of nappy rash, you can utilize it as a characteristic cure by tenderly rubbing it on their bottoms until the point when the rash vanishes.

• If you have tired eyes, the coconut oil can be utilized to lessen the puffiness around the eyes.

• If you are inclined to bug nibbles then you can utilize it to ease the tingling caused by these bug chomps.

• It is additionally a decent method to mend different substantial injuries.

• You can utilize it to enable lower to circulatory strain.

• It is a characteristic method to get help from agonizing or awkward hemorrhoids.

• If you have influenza, you can utilize it as an additional fixing in cool syrup or in a sore throat cure.

• Coconut oil can be utilized as a medical aid solution for stop or to avoid nose drains.

• Use it as a characteristic testosterone supporter. This will help with muscle building exercises.

• It can be utilized to slaughter off Candida yeast development and also to help cure bacterial abundance in the small digestive tract.

• Use it to diminish an insulin spike or to animate your thyroid.

• For those with tummy fat issues, it can be utilized it to consume fat around the stomach.

Coconut oil is a characteristic fixing that has numerous recuperating properties for the human body. It has a large number of advantages and applications which you can use in your day by day exercises. Make sure to dependably get the counsel of a specialist before taking any kind of home cure and apply it to a little territory initially to check whether you don't have any unfavorably susceptible responses to this fixing.

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Creatine - Recommended By Most Bodybuilders

Two things come up when somebody requests working out exhortation: protein and creatine. Protein, the vast majority can get it. It enables work to muscle and gives vitality to more exercise reps. More exercise reps create muscle speedier, which is likewise something supported by protein. Creatine works nearly an indistinguishable route from protein, in spite of the fact that the approach is unique. On the off chance that it capacities the same as protein powder, why take one over the other?

How It Works

Supplements work in different confounded ways. Just consider it along these lines with creatine: it takes a ton of water from your body and stores them in your muscles. This prompts an impermanent pick up in bulk, which is quite water, and it gives the vast majority of the advantages that protein powder has.

With respect to the reason that it is prominent, here are the main three.

It's Effective

Creatine is turned out to be powerful over and over. Various investigations have been led on it and the outcomes have been the same: it works. It assembles vitality, supports muscle development, and enhances quality. Like protein powder, it takes into account more reps, gives vitality blasts, and go past the standard set exercise regimen.

No Side Effects

Maybe the most well known reason that creatine is prescribed is the way that it has no antagonistic symptoms. Similar examinations that have indicated creatine to be compelling additionally have not possessed the capacity to locate any symptoms identified with it. In any case, it doesn't stop the various reports of liver or kidney disappointment supposedly caused by the supplement. The kidney reports regularly originate from abuse of the item. Since the supplement utilizes your body's water saves, it is vital to drink a lot of water to maintain a strategic distance from lack of hydration. Other than that, there is nothing else to keep an eye out for.

Water Weight

While protein straightforwardly helps in building mass, building muscle with creatine is more "regular." You get an indistinguishable advantages from protein, however when you get off creatine, you lose the water weight and your muscles backpedal to their unique, if enhanced, shape. The best part is, the quality you have gained from your creatine exercises remains with you.

While creatine is as sheltered as protected can be, it is as yet a smart thought to counsel your specialist before sharing in the supplement. For example, while the supplement does not do any immediate harm to your kidneys, those with previous kidney issues ought to keep away from creatine.

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Check Out Nutritional Advice for Muscle-Building

Despite the fact that you may regularly relate 'getting fit as a fiddle' with losing fat and conditioning up, there are a lot of individuals out there whose principle concern isn't to get thinner, however to put it on. I'm discussing those of you who have been marked 'thin' or 'slender' their entire life, and maintain a strategic distance from the exercise center by all methods in the dread it will bring about losing more weight.

This is a typical misguided judgment, however talking as a matter of fact I can sincerely say that it is conceivable to totally change your body and pick up the solid, conditioned constitution you've generally longed for yet felt you'd never have the capacity to accomplish. On the off chance that you need it anyway, you should to be set up to work for it; bulk does not come quick, regardless of your age, sex or body shape. In any case, on the off chance that you invest the exertion by eating admirably and preparing hard, you can hope to accomplish some phenomenal outcomes.

Sustenance

Sustenance truly is the most essential factor with regards to picking up bulk - all things considered, in the event that you don't expend a larger number of calories than you consume you won't pick up, regardless of how hard you prepare. The development procedure requires a considerable measure of calories, and figuring out how to devour them consistently can be harder than you may might suspect. My recommendation is to eat three expansive suppers, in addition to a few littler ones every day. This implies setting up your sustenance ahead of time so you have sound dinners to eat when you're grinding away or in a hurry.

Protein

Protein is basic for development and the working of new tissue and also the repair of tissue that has been separated (which happens when you work out). The general decide is by all accounts that you require between balanced and a half circumstances your body weight in grams of protein on the off chance that you need to reliably pick up muscle. Notwithstanding, this will fluctuate from individual to individual so you have to find what works best for you. As you put on weight, you should expand your admission likewise. Extraordinary wellsprings of protein incorporate red meat, angle, poultry bosom, eggs, dairy and whey; the last is the base of the greater part of the protein shakes I drink post-exercise.

Protein shakes are an ease choice which work fine as a substitute for one of your 'littler dinners' for the duration of the day. I mix mine with skimmed drain, and eat a banana or a modest bunch of unsalted nuts to go with it post-exercise at the rec center. Refueling instantly subsequent to preparing has worked ponders for me - it's as of now your body is longing for the important supplements expected to make its repairs. As they're fluid, protein shakes are additionally processed less demanding and quicker than entire nourishments, while giving you a fantastic wellspring of protein and carbs. They are additionally adjusted fittingly for a post-exercise dinner, as they contain no fat or different components that may thwart the stomach related process. By getting the essential supplements to the source speedier, your body won't be committed to take from different stores it as of now has.

Starches

Starches regularly get a terrible rep, yet in spite of what Mr Atkins says, carbs are our companions! They are a fundamental macronutrient your body requires with the end goal for it to have the capacity to take advantage of its glycogen stores amid an exercise. In the event that you don't eat enough of them, your body won't have any vitality stores and it will begin to separate muscle.

Go for complex (solid) carbs, for example, cereal, grain and quinoa, and in addition wholegrain other options to rice, pasta and bread. These will furnish your body with heaps of fundamental supplements and discharge their vitality gradually. Since complex starches are separated gradually and have a low-glycaemic file, they are great nourishment sources to eat post-exercise and at breakfast time (the most critical dinner of the day!).

Fats

Fats can't be extensively arranged, in light of the fact that not all sources are made equivalent. It is exhorted that around 20 - 30% of your day by day calorie admission ought to be conveyed from 'solid fats'.

Monounsaturated and polyunsaturated fats are what are known as 'great fats'. These are the ones you ought to consolidate into your eating regimen; prove recommends eating 'sound' fats is in reality bravo! Most 'solid' fats are gotten from plant sources, and incorporate sustenances, for example, angle, soya, tofu, seeds, nuts and plant-based cooking oils.

Immersed and trans fats are the 'terrible fats'; these should make up under 10% of our eating regimen (soaks) and close to 1% for trans fats. It will not shock anyone that these awful fats represent every one of those characteristically 'undesirable' nourishments, for example, frozen yogurt, desserts, chocolate, fricasseed sustenance, spread, high-fat cuts of meat and bundled nibble sustenances. These fats are by and large gotten from creature items and ought to be eaten with some restraint.

Supplements

I wouldn't try sprinkling out on all the favor supplement prevailing fashions that travel every which way; these have a tendency to be a misuse of cash. There are as of now attempted and tried items accessible that do precisely what you require them to, less the robust sticker price. Stick to superb multi-vitamin tablets or mineral supplements that give you 100% of your every day RDA, and in addition whey-based protein powder for protein shakes, et cetera. Creatine is the main other supplement I consolidate in to my eating regimen, as it helps increment unadulterated bulk and recover muscles when you're not working out.

So there you have it, my healthful manual for building. I trust this article will get you on your approach to accomplishing your objectives, and on the off chance that you just remove one things from this, simply recollect change doesn't occur without any forethought. You must keep at it, buckle down and adhere to your schedule. On the off chance that you foul up one day, don't thrash yourself about it or surrender, simply begin once more the following. Try not to squander your cash on costly favor supplements, and certainly don't surrender to the impulse to cheat your way up to the best. Do it my way, do it the correct way, and in the end you'll receive the benefits. Good fortunes

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Free Weights Vs Machines

Presentation:

Amid the development of working out humanity has seen an innovative progress in weight training machines. These days machines are planned and made better then ever. In any case one may ask which is better. That answer will be found in the conclusion segment of this article, however first lets begin with the upsides and downsides between the two!

Machines:

The machines that are discovered today everywhere throughout the world are composed and made better then ever. One must understand that machines simply like free weights are apparatuses that are utilized to shape and manufacture ones body to the most extreme one can accomplish conceivable. Additionally one must be grateful and keen to the machines that are discovered today, take a gander at the machines from the 1960's and 1970's and you will perceive what I mean.

Without facilitate farewell, how about we begin - machines help separate one's muscle. What I mean by that is suppose one does straight bar twists for the bicep muscle, while utilizing the free weight, one's front deltoid and lower arms will help with lifting the weight. In any case in the event that one goes on a machine that is made entirely for the bicep muscle, the bicep will entirely take the necessary steps and lift the weight up. This disengagement that ones gets from a machine will influence the muscle to work harder and stricter. However machines have cons as well, cons, for example, not working the stabilizer muscles and not getting the majority of ones normal testosterone creation. General machines help seclude the muscle amass one works out on, yet confines the other muscle bunches as far as development and quality.

Free Weights:

The muscles found in the human body where planned by development to beat the draw of gravity somewhat then to conflict with machines protection. In this manner one's greatest picks up in quality and muscles size will originate from lifting free weights, for example, dumbbells, barbells and straight bars. Lifting free weights will likewise expand ones common testosterone generation which is requirement for muscle development and recuperation. However this all accompanies a cost. When utilizing free weights distinctive muscle gatherings will become possibly the most important factor, in this way making ones exercise less productive. In any case, general the masters exceed the cons when one uses free weights!

Conclusion Which Is Better?:

Neither in light of the fact that both are instruments one needs to develop their bodies to the most extreme they can accomplish conceivable. Hence I suggest one has both machine and free weight practices in their weight-preparing schedules!

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Big changes in the world of VAP?

As you may or may not be aware, the four main professional societies in the US that include large critical care constituencies, AACN, Chest, SCCM and ATS, have created something called a Critical Care Societies Collaborative (CCSC). Its purpose is essentially to give the critical care community a voice in shaping public policy. And, as you can imagine, one of the current-day issues they are tackling is performance measures.

Now, on this web site we have spent a lot of virtual ink talking about quality metrics, particularly where ventilator-associated pneumonia, or VAP, is concerned. Well, I am happy to report that finally, a strong voice in Critical Care medicine is in agreement with what we have been saying: the VAP bundle needs to go! In fact, here is the sum of the recommendations made to the National Quality Forum in a letter dated February 9, 2012, from the CCSC leaders about VAP (emphasis mine):

The Task Force felt that the VAP “care bundle” minimizes the importance of each individual component measure and neglects the fact that many elements of the existing VAP bundle are known to have important effects outside of VAP reduction, including improved patient survival. The task force also notes that one of the components of the VAP care bundle, stress ulcer prophylaxis, may actually increase the risk of VAP.51Therefore, the Task Force would like to make the following recommendations regarding measure gaps related to VAP:(1) Dissolve the VAP care bundle and instead develop a new group of quality measures related to general evidence‐based practices for patients requiring mechanical ventilation (described above.) These potential measure gaps would include care processes known to reduce morbidity and mortality in patients who are ventilated.
(2) Develop measures using the VAP‐specific measure gaps supported by recent guidelines.52,53 These may include measures for the following evidenced‐based practices:
• Orotracheal rather than nasotracheal intubation to prevent VAP54;
• Subglottic secretion drainage to prevent VAP55;
• Elevating the head of bed to 45 degrees to prevent VAP56;
• Oral antiseptic administration to prevent VAP57;
• When empiric antibiotics are used to treat VAP, initial treatment based on qualitative endotracheal aspirates rather than quantitative bronchoscopic aspirates58; and
• No more than an 8‐day course of antibiotics as treatment for uncomplicated VAP.59
All of these VAP prevention strategies are supported by randomized‐controlled trials. However, not all have favorable cost‐benefit profiles, and all have significant barriers, which may make widespread adoption unfeasible. Although we list them all here, we note that all may not be good quality measures.

So, here it is -- the recommendation. But will it be followed? When I was at SCCM, I heard a presentation that talked about some new metrics being developed by the CCSC in collaboration with the CDC, which will likely replace VAP as the focus of mechanical ventilation complications. I am in the process of learning more about these developments even as we speak, and will update my readers on what I learn. Suffice it to say, change is coming to the world of VAP. And it's about time. 

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Teach one thing, or the rule of thirds

When I was a medical student, I did a lot of rotations at the Boston VA in JP. I loved my patients there -- they were patient and kind and stoic. One of the best rotations I did was Hematology, where Lou Fiore was my preceptor. Lou was not only an excellent teacher, but also a terrific doctor and a good human being all around. He used to start our days together by saying, "I'm gonna teach you one thing today." And teach us he did, at least one thing per day. Now I teach. And on occasion I have used the Lou Fiore "I'm gonna teach you one thing today" promise. Well, today is one of those days: I'm gonna teach you one thing.

And here is that thing. I am sure I am not the first one to notice this, but I still think of it as the "Zilberberg rule of thirds." The gist of it is that, for clinical research purposes, one can think of patient populations crudely in thirds: there is one third who are too sick to benefit from any of our interventions, there is one third who are too healthy, so that no matter how we try to tweak, their outcomes will not change, and the middle third, which comprises the "sweet spot" for intervention. So it is a fool's errand to pursue proof of concept studies in either of the bracketing thirds, since it is only the middle third that is likely to show a signal.

Pharmaceutical manufacturers do not always appreciate this trichotomy. Look at Vioxx, for example: when used in patients who were essentially healthy, an unacceptable safety signal arose that drove the drug off the market. Same for SSRIs, where the ill-conceived enthusiasm for treating marginal depression cases seems to be debunking the entire serotonin hypothesis. The flip side is sepsis research: septic shock patients are so far gone that it is difficult for any single therapy to alter their outcomes. Just look at the Xigris story, as well as myriad other therapies that tried and failed. This is the rule of thirds at its most pronounced.

In HEOR the rule of thirds holds as well. To prove cost effectiveness the following questions need to be asked:
1. Is the disease in question prevalent?
2. Is the economic impact of the disease known and substantial?
3. Does the diagnostic/therapy in question alter the course of the disease in such a way as to be significant?
If the answer to any of the questions above is "no," you really need to think carefully about the value proposition.

Some of you will bring up the inter-individual differences, the heterogeneous treatment effect, etc. And yes, these are supremely important. However, though the framework I propose here is simplistic, we have to start somewhere. To be sure, there is a more nuanced approach to this beast, but generally, one will not go wrong by asking these questions before committing huge resources to a project, particularly if the answer to question 2 or 3 is a resounding "no." So, even in health economics it behooves one to know the Zilberberg rule of thirds: choose the right population where the diagnostic/therapeutic advance and its costs can be justified by a substantial gain in the outcomes.

And that is your one thing for today.    

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Marie Curie, Geiger counters and mass hysteria: more in common than meets the eye

What do Marie Curie, a Geiger counter and mass hysteria have in common? Well, to answer this question we need to go Sir Arthur Eddington, who was a British astrophysicist and philosopher of science at the turn of the 20th century. He came up with what is frequently referred to as the Eddington parable, which has nothing to do with the stars specifically and everything to do with how we make scientific progress. Here it is for your reading enjoyment, as told in this editorial (available by subscriptionby Diamond and Kaul, two highly respected clinician-researchers:

Let us suppose that an ichthyologist is exploring the life of the ocean. He casts a net into the water and brings up a fishy assortment. Surveying his catch, he [concludes that no] sea-creature is less than two inches long. An onlooker may object that the generalization is wrong. "There are plenty of sea-creatures under two inches long, only your net is not adapted to catch them." The ichthyologist dismisses this objection contemptuously: "Anything uncatchable by my net is ipso facto outside the scope of ichthyological knowledge, and is not part of the kingdom of fishes which has been defined as the theme of ichthyological knowledge. In short, what my net can't catch isn't fish”.

Suppose that a more tactful onlooker makes a rather different suggestion: "I realize that you are right in refusing our friend's hypothesis of uncatchable fish, which cannot be verified by any tests you and I would consider valid. By keeping to your own method of study, you have reached a generalization of the highest importance—to fishmongers, who would not be interested in generalizations about uncatchable fish. Since these generalizations are so important, I would like to help you. You arrived at your generalization in the traditional way by examining the fish. May I point out that you could have arrived more easily at the same generalization by examining the net and the method of using it?"

So,you see my point? Tools determine knowledge. Period.

  

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Physician Payment Sunshine Act: More marginal thinking

It never ceases to amaze me how we gravitate to the margins in our thinking: margins seem to have a centrifugal force that is nearly impossible to overcome in today's political discourse. Yet the truth almost always lies at the center, the place that does not generate Op-Eds or produce votes.

I have said this before, and I will say it again: industry-physician relationship is not all bad or all good, there is no one within this relationship that is all bad or all evil, and it does not always benefit or always harm patients! The truth, of course, is somewhere in the middle. Contrary to Stossel's thesis, there is plenty to worry about with respect to corruption promoted by the big money exchanging hands between Pharma and doctors. On the other hand, just because there are instances of corruption and its consequences, not all interaction, financial or otherwise, is counterproductive. I am the first to admit that the much-touted innovation in medicine is rare, and we have largely given up its pursuit in favor of predictable markets and returns. Yet without a robust and transparent collaboration between industry and practitioners there is not only little hope of innovation, but any innovation that may stand a chance is likely to be irrelevant.

Yes, I agree with Stossel that the new reporting regulation is overly punitive and will inevitably result in undue administrative burden. But it would be disingenuous of me to disagree with the fundamental idea that there needs to be at least some degree of transparency in the financial dealings between industry and clinicians, if only to avoid the appearance by the docs of serving two masters.

As in everything in life, the devil is in the details. And it is these details that get buried by the gravitational pull of peripheral thinking and discourse. The solution? How about we stop paying attention to these marginal fallacies and start putting our heads together for real to solve these significant problems? How about we start a rational discussion about what is best for the people and not for the corporations or the economy or reputations? The discussion has been subverted by extremism. It is time to give in to the centripetal pull of reason.      

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3 ways to sink a new drug

I don't just rant about methods and evidence -- in my work life I also rant about health economics and outcomes! This is why I was so interested in this post by the health economist Ulf Staginnus called
"New Models for Market Access." I want to give a hat tip to Healtheconomics.com for pointing me here.

The thesis of the article is that we need to refocus our discussion from market access to true innovation in the biopharma sector. There are some priceless quotes here, like this one, for example:

It is amusing, at least to me, to see the continued flood of articles, consultant presentations, blogs, congress announcements, workshops, summits, reorganizations, speeches, etc. all over the place, basically suggesting how the industry just needs to throw a few more people with fancy titles here and there, coupled with slight organizational changes, onto the problem and involve stakeholders and—guess what?!—actually talk to patients and perhaps even payers and all of a sudden, like Alice in Wonderland, everything will be good, after all.

The uncomfortable truth is, it won't be. All this “noise” is only good for one thing, paying the bills of the consultants, which is fine, too, as I have been one myself so I can understand. But it will not address the problem the research-based pharmaceutical industry and its employees are facing. Without a substantial increase in R&D productivity, the pharmaceutical industry's survival (let alone its continued growth prospects), at least in its current form, is in great jeopardy.

Don't you love it? It is hard to disagree. He also calls for more of a focus on the long-term returns than the short-term (duh!), as well as more internal honesty, or having the courage to stand up to the pathologic internal enthusiasm about a late-stage product that will obviously go nowhere. And all of this is on target.

He has this to say about health economics and outcomes and such:

Of course, you need experience in areas such as HE, outcomes research, pricing, economics, policy, advocacy, etc. and all needs to work in sync and early on and with the payer in mind and, yes, most people have understood that by now. So the problem is essentially not in the capabilities, although some are more advanced than others, but rather in the company cultures.

And this, I think, is where I have to disagree with him. In my experience there are glaring deficits in the approach to HEOR within biopharma, though of course there are exceptions to the rule. It starts with the fact that disease burden, and especially its costs, are initially assessed through less than, shall we say, rigorous methods. I have seen this critical information get pieced together through market "research", where 5-10 "thought leaders" are asked for their opinions, and the quantification is based on this tiny non-representative sample of nothing more than guesses. This is a shame because the data usually exist which can give a much more bona fide estimate of the extent of the problem.

The second problem is that articulating the value proposition of a nascent technology is usually an afterthought. In fact it is self-evident that drug pricing must be fed using the information on the burden of disease, and the impact the new technology can make in mitigating such burden. Unfortunately, time and time again I see companies backing into a price simply in reaction to what their Boards perceive the returns should be. And frequently this is based on the overly optimistic market projections flowing from, you guessed it, market "research."

So, the direct result of all this short-sightedness and business as usual is that even innovative useful products are driven into oblivion because there is no realistic look at what the technology is worth or where best to use it. And fixing the problem after the drug or device is on the market is a much bigger challenge for several reasons. First, the acquisition costs of new technologies are bound to be higher than of those already in use. This puts them at a disadvantage in that they get niched into populations that have much greater burdens of illness and therefore less of a chance of doing well. In other words, they are used as a last ditch therapy, which very rarely ends well. Ironically, these are usually not the populations who were studied in the pre-approval studies, and thus the use turns out to be off-label. But here is the real problem: When these technologies are in the "kitchen sink" category, they will almost always end up looking worse in terms of the outcomes than their older counterparts. And to the untrained eye, or an eye who does not have the time to discern the truth, particularly in the setting of perceived high expenses on the new product, this rings the death toll for the drug. But the reality, of course, is that the abysmal outcomes are the result of confounding by indication, where the drug was inappropriately given to those patients who were very unlikely to benefit from in the first place. But you see how this early lack of attention to the articulation of appropriate populations and health economic data can snowball into failure of a promising therapy.

So, if you want your drug to fail, do the opposite of what I recommend below. In other words DO NOT
1. Develop your market understanding
Do it not from the opinions of a handful of "experts" -- experts will rarely tell you the truth. Instead, do epidemiology studies to understand your population and its subpopulations so as to get the most reasonable idea of the disease.
2. Start thinking about the value proposition early 
At the end of a successful Phase 2 program is a good time to do this. The surprise to most companies is how little HEOR studies cost in comparison with their clinical trials program. Yet, as you can see from above, this drop in the ocean can make or break a product.
3. Focus on transparent pricing methods
When pricing the technology, be very very sure that you have all of the ducks in a row, meaning:
                    a. do understand your market 
                    b. do understand the burden and costs of the disease
                    c. do understand how your product impacts these costs
                    d. do price the product to reflect this balance
It is truly embarrassing to have to admit that your price reflects nothing more than the greed of your investors. Trust me, you will not score points with your customers.

Staginnus makes one other important point which I generally agree with:

And let's face it, if you need a major workshop and intensive external “coaching” to help define the value of your product … well, there actually is little to none. If it was really good, it would have been obvious from the start. So maybe we ought to stop beating around the bush and move on if there is nothing to be done anymore. 

There is a nuance here, however, as in most things. Given what I have said above, products are more likely to gut than sell themselves. So, while I agree that you do not need a throng of consultants in suits and hair gel to pollute your offices, you do need to understand how to articulate this value, even when it appears obvious.

          

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When end of life is not

Twenty years ago, I helped save a man's life.

So begins this New York Times essay by Peter Bach, MD, where he talks about the inadequacy of resource use at the end of life as a policy metric. Now, I am not very fond of policy metrics, as most of you know. So, imagine my surprise when I found myself disagreeing vehemently with Peter's argument. Well, to be fair, I did not disagree with him completely. I only disagreed with the thesis that he constructed, skillfully yet transparently fallaciously (wow, a double adverb, I am going to literary hell!) Here is what got me.

He describes a case of a middle-aged man who was experiencing a disorganized heart rhythm, which ultimately resulted in dead bowel and sepsis. The man became critically ill, the story continues, but three weeks later he went home alive and well. This, Dr. Bach says, is why end of life resource utilization is a bad metric: if this guy, who had a high risk of dying, had in fact died in the hospital, the resources spent on his hospital care would have been considered wasted by the measurement. And I could not agree more that lumping all terminal resource use under one umbrella of wasteful spending is idiotic. Unfortunately, knowingly or not, Peter presented a faulty argument.

The case he used as an example is not the case. Indeed it is a straw man constructed for the cynical purpose of easy knock-down. When we talk about futile care, we are not referring to this middle-aged (presumably) relatively healthy guy, no. We are talking about that 95-year-old nursing home patient with advanced dementia being treated in an ICU for urosepsis, or coming into the hospital for a G-tube placement because of no longer being able to eat or drink. We are talking about patients with advanced heart failure and metastatic cancer, whose chances of surviving for the subsequent three months are less than 25%. And yes, we are also talking about some middle-aged guy with gut ischemia, sepsis and worsening multi-organ failure whose chances of surviving to hospital discharge are close to nil; but in his case, instead of being clear from the beginning, the situation evolves.

So, yes, the costs of end of life care, and specifically hospitalizations, are staggering. But more importantly, among patients with terminal illnesses like metastatic cancer, advanced heart failure and dementia, hospitalizations and heroic interventions at the end of life cause unnecessary pain and suffering, and without much, if any, benefit in return. Their families and caregivers suffer as well, and many studies suggest that these caregivers are not interested in prolonging suffering, provided they are aware of the prognosis. Unfortunately, just as many studies suggest that communication between doctors and patients' families about these difficult issues is less than stellar.

So, let me play the devil's advocate and pretend that I support end of life resource utilization as a quality metric. If I did, I certainly would not be interested in depriving Dr. Bach's middle-aged acutely ill patient of the chance to survive. In fact, my aim would be to make sure that we align resource use with where it can do most good, and turn away from interventions that are apt merely to prolong dying.        

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Lessons from Xigris

I have been wanting to write for a while about the demise of Xigris, but work and other commitments have stalled my progress. But it is time.

Here is my disclosure: I have received research funding from BioCritica, a daughter company of Eli Lilly, the manufacturer of Xigris. I also happen to know well and hold in high esteem the depth of knowledge and integrity of several colleagues who worked on Xigris internally at Lilly.

But on to the story. Xigris has had a short and bumpy life. When the PROWESS study, the Phase III Xigris trial, was first published in the NEJM in 2001 [1], it was the first therapy to succeed in sepsis, reducing mortality by 6% from about 31% to about 25%, yielding the number needed to treat of 16. This was huge, as so many trials to date had failed, and no progress had been made in sepsis management for years. These data opened the door to the FDA approval, despite a hung advisory committee, where equal numbers of members voted for and against approval. The controversy centered on concerns for bleeding complications, as well as some protocol changes during the trial and a switch in the manufacturing process. The latter concern was allayed by the Agency's detailed analysis and the finding of equivalence. There was a signal in a subgroup analysis that the drug might have been most effective among the most ill patients with a high probability of death, but not in their less ill counterparts. And despite the fact that the pivotal trial was not specifically performed in these patients, the approval for use specified just such a population.

So, despite the controversy, the drug was approved, though several post-marketing commitment studies were mandated. ENHANCE [2, 3] was an international study whose findings broadly confirmed the safety and efficacy of the drug, while the ADDRESS study [4], done in patients at low risk for death, was terminated early for lack of efficacy.

It seemed that PROWESS ushered in an era of positive results in sepsis. Shortly after its publication, other studies on the use of early goal-directed therapy [5], low-dose steroids [6] and tight glucose control [7] appeared in high impact journals, and the years of failure in sepsis management seemed to be over.  

In the meantime, and amid further controversy [8], Lilly supported the creation of the Values, Ethics and Rationing in Critical Care (VERICC) Task Force [9, 10], in addition to giving funding for the international Surviving Sepsis Campaign (SSC), which has resulted in the evidence-based practice guideline for sepsis management [11, 12] and an implementation program for the sepsis bundles, jointly sponsored by the SSC and the Institute for Healthcare Improvement [13]. The latter 2-year program enrolled over 15,000 patients world-wide, and achieved a doubling of bundle compliance from 18% to 36% with a concurrent drop in adjusted mortality of 5%. Because of several methodological issues and the lack of transparency about what it took to implement the bundle, it has never been clear to me a). whether there was causality between the bundle and mortality, and b). whether this effort was cost-effective.

But that aside, Xigris continued to stir up controversy, and there were still safety concerns. Some very well done observational studies, however, continued to confirm its effectiveness and safety in the real world setting [14]. Yet the final trial, PROWESS-SHOCK (done because of fears of an increase in bleeding complications), where patients in septic shock received Xigris as a part of their early management, brought doom. It was this study, whose preliminary results appeared in the press release from October 25, 2011, that prompted Lilly to pull the drug off the world market, since no difference in the 28-day mortality was detected between placebo and Xigris arms. Ironically, the preliminary reports indicate that no excess bleeding was noted in the treatment arm.

So, after roughly 10 years and millions of dollars, Xigris disappeared. But what can we learn from its story? There are many lessons that we should carry away, some about the way we do research, some about marketing practices, but all of them are about the need for a higher level of conversation and partnership. The biggest elephant in this room is whether a manufacturer should be allowed to fund guideline development. It is a complicated issue, particularly given our native proneness to cognitive bias, but in my opinion yes. This certainly cannot be done in a quid pro quo way. Perhaps this is naïve but should it not simply be a question of good data? And why wouldn't a manufacturer give money for the development of sensible guidelines without strings attached when the data are good?

Unfortunately, to me, Xigris is the poster child for how broken our research enterprise is, as I have discussed in this JAMA commentary [15]. Until all stake holders start talking to each other and arriving at common, useful and achievable goals, this is a story that will repeat itself again and again. The fact that regulatory trials, with all of their expensive and flashy internal validity, concern themselves only with statistical issues and care nothing about what happens in the real world is a travesty on many levels. The fact that it costs nearly $1 billion to bring a drug to market means that only big Pharma can bankroll such a gamble, and in return must demand big profits. The fact that this $1 billion fails to bring us studies that help clinicians and policy makers understand fully how to optimize the use of a drug once it is on the market is inexcusable. What we need is more intellectually honest discussions leading to novel pragmatic ways to answer the relevant questions in a timely manner and without bankrupting the system.

So, does the obvious financial interest mean that manufacturers should stay out of these discussions? I happen to think that they need a prominent place at the table. I actually think that the current fiasco is largely the result of too little interaction and too little cross-pollination of ideas: when we all sit around the table a nod in agreement, there is little progress. Deeper and novel understanding is built on disagreement and debate. Therefore, to leave the manufacturers out would invite further irrelevance. The bottom line is that we are all conflicted, and, according to the editors of PLoS, non-financial conflicts of interest, though more subtle and difficult to discern, may present an even bigger threat to much of what we do [16]. Elbowing out a party with an obvious conflict may have the unintended consequence of leaving some of the more insidiously conflicted others to run the show. And although we can argue whether profit is the healthiest driver for performance in healthcare, the reality is that our entire healthcare "system" is built around profit-making. Therefore it is disingenuous to single out one player over others.

On the positive side, the halo effect around Xigris brought a ton of attention to sepsis and its management. As Wes Ely conjectured in this piece, our improved understanding of sepsis (largely due to all the attention Xigris brought to it, in my opinion), is probably what rendered the drug useless in PROWESS-SHOCK. So, after all the hype, the noise and the hoopla, what is left is a company less one drug and hundreds of millions of dollars, and a disease area with a whole lot of what amounted to public health investment, with a vastly improved understanding of the disease state. How much is this benefit worth?

References

[1] Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699–709
[2] Bernard GR, Margolis BD, Shanies HM, et al. Extended Evaluation of Recombinant Human Activated Protein C United States Trial (ENHANCE US). A Single-Arm, Phase 3B, Multicenter Study of Drotrecogin Alfa (Activated) in Severe Sepsis. Chest 2004;125:2206-16
[3] Vincent JL, Bernard GR, Beale R et al.
Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med 2005;33: 2266-77
[4] Abraham E, Laterre P-F, Garg R, et al. Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death. New Engl J Med 2005;353:1332-1341
[5] Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377
[6] Annane D, Seville B, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871
[7] van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients.  N Engl J Med 2001;345:1359-1367 

      [8] Eichacker PQ, Natanson C, Danner RL. Surviving Sepsis – Practice Guidelines, Marketing Campaigns and Eli Lilly. N Engl J Med 2006;355:1640-2 

      [9] Sinuff T, Kahnamui K, Cook DJ, et al. Rationing critical care beds: A systematic review. Crit Care Med 2004;32:1588-97

      [10] Truog RD, Brock DW, Cook DJ, et al. Rationing in the intensive care unit. Crit Care Med 2006;34:958-63

      [11] Dellinger RP, Carlet JM, Masur H, et al: Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. 2004;32:858-73 

      [12] Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327. Erratum in Crit Care Med 2008;36:1394-96

      [13] Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: Results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010;38:367-74

      [14] Lindenauer PK, Rothberg MB, Nathanson BH, et al. Activated protein C and hospital mortality in septic shock: A propensity-matched analysis. Crit Care Med 2010;38:1101-7

      [15] Zilberberg MD. The clinical research enterprise: Time for a course change? JAMA 2011;305:604-5 

      [16] The PLoS Medicine Editors (2008) Making Sense of Non-Financial Competing Interests. PLoS Med 5(9): e199. doi:10.1371/journal.pmed.0050199

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Massachusetts' unwinnable gamble

It is ironic how, just a few days following the startling (?) confirmation by the Robert Wood Johnson Foundation-funded research that an ounce of prevention is indeed worth a pound of cure, the Massachusetts legislature with reckless abandon ushered in yet another mechanism for the erosion of public health: legalized gambling. Really, I have nothing against a little gambling. The issue is that this legislative move does not just open the door to a trickle of small local gambling operations. No, what it does is turn the crank to open a fire hose of "big box" gambling establishments descending upon our state. And it is not just anywhere in the state: it is in the Western part, far removed from the back yards of the legislators who are salivating over the projected licensing and tax revenues.

But I don't want to get into the NIMBY aspect of this misguided bill. I would rather stick to the real issue: selling us out to raise short-term revenue. The move projects 15,000 new jobs (menial with no benefits mostly), $40 million annually in tax income, on top of $85 million licensing fees from each of the three casinos, all this in addition to construction investment and the like. Already the bill allocates $50 million to overhauling healthcare reimbursements in the state. As well, there is a $25 million provision to shore up research into and prevention of problem gambling. And even people who are in staunch opposition to legalizing gambling seem appeased by this provision, which they say makes it the best bill of its kind. But we still have to ask, if prevention is better than cure, why settle for good mitigation strategies when we have the best prevention available to us already: keep casinos out!

Some of you will probably say that I am naive. After all, reason fades when we are talking about such big bucks for the state coffers. Well, just because this kind of a trade-off is something we have come to expect from our politicians does not mean that we should tolerate it. Others will bring up the old free will argument. No, I am not against people exercising their personal decision making, but haven't you read "Nudge?" We are all deeply flawed human beings, and in the face of temptation we fail miserably! And since we know that casinos increase the risk of problem gambling, why not just steer clear of them altogether? This is simply not a winnable gamble.

I hope that some of you are hearing echoes of the food-obesity debate. We deem it an individual rather than a societal problem, and look how well we have done mitigating the obesity epidemic! There is no rocket science here, and it is disingenuous to say that we do not understand the causes of obesity. Human physiology has not changed over a couple of generations, no. What has changed is our constant access to high-calorie cheap concoctions that pass for food; what has changed is our limited access to physical activity; and what has changed is the degree to which we as a society are willing to sign on to corporate and political propaganda designed to get votes and make money at the expense of our health.

So, am I shocked that this casino bill is likely to become law? Not at all. Am I surprised that the public is allowing this to happen in a pathetic perversion of personal freedom? Of course not. Am I going to shut up about what a mistake this is? You bet I am not. And in a decade I will say "I told you so." But I am sure that then, not unlike now, no one will be listening.              

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