Pro-inflammatory cytokines serve an important purpose, in marshaling the inflammatory response that fights off viruses, bacteria, and other pathogens. That’s the protective mechanism of inflammation at work. But for the pro-inflammatory cytokine response to be beneficial, it must be proportional to the threat. A too vigorous response of pro-inflammatory cytokines creates a dangerous amount of inflammation—and can actually serve to spread the viral infection, rather than tamping it down. It is this inflammatory overreaction and viral spread that appears to take place in the most serious cases of COVID-19.
I spent 10 minutes on the Internet trying to find the appropriate dose of melatonin for its possible preventative and treatment powers. But no luck. It’s likely in the range of 1 to 10 mg/day, typically taken at night or bedtime. For insomnia in my hospitalized patients, I start at 1.5 mg. Most of my colleagues use a much higher dose. Dr Josh Farkas at emcrit.org suggests that the treatment dose is 5 mg/day.
As always, check with your personal physician first.
Low-carbohydrate diets help many folks, but not all, lose excess fat weight. When low-carb diets help, it may be related to Total Energy Expenditure (TEE). When you read “energy,” think calories. TEE is a combination of calories needed for 1) basic life processes (i.e., basal metabolic rate, as needed to maintain heart beats, breathing, steady body heat, growth and repair of tissues, etc.), 2) processing of ingested food (dietary thermogenesis), and 3) physical exercise.
Here’s the abstract of an article in The Journal of Nutrition that examines the headline question. It’s complicated and I haven’t read the full study yet.
Many obesity experts believe that to lose excess fat weight, you have to ingest fewer calories than you burn on a daily basis for physical exercise and basal metabolic rate. This creates a calorie (energy) deficit. Your body satisfies that deficit by converting fat tissue to weightless energy. The authors of the study at hand are essentially saying that, after 2-3 weeks, a low-carb diet “revs up your metabolism” to burn more calories. That can help you lose weight or maintain weight loss, unless you over-eat.
Here you go, nutrition nerds:
The effect of macronutrient composition on total energy expenditure (TEE) remains controversial, with divergent findings among studies. One source of heterogeneity may be study duration, as physiological adaptation to lower carbohydrate intake may require 2 to 3 wk.
We tested the hypothesis that the effects of carbohydrate [expressed as % of energy intake (EI)] on TEE vary with time.
The sample included trials from a previous meta-analysis and new trials identified in a PubMed search through 9 March 2020 comparing lower- and higher-carbohydrate diets, controlled for EI or body weight. Three reviewers independently extracted data and reconciled discrepancies. Effects on TEE were pooled using inverse-variance-weighted meta-analysis, with between-study heterogeneity assessed using the I2 statistic. Meta-regression was used to quantify the influence of study duration, dichotomized at 2.5 wk.ResultsThe 29 trials ranged in duration from 1 to 140 d (median: 4 d) and included 617 participants. Difference in carbohydrate between intervention arms ranged from 8% to 77% EI (median: 30%). Compared with reported findings in the prior analysis (I2 = 32.2%), we found greater heterogeneity (I2 = 90.9% in the reanalysis, 81.6% in the updated analysis). Study duration modified the diet effect on TEE (P < 0.001). Among 23 shorter trials, TEE was reduced on lower-carbohydrate diets (−50.0 kcal/d; 95% CI: −77.4, −22.6 kcal/d) with substantial heterogeneity (I2 = 69.8). Among 6 longer trials, TEE was increased on low-carbohydrate diets (135.4 kcal/d; 95% CI: 72.0, 198.7 kcal/d) with low heterogeneity (I2 = 26.4). Expressed per 10% decrease in carbohydrate as %EI, the TEE effects in shorter and longer trials were −14.5 kcal/d and 50.4 kcal/d, respectively. Findings were materially unchanged in sensitivity analyses.
Lower-carbohydrate diets transiently reduce TEE, with a larger increase after ∼2.5 wk. These findings highlight the importance of longer trials to understand chronic macronutrient effects and suggest a mechanism whereby lower-carbohydrate diets may facilitate weight loss.
This finding supports a prediction of the carbohydrate-insulin model and suggests a mechanism whereby dietary carbohydrate reduction could aid in the prevention and treatment of obesity. According to this model, the high insulin-to-glucagon ratio with a diet high in glycemic load (mathematical product of glycemic index and carbohydrate amount) shifts the partitioning of metabolic fuels from oxidation in lean tissue to storage in adipose tissue. If the effects observed here persist over the long term, then reducing dietary carbohydrate intake by half from 60% of energy intake (a typical level for low-fat diets) would increase energy expenditure by ∼150 kcal/d, counterbalancing (if not compensated for by other factors) much of the secular increase in energy intake thought by some to underlie the obesity epidemic.
The clinical efficacy and utility of ivermectin in SARS CoV-2 infected patients are unpredictable at this stage, as we are dealing with a completely novel virus. However, repurposing existing drugs as possible COVID-19 treatment is astute usage of existing resources, and we await results of well-designed large scale randomized controlled clinical trials exploring treatment efficacy of ivermectin to treat SARS-CoV-2.
The authors of this letter mention current clinical trials (~38) with a dose [presumably by mouth] ranging from 200 to 1200 mcg/kg body weight, for a duration of 3–7 days, which is showing promising results both in terms of symptoms as well as viral load reduction. Another article mentioned the usual treatment dose is 0.2mg/kg on day 1 and day 3 followed by Days 6 and 8 if not recovered.
The authors cite the Broward Health hospital system study from South Florida. In this small pilot study, hospitalized patients treated with ivermectin had a better survival rate compared with “standard care,” whatever that was back in Spring 2020. The ivermectin-treated patients received “at least one dose” of the drug at 200 mcg/kg, by mouth. Has this report been peer-reviewed and published yet? If not, why not?
Another study: “Two-dose ivermectin prophylaxis at a dose of 300 μg/kg with a gap of 72 hours was associated 73% reduction of COVID-19 infection among [hospital] healthcare workers for the following one-month. Further research is required before its large scale use.”
A small study in Barcelona found no benefit from a single standard dose (200 mcg/kg) of ivermectin in patients hospitalized with severe disease. They suggest that a higher dose might be useful.
I’ve spent about 90 minutes on my day off trying to figure out if I should prescribe ivermectin to my hospitalized patients. My conclusion is that we need more and better data before it’s ready for prime time. I agree with Dr Ananda Swaminathan, who probably spent many hours more on the subject:
Evidence for the use of Ivermectin is based on in vitro [lab studies, not living animals], prophylaxis, clinical, safety, and large-scale epidemiologic studies (heterogenous populations in multiple different settings) BUT…
Many of the trials thus far are methodologically flawed without enough information about baseline demographics, multiple primary outcomes, soft/subjective outcomes, convenience samples, and unclear definitions, just to name a few
Additionally, a valid concern in evaluating the literature is that many of the trials have not yet passed the peer review process and are in pre-print format
Although Ivermectin is cheap, readily available, with a fairly safe side effect profile, based on the evaluation of the literature above, at this time, Ivermectin should not be recommended outside of a clinical trial to ensure we get a true answer of effect
Ivermectin is interesting, there is certainly signal to evaluate further, but in our desire to want a treatment option, let’s not continue to do the same thing over and over again, as we saw play out with Hydroxychloroquine
Like they say, “more studies are needed.”
Steve Parker, M.D.
PS: Something you can do to help prevent and survive COVID-19 is to get and stay as healthy as possible. Let me help:
Here’s the abstract of an article in Advances in Nutrition. This is the first I’ve heard of “gray literature.”
Alzheimer disease (AD) is a global health concern with the majority of pharmacotherapy choices consisting of symptomatic treatment. Recently, ketogenic therapies have been tested in randomized controlled trials (RCTs), focusing on delaying disease progression and ameliorating cognitive function. The present systematic review aimed to aggregate the results of trials examining the effects of ketogenic therapy on patients with AD/mild cognitive impairment (MCI). A systematic search was conducted on PubMed, CENTRAL, clinicaltrials.gov, and gray literature for RCTs [randomized controlled trials] performed on adults, published in English until 1 April, 2019, assessing the effects of ketogenic therapy on MCI and/or AD compared against placebo, usual diet, or meals lacking ketogenic agents. Two researchers independently extracted data and assessed risk of bias with the Cochrane tool. A total of 10 RCTs were identified, fulfilling the inclusion criteria. Interventions were heterogeneous, acute or long term (45-180 d), including adherence to a ketogenic diet, intake of ready-to-consume drinks, medium-chain triglyceride (MCT) powder for drinks preparation, yoghurt enriched with MCTs , MCT capsules, and ketogenic formulas/meals. The use of ketoneurotherapeutics proved effective in improving general cognition using the Alzheimer’s Disease Assessment Scale-Cognitive, in interventions of either duration. In addition, long-term ketogenic therapy improved episodic and secondary memory. Psychological health, executive ability, and attention were not improved. Increases in blood ketone concentrations were unanimous and correlated to the neurocognitive battery based on various tests. Cerebral ketone uptake and utilization were improved, as indicated by the global brain cerebral metabolic rate for ketones and [11C] acetoacetate. Ketone concentrations and cognitive performance differed between APOE ε4(+) and APOE ε4(-) participants, indicating a delayed response among the former and an improved response among the latter. Although research on the subject is still in the early stages and highly heterogeneous in terms of study design, interventions, and outcome measures, ketogenic therapy appears promising in improving both acute and long-term cognition among patients with AD/MCI. This systematic review was registered at http://www.crd.york.ac.uk/prospero as CRD42019128311.
I’ve run across a number of people who slowly increased their alcohol consumption over months or years, not realizing it was causing or would cause problems for them. Alcohol is dangerous, lethal at times.
From a health standpoint, the generally accepted safe levels of consumption are:
no more than one standard drink per day for women
no more than two standard drinks per day for men
One drink is 5 ounces of wine, 12 ounces of beer, or 1.5 ounces of 80 proof distilled spirits (e.g., vodka, whiskey, gin).
Dry January was conceived in the UK in 2012 or 2014. The idea is simply to abstain from all alcohol for the month of January. The Alcohol Change UK website can help you git ‘er done. Many folks notice that they sleep better, have more energy, lose weight, and save money. There are other potential benefits.
If you think you may have an unhealthy relationship with alcohol, check your CAGE score. It’s quick and easy.
Alternatively, if you make a commitment to a Dry January but can’t do it, you may well have a problem.
PS: I did the Dry January in January 2020. The only definite change I saw was that I was more productive. E.g., I blogged more regularly, worked out a bit more. The lesson for me is that alcohol makes me a little lazy. At three weeks in, I started thinking maybe I was able to fall asleep sooner but still woke up often, as usual. I also lost three pounds of body weight fat, but had consciously cut back on food intake.
I often get pages from hospital nurses regarding a patient’s request for a sleeping pill. (Or is the request really from the nurse because a sleeping patient is less hassle? LOL.) My hospital’s formulary limits me to ambien, restoril, trazodone, benadryl, and melatonin. Of those, melatonin seems to be the safest in terms of adverse effects and drug interactions. But does it work?
The evidence is mixed and weak. There is some positive evidence for melatonin, and side effects are mild. I wouldn’t discourage anyone who wants to give it a try, but I think good sleep hygiene measures would be a better first step for treating insomnia.
The optimum dosage has not been established. In studies, the doses have ranged from 1 to 12 mg. Supplements typically contain 1-3 mg. Dosages between 1 and 10 mg can raise melatonin levels to 3-60 times the levels normally found in the body.
Caution is advisable, since quality control is a documented problem. 71% of products did not contain within 10% of the labelled amount of melatonin, with variations ranging from -83% to +478%, lot-to-lot variability was as high as 465%, and the discrepancies were not correlated to any manufacturer or product type. To make matters worse, 8 out of 31 products were contaminated with the neurotransmitter serotonin.
If melatonin works by placebo effect alone, it will help ~10% of users, almost always without adverse effects. I dose it at 1.5 mg, with a repeat dose an hour later if needed.
I know it’s a little early to be asking that question. Within a year, an unknown number of you will be asking. Where do you go for satisfaction? The CICP: Countermeasures Injury Compensation Program. Forget about suing the vaccine manufacturer, distributor, or medical practitioner who jabbed you. They got the federal government to absolve them of liability in most cases. If injured, you need to file your claim within a year of vaccination.
As far as I know, this program only applies to U.S. residents. Perhaps only U.S. citizens.
Here’s an excerpt from a related fedgov program, the NVICP web page:
Vaccines save lives by preventing disease.
Most people who get vaccines have no serious problems. Vaccines, like any medicines, can cause side effects, but most are very rare and very mild. Some health problems that follow vaccinations are not caused by vaccines.
In very rare cases, a vaccine can cause a serious problem, such as a severe allergic reaction.
In these instances, the National Vaccine Injury Compensation Program (VICP) may provide financial compensation to individuals who file a petition and are found to have been injured by a VICP-covered vaccine. Even in cases in which such a finding is not made, petitioners may receive compensation through a settlement.
Many physicians in my community are excited and lined up to take the COVID-19 vaccine. But not me. I even have risk factors for more serious COVID-19 disease: age 66 and hypertension. After reviewing what little data are available from the Warp Speed vaccine trials, I’m not convinced the vaccines are safe enough for me. I’ll take my chances with the virus rather than the vaccine. I’m not afraid of dying from COVID-19; if that happens I’ll be in heaven with Jesus. I’ve lived a full and lucky life, blessed by a wonderful wife, fantastic children, good health, missed Viet Nam by a few years, no major economic upheaval. My biggest concern about catching the virus is the burden it would lay on my co-workers if I’m off-duty for 1 to 3 weeks.
That said, if I were older and had other co-morbidities, I might take the vaccine now. When we have more long-term data on vaccine safety, I might take the vaccine. It could take up to a couple years before we have that data.
I am not anti-vaccine, in general. As a child I got the vaccines for polio, measles, mumps, rubella, tetanus, and probably diphtheria, maybe others. I took the hepatitis B vaccine as an adult because I’m exposed to blood from my patients. I’m due for another tetanus booster and will take it without reservation.
Steve Parker, M.D.
PS: I’m doing everything I can to optimize my health and immune system, including weight management and regular exercise.
Most of you don’t remember the 1976 flu epidemic. Early on, it appeared to be on track to equal the 1918 Spanish Flu death rates. Politicians and public health authorities felt like they better do something, anything, to avert disaster. Their response didn’t work out too well. COVID-19 isn’t the flu, but it’s a viral illness that often looks like the flu clinically.
From Discover magazine:
Vaccines were once thought of as an axiomatic good, a longed-for salvation in the form of a syringe, banishing crippling and deadly infections like polio, smallpox and tetanus. But within the past few decades we have seen the emergence of anti-vaccination movements and a rise in cases of childhood diseases that are entirely preventable with a quick jab to the arm.
Some of the American public’s hesitance to embrace vaccines — the flu vaccine in particular — can be attributed to the long-lasting effects of a failed 1976 political campaign to mass-vaccinate the public against a strain of the swine flu virus. This government-led campaign was widely viewed as a debacle and put an irreparable dent in future public health initiatives, as well as negatively influenced the public’s perception of both the flu and the flu shot in this country.
* * *
But while the World Health Organization adopted a cautious “wait and see” policy to monitor the virus’s pattern of disease and to track the number of emerging infections, President Gerald Ford’s administration embarked on a zealous campaign to vaccinate every American with brisk efficiency. In late March, President Ford announced in a press conference the government’s plan to vaccinate “every man, woman, and child in the United States” (1). Emergency legislation for the “National Swine Flu Immunization Program” was signed shortly thereafter on April 15th, 1976 and six months later high profile photos of celebrities and political figures receiving the flu jab appeared in the media. Even President Ford himself was photographed in his office receiving his shot from the White House doctor.
* * *
The American public can be notably skeptical of forceful government enterprises in public health, whether involving vaccine advocacy or limitations on the size of soft drinks sold in fast food chains or even information campaigns against emerging outbreaks. The events of 1976 “triggered an enduring public backlash against flu vaccination, embarrassed the federal government and cost the director of the U.S. Center for Disease Control his job.”
One aspect of the fiasco was that of the 45 million U.S. residents hastily vaccinated against Swine Flu, 450 developed a severe neurological disorder called Guillain-Barre syndrome.
Peter Doshi, an associate editor at British Medical Journal, is not favorably impressed with the recent vaccine trial announcements. “90% effective.” “95% effective!”
Coronavirus guru Anthony Fauci assures us that a coronavirus vaccine will only be FDA-approved if it’s “safe and effective.”
But what will it mean exactly when a vaccine is declared “effective”? To the public this seems fairly obvious. “The primary goal of a covid-19 vaccine is to keep people from getting very sick and dying,” a National Public Radio broadcast said bluntly.
Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, said, “Ideally, you want an antiviral vaccine to do two things . . . first, reduce the likelihood you will get severely ill and go to the hospital, and two, prevent infection and therefore interrupt disease transmission.”
Yet the current phase III trials are not actually set up to prove either. None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus.
Switching gears to the flu vaccine for a minute. The flu vaccine’s been a godsend in preventing influenza death among the frail elderly, right? Not so fast there, pardner. Doshi again:
But the truth is that the science remains far from clear cut, even for influenza vaccines that have been used for decades. Although randomised trials have shown an effect in reducing the risk of symptomatic influenza, such trials have never been conducted in elderly people living in the community to see whether they save lives.
Only two placebo controlled trials in this population have ever been conducted, and neither was designed to detect any difference in hospital admissions or deaths.
Moreover, dramatic increases in use of influenza vaccines has not been associated with a decline in mortality.
The Moderna and Pfizer trials enrolled 30,000 and 44,000 participants, respectively. That sounds like a lot of people to be vaccinated. But they only vaccinate half the folks. The other have serve as a control group. Next, the investigators track the occurrence of coronavirus events over time, then compare the two groups. An “event” may be anything from a cough plus positive COVID-19 PCR test, to hospitalization or death. Of course, they also look at potential adverse effect of vaccination, comparing the two groups.
The trials aren’t going to give us good information on COVID-19 hospitalizations and death rates because those outcomes are so infrequent. Most people with symptomatic COVID-19 experience only mild symptoms; there are relatively few cases of serious disease in a general population of 30,000.
Who needs a safe and effective vaccine the most?
Those over 60-65
Anybody seriously immunocompromised (i.e., a poor immune system too weak to fight infection).
Immunocompromised people are excluded from the seven ongoing trials. So these trials focus on those over 60, right? Wrong. The Moderna trial eligibility started at age 18. Pfizer’s accepted 12-year-olds.
Surely the vaccine trials will have some participants over 60-years-old. There just may not be enough to generate clinically meaningful data on serious disease outcomes and adverse effects in the elderly.
Steven Novella says Moderna developed their vaccine with a grant from the U.S. government, and Pfizer funded themselves. Each vaccine has cost over two billion dollars to develop. They will be the first ever mRNA vaccines approved by the FDA. Our other vaccines are based on different technology. Both vaccines require two shots, 28 days apart.
Insulin is a blood-borne hormone that the pancreas gland secretes in order to keep blood sugar levels from getting too high. (Insulin does many other things, but table that for now.) Insulin triggers certain body cells to absorb glucose from the bloodstream. “Insulin resistance” means that these cells don’t respond to insulin as well as they should, so either the pancreas secretes even more insulin (hyperinsulinemia) or blood sugar levels rise. Insulin resistance is a harbinger of type 2 diabetes mellitus. Most overweight or obese type 2 diabetics have insulin resistance. Many experts think hyperinsulinemia causes disease by itself, regardless of blood sugar levels. So it may be best to avoid insulin resistance and hyperinsulinemia.
The aim of the study was to investigate the effects of 6 weeks of resistance exercise training, composed of one set of each exercise to voluntary failure, on insulin sensitivity and the time course of adaptations in muscle strength/mass. Ten overweight men (age 36 ± 8 years; height 175 ± 9 cm; weight 89 ± 14 kg; body mass index 29 ± 3 kg m−2) were recruited to the study. Resistance exercise training involved three sessions per week for 6 weeks. Each session involved one set of nine exercises, performed at 80% of one‐repetition maximum to volitional failure. Sessions lasted 15–20 min. Oral glucose tolerance tests were performed at baseline and post‐intervention. Vastus lateralis muscle thickness, knee‐extensor maximal isometric torque and rate of torque development (measured between 0 and 50, 0 and 100, 0 and 200, and 0 and 300 ms) were measured at baseline, each week of the intervention, and after the intervention. Resistance training resulted in a 16.3 ± 18.7% (P < 0.05) increase in insulin sensitivity (Cederholm index). Muscle thickness, maximal isometric torque and one‐repetition maximum increased with training, and at the end of the intervention were 10.3 ± 2.5, 26.9 ± 8.3, 18.3 ± 4.5% higher (P < 0.05 for both) than baseline, respectively. The rate of torque development at 50 and 100 ms, but not at 200 and 300 ms, increased (P < 0.05) over the intervention period. Six weeks of single‐set resistance exercise to failure results in improvements in insulin sensitivity and increases in muscle size and strength in young overweight men.
“No temptation has overtaken you except what is common to mankind. And God is faithful; he will not let you be tempted beyond what you can bear. But when you are tempted, he will also provide a way out so that you can endure it.”