All about Obesity -By Dr Srikant Sharma
September is childhood obesity awareness month and to commemorate it Dr Srikant Sharma has written about all the salient features embracing Obesity.
Obesity is a disease that adversely affects mortality, morbidity, and quality of life (QOL), as a result of its associated complications, like cardiometabolic, mechanical and lifestyle based. The health risks include diabetes, cardiovascular disease (CVD), hypertension, dyslipidemia, sleep apnea, musculoskeletal disease, infertility, and dementia. Moderate weight loss (5-10%) has been associated with improvements in these obesity-related comorbidities.
Obesity has assumed an Epidemic Proportion-
- Worldwide obesity has nearly tripled since 1975.
- Most of the world's population live in countries where overweight and obesity kills more people than underweight.
- 41 million children under the age of 5 were overweight or obese in 2016.
- Over 340 million children and adolescents aged 5-19 were overweight or obese in 2016.
- n 2016, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 650 million were obese.
- 39% of adults aged >18 years were overweight and 13% were obese.
Worldwide, the highest percentage of obese seen in Cook Islands of Australia, followed by Middle Eastern countries (like Qatar, Kuwait) and developed countries like United States of America, Australia, Canada, and New Zealand. Least in Japan.
In India, 11.0% of men and 15.0% of women are obese.
The state of Punjab has a maximum percentage of obese, female being 30%, and male being 22% of general population.
World Health Organization (WHO) defines obesity as body mass index (BMI) greater than or equal to 30kg/m2. BMI is calculated by dividing the body weight in kilograms(kg) by the square of the height in meters (m).
However, not only the total body fat matters but also the pattern of fat distribution is important. Excess visceral fat in the abdomen, also known as central “apple shape” obesity, (has a stronger association with CVD, insulin resistance and type 2 diabetes).“Pear-shaped” obesity where a fat deposition is mainly around the hips and buttocks. This distribution is reflected in Waist: Hip ratio (WHR). Waist circumference (WC) measurement is also a prognostic marker for obese. Neck circumference enlargement is also a risk factor for obstructive sleep apnea and metabolic syndrome.
WHO classification of obesity by BMI, Waist circumference and associated disease risk.
|Disease Risk (Relative to normal Waist Circumference|
|Men ≤40 inches (≤ 102 cm) Women|
≤ 35 inches (≤ 88 cm)
|>40 in (>102 cm)|
>35 in (>88 cm)
|≥ 40||III||Extremely high||Extremely high|
Indians are at more risk for developing obesity-related comorbidities at lower levels of body mass index and waist circumference. (cardiovascular risk factors and type 2 diabetes).
Indians have a greater total, truncal, subcutaneous and intra-abdominal adipose tissues compared to white Caucasian.
Indian men more than 90 centimeters and women more than 80 centimeters of waist circumference seek medical help so that obesity-related morbidities could be investigated and managed.
Hence in India, the patients are categorized as per BMI as underweight (<18.5 kg/m2), normal or lean (18.5–22.9 kg/m2), overweight (23.0 –24.9 kg/m2) and obese (≥25 kg/m2); based on the revised consensus guidelines for India.
Obesity is generally caused by physical inactivity rather than consuming more calories, for example, spending lots of time sitting down at desks, on sofas, watching TV, using lift rather than stairs, or in the car; children playing indoor games more than outdoor, use of mobile and a computer at peak.
Obesity is an increasingly common problem because of our lifestyle which involves eating excessive amounts of high-calorie food and particularly those which are fatty and sugary. Processed foods and some high energy foods are cheaper than fruits/vegetables. Fast food meals have tripled it's frequency, leading to quadrupling risk of obesity. The excess energy is stored by the body as fat.
Gastrointestinal hormones changes: Ghrelin secreted by stomach and duodenum is an orexigenic hormone (and decrease Ghrelin level results in satiety). GLP1 (glucagon-like peptide 1), PYY and GIP(glucose-dependent insulinotropic polypeptide) are also insulinotropic hormones. Whereas, the obestatin hormone decreases appetite by slowing the gastric emptying process and blocking the ghrelin action. Ghrelin in obese subjects may be a response to hyperinsulinemia.
Obesity is also a finding in many single gene disorders such as Prader Willi syndrome (abnormality of proximal arm of chromosome 15 with an associated characteristic of obesity, hypotonia, mental retardation, hypogonadotropic hypogonadism, short stature, small hands, and feet.) etc.
Epigenetic risk factors for obesity are passed on generationally. Epigenetics most often denotes changes that affect gene activity and expression and may result from external or environmental factors.
Growing evidence points to short sleep duration and poor sleep quality as a new risk factor for the development of obesity. Sleep loss has been shown to result in metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, increased evening concentration of cortisol, increased level of ghrelin, decrease the level of leptin, and hence increased hunger and appetite. In adults, a significant association between short sleep (less than 6 hours per night) and increased obesity has been established. Leptin and ghrelin are peripheral signals directly interacting with the arcuate nucleus of the hypothalamus, and ultimately modulating the orexin system activity to decrease and increase food intake, respectively. Their secretion is also modulated by the autonomic nervous system activity. A shift of the sympathovagal balance to higher sympathetic activity has been observed in studies of sleep deprivation. Noradrenergic activation of Beta-3 receptors on adipocytes would inhibit leptin production, predisposing to obesity. Decreased body temperature has been shown in conditions of prolonged total sleep deprivation, may leading to decrease metabolism and increase weight.
Gut Flora has been shown to differ between lean and obese humans. There is an indication that gut flora in obese and lean individuals can affect the metabolic potential. This alteration of the metabolic potential is believed to confirm a greater capacity to harvest energy contributing to obesity. Use of antibiotics among children has also been associated with obesity later in life, due to a change in the gut microbiome. For obesity prevention, treatment is targeted through the consumption of probiotic( live bacteria), prebiotic (nondigestible or limited digestible food constituents such as oligosaccharides)or both. Consumption of high fat, high sugar diet consistently led to a decrease in Bacteroides and increase Firmicutes, which is a composition of an obese individual. These results emphasize the importance of diet on microbiota composition. There is no relationship between the metabolism, liver, immune system, and gut microbiota.
Increased alcohol consumption and decreased rate of smoking may also increase weight. Giving up smoking induces a fall in energy expenditure and leads to an average weight gain of 2.5 kg in males and 3.5 kg in females. Nevertheless, the risk of smoking is so substantial that a rise in weight of 11 kg would be required to negate the benefit of giving up smoking 20 cigarettes per day.
Environmental pollution also interferes with Lipid metabolism causing increased weight.
Environmental pollutant and chemicals disrupt the development of the endocrine system, and that effects of exposure during development may lead to obesity.
Obesity also maybe because of decreased variability in ambient temperature.
Pregnancy at a later age may cause increased susceptibility for the obese child.
Assertive positive mating is a mating process in which, individuals with similar phenotype meet with one another more frequently, by choice, that would be expected, under random meeting pattern. Charles Darwin popularised the term “natural selection” which is a natural unintentional selection of similar phenotypes. Similar(obese) phenotypes of body size mate each other, can increase genetic predisposition of obesity within the family. Leading to increase the concentration of obesity risk factors.
Vitamin D deficiency is related to diseases associated with obesity. The relationship between these conditions is not well understood.
An association between viruses and obesity has been found in humans and several different animal species also, but it is yet to be determined.
● Secondary causes of obesity include Polycystic ovarian syndrome, hypothyroidism, Cushing syndrome, hypothalamic diseases, and drug-induced (insulin, sulphonylurea, steroid, mood stabilizers, antidepressant, antiepileptic etc ).
MORBIDITIES RELATED TO OBESITY: BMI of 30 to 35kg/m2 reduces life expectancy by 2 to 4 years, while severe obesity reduces life expectancy by 10 years. For individuals aged between 30 and 42 years, the risk of death increases by 1% for each 0.5 KG weight rise. For individuals between the ages of 50 and 62, this figure becomes 2% for each 0.5 KG weight rise.
Obesity is associated with impaired glucose tolerance or type 2 diabetes mellitus due to insulin resistance. In the Framingham study, the relative risk of hypertension in overweight men and women were 1.46 and 1.75 respectively, after adjusting for age. In the Asian Pacific Cohort Collaboration study in which more than 300,000 participants were followed, there was a 9 percent increase in events of ischaemic heart disease for a unit change in BMI. Dyslipidaemia, manifested by reduced high-density lipoprotein (HDL) and increased triglycerides. Very low-density lipoprotein (VLDL) clearance in plasma is dependent on the rate of hepatic synthesis and catabolism by lipoprotein lipase, an enzyme which is also involved in the formation of HDL. In obesity, insulin resistance is associated with increased hepatic synthesis of VLDL and impaired lipoprotein lipase. The risk of hemorrhagic and ischemic stroke in relation to obesity is increased in men. The mechanism linking obesity and asthma includes airway hyper-responsiveness, decreased functional and tidal volumes, chronic inflammation driven by increased inflammatory cytokines and chemokines, adipocytes derived factor leptin, adiponectin, and plasminogen activator inhibitor. According to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP: ATP III), the metabolic syndrome is defined when an individual has any 3 of the following 5 features: (i) waist circumference above 40 inches for men and >35 inches for women, (ii) Triglycerides above 150mg/dl, (iii) HDL cholesterol below 40mg/dl for men and 50mg/dl for women, (iv) Blood pressure above 130/85 mmHg, (v) Fasting glucose above 100mg/dl.
Obstructive sleep apnea, in which breathing is repeatedly interrupted during sleep because the tissues in the throat fail to keep the airway open. Snoring is a primary symptom of sleep apnea, and more than five apnea events per hour can lead to Chronic daytime sleepiness, Difficulty concentrating, Learning and memory difficulties, Falling asleep while working or driving, Depression, and Cardiovascular disease. Obesity hypoventilation syndrome (OHS) is a condition in which an inability to breathe deeply enough and quickly enough results in a low level of oxygen and a high level of carbon dioxide in the blood. OHS was historically known as the Pickwickian syndrome. Polycystic ovary syndrome (PCOS), characterized by anovulation, hyperandrogenism and a polycystic ovary, is associated with obesity as well as insulin resistance. Men, abdominal obesity has been associated with impotence and infertility.
Obese females, for example, were found to be less likely to complete school, had a 20% less chance of getting married, earned less and had more household poverty in comparison to females that were not overweight. In one study involving psychiatric evaluation of 294 patients before bariatric surgery, the prevalence rates were as follows: somatization (29.3%), phobia (18%), hypochondriasis (18%) and obsessive-compulsive disorders 13.6%.
Follow up of these patients after surgery showed that these psychopathologies had been reduced significantly.
According to the National Cancer Institute, obesity is associated with a higher risk of the following types of cancer: Breast (in postmenopausal women), Colon and rectum, Endometrium, Esophagus, Gallbladder, Kidney, pancreas, Thyroid. The possible reasons for this have been suggested, including Fat cells produce high amounts of estrogen, which may promote certain cancers. Fat cells produce hormones called adipokines, which may stimulate cell growth. Obese people often have high levels of insulin and insulin-like growth factor, which may also promote some kinds of cancer. Obese people often have chronic low- level inflammation, which may raise cancer risk.
Other Complications of Obesity, fatty liver disease, which can progress to inflammation and scarring of liver tissue. Nonalcoholic fatty liver disease (NAFLD)is present in 57 % of overweight individuals, but in 98% of obese patients, in contrast to 10 to 30 % of adults in the general population.
Gastro-esophageal reflux disease, Osteoarthritis (knee), Periodontitis, Reduced physical mobility, Skin problems, including inflammation and infection in skin folds (such as the armpits and the underside of the breasts or belly), Acanthosis nigricans, eruptive xanthomas, Hidradenitis suppurativa, and psoriasis are other diseases associated with obesity.
Surgical and post-surgical risks, including wound infection, deep vein thrombosis, pulmonary embolism, and postoperative pneumonia.
Overweight in adolescent are also more susceptible than their Leaner peer to hypertension, type 2 diabetes, dyslipidemia, lung problems (asthma, obstructive sleep apnea), Orthopaedic problems(venue varum, slipped capital femoral epiphysis) and nonalcoholic, steatohepatitis. Obese adolescents may also suffer from depression and low self- esteem.
In obese individuals, there is the considerable health benefit from a moderate weight reduction. A 10 KG loss in weight will lead to more than 20% fall in total deaths, more than 30% fall in diabetes-related deaths, and more than 40% fall in obesity-related cancer deaths. As well there is a fall of 10 mm of mercury systolic BP and 20 mm mercury diastolic BP. Fasting blood sugar also falls by 50%. Total cholesterol also decreases by 10%, LDL cholesterol by 15%, triglyceride by 30% and increase in HDL cholesterol by 8%.
An intervention of treatment may be suggested for obese children of minimum <3 years age.
An average physically active man requires 2,500 calories and woman requires 2000 calories per day. Lose weight at a safe and sustainable rate of 0.5 to 1kg per week is advised. This means calorie counts allowance is decreased up to 1900/day for men and 1400/day for women. This 600kcal decrease per day can be achieved by decrease food intake of 300 kcal, and by an increase, exercise to burn 300 kcal. Setting an initial weight loss goal of 8-10 percent over six month is a realistic target.
The best way to achieve this is to swap unhealthy and high energy food choices- such as fast food, processed food, refined carbohydrates and sugary drinks (including alcohol).
The United States Department of Agriculture dietary guidelines which focus on Health Promotion and risk reduction include maintaining a diet rich in whole grains, fruits, vegetables, and dietary fibers. Limiting sodium intake to less than 2.3 gram per day, consuming 3 cups of milk per day, limiting cholesterol intake to less than 300 milligrams per day, and keeping total fat intake at 20 to 35 percent of total calories, and saturated fat intake at less than 10 % of daily calories.
The Institute of Medicine recommends that 45 to 65% of calories should come from carbohydrates, 20-35 percent from fat and 10-35% from protein. The guideline also recommends daily fiber intake of 38 g (men) and 25 g ( women) for persons over 50 years of age and 30 g ( men) and 21 g (women) for those under age 50.
Use of meal replacements in the diet concept has been shown to result in 7 to 8% weight loss. Numerous randomized trials comparing diets of different macronutrients composition (e.g., low carbohydrate, low fat, mediterian diet) have shown that weight loss depends primarily on reduction of total caloric intake and adherence to the prescribed diet, not the specific proportions of carbohydrate, fat, and protein in the diet.
Another dietary approach to consider is based on concept of energy density, which refers to the number of calories of a food contains per unit of weight. Adding water or fiber to a food decreases its energy density by increasing weight without affecting calorie contents. Foods with low energy density include soups, fruits, vegetables, oatmeal, and lean meats. Dry foods and high-fat foods such as pretzels, cheese, egg yolk, potato chips, and red meat have a high energy density. Diets containing low energy dense foods have been shown to control hunger and thus to results in a decreased caloric intake and weight loss.
Very low-calorie diet ( VLCD) is prescribed as a form of aggressive dietary therapy. The primary purpose of vlcd is to promote a rapid and significant short-term weight loss over 3 to 6 months period. The proprietary formulas designed for this purpose typically supply 800 kcal, 50 to 80 gram of protein, and hundred percent of the recommended daily intake of vitamins and minerals. This is done for the individual whose BMI is more than 30, and have failed at more conservative approaches to weight loss therapy and have medical conditions that would be immediately improved with rapid weight loss.
The ketogenic diet can be a useful tool to treat obesity, with the supervision of a physician. A ketogenic diet with high fat, appropriate proteins and with low carbohydrate may help to control hunger and may increase fat oxidative metabolism, and therefore reduce body weight. Attention should be paid to the patient’s renal function, and to the transition phase from a ketogenic diet to a normal diet that should be gradual and well controlled. The duration of a ketogenic diet may range from a minimum of 2–3 weeks to a maximum of many months (6–12 months). Since the concentration of Ketone bodies never rises above 8 moles per liter, the risk of acidosis is virtually non-existence, in subjects with normal insulin function. European studies demonstrated that an increase in protein content and reduction in carbohydrates lead to better maintenance of weight loss. But Noto and colleagues
suggested a possible harmful effect of low Carbohydrate and high protein diet, i.e., an increase in all-cause mortality risk while there was no effect on CVD mortality. A long-term ketogenic diet ( 22 weeks) caused dyslipidemia, a proinflammatory state, sign of hepatosteatosis, glucose intolerance and reduction in beta and alpha cell mass in mice. Long-term children using these diet may lead to the progressive reduction in bone minerals.
Ephedrine-containing dietary supplements had convincing evidence of the reduction in body weight. Food supplements like guar gum, chromium, Chitosan are a good source for weight reduction.
PRECAUTION: The risk for gallstone formation increases exponentially at rates of weight loss more than 1.5 kg per week. Prophylaxis against gallstone formation with ursodeoxycholic acid 600 mg per day is effective in reducing this risk. Starvation diets are potentially dangerous due to a risk of sudden death from heart disease, exacerbated by the profound loss in muscle mass, and development of arrhythmias secondary to elevated free
fatty acids and deranged electrolytes. The composition of diet should ensure a minimum of 50 g of protein each day for a man and 40 g of protein for women to minimize muscle degradation. Energy content intake should be a minimum of 500 kcal daily, carbohydrates intake being minimum of 100 grams(so that ketosis is prevented).
FOOD TO BE AVOIDED
01 Sweets, cakes, pastries, chocolates, and high-calorie desserts.
02 Aerated beverages, sweetened fruit juices, and alcohol.
03 Nuts like peanuts, almonds, walnuts, etc.,
04 Red meat and organ meats like liver, kidney, and brain.
05 Cream, butter, desi ghee, hydrogenated vegetable oil, and coconut oil.
06 Fried food like samosa, kachori, dosa, puri, paratha etc.
FOOD TO BE TAKEN IN LIMITED AMOUNTS
01 Sugar, jaggery, jam, and honey
02 Root vegetables like potato, sweet potato, colocasia (arbi) and yam (jimikand)
03 Fruits like banana, mango, grapes, chikoo, apricot (dry), dates, black currants, and raisins.
04 Salt to be limited to 4 gms/day
( 3/4 teaspoon/day)
05 Use soyabean oil along with sunflower oil or corn oil or canola oil for cooking Rich gravies and oil-based salad dressings pickle, papad, chutney, etc. that are made in oil.
FOOD TO BE TAKEN LIBERALLY
01 Clear soups, plain soda and lemon juice (without sugar/salt)
02 Salads without oil-based dressings
03 Green leafy vegetables such as mustard leaves (Sarson ka saag), radish leaves, spinach, and bathua leaves and other vegetables like gourds (Ghia/lauki, prewar, hacienda, kinda)
04 Fruits like muskmelon (kharbooja), watermelon (taboo), papaya, sweet lime (mausambi), figs and guava.
List of Low-Calorie Snacks
01 Fresh fruits
02 Salads without oil-based dressings
03 Sandwiches made with low-fat drained curd with chopped fruits or vegetables.
04 Suji/daliya/upma with less fat and lots of chopped vegetables.
05 Steamed snacks such as idli or dhokla.
06 Roasted snacks like roasted gram (chana), murmur, etc.
List of Low-Calorie Desserts
01 Fresh fruit sundae-low fat frozen milk or frozen curd topped with unsweetened chopped fresh fruits.
02 Boiled fruit with a dash of cinnamon, garnished with a strawberry or mint leaf and fruit placed under the heater for 5-10 minutes.
03 Custard, kheer, ice cream (out of the milk and sugar saved from the prescribed diet) and served with chopped fresh fruits.
04 Cold or hot fruit compote (cook fruits such as apples, peaches, and berries in a small amount of water until tender but still crisp and flavor with cinnamon).
06 Fresh fruit salad with a combination of a variety of diced fresh fruits, tossed lightly with a bit of fruit/lime juice and sprinkled with ground nutmeg, cinnamon or crushed ginger.
BEHAVIORAL THERAPY: “TASTE MAKES WAIST.”
Greater weight loss is achieved using treatment in a group, than in individual consultations. Behavioral strategies include self-monitoring technique; weighing, measuring food and activity daily. To dampen dopaminergic appetite effect (motivational/reinforcement stimulus) use smaller plates with colored boundaries, smaller bowls, use buffet system of eating, eat while standing, avoid eating together, avoid taking appetizers. Avoid eating in
front of the television, or in the car. Also, fast eating should be avoided. Eating at a restaurant with family, exert less control over food choices than do at home. Hence avoid. Stress management, Social support, problem-solving and cognitive restructuring, to help patients develop more positive and realistic thoughts about themselves. Gradual, long-term weight changes will be more successful than multiple, frequent changes.
EXERCISE: It is recommended that adults should do at least 150 minutes of moderate- intensity activity a week – for example, five 30-minute bouts a week ( additional weight loss of 1kg per month). Actually, health gain is achieved at the modest level of exercise, as long as these are maintained for long periods. This will regulate the appetite/satiety center in the hypothalamus, so that weight gain is prevented. Moderate-intensity activity is any activity that increases your heart and breathing rate, such as brisk walking, cycling, swimming, and dancing.
Alternatively, one should do 75 minutes of vigorous-intensity activity a week, or a combination of moderate and vigorous activity. During vigorous activity, breathing is hard, heartbeats are rapid, and may be unable to hold a conversation. Examples include: running, most competitive sports, circuit training etc.
PHARMACOTHERAPY: Pharmacotherapy for Indian should be initiated for BMI more than 27 or a BMI above 25 with comorbidity. The cut off for waist circumference for initiating pharmacotherapy measurement is 10 cm more than the upper limit of gender-specific normal values for adult Indians.
Medications for obesity may be of two major types: Anorexiants and Gastrointestinal fat blocker(orlistat). Anorexiants target 3 monoamines receptors in the hypothalamus: noradrenergic, serotonergic and dopaminergic receptors.
Lorcaserin is a selective 5-HT2C receptor agonist, activating pro-opiomelanocortin, decreases food intake. Bupropion and naltrexone-a dopamine and norepinephrine reuptake inhibitor and a
opioid receptor antagonist, are combined to dampen the motivation/reinforcement that food brings (dopamine effect) and the pleasure/palatability of eating (opioid effect).
Sibutramine is the drug of choice unless contraindicated. Sibutramine is a serotonin and noradrenaline reuptake inhibitor, which induces weight loss by enhancing both satiety and energy expenditure. The subcutaneous /visceral fat ratio was found to increase significantly under sibutramine treatment, indicating that relatively more visceral fat then subcutaneous fat is lost. Sibutramine is a well-tolerated drug with a good safety profile. Orlistat should be used as a second line drug because of its frequent and disturbing adverse effects, lesser ability to induce weight loss, and higher cost. Orlistat works by preventing absorption of fat by one third. The undigested fat is passed out with your feces. This will help in preventing weight gain but won't necessarily cause weight loss. A balanced diet and exercise programme should be started before beginning treatment with orlistat, and one should continue this programme during treatment and after one stops taking orlistat.
Phentermine/Topiramate, clinical and statistical dose-dependent improvements were seen in selected cardiovascular and metabolic outcome measurements that were related to weight loss.
The class sympathomimetic adrenergic agents (benzphetamine, phenmetrazine, diethylpropion, Phentermine) function by stimulating norepinephrine release or by blocking its reuptake. These drugs increase satiety and decrease hungering hypothalamus.
Metformin and exenatide can be used in special clinical scenarios as add on therapy. Liraglutide and SGLT2(Sodium Glucose Transport 2) Receptor blockers used in diabetes also decreases weight.
SURGERY: Surgical therapy provides approximately 25 to 75 kg of weight loss after 2 to 4 years. Bariatric surgery, is used to treat people who are having BMI >40 or 35 with comorbid conditions.
Surgery done are: Vertical banded gastroplasty roux-en-Y gastric bypass, Laparoscopic adjustable gastric banding, Sleeve gastrectomy, Biliopancreatic diversion and duodenal switch.The long-term side effects of bariatric surgery are vitamin B12 deficiency, incisional hernia, a possible need for Repeat surgery, gastritis, gallbladder disease, and malabsorption.
What are the predictors of diabetes remission after bariatric surgery: Remission of type 2 diabetes was seen in patients with C peptide level more than equal to 3, duration of diabetes type 2 less than 5 years, BMI more than 40, and in patients who were not on insulin preoperatively.
The effectiveness of bariatric surgery: remission of type 2 diabetes was achieved in 64.7 % of the patients. Bariatric surgery is not effective in patients with latent autoimmune diabetes in adult (LADA). Nonalcoholic fatty liver (NAFLD) and nonalcoholic steatohepatitis (NASH) also after bariatric surgery showed significant improvement.
Hence most nutritional and metabolic diseases can be prevented by awareness, lifestyle modification, persistent moderate exercise, good adequate sleep, healthy balanced dietary habits, cessation of smoking, alcohol and unnecessary drugs (including antibiotics), maintaining environmental hygiene, and last but not least positive thinking.