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Primary Care Corner with Geoffrey Modest MD: Sugary beverages and Alzheimer’s

4 May, 17 | by gmodest

​​​The second study from the Framingham Study Offspring cohort database found that increased intake of sugary sweet beverages was associated with lower total brain volume by MRI and poorer performance on neuropsychological testing (see ). For first study, see here


–4276 participants had neuropsychological testing and 3846 had brain MRI imaging

–mean age 54, 46% male, 21% high school degree/31% some college/46% college grads, systolic BP 121 mmHg/17% on BP treatment, total chol 194/HDL 57, 8% diabetes, 2% atrial fibrillation, 10% current smoker, waist-to-hip ratio 0.9 (the WHO defines abdominal obesity as >0.90 for men and >0.85 for women)

–total consumption of sugary beverages:

–< 1x/d in 56%

–1-2 x/d in 29%

–> 2x/d in 15%

–31% consumed fruit juice ≥​​ 1x/d

–diet soft drinks were consumed more regularly than sugar-sweetened ones:  49% no diet soft drinks, 35% up to 6/wk, 16% ≥​​ 1/d

–total calorie intake 1942 cal/d, but increased from 1782 in those consuming <1 sugary beverage/d, to 2007 if 1-2/d, to 2413 if >2/d; similarly, saturated fat increased from 22 to 24 to 27 g/d


–as compared to consuming <1 sugary beverage/day, higher intake was associated with:

–lower brain volume (more so if >2/d than1-2/d)

–poorer performance on memory tests: both immediate and delayed recall

–lower hippocampal volume, borderline significant [the hippocampus is the part of the brain that consolidates short-term information into long-term memory]

–daily fruit juice intake was associated with:

–lower total brain volume, hippocampal volume, and poorer immediate and delayed recall

— however, none of these associations reached statistical significance in the most highly adjusted model, which included not just age, sex, caloric intake, education, blood pressure, smoking, cardiovascular disease, or cholesterol, but also included saturated fat, trans fat, dietary fiber, and physical activity.

— Diet soft drinks had only a small effect on total brain volume and on poor performance on the test of similarities but not other memory tests.

— Essentially no difference in subclinical markers of vascular brain injury (silent brain infarcts and white-matter hyperintensity volume)


–11 million metric tons of sugar were consumed by Americans in 2016 (per the US Dept of Agriculture)

–a recent blog  highlighted the remarkable statistic that “on average 26.3% of US adults consume at least one sugar-sweetened beverage daily, up to 41.4% in Mississippi, the highest of states, and that soda by itself was consumed by 24.5% of those 18-34 yo, and 47.4% in Mississippi). And a NHANES study (Welsh JA. JAMA 2010; 303(15): 1490) found that on average, 15.8% of calories came from added sugars, and that >25% of the patients got >25% of their total energy from added sugar.”

— Interestingly, there was not much of an association between sugar intake and vascular brain injury, despite studies showing that sugar consumption is associated with cardiovascular disease. Instead the current study found a more profound association with several markers of preclinical Alzheimer’s disease. This is also found in mice, where sucrose intake is associated with increased tau phosphorylation, amyloid-beta aggregation, hippocampal atrophy, and reduced brain-derived neurotrophic factor, BDNF. In the Framingham study cohort, these researchers have found that one standard deviation increase in BDNF was associated with a 33% lower risk of Alzheimer’s disease, suggesting that BDNF might be a factor in mediating the association between dietary sugar and Alzheimer’s. Other studies have found that impaired glucose tolerance and chronically elevated blood glucose are associated with poor memory, perhaps related to changes in the hippocampal volume and microstructure

— as a clinical perspective, daily fruit juice intake was equivalent to 1.5 years of brain aging in terms of  total brain volume and 3.5 years of brain aging for the delayed memory scores. And, relative to no intake, consuming more than 3 sugar-sweetened soft drinks per week was associated with lower brain volume equivalent to 2.6 years of brain aging, and lower immediate memory recall equivalent to 13.0 years!!!

— this trial also highlights the potentially bad effects of fruit juice, noting that the general public underestimates the sugar content of fruit juice by an average of 48%, even though 100% fruit juice, without added sugar, contains lots of fructose with negligible fiber content

— see here which reviews the sordid (ie not so sweet) history of the sugar industry in promoting sugar and shifting the blame away from sugar in increasing heart disease, dental caries, etc, since the 1950s, despite lots of scientific evidence to the contrary
–and, a couple of more references on lifestyle and cognitive function:

— lower adherence to a Mediterranean diet has been associated with increased brain volume loss, supplementing other studies finding higher incidence of clinical dementia related to lifestyle issues, especially diet and exercise (see review)

​– a just published systematic review/meta-analysis of exercise interventions for cognitive function in adults older than 50, found that physical exercise improved cognitive function regardless of the cognitive status of the participants. This was true for both aerobic and resistance exercise of at least moderate intensity with the duration of 45 to 60 minutes per session, done on as many days of the week as feasible (see doi.10.1136/bjsports-2016-096587.)

so, these 2 articles (including the earlier one) confirm and extend the bad health effects of excess sugar and artificial sweeteners to include adverse effects on cognition and stroke. These studies are observational ones from the Framingham Heart Study, and therefore do not definitively confirm causality, but they do add to the growing literature on their adverse effects on the brain. And, in terms of lifestyle interventions, over the years I have found that it is much easier to help people stop sodas and juices, substituting water, than other dietary interventions.​ The low-hanging fructose….

Primary Care Corner with Geoffrey Modest MD: Stroke and dementia, and artificial sweeteners

2 May, 17 | by gmodest

by Dr Geoffrey Modest

Two studies came out from the Framingham Heart Study database by the same authors in 2 different journals, one on the association between consuming artificially-sweetened beverages and the later development of stroke and dementia, and the other on sugary beverages and preclinical Alzheimer’s disease. I will divide these into 2 blogs.

An evaluation of the Framingham Heart Study Offspring cohort, with data from 1971 and evaluated over 9  examination cycles, found that artificially-sweetened soft drink consumption was associated with a higher risk of stroke and dementia (see DOI: 10.1161/STROKEAHA.116.016027).



— 2888 participants >45yo were evaluated for incident stroke;  1484 who were >60yo were evaluated for incident dementia

— mean age 62 for the younger group and 45% men, 69 for the older group and 46% men

— beverage intake was quantified at cohort examinations 5 (1991-5), 6 (1995-8), and 7 (1998-2001). Total sugar-sweetened beverages included soft drinks, fruit juice, and fruit drinks.

— surveillance for incident events began at examination 7 and continued for 10 years

— there were 97 cases of incident stroke (82 ischemic), and 81 cases of incident dementia (63 consistent with Alzheimer’s)



— controlling for age, sex, education (for the dementia cohort), calorie intake, diet quality, physical activity, and smoking; when compared to a daily cumulative intake of 0 artificially-sweetened drinks per week:

— hazard ratio for ischemic stroke was 2.96 (1.26-6.97), p=0.01 (ie, about 3x higher). Relationship was strongest for ischemic stroke

— hazard ratio for Alzheimer’s disease 2.89 (1.18-7.07), p=0.02. There was also an association with all-cause dementia of similar magnitude, 2.47 (1.15-5.30), p=0.02. Both were statistically significant in the group having at least one drink per day.

— sugar-sweetened beverages were not associated with the stroke or dementia, only artificially-sweetened soft drinks

— the curves for event-free survival for both of these outcomes continued to decrease through year 10 (i.e. it was not plateauing), and there was a dose-response curve with the more artificially-sweetened soft drinks, the lower the event-free survival

— there was no interaction in the above analyses with waist-to-hip ratio, diabetes mellitus, or with the presence of apolipoprotein E4

— there was not much change in the associations when excluding diabetes from the analysis, given the potential interaction of those with diabetes drinking more artificially-sweetened beverages (diabetes was found to be only a partial mediator of the association).



— the Nurses’ Health Study and Health Professionals Follow-Up Study both reported a higher risk of incident stroke with greater consumption of sugar-and artificially-sweetened beverages. The above study is reported to be the 1st showing association between artificially-sweetened drinks and an increase in both all-cause dementia and Alzheimer’s.

— The above study predated the approval of Stevia

— there are studies which have shown that artificial sweeteners cause glucose intolerance in mice by altering the gut microbiome, and they are associated with glucose intolerance in humans. See here for a detailed review of these animal and human studies.

— Generalizability of these results: the Framingham study served as a model for epidemiologic studies given its long-term nature (began in 1948) and in the regular intensive follow-ups done over the years. However, it was limited by the lack of ethnic variation. It also was an observational study which limits drawing conclusions regarding causality.


So, bottom line (again): these no-calorie artificial sweeteners seem to be associated with significant problems, including glucose intolerance (despite the fact that we used to push diabetic patients to drink these over regular sodas). And there are suggestive data that they do not help even with weight loss (see here ). so, all in all, we should be promoting water as the best drink….

Primary Care Corner with Geoffrey Modest MD: 23andMe genetic analysis approved for direct advertising

20 Apr, 17 | by gmodest

 by Dr Geoffrey Modest

The FDA just approved direct-to-consumer marketing for genetic risk information (23andMe Personal Genome Service Genetic Health Risk) for 10 conditions, though noting that “the tests cannot determine a person’s overall risk of developing a disease or condition … there are many factors that contribute to the development of a health condition, including environmental and lifestyle factors.” This approved test involves saliva samples, assessing more than 500,000 genetic variants associated with increased risk of: Parkinson’s disease, late-onset Alzhemer’s, Celiac disease, Alpha-1 antitrypsin deficiency, Early-onset primary dystonia, Factor XI deficiency, Gaucher disease type 1, Glucose-6-phosphate dehydrogenase deficiency, Hereditary hemochromatosis, Hereditary thrombophilia. see

The FDA reviewed the data for 23andMe through a premarket review pathway for low-to-moderate risk devices, with expectations about assuring test accuracy, reliability and clinical relevance, and also to make sure the results be clearly understandable by consumers. But the FDA now intends to exempt further tests added on by 23andMe from further premarket review, and may well exempt other genetic testing companies after submitting their first premarket notification.  These exemptions “would allow other, similar tests to enter the market as quickly as possible and in the least burdensome way”. [and, I might add, this is before confirmation of Trump’s pro-industry FDA nominee Scott Gottlieb, who has “received millions of dollars from various investment and pharmaceutical firms” per Bloomberg Technology…..]

Statnews had a really impressive review of the 23andMe test, at the cost of $199, revealing many of its limitations (see​ ). For example, they note that those having the specific variant for Parkinson’s disease tested increases their risk 3-fold, from a baseline of 0.3% to 1%…. Or, that those with Apo ℇ4 alleles may not get Alzheimer’s, and those without it may (the frequency of the Apo ℇ4 allele varies by ethnicity, 15% in Caucasian, 25% African-Americans; the presence of one allele increases the risk of Alzheimer’s by 2-3 fold, and two alleles by 8-12 fold).  So, the presence of a genetic variant, either for the Parkinson’s gene or if only 1 allele of Apo ℇ4, still makes the development of the disease unlikely (and actually rare, in the Parkinson’s case). And still about 10% or so of those who are homozygous for Apo ℇ4 do not get dementia.


–the big issues here, to me, are:

–these tests may well have pretty low sensitivity and specificity, as well as low positive predictive value

–patients may have trouble understanding the wording: 3x higher incidence of Parkinson’s sounds like a lot, but the actual 1% incidence not so much. Can be very confusing

–and, there are real concerns about the psychological effects of finding out one has a somewhat higher likelihood of a bad disease for which there is no current treatment. Will there be more depression, anxiety, decreased social cohesion/more isolation, hopelessness/even suicide?

–focusing on the genes undercuts the very important role of environmental/lifestyle factors: it really reinforces the conceptual deterministic framework that one’s future is set by one’s genes, undercutting the oftentimes dominant message that our environment and lifestyle are really important

–and it reinforces the conception that technology is the answer to our ills…



Some recent article on dementia are tangentially related to the above.

–The WHO reported that dementia deaths have increased, unseating AIDS as one of the top killers in the world (see ), and taking over the number 7 slot of the top 10 causes of death. And, as per this article in Bloomberg News, about 100 experimental treatments for dementia have failed to make matters better. Part of the issue causing the “elevation” of dementia is the aging population and probably that it is more often diagnosed now. But, so far, drugs do not seem to be the answer

–in this light, and complementing the above point that genes often do not play a decisive role, there was a recent study finding that lower adherence to a Mediterranean diet was associated with more significant loss of brain volume (see Luciano M. Neurology 2017;88:1)..

–Background: increased adherence to Mediterranean diet (lots of fruits, veges, legumes, cereals, olive oil as primary fat, moderate consumption of fish, low to moderate intake of dairy and wine, and low intake of red meat and poultry) is associated with less inflammation, better cognitive function, and lower risk of Parkinson’s and Alzheimer’s, as well as cardiovascular and cancer mortality. And cross-sectional studies have found higher consumption of components of the Mediterranean diet are associated with larger MRI-based brain volumes and cortical thickness. Higher fish and lower meat intake seemed to be the most important players.

–The current study was a prospective one of 562 Scottish men and women, assessing diet and brain structural changes from age 73 to 76

–50% female, 30% Apo ℇ4 positive, 4% diabetic/38% hypertensive/22% cardiovascular disease/BMI 28

–baseline cognitive ability: Mini-Mental Status Exam 29 (30=max, so no significant baseline dementia), and they assessed reading ability and general cognitive ability which relates to IQ (no comment on the scales they used or their validity). Diet was assessed only at baseline, age 70.

–change in brain structure from age 73 to 76:

–total brain volume: decreased 19 ml (from 990), gray matter volume decreased 9 ml (from 465), mean cortical thickness decreased 0.05 mm (from 3.11 mm)


–the group with highest adherence to Mediterranean diet had more carriers of Apo ℇ4 alleles (reason for this unclear in this healthy population who did not have underlying dementia), yet had greater total brain volume and gray matter volume at age 76

–in the fully adjusted model (controlling for those factors found in prior studies related to Mediterranean diet and brain MRI measures: age, sex, education, BMI, diabetes, general cognitive ability, MMSE), there was significant association between Mediterranean diet components and total brain volume change between age 73 to 76 (p=0.04), and presence of Apo 4 genotype did not change this. Fish and meat consumption were not found to be the drivers of this association. [perhaps it is a different combination, or even the all of the components together: parsing out specific components may be a tad reductionist and undercut potential interactions between the individual components. Better to eat well overall]


–so, there was a significant association between the diet and brain volume changes over this 3-year period

–and, the effect size of the Mediterranean diet on brain volume was substantial: half the size of that due to normal aging

​–of course, this was not a randomized controlled trial, so there could well be confounders (do those choosing to adhere to a more Mediterranean-type diet do other, unmeasured healthful things that may really be the ones that decrease cognitive decline, such as exercise??)

but, all in all, this study supports the concept of environmental/lifestyle factors being really important in the development of Alzheimer’s/cognitive decline, that this appeared to be  independent of the known genetic risk factor of Apo ℇ4​​, and adds to the argument against a genetic-determinant view of the development of this important condition (as is conceptually promoted by 23andMe etc)


Primary Care Corner with Geoffrey Modest MD: Fructose and NASH

7 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent study found that fructose consumption and serum uric acid were independently associated with non-alcoholic steatohepatitis (NASH) in obese kids with non-alcoholic fatty liver disease (NAFLD), (see


  • 271 obese children (by BMI) with NAFLD were studied
  • NASH was diagnosed by biopsy, with a NAFLD score of at least 5, and by the fatty liver inhibition of progression (FLIP) algorithm (another algorithm for the diagnosis of NASH)
  • Fructose intake was determined by a food frequency questionnaire
  • Hyperuricemia was defined as a serum uric acid level >5.9 mg/dl


  • NASH occurred in 37.6% of the children
  • Mean age 11.5, 38% female, BMI 27, waist circumference 87cm, AST 48/ALT 62, uric acid 5.8, LDL 100/HDL 45, BP 112/68, TNF-a Of note, there were significant differences between those with NASH and those without, but only for: waist circumference, AST/ALT, total cholesterol (but not LDL, HDL alone), triglycerides, fructose consumption, and TNF- a
  • Hyperuricemia was found in 47% of the kids with NASH, vs 29.7% without NASH (p=0.003)
  • Adjusting for multiple measured confounders:
    • Uric acid level was associated with NASH, OR 2.49 (1.87-2.83), p=0.004
    • Fructose consumption was associated with NASH, OR 1.61 (1.25-2.85), p=0.001
    • These associations with NASH were independent of each other
    • Though, fructose consumption was still independently associated with hyperuricemia, OR 2.02 (1.66-2.78), p=0.01
    • These data on NASH were confirmed by using the FLIP algorithm


  • As noted in prior blogs, there seems to be a pretty consistent relationship between fructose consumption and uric acid levels, as was shown in this study. And there are data suggesting that dietary fructose can be part of the pathogenesis of NAFLD (induction of de novo lipogenesis, inflammation, insulin resistance). Studies in adults have found that hyperuricemia is associated with insulin resistance, type II diabetes and metabolic syndrome.
  • There are many dietary sources of fructose. The major ones for most people are table sugar (sucrose, a disaccharide of glucose and fructose) and high fructose corn syrup (in a surprising number of foods, as a very cheap and potent sweetener). Perhaps the “low-hanging fruit” here is sodas, consumed by very large numbers of people ( , finding that on average 26.3% of US adults consume at least one sugar-sweetened beverage daily, up to 41.4% in Mississippi, the highest of states, and that soda by itself was consumed by 24.5% of those 18-34 yo, and 47.4% in Mississippi). And a NHANES study (Welsh JA. JAMA 2010; 303(15): 1490) found that on average, 15.8% of calories came from added sugars, and that >25% of the patients got >25% of their total energy from added sugar. My experience is that it is easier to help people stop sodas and juices, substituting water, than other dietary interventions.
  • I am not sure why we focus so exclusively on BMI, since the data are pretty consistent over the decades that abdominal obesity is really the bad actor, more metabolically active and associated with inflammatory markers, diabetes/insulin resistance/metabolic syndrome and is independently associated with cardiovascular risk (BMI is not: its association is mediated by its association with other risk factors, such as blood pressure, lipids). Waist circumference is a much better, though not perfect, marker of visceral obesity than BMI. That being said, there is a pretty strong relationship (but not always) between BMI and waist circumference, especially in those with BMI >35. The most reasonable recommendations I have seen is to measure the waist circumference regularly, especially if the BMI is between 25-35. Although practically we should reinforce lifestyle changes in all patients with high BMI, independent of waist circumference, I think the patient should understand that for those with a high waist circumference, their cardiometabolic risk is even higher. See for the fuller argument

So, this study does add some important information: it confirms that both uric acid levels and fructose are associated with NASH in kids that they are associated with each other, but that they are also independent predictors (and there are several studies which show that decreasing fructose consumption, as in sodas, is associated with decreased uric acid levels. See blogs below). So, bottom line is that fructose consumption is bad and should be decreased, even if the uric acid level is just fine.

See for prior blog of fructose consumption in kids and cardiometabloic and weight improvements is one of 3 articles on NAFLD, highlighting an important role of fructose  more on the microbiome and hepatic changes with fructose

Primary Care Corner with Geoffrey Modest MD: Microbiome 2

24 Jan, 17 | by EBM

By Dr. Geoffrey Modest

This is the second of two blogs on the microbiome, inspired by a recent review that highlighted several other health-related data besides the non-caloric artificial sweeteners (see Lynch SV. N Engl J Med 2016;375:2369).


  • ​The microbiome is huge, with 9.9 million microbial genes represented, as found from studying 1200 people in the US, China, and Europe. And it has >1000 species of microbes
  • Although the microbiome was previously felt to develop after birth, bacteria are found in the placentas of healthy mothers, in the amniotic fluid of preterm infants, and in meconium. And, the mode of infant delivery does influence postnatal microbial exposure: intravaginal delivery does seem to confer an infant microbiome taxonomically similar to the maternal gut and vaginally microbiota. Also the infant microbiome does become more similar to the adult one with the cessation of breast-feeding, and over the years bacterial diversity and functional capacity expand. The microbiome becomes less diverse in elderly, which could reflect coexisting conditions and age-related declines in immunocompetence.
  • Things that affect the microbiome include sex, age, diet, exposure to antimicrobial agents, changes in stool consistency, PPIs and other meds, travel, malnutrition, exercise (the effect of exercise on the microbiome is pretty clear in mice, not so clear in humans, since it is hard to sort out the effect of exercise vs different diets in those who exercise more). Also, host genetic features, host immune response, xenobiotics (including antibiotics), other drugs, infections, diurnal rhythms (see below), and environmental microbial exposures.
  • Clostridium difficile infections
    • This is probably the most advanced and practicable microbiome application. See for many studies and analyses. However about 90% of patients affected with severe, recurrent antibiotic-resistant C. difficile infections respond to fecal microbial transplants
  • Effects on immunity:
    • There are data that the infant microbiota at one month of age is significantly related to allergy in two-year-old children and to asthma in four-year-old children. Several of the products of the higher risk microbiota are associated with subclinical inflammation, which precedes childhood disease. Also other studies have found that children born by cesarean section, who do have differences in their microbiota, are more likely to develop type I diabetes, celiac disease, asthma, hospitalizations for gastroenteritis, and allergic rhinitis.
  • Obesity/metabolic syndrome/insulin resistance/diabetes
    • There are several studies finding that there are significant differences in the microbiome between obese and lean human subjects, with a decrease in Bacteroidetes and an increase in Firmicutes species in obese individuals. Studies have shown that taking microbiome samples from pairs of identical human twins, one lean and one obese, and placing them into genetically identical baby mice, have found that the mice with the microbiota from the obese twin develops more weight gain and more body fat, along with a less diverse microbiome, than those from the lean twin. Also, interestingly, women in their third trimester of pregnancy have an altered microbiome, which, when transplanted into mice, leads to more obesity, and that pro-obesity microbiome is more efficient in extracting energy from food [one common clinical issue with overweight/obese patients is that they may often eat much less than others but still do not lose weight, which has been shown in several studies, and attributed to their being more efficient in metabolizing foods. But perhaps this is mediated through the microbiome???]
    • Some proteins elaborated by E. coli stimulate glucagon-like peptide-1 (GLP-1) secretion, which could augment glycemic control in diabetics, where this hormone is less active than in nondiabetics. In addition, E. coli can elaborate peptide YY (produced in the ileum in response to feeding), which can activate anoxeretic pathways in the brain, mediating satiety.
  • Atherosclerosis/cerebral artery occlusion
    • There are pretty convincing studies that eating red meat leads to changes in the gut microbiota, which leads to increase production of trimethylamine-N-oxide (TMAO), which is a very strong risk factor for human atherosclerotic disease. And feeding meat to vegetarians does not increase TMAO until there are these microbiota changes from recurrent red meat diets. See blogs listed below for more details. Also, experimental data on mice show that cerebral arterial occlusion leads to 60% less damage in those with microbiota which are sensitive to antibiotics; mice given probiotics have less impairment after spinal cord injury.
  • Cancer
    • In mice, specific gut bacteria (most clearly shown for Bifidobacterium) enhance the efficacy of cancer immunotherapy, delaying melanoma growth. Human data has shown that certain microbiota species (B. Thetaiotaomicron or B. fragilis) can improve the effects of anti-tumor therapy targeting cytotoxic T-lymphocytes-associated antigen 4.
  • Autism
    • There are even some suggestive data that the microbiome may play a role in autism spectrum disorders. MIA mice, a maternal immune activation mouse model, exhibits autistic-like behavior, gut microbiome dysbiosis, increased gut mucosal permeability, and an increase in 4-ethylphenylsulfate (4EPS, a metabolite of gut bacteria). Injection of 4EPS into healthy, normal mice results in anxiety. And, feeding the MIA strain of mice a strain of Bacteroides fragilis normalized these adverse gut changes and decreased behavioral abnormalities, associated with decreasing circulating 4EPS levels. There are other neuropsych issues potentially related to the microbiome: gut bacteria can produce several neurotransmitters (eg norepinephrine, serotonin, dopamine, GABA, acetylcholine), and can change emotional behavior of mice (which seems to be related to central GABA receptor expression).
  • Other diseases with suggestive data of a linkage to microbiome dysbiosis include inflammatory bowel disease, kwashiorkor, juvenile rheumatoid arthritis, and multiple sclerosis. Also, in mice, stress leads to altered microbiota (less Bacteroides and more Clostridia), and in humans undergoing bariatric surgery, there are huge differences in the microbiome by either the Roux-en-Y gastric bypass or vertical banded gastroplasty, and this microbiome transplanted into germ-free mice leads to reduced fat deposition, suggesting that these microbiome changes themselves might play a direct role in decreasing adiposity (see Tremaroli V. Cell Metabolism2015; 22:228)​. And perhaps the changes in the microbiome, through the gut-brain relationship is part of the reason for the documented improvement in memory noted after bariatric surgery.
  • Diurnal rhythms (see Thaiss CA. Cell. 2014; 159: 514): the gut microbiota has diurnal variations that reflect feeding rhythms; humans with jet lag have dysbiosis; this jet lag leads to microbiome changes promoting glucose intolerance and obesity and are transferable to germ-free mice.


  • We should approach these studies on the microbiome with caution: some of the most impressive studies were done in animals in highly controlled conditions, and predictions in humans based on the studies is always fraught. For example, in general the use of probiotics in human adults has not shown as dramatic a response as found in rodents. (Although an interesting study of human neonatal probiotic supplementation in the first month of life was associated with a 60% reduction in the risk of pancreatic islet cell autoimmunity, a precursor to type 1 diabetes, before school-age). In addition, a stool sample may not be an adequate proxy for the microbial content of the entire GI tract. And, most of these studies have focused primarily on bacterial species in the microbiota, not taking into account the many other types of microorganisms found or their complex interactions.
  • One concern I have in general is our tendency towards reductionism. The microbiome appears to be a quite complex organ, composed of many different varieties of organisms which undoubtedly interact with each other in complex ways, and which are influenced by many known and undoubtedly unknown external cues (diet, antibiotic use, etc., etc.). So, for example, simply attempting to manipulate that microbiome through the introduction of one species or another of probiotics (i.e., our usual medical fix) may not deal with the complexity of this situation.
  • There have been a slew of other blogs on the microbiome over the years. See . One particularly interesting finding in one of the blogs was that one of metformin’s major action might be in its effects on the microbiome (see, which also reviews some of the TMAO data.
  • So, although I am pretty convinced of the importance of a healthy microbiome, it does seem to me that the major initiative should be around lifestyle changes overall: a healthy diet (and specifically one which is predominantly vegetarian), adequate exercise, perhaps adequate sleep (would be great to have more data on the effect of sleep patterns overall on the microbiome and if changing those patterns changes the microbiome), and minimizing exposure to unnecessary antibiotics (both in humans and in animals that make it into our food chain).

Primary Care Corner with Geoffrey Modest MD: Artificial Sweeteners Microbiome1

23 Jan, 17 | by EBM

By Dr. Geoffrey Modest

As mentioned in prior blogs, I think that the microbiome represents a very important mediator between the external environment and health/disease. A few recent articles supplement and strengthen this understanding. The first in a series of two is a study reinforcing the potentially deleterious effects of non-caloric sweeteners on the microbiome and health outcomes. The second (to be sent tomorrow) is a broader description of our understanding of the microbiome overall and its potential relationship to health.

​Non-caloric artificial sweeteners (NAS) were developed from the biological perspective that these potent sweeteners (more than 100 times sweeter than sucrose) are non-caloric and  are excreted unchanged; they should therefore be an important sugar alternative to help people lose weight and control glucose intolerance. Although a study done in the 1980s, prior to DNA sequencing capabilities, did show that saccharin could alter the rat microbiome, it is only relatively recently that we understand the fuller effects of NAS on both the microbiota as well as clinical outcomes. Many of the clearest studies were done on animals, since it is easier to control the environment completely and isolate the effects attributable to NAS. A recent study looked further into the relationship between NAS, the microbiome, and the clinical effects (see Suez J. Gut Microbes 2015; 6(2), 149). This is an update of a prior article in Nature (see prior blog:​ )


  • The human weight control studies here are a bit mixed. However it should be noted that most of the comparisons were between individuals consuming NAS to those consuming caloric sweeteners, with very few comparing NAS consumption to avoiding all sweeteners.
  • Several studies have shown NAS leads to weight gain in rats (including saccharin, sucralose, aspartame and Stevia), and are associated with increased adiposity
  • NAS can also induce hyperinsulinemia, impaired insulin tolerance, impaired glucose homeostasis, and worsened atherosclerosis in genetically susceptible mice
  • It should be noted that there are some genetically-altered mice where there are some discordant defects: some with decreasing glucose and insulin levels but increasing adiposity, and in some cases hyperinsulinemia

Details of the current study:

  • Mice drinking water supplemented with high doses of commercial saccharin, sucralose, or aspartame, after 11 weeks had marked glucose intolerance, as compared to controls drinking water, sucrose, or glucose.
  • Further studies of saccharin showed that mice on different baseline diets (e.g. high-fat or other) and at different doses of saccharin had increased glucose intolerance
  • The glucose intolerance induced by NAS was ameliorated by prior dosing with antibiotics (ciprofloxacin and metronidazole, in an attempt to sterilize the gut)
  • There were specific changes in the microbiome associated with NAS, including enrichment of Bacteroides and some Clostridiales and decreases in Lactobacilli and some other members of Clostridiales, several of the microbiota changes previously associated with type II diabetes in humans
  • Fecal microbiomes from mice consuming either water or commercial saccharin were then transplanted into germ-free mice, finding that those germ-free mice receiving the saccharin-associated microbiome developed glucose intolerance
  • In 381 nondiabetic humans, NAS consumption was associated with increases in BMI, blood pressure, hemoglobin A1c, and fasting glucose levels. Also there were changes in microbial taxa in the microbiome: more Actinobacteria, Enterobacteriales, and certain Clostridiales.
  • A preliminary small-scale human study found that supplementing the regular diet with higher doses of saccharin led to elevated glycemic responses in four of the seven volunteers, those 4 had microbiome alterations. And when these microbiomes were transplanted into germ-free mice, these mice also developed the same abnormal glycemic responses. Of note, in two of these 4 volunteers, their microbiome changes reverted to normal within 2 to 8 weeks.


  • NAS is consumed by approximately 32% of adult Americans.
  • The microbiome can be rapidly altered by diet, as noted in diets rich in fat (for example, see
  • There are a remarkable number of largely unregulated food additives in the current food supply, many added for purely commercial ends, such as preservatives to extend the shelf life of some foods. I believe this NAS data challenges the concept that even those ingredients that are not absorbed and internalized could conceivably adversely affect the human microbiome. The main point here is not that all additives or chemicals are necessarily bad, but that we should be very circumspect about assuming that they are probably benign based on our often incomplete models (i.e. It did make intuitive sense at the time that a non-absorbed sweetener would lead to less obesity and diabetes; but as our understanding and models have expanded/become more complex, our “intuitive” sense has changed). But, I think all of this reinforces what Michael Pollan (author or many books, including The Omnivore’s Dilemma) has suggested: it really does make sense to eat natural foods, especially ones which our bodies have evolutionarily adapted to, and avoid foods with ingredients that your grandmother would not know.

In my practice, I have focused on trying to get patients to decrease their consumption of sodas, and with some reasonable success. I think this is often the low-hanging fruit (though less healthy than other fruits), and at least most of my patients say they have dramatically decreased or eliminated sodas by either substituting water (best) or water slightly flavored by fruit juice. For regular sodas, the attempt is to decrease the consumption of high-fructose corn syrup (a bad actor with multiple bad effects, including increasing uric acid levels), was well as “diet” sodas (commenting on the fact that they really are not benign, non-sugar alternatives, as above). I think my patients have been able to change this soda habit by our regularly and repeatedly targeting this issue (with motivational interviewing) over the past several years, especially with my patients who are overweight, glucose intolerant/diabetic or hyperuricemic.

Primary Care Corner with Geoffrey Modest MD: W-3 Fatty Acids Decrease Heart Disease

15 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A meta-analysis including 19 studies and >45K individuals from 16 countries supported a small but significant cardiovascular benefit for both seafood and plant-derived w-3 fatty acids (see doi:10.1001/jamainternmed.2016.2925).


  • 19 studies from 16 countries (US, Australia, Costa Rica, UK, Italy, Finland, Sweden, Singapore, France, Ireland, Germany…) with  45,637 individuals and 7973 total CHD (coronary heart disease), 2781 fatal CHD and 7157 nonfatal MI events (the studies did not all break down the CHD events the same way, so these numbers do not add up)
  • Median baseline age 59, 63% male, BMI 26, up to 30% current smokers. Most were white, though some studies had racial/ethnic diversity. Overall alcohol consumption, mostly up to 1 drink/d. Fish oil supplements used infrequently. Median 10 year of follow-up
  • Assessed biomarkers for w3 polyunsaturated fatty acids (measured in whole plasma or tissue, which turned out to be better predictors than adipose tissue and cholesterol ester estimates):
    • Seafood-derived: eicosapentaenoic acid (EPA; 20:5w-3), docosapentaenoic acid (DPA; 22:5w-3), and docosahexaenoic acid (DHA; 22:6w-3)
    • Plant-derived: a-linolenic acid (ALA; 18:3w-3)
  • Results: significant associations were as follows, with multivariate-adjusted analyses, per 1-SD increase in the biomarkers:
    • ALA:
      • Fatal CHD: 9% decrease, RR 91 (95%CI, 0.84-0.98)
    • DPA:
      • Fatal CHD: 10% decrease, RR 90 (95%CI, 0.85-0.96)
      • Total CHD: 6% decrease, RR 0.94; 95%CI, 0.90-0.99),
    • DHA:
      • Fatal CHD: 10% decrease, RR 90 (95%CI, 0.84-0.96)
    • EPA:
      • Only reached borderline significant benefit


  • The prior studies on w-3 polyunsaturated fatty acids and CHD events are a bit mixed, with many methodologic problems (including relying on dietary recall), and few have looked at plant-derived w-3’s
  • Though there was no comment on what “fully-adjusted multivariate analysis” meant, likely because the studies varied, there was a comment that “No significant differences in associations of ω-3 PUFA biomarkers with incident CHD events were observed by age, sex, ω-6 PUFA (linoleic acid or arachidonic acid) concentrations, type 2 diabetes status, statin use, regular aspirin use, year of biomarker sampling, or (for ALA) EPA, DPA, and DHA concentrations”
  • In terms of biological plausibility, there are randomized controlled trials showing these w-3 fatty acids lower triglyceride levels, blood pressure, heart rate, and improve endothelial function, membrane stabilization through changes in lipid composition (which could decrease ischemia-mediated ventricular fibrillation, and possibly explain why the clinical improvement was more evident for fatal events) and myocardial oxygen demand, all of which could translate into improved clinical cardiac outcomes.
  • One highlight in the above study is the equal association of the plant-derived ALA to the seafood-derived rest of them: there are also data showing ALA decreases thrombosis, arrhythmias and inflammation, and improves endothelial function. And for much of the world, plant-derived w-3 is more affordable and accessible. By my review, the best single source of ALA is flaxseed, then also canola oil, and walnuts (esp. English). Other pretty high sources (actually, better than fish on a weight basis when comparing to the fish w -3’s) include soybeans, oats (germ), dried beechnuts and butternuts).
  • There were some interesting subgroup analyses, showing that Chinese and African-American individuals may benefit more from w-3. ?why ?genetic component. ?how the food was prepared (minimally cooked vs deep-fried, etc.). It was also interesting that taking statins or aspirin did not affect the overall outcomes much, since they accomplish at least some of the positive biological effects as the w-3’s.
  • I am always concerned about looking at single foods or food additives. In part because we eat a variety of foods, vitamins, etc., and there are likely interactions between the food components as well as optimal balances of different ones. And, even though this study was perhaps the best of the w-3 ones I’ve seen (in the sense that it combined lots of different studies from different areas, looked at hard-evidence both of actual w-3 levels in the body (vs dietary recall) as well as hard clinical endpoints, and seemed methodologically rigorous), there is always concern about the causal relationships in observational studies (i.e., did those who ate more w-3’s also do more other healthful behaviors (eat less red meat, eat more natural foods, do  more exercise, etc.)?
  • So, I do think this study adds to and deepens the literature that w -3’s are good for you (and, contrary to some prior articles/concerns, it seems that w -6’s did not counteract the benefits of the w-3’s).


Primary Care Corner with Geoffrey Modest MD: Nutrition Guidelines

11 Jan, 16 | by EBM

By Dr. Geoffrey Modestdietary guidelines

The feds just came out with their final dietary guidelines, which are updated every 5 years, with general dietary recommendations. Of note, these guidelines do have real impact: they affect the foods provided in federally-funded school-lunch programs and the WIC program for low-income women, infants, and children. For a review of the draft guidelines including more detail about current eating patterns and obesity, see blog:​ ​, which also includes an older blog about the role of potassium in decreasing blood pressure.  In general, these new guidelines try to focus more on healthy eating patterns than specific nutrients (though they in fact are not so consistent in this). And, per the NY Times (​),

“Last year, an advisory committee of nutrition experts assembled by the government recommended that the dietary guidelines encourage all Americans to consume more plant-based foods and less meat to help promote environmentally sustainable eating habits. That suggestion elicited intense lobbying and criticism from the food and meat industries, leading to a congressional hearing on the topic last year. In December, Congress passed a spending bill that contained a provision calling for a review of the dietary guidelines by the National Academy of Medicine and restricting the scope of the guidelines to nutrition, which essentially eliminated the advice about following an environmentally-sustainable diet.”

A review of the recommendations:

  • Follow healthy eating pattern across the lifespan, to achieve and maintain a healthy body weight, support nutrient adequacy and reduce risk of chronic disease
  • Esp veges, whole fruits, grains (at least half being whole grains), fat-free and low-fat dairy, proteins (seafood, lean meats/poultry, eggs, legumes, nuts, seeds, soy), oils. [On average we eat about 1/2 the fruits and vegetables recommended and are way below target for dark green veges; are right on target for grains; and for those >13 years old, consume only about 1/2 the dairy recommended; males, esp 19-70 yo, eat more protein than recommended, though are very very low on fish-derived protein; we are also high on solid fat consumption; and are very high on added sugars, esp age 4 to 50 but are high in all age categories]
  • Focus on variety, nutrient density, and amount
  • Limit calories from added sugars and saturated fats and reduce sodium intake. Cut back on foods and beverages high in these components
    • Limit saturated (<10% of calories) and trans fats, added sugars (<10% of calories) and sodium (<2,300 mg/d) and alcohol (up to 1 drink/d for women, 2/day for men) [males from age 14-70 consume average >4000 mg sodium, females 3000 mg/d]
  • Shift to healthier food and beverage choices. Consider cultural and personal preferences in making those shifts. [Overall 47% of added sugars come from beverages.]
  • Support healthier eating patterns for all, in different settings (home, school, work, communities)
  • And, they comment, all should be involved in physical activity, as per the Physical Activity Guidelines for America. Not shockingly, the amount of physical activity decreases pretty dramatically with age (though still only peaks at about 30% for those in those 18-24 yo who do the most physical activity, and less than 20% for pretty much the rest of us, though overall somewhat higher %’s in 2013 than 2008)​

So, a few comments:

  • There are a few helpful tables, such as Appendix 2 which has estimated calorie needs/day, by age, sex, physical activity level; appendix 4 with Mediterranean-style diet food composition corresponding to different calorie levels, the same for a healthy vegetarian diet (appendix 5). And a general food quantity recommendation for omnivores (appendix 2)
  • Other useful appendices (which may be useful to copy and give to patients (if they read and write English) are:
    • High potassium foods (appendix 10)
    • High calcium ​foods (appendix 11)
    • High vitamin D foods(appendix 12)
    • High fiber​ foods (appendix 13)
  • Unlike other guidelines I’ve seen, this one has whole sections on community approaches to having access to healthy, safe, affordable food choices (and noting that 48 milllion!! people in the US have food insecurity), as well as “meeting people where they are” (understanding the individual factors/motivators that determine diet and how to effect interventions).
  • As with the draft guidelines, no direct mention of cholesterol consumption (e.g. eggs). It has been mentioned in the press that the egg lobby was active in this, though I should add (from my comments on the draft recs):
    • It has long been known that the hypercholesterolemic effect (i.e., increase in serum cholesterol) of eating cholesterol is about 1/3 that of eating saturated fats and about 1/9 of that of eating trans fats. Several very large observational studies have not found that eating foods high in cholesterol is much of a cardiovascular risk factor. Also, as a perspective, only a small minority of circulating cholesterol (about 20%) is from diet, most is from genes….
    • Saturated fats: there are some recent data that, in terms of cardiac outcomes, plant-derived saturated fats are much better health-wise than animal-derived ones.
    • Trans fats: the worst. Finally, there are significant public health initiatives to decrease their use.
    • Sodium: for IOM (institute of medicine) report on sodium intake (which proposes a less-aggressive approach, but still targets much lower than current consumption), see
    • Potassium: see appended blog in​​. Seems like this is a really important clinical target for intervention
    • Caffeine: good news that we don’t have to cut back…

Primary Care Corner with Geoffrey Modest MD: New Diabetes Cases Decreasing

14 Dec, 15 | by EBM

By Dr. Geoffrey Modest 

The CDC just released a somewhat encouraging report showing that newly diagnosed cases of diabetes in the US has started to decline (see overall graph below, and the various articles/subgroup analyses at ). A few observations:

  1. There seems to be an overall consistent trend to fewer cases since 2009, though the number of new cases is way above 1980 (the age-adjusted incidence in 1980 was about 3.5/1000 and in 2014 was 6.6/1000) and is basically the same as in 2004-5. Of note, the criteria for diagnosis of diabetes did change in 2010 to include the A1C>=6.5. No doubt this increased the number of diagnoses of diabetes, so the subsequent falloff may even be more significant.
  2. These data includes only those with diagnosed diabetes, and from current epidemiologic studies, it seems that about 25% of diabetics are currently unaware of their diagnosis
  3. The age-adjusted incidence of diagnosed diabetes has trended down for whites, blacks and hispanics, but was only significant for whites. Also, the overall incidence has consistently been much lower in whites (in 2014, was 6.4/1000, in 2009 was 8.0/1000) than blacks (was 8.4/1000 in 2014 and 11.5/1000 in 2009) and hispanics (was 8.5/1000 in 2014 and 11.9/1000 in 2009)
  4. The age-adjusted incidence of diagnosed diabetes has trended down for those with less than high-school education, those with high-school education and those with greater than high-school education, but was only significant for those with greater than high-school education. Also the overall incidence has consistently been much lower in those with greater than high-school education (in 2014, was 5.3/1000, in 2009 was 6.7/1000) than those with high-school education (was 7.8/1000 in 2014 and 9.0/1000 in 2009) and those with less than high-school education​ (was 11.1/1000 in 2014 and 15.4/1000 in 2009)​

So, what does this all mean and how do we interpret it?

  • Part of the issue may be that diabetes has a strong genetic component and some of the leveling off of new cases may be that the steep rise prior to 2008 reflected obesity/lifestyle issues in conjunction with genes, and we have perhaps reached the saturation point for the genetic component (i.e., those predisposed genetically to diabetes have largely already become diabetic)
  • Part of the issue may be changes in obesity. Hard to compare CDC data over the past 20 years, since there was a change in CDC methodology in 2011, but it appears at least that obesity has plateaued and downtrended a bit in adolescents.
  • Some really positive changes have been the decrease in soda consumption: over the past 20 years, there has been a >25% decrease in sales of full-calorie soda, with a “serious and sustained decline”. From 2004-12, children consumed 79% fewer sugar-sweetened beverage calories a day (4% cut in overall calories) — see
  • These changes seem to reflect public health initiatives to decrease soda consumption (since the changes are not related to increased taxes or other financial incentives)
  • McDonalds, for the first time, is closing more stores than they are opening…
  • More people are doing daily exercise than before
  • Unfortunately, the CDC data really shows that the significant changes in new diabetes incidence pertains mostly to white and more-educated people. That being noted, I should add that my experience in a poor minority community is that there really have been pretty consistent improvements overall in lifestyle. I have many more patients who eat better (much less soda/more water for drinks, decreases in junk food) and much more consistently do exercise (mostly walking outside when the weather is nice, or climbing up and down stairs for 10-15 minutes when not. And some who ride bikes or have some home exercise machines, or go to gyms). This has been a pretty striking change over the past 10 years or so. I suspect part of the issue is that I have spent a long time discussing lifestyle changes with my patients over many years, but also (and perhaps more important) is that there has been more general awareness of the importance of eating well and exercising which i am supporting and reinforcing.
  • Though, an important cautionary note. One concern I have raised in many past blogs is that we (scientists and physicians alike) often develop our models of disease based on what seem to be reasonable physiologic data, then generalize it and formalize it as recommendations. We always do this, and there really is no way around it. But we are often wrong. In the 1970s, it seemed reasonable to note that dietary fats are related to atherosclerotic disease (which was a particularly big killer then), and that some fats were worse than others (saturated fats seemed to be the worst then, though there were early data that trans fats were actually the worst by far and still took another 4 decades to be reduced/eliminated, polyusaturated were better but lowered HDL as well as LDL, then the best were monousaturates which raised HDL while lowering LDL). So, we endorsed a low-fat diet, which translated to a high-carb diet (e.g., low fat ice cream, etc., had fewer fats and more carbs). Many of us realized subsequently (though a lot of the data was available many years ago), that eggs really were not so bad in terms of clinical outcomes, and that the high glycemic/high carb diets may well have been the major factor propelling the obesity epidemic and diabetes. So, I think the take-home message here is that we will always be constucting biological/medical models (whether they be about dietary fat, homocysteine, postmenopausal estrogens, etc. etc.); that these models are natural for us to do and really important in determining policy (though best after the appropriate studies with important clinical outcomes are performed, but these often take many years to do, if done at all); but that we always need to be really vigilant in continually questioning the basis of these models through introspection and further studies, and not allowing a model such as the low-fat diet above to last for so long (I believe the goal is something like: do no harm….)


Primary Care Corner with Geoffrey Modest MD: Drink Coffee and Live Longer

7 Dec, 15 | by EBM

By Dr. Geoffrey Modest

An analysis of the Nurses’ Health Studies (NHS, which began in 1976 with RNs aged 30-55 and  NHS2 which began in 1989 with RNs aged 25-42) and the Health Professionals Follow-up Study (HPFS, which began in 1986, with male health professionals aged 40-75) assessed total and cause-specific mortality in drinkers of caffeinated and decaffeinated coffee (see  or DOI: 10.1161/CIRCULATIONAHA.115.017341).


  • 74,890 women in NHS, 93,054 women in NHS2, and 40,557 men in HPFS, with extensive semi-quantitative food frequency questionnaires (131 items, administered every 4 years), and 4,690,072 person-years of follow-up. 95% white.
  • Up to 30 years of follow-up, with extensive data on known or suspected confounders (biennial questionnaires asking about age, weight, smoking, physical activity, medication use, fam history of diabetes, and self-reported diagnoses including hypertension, hypercholesterolemia, cardiovasc disease, and cancer), and 31,956 deaths


  • Never coffee drinkers, included 12% of those in NHS, 30% in NHS2, and 17% in HPFS
  • Drinkers of >5 cups/d, included 24% of those in NHS, 35% in NHS2, and 25% in HPFS
  • Compared to non-drinkers, coffee consumption of 1-5 cups/d was associated with decreased total mortality (HR for death was 0.95 for <=1cup/d, 0.91 for 1.1-3 cups/d, 0.93 for 3.1-5 cups/d, all of which were statistically significant, and a nonsignificant HR of  1.02 for >5 cups/d). No diff between caffeinated and decaffeinated coffee consumption
  • When analysis was restricted to never smokers (there were 10,505 deaths in 2,451,970 person-years in this group), compared to nondrinkers:
    • <=1cup/d, HR for mortality 0.94 (0.89-0.99)
    • 1-3 cups/d, HR for mortality 0.92 (0.87-0.97)
    • 1-5 cups/d, HR for mortality 0.85 (0.79-0.92)
    • >5 cups/d, HR for mortality 0.88 (0.78-0.99)
    • Overall p<0.001 for the trend
    • The association with total mortality was especially strong for those <70yo; no differences if stratify by diet quality (they calculated the Alternate Healthy Eating Index), BMI, physical activity, sex, and the cohort studied (NHS vs HPFS)
    • For caffeinated coffee, the trend had p<0.001. For decaffeinated coffee, the trend had p=0.022 (still significant)
    • Association with 1-cup increments of coffee/d found significant inverse associations for cardiovascular disease, neurological diseases, and suicide. No significant association with total cancer mortality

So, really great news…

  • Why does this make sense, especially since the association was not really with caffeine?
    • For cardiovascular disease: chlorogenic acid, lignans, quinides, trigonelline, and magnesium in coffee reduce insulin resistance and systemic inflammation
    • For neurological diseases (other studies have also found coffee consumption was associated with lower risk of Parkinson’s): for MPTP-induced Parkinson’s, there is loss of striatal dopamine transporter binding sites, and dopaminergic neurons, which is attenuated by caffeine
    • For suicides (also found in other studies): ???coffee has antidepressant effects, also it turns out that mice in stressful situations given caffeine have less stress-induced changes in their brains and behavior, but this doesn’t really answer the question about coffee or esp about decaffeinated coffee in humans
  • And, unfortunately, this study just reveals an association, so hard to say that this is causal. Though this was based on really long-term studies of people with extensive food diaries and controlling for many of the underlying possible confounders (and, perhaps the major confounder of smoking). But, then again, it is all self-reported/not verified, and is in a largely white population of professionals, limiting the generalizability of its conclusions.
  • But, at least coffee is not being demonized as being bad for your health….. In fact, it probably should be added to the food pyramid, and at the bottom (right next to the dark chocolate).

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