Wednesday, January 12, 2022

Methylfolate versus folic acid for MTHFR polymorphisms

Methylfolate is a very expensive pharma-patented ingredient in a supplemental form that is not generally required by people. Even those with genetic polymorphisms can convert folic acid to methylfolate, though less efficiently due to their genetic differences, and still benefit from folic acid supplementation. 

Since a main concern with MTHFR polymorphisms is the production of less active forms of the MTHFR enzyme due to genetically driven variations in its composition (such as the substitution of alanine with valine), the polymorphisms are most noted for increasing the need for folates (of any form, rather than a particular form). This is because higher quantities of these weaker MTHFR enzymes are needed to compensate for their lower activity levels and methylfolate is a cofactor in the enzyme production, so more dietary folic acid or folates are also needed. 

The medical literature on folic acid has been misrepresented on the Internet to falsely imply that folic acid will not work in individuals with MTHFR polymorphisms. But even people with the most severe polymorphisms can still convert folic acid to methylfolate and eliminate signs of folate insufficiency, particularly high homocysteine levels, according to clinical trials. Here is one example where increasing folic acid intake for individuals with these polymorphisms resolved the problem of high homocysteine levels caused by their weaker MTHFR enzymes:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601299

The folic acid was converted to methylfolate and utilized by these study subjects to make more of these enzymes, which is needed to resolve the health concerns over high homocysteine levels, despite the subjects having polymorphisms that cause weaker versions of the enzymes to be produced. 

The CDC is even more direct, reporting, “You might have read or heard that folic acid is not safe if you have one or two copies of the MTHFR C677T variant. This is not true. Even if you have one or two copies of the MTHFR C677T variant, your body can safely and effectively process the different types of folate, including folic acid.” 

https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.htm

So the widespread myth that people with MTHFR polymorphisms cannot process folic acid has been disproven in authoritative research showing that they actually need to increase folic acid intake (or methylfolate intake) to produce enough of the weaker enzymes to resolve the health concerns, including elevated homocysteine levels and potential neural tube defects in their offspring. 

Monday, November 22, 2021

Plant-based diets, pescatarian diets and COVID-19 severity

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219480/pdf/bmjnph-2021-000272.pdf 

After adjusting for important confounders, participants who reported following ‘plant-based diets’ and ‘plant-based diets or pescatarian diets’ had 73% (OR 0.27, 95% CI 0.10 to 0.81) and 59% (OR 0.41, 95% CI 0.17 to 0.99) lower odds of moderate-to-severe COVID-19 severity, respectively, compared with participants who did not follow these diets. 

Compared with participants who reported following ‘plant-based diets’, those who reported following ‘low carbohydrate, high protein diets’ had greater odds of moderate-to-severe COVID-19 (OR 3.86, 95% CI 1.13 to 13.24).


Neil E. Levin, CCN, DANLA


Thursday, September 16, 2021

Macrobiotic Diet lecture presented in 1996

Originally presented on 1/24/1996 In Chicago for Nutrition for Optimal Health Association, a non-profit educational charity. I recovered this from a floppy drive today. This was one of my early lectures. As the buyer for the leading Midwestern retailer of macrobiotic foods in the late 1980s, I was the person to whom the Kushi Institute referred people with questions or seeking dietary staples (like sea vegetables, soba pasta, condiments, etc.) in that era. 

NOHA CLASS on The MACROBIOTIC DIET

JAN. 24, 1996

Presented by NEIL EDWARD LEVIN, CCN

           Macrobiotics is the group of diets which reflect balance between natural forces to promote health and normal body-mind function. Using the unifying principle of yin and yang to describe the expansive or contractive properties of foods, one can correct the diet for any number of imbalances. Such a balanced diet is shown to reduce and reverse chronic diseases such as cancer and food allergies, while reducing social problems such as crime and violence.     

       Adhering to a macrobiotic diet is an environmental act. One chooses to eat foods appropriate for one's climate and past imbalances. Organically-grown wholesome foods are preferred. Locally grown foods eaten in season are preferred. Animal products are a rarity, including mostly seafood.     

      All traditional diets are macrobiotic with a small "m". The so-called Standard Macrobiotic Diet is a remnant of traditional Japanese diet. It is high in grains, vegetables from sea and land, some non-stimulant spices, and beans.

      The new Food Pyramid of the Mediterranean Diet is fairly similar to the Standard Macrobiotic Diet. Both rely on grains as the main staple, vegetables as the main side dish, and beans, animal products and fruits used sparingly. Olive oil vs. sesame oil. Brown rice vs. wholegrains and pasta. 

      Yin foods are expansive, leafy, and watery. They tend to be high in sugars and potassium, low in calcium. They are fairly perishable. They tend to be eaten fresh (in season), dried, or pickled in sea salt. Salads and fruits are yin. Yin foods tend to be acidic. 

      Yang foods are contractive, compact, drier. They tend to be high in contractive minerals like calcium, low in expansive ones like magnesium. They have a longer shelf life than yin foods. They can travel farther and still be fresh and wholesome. Salt is very yang, but sea salt is more balanced, due to some yin minerals comprising up to 5% of the total weight. Gray sea salt has a lot of magnesium, and can possibly be too strong for some, leading to constricting effects like kidney stones. Many root vegetables and small grains and beans are yang. Yang foods tend to be alkaline.

      Of course, foods are rarely all yin or yang. These are relative terms. 

      We can select foods for their properties to compensate for seasonal and daily changes. Breakfast should be somewhat yin, with more water used to cook breakfast grains. This will help us to expand our energy. Lunch should be similar. Supper should be larger, more yang, and cooked more, as befits the contractive energy of the day as it is condensing inward. 

      Grains, esp. brown rice, should be eaten daily, preferably at nearly every meal. White rice is never used, as it is far inferior to the wholegrain brown rice. Smaller grains are more yang than larger. Short or medium grain rices are preferred for daily use. Long grain and basmati for occasional warm weather use only. Rice is high in every B vitamin plus a host of other nutritional factors. 

      This emphasis on grains is based on history, biology and anatomy. The 20 molars in an adult mouth are named for the Latin word for "millstone". They are used to grind plant foods to a pulp. The eight incisors are for cutting, and the four canine teeth are for ripping. They are nothing like a cat or similar carnivore's teeth, which consist largely of large canine-type teeth. Our digestive tract is similar to plant-eaters rather than like predators, who eat a low fiber diet. These factors indicate the ideal ratio of 7 to 1 for plant to animal foods, or carbohydrates to protein. This is shown as 5 parts grains and other fibrous foods, 2 parts vegetables and 1 part beans or animal food. Meat is suited to cold climates, and is associated with many diseases such as cancer. Traditional cultures in temperate zones use meat sparingly. As a culture shuns their traditional diet for the modern, processed foods, the rate of degenerative diseases increases greatly.

      Grains have always been the historical dietary staple. The word "meal" means ground grains as well as general eating. In China, people used rice, millet, and buckwheat. In India: rice and wheat. In the Mideast: wheat and barley. In lower Africa: sorghum. In the Americas: corn. And in Northern Europe: wheat, barley, rye, and oats. Grains provide steady fuel. Brown rice releases 2 kilocalories of glucose per minute into our bloodstream versus over 30 for a candy bar. This is due to the starches, or complex carbohydrates, in the grains. For athletes, the amount of glycogen reserves doubles using a starchy diet versus a high-protein one. Americans use an average of about 2,000 pounds of grain per year apiece for our animal-based diet. Plant food-based cultures get by very well on 400 pounds per person. 

      Food is nutrition: energy and components of our bodies. Food choices are the largest controllable variable to create healthy body cells. Eating one extreme will create a desire for the opposite, to create a rough balance. This balance of extremes is not very healthy. The classic example is of meat eaters craving alcohol, sweets, potatoes, and other very yin foods. This leads to an excess of fats, protein, carbohydrates, and water.

Poor diet often includes refined table salt, white sugar, animal protein, saturated fats, and poor-quality water. Mixing meat + dairy + sugar + cold drinks will lead to sticky deposits and kidney stones.

      These principles often lead to natural remedies. Kidney stones represent excess yang energy. Warm ginger compresses over the painful area will expand the ducts and allow the stone to pass more easily. Hot green tea will help internally. For a fever, one can use a fresh green leaf to the forehead or a tofu plaster. These will more reliably ease a fever within minutes than ice, which is too cold and may trap the excess in the body as the fever tries to force it out. 

      Dietary diversity is also important. We must try to eat a variety of foods to enlarge our supply of nutrients. Other general factors apply:

Men can tolerate more meat than women. Women can tolerate more salads and sweets. Babies, small and compact are more yang than adults, which creates a need for soft, sweet, low salt yin foods to allow proper growth. However, if children eat lots of sugar, they will tend to be hyperactive, emotional, and cry easily. Mother's milk is very yin, the perfect small baby's food. Milk is made even more yin when it contains antibiotics and bovine growth hormone. 

      Meat is yang and leads to aggressive tendencies. It is appropriate for nomadic, isolated people. Grains lead to mental conditions of cooperation, community, support, and family life. Look at our Big Mac diet versus the Japanese rice-based diet, and consider the degree of community cooperation in each culture. Tomatoes and other nightshade plants are very yin, and contain nicotine-like substances which are addictive and depress the mind. 

      The Standard Macrobiotic Diet consists mostly of cooked foods. The food enzymes are largely provided by fermented foods such as miso, naturally brewed tamaris, tempeh, umeboshi plums, etc. The balance of foods and the amount of cooking depends on the coolness of the climate. 

      Like all substances, food has a vibrational energy. As in homeopathy, you can activate the energy in a food by cooking, dilute the foods by chewing with saliva to increase the power of the food, and thus liberate the nourishing, healing powers of our diet. 

      Yang energies activate the nerves, while yin dulls the sensations. Grains are high in serotonin enhancers, leading to calmness and thoughtful behavior. Animal foods activate acetylcholine, which leads to impulsive behavior linked to low blood sugar and low serotonin levels. Testosterone, being yang, is increased by animal foods. An explosive discharge of yang energy is likely to lead to violence. Refined sugar, in a Yale U. study, dramatically increases adrenaline levels. When children were given the amount of sugar in two cupcakes, their adrenaline levels increased tenfold; leading to rapid heartbeat, shallow/quick breathing, nervousness, and aggressive/hyperactive/erratic behavior. Excess sugar can deplete minerals, leaving white spots on nails, low zinc, manganese, magnesium, sodium, chromium, vanadium, and the like. 

      These same forces influence depression. Late in the day and in the year the air is contractive, yang. Depression is linked to hypoglycemia, produced by an imbalanced diet, esp. meat and animal foods. Yang accumulation in the pancreas inhibits secretion of glucagon, the yin hormone which increases blood glucose. The pancreas gets hard and tight. The more yang hormone insulin still secretes and reduces blood sugar, but the new imbalance lowers blood sugar to the point of craving. The yang, stimulating neurotransmitters are reduced, which can lead to depression. Short of its blood sugar for fuel, the higher brain functions decrease and alcohol and sugar cravings increase. 

      Schizophrenics usually have chronic low blood sugar, leading to cravings for refined sugar, alcohol, chocolate, and drugs. These yin substances expand the brain and nerve cells. These expanded cells are overly sensitive to yang stimuli, including dopamine. Chronic overstimulation makes one ignore external, more distant factors. In schizophrenics this leads to overload, loss of abstract thought, and the breakdown of the yang powers of concentration and thought coordination. A niacin deficiency is linked to some 10% of schizophrenic cases, and may be linked also to glucose tolerance factors. 

      High blood sugar is likewise linked to excess yin foods in the diet, so the pancreas releases more of the yang hormone insulin to rebalance. This also increases the stimulating, yang neurotransmitters to arouse motor activity. 

      Too many animal foods can lead to graying hair, baldness on the top of the head, being oversexed and short tempered, a tendency to brain hemorrhage, heart attacks, rheumatism, and arthritis. Cutting out the sugar in the diets of teen offenders reduced their violent episodes between 45 and 80%. Animal foods and excess dietary fats and calories are all linked to cancer. About 10-15% of our caloric intake should be healthy types of fats and oils, compared to 30-50% in our modern diet. Excess fat blocks the energy flow in the body. Plant foods tend to inhibit cancers. Soybean foods are specifically linked to low cancer rates. Miso eaters have much lower cancer rates than the control groups. 

      Some of the staple foods of the Standard Macrobiotic Diet include: 

*Brown Rice for the main grain, also appearing in rice milk, rice cakes, mochi cakes, amazake drink, and pastas. Brown rice should be organic, be rinsed until the water is clear, and can be pre-soaked for higher digestibility. It is normally cooked with at least 2 parts water for about an hour. As the rice cooks, the water drops below the surface. Do not stir the rice after this point or it will get very sticky. Poke down into it with a wooden spoon occasionally to check the water level. 

*Soy products, often fermented, including tofu, tempeh, miso, shoyu & tamari, and soy milks. 

*Sea vegetables, mostly cooked in soups, stews and bean dishes. These foods are extremely rich in minerals. For example, kelp has 150x the iodine of any land plant; while dulse has 200x the iron of beet greens, the richest land source. Other types are wakame for soups, stews and beans; hijiki and arame for beans and soups; nori for sushi rolls. 

*Soups and stews

*Beans, esp. small ones which are more yang and meat-like. Look for aduki, chickpeas, lentils, soy, peas, and kidney beans. Sea vegetables help us to digest the beans.

*Pickled foods to stimulate digestion, provide beneficial bacteria for the gut, and provide a source of lactic acid.

*Nuts and seeds can be used in moderation, best if from your climate/continent. This is the main oil source in the macrobiotic diet. Avoid tropical items.

*In season: fruits and land vegetables.

*Whole grain pastas. This is one of the few products using flour. Whole, unground grains are healthier than flours. Flours are stickier, more mucus-forming, more acidic, and harder to digest.

*Rolled and cracked cereals.

*Fish should be used at most 1-2 times a week.

*Sea salt and foods pickled with sea salt. For flavor and digestion. Do not overuse! Signs of overdose include:   fluid retention, thirst after meals, overeating, craving for fruits, sweets, and alcohol, and emotional tension. Signs of too little salt include:

weak muscle tone, poor circulation, and mental spaciness. 

*Condiments:     sesame salt, horseradishes, mustards, rice and cider vinegars, Ume plums.

*Fresh water and green teas. Grain beverages.

*Fermented dairy products like yogurt, kefir, etc.

      It is good to eat a variety within each of these food categories. Cooking methods include boiling, steaming, sautéing, frying, and pressure cooking. The heat intensity and cooking techniques affect the yin/yang energy in the food. 

      Organic foods are so important because the microorganisms in both the human gut and the soil aid digestion and assimilation of nutrients to either us or plants. Vitamin B-12 is made only by these types of bacteria. The traditional Japanese diet provides different, simpler intestinal microbes than average Americans (Western J of Med, 1974), and such simpler populations were associated with lower rates of bowel cancer (Cancer Research, 1975).

     Illness is a symptom of imbalance. Look for the lesson of how your energies are affecting that manifestation. Sickness becomes inevitable if our foods and actions are out of harmony with nature.

      If the skin is pale, you may be eating too much fruit. Bad skin indicates excess sugar. Gluten and grain allergies indicate an excess of dairy and sugar in the past. Diets high in meats, fats and sugar show increased rates of tooth decay and weakened bones.

Lotus root tea reduces mucus in the lungs. 

      Yang foods are salts, hard cheeses, eggs, and meat. Illnesses from excess yang foods include:   duodenal ulcer, hepatitis, appendicitis, jaundice, gout, liver cancer, and headache in the back of the head.

      Yin foods include most dairy, sweets, juices, alcohol, spices, coffee and tea.

Illnesses linked to excess yin include: colitis, hernia, diabetes, asthma, pleurisy, leukemia, meningitis, detached retina, varicose veins, gum disease, stomach ulcers, cystitis, frequent bloody noses, and headaches in the front of the head.

      More balanced foods include grains, beans, vegetables, seeds, nuts, and seasonal fruits. When one eats at the extremes there are other associated illnesses including:

arteriosclerosis, gallstones, arthritis, breast cysts and cancer, lung cancer, cataracts, and pneumonia.

      It is recommended to not eat for 3 hours before bedtime.

      Cancer is yin, expansive. Avoid overeating and indigestion by chewing foods to liquid. Avoid all fruit, animal fats, and greasy foods.

In studies, macrobiotic-type diets are very healthful:

 Lowering and stabilizing blood pressure (AmJ of Epidemology, 1974)

 Lowering blood cholesterol and triglycerides (NEJ of Med, 1975)(Atherosclerosis, 1982)

 Lowering cancer rate by 60% and death rate by 40% in Denmark during a blockade and shortage of animal and dairy foods (JAMA, 1920)

 Sea vegetables removed most of the strontium 90 from contaminated subjects (McGill University, 1964)

 Daily eaters of miso had 33% lower rates of stomach cancer (1981, Nat. Cancer Center of Japan)

 Mice fed naturally fermented soy sauce had a 26% lower rate of stomach cancer and a 75% drop in tumors (1991, U. of Wisconsin)

 Patients with pancreatic cancer. 24 on macrobiotic diet survived an average of 17.3 months vs. 6.0 months for matched controls. The one year survival rate was 54.2% vs. 10% for controls. (1984-85, Tulane U.)

 Macrobiotic Diet is a healthful way of eating (AmerMedAssn Family Medical Guide, 1987)

 A high fat diet is linked to higher breast, lung, and skin tumors in mice. (CancerResearch2)

 A 41 country study linked high intake of refined sugar with high breast cancer rates (BritJ of Cancer, 1976)

 Soy protein reduces serum cholesterol and triglycerides (JAMA, 1982)

 People who regularly eat cheese have a 50% greater risk of breast cancer than those who don't. With milk it's an 80% increase (Journal of the National Cancer Institute, 1986)

 A diet high in meat and animal products is linked to colon cancer    (NCI, 1974 in CANCER) (JAMA, 1920)  (Gut, 1969) (Journal of the NCI, 1975)

 Macrobiotic eaters versus the Framington Heart Study participants: the macro eaters had average cholesterol readings of 126 mg./dl. compared to 184 for the normal diet. Harvard study in the New England Journal of Medicine, 1975)

 Fermented soy sauce shows anti-tumor activity (Science News, 1991, U. of Wisc.)

  21 Macrobiotic eaters added 250 grams of beef a day to their diets for 4 weeks. Within 2 weeks their serum cholesterol levels were up an average of 19%. Harvard study in JAMA, 1981)

 Wakame and hijiki seaweeds, also shitake mushrooms lower serum cholesterol Atherosclerosis, 1972)

 A high sucrose diet (20% of daily caloric intake) linked to liver cancer Huntington Research Centre, Huntington, England, 1978)

 Diet should consist of Carbs (50-60% of caloric intake), with glucose, sucrose, and lactose restricted. People should eat natural foods with unrefined carbs. High levels of fats should be restricted. (Journal of the ADA, 1979)

 Shitake mushrooms showed almost complete regression of tumors (Cancer Research, 1970)

 Kombu given to mice with implanted sarcomas: 89-95% inhibited. Also good results with leukemia (Japan Journal of Experimental Med, 1974)

 Leukemia in chickens was reversed by feeding them whole grains and salt (Tokyo Red Cross Blood Center, 1972)

USDA recommends partial replacement of animal foods with cereals and legumes, esp. soy. (Am J of Clin Nutr, 1983)

 Tofu as a substitute for meats and dairy products is closer to the national dietary guidelines than beef, chicken, eggs, or cheese. It is also preferred by preschoolers in taste tests (Journal of the ADA, 1990)

 Men with AIDS put on macrobiotic diet stabilized, did better than other patients. (Boston U. School of Med in Lancet, 1985)

 Chewing thoroughly (saliva) inhibits HIV-1 infectivity (Journal of the American Dental Assn, 1988)

 

Wednesday, September 15, 2021

JAMA posted my comment yesterday on a study reviewing vitamin C and Zinc for Covid-19 patients

JAMA edited my comment and changed the final sentence (adding ‘or some other dose’, which doesn’t make sense), but the gist is there.  

Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial | Complementary and Alternative Medicine | JAMA Network Open | JAMA Network

My original submission:

It is unclear what dose of elemental zinc was used in this study from the text provided. Fifty mg of 'zinc gluconate' is described, but that is 50 mg of a compound that is only about 1/7 elemental zinc. PubChem lists the molecular weight of zinc gluconate at 455.7 and of elemental zinc at 65.4; so zinc gluconate contains about 14.35% elemental zinc (a maximum value since 'as is' measurements include impurities, including moisture). If 50 mg. of ‘zinc gluconate’ was used, as described in the text, it would represent only about 7 mg of actual zinc; not a "high dose" since it would be below the FDA's current (and recently lowered) Daily Value of 11 mg. 

If 50 mg of elemental zinc from a much larger amount of zinc gluconate (typically 350- 400 mg) was used, it should have been described more precisely as that to avoid any confusion. The amount of zinc used was either a low dose erroneously described as a high dose or the authors mistakenly used the compound name (zinc gluconate) in place of the element's (zinc) when describing the 50 mg amount. 

Either way, how the supplement was described in this paper leads inevitably to confusion. The amount of actual zinc should be clearly specified, but the authors did not do so; nor did they relate the amount of this mineral to its RDA, Daily Value, or Upper Limit as a relevant reference point. The implication from the description of a ‘high dose’ is that the amount of zinc was 50 mg, not the amount of zinc gluconate, and that the authors misstated the description of the supplement. But they just as plausibly mistook 50 mg of zinc gluconate for 50 mg of elemental zinc, and then inaccurately described both the supplement and the dosing. 

How did this pass peer review without catching this internal conflict of description that would be obvious to chemists who work with mineral compounds and understand how to appropriately label them by either compound or element? And exactly which dose of elemental zinc was used; 50 mg or 7 mg?


Thursday, July 08, 2021

 My half-hour presentation on Essential Oils will be aired on Wednesday, July 14th at 7pm Central time (6pm Mountain time)

https://www.eventbrite.com/e/choosing-essential-oils-understanding-labels-standards-tickets-161158512449

Thursday, June 10, 2021

Is There L-Glutamine in Pea Protein?

Reputable sources only list glutamic acid, a nonessential amino acid, in pea protein, which the body readily synthesizes and that readily converts into l-glutamine inside our bodies. Glutamine and glutamic acid typically comprise between 5% and 15% of dietary proteins, but we require so much of these two amino acids that most of our fairly large body stores are actually synthesized endogenously (internally). 

Glutamine is used to make glucosamine and is required by the immune system, for wound healing, for acid-base balance, for brain function, and for gluconeogenesis. Both amino acids are conditionally essential during pregnancy, lactation, and growth phases. 

Commercially produced MSG is related to, but not identical to, glutamine because it is a salt of glutamine; a glutamate, rather than an amino acid found in common proteins. Glutamate has been classified as an excitotoxin that can overexcite our nervous systems; but that is dependent on the brain lacking proper controls, such as can be provided by the essential nutrients magnesium and antioxidants. 

This study indicates that pea protein contains glutamic acid, not l-glutamine:  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245118/

Protein content and amino acid composition of commercially available plant-based protein isolates (nih.gov)

Friday, May 14, 2021

Lecithin extraction

All lecithin is chemically extracted from bulk oils. For organic lecithin (not available in all forms and grades and very expensive due to limited supply and manufacturing capacity) organic ethanol (alcohol) is the solvent. 

All lecithin extraction processes currently employ solvents, such as hexane, to extract the oils. Hexane extraction is the most common method used in the industry to produce lecithin due to its high oil recovery and lower production cost; also, lecithin is actually defined as hexane-soluble components. These solvents are commonly recovered during the extraction step of edible oil processing through distillation and evaporation. 

To remove the hexane from lecithin, the material is treated in a vacuum distillation process because hexane is volatile and vaporizes at a relatively low temperature. The hexane evaporated during the distillation is condensed and separated from water in a decanter. The recovered hexane is then reused in the extractor. 

The European Union standard for hexane in bulk oils is a maximum residue limit (MRL) of 1 mg/kg by weight. One study published in the Journal of Experimental and Clinical Toxicology reported that the detected mean amount of hexane residue in product samples tested was 0.56 mg/kg; only 56% of the allowable amount. The EFSA Journal published a 2017 safety review concluding that there was no safety concern; even for infants and children using lecithin for special medical purposes. 

https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2017.4742

https://openaccesspub.org/ject/article/622#ridm1841927052