Iron-Deficiency Anemia & Hearing Loss

Can Iron Deficiency Indicate Future Hearing Problems?

Researchers have recently discovered a possible link between iron-deficiency anemia and hearing loss—particularly those under the age of 45.
Conducted in Taiwan, the new research found that the rate of prior iron-deficiency anemia was 45% higher among those who experienced sudden sensorineural hearing loss than among controls (4.3% vs. 3.0%).  The correlation was more pronounced in those 44 years or younger. For those 60 years and older, there was no significant increase in the association between prior iron-deficiency anemia and sudden sensorineural hearing loss.
After analyzing the study’s data, Dr. Shih-Han Hung from Taipei Medical University Hospital said, “…I think having patients with hearing loss, whether sudden or not, checked for their iron status might be a reasonable recommendation.”
According to Dr. Hung, it is still unclear if complete correction of iron-deficiency anemia status would help directly avoid the development of hearing difficulties. However, early detection and management of both health issues will significantly benefit one’s quality of life.
Independent studies show that early acceptance of hearing difficulties and utilization of hearing devices can positively affect nearly every aspect of a person’s life as well as lessen their risk of developing other health concerns linked with untreated hearing loss, especially in children.

The association between iron deficiency anemia and hearing loss is explored in a recent study, published in JAMA Otolaryngology - Head & Neck Surgery. Could such a common blood condition impact our ability to hear?

Hearing loss and anemia appear to be linked, according to recent studies.

An estimated 15 percent of adults in the United States are affected by some degree of hearing loss.
Up to two thirds of adults over 65, and 80 percent of those over 85, have reduced hearing.
In the U.S. population, hearing loss is linked to poorer health, high blood pressure, smoking, diabetes, and hospitalization.
Because hearing loss can have a significant impact on an individual's well-being, and because the causes are not fully understood, research into novel risk factors is ongoing.
For instance, sudden sensorineural hearing loss (SNHL), during which an individual's hearing is reduced severely over a 72-hour period, was recently shown to be associated with iron deficiency anemia (IDA).
Researchers led by Kathleen M. Schieffer, from the Pennsylvania State University College of Medicine, set out to investigate IDA's relationship with hearing loss in more detail.

Iron deficiency anemia and hearing loss

IDA is a common condition that is caused by a lack of iron in the body, leading to a reduced number of red blood cells. Because red blood cells ferry oxygen around the body, IDA reduces the amount of oxygen available to tissues.
Worldwide, IDA affects hundreds of millions of people, including an estimated 5 million people in the U.S.
Because hearing loss impacts approximately 15 percent of U.S. individuals, and because IDA is generally easy to treat, any ties between the two conditions could be important.
The research team used data from deidentified electronic medical records from the Penn State Milton S. Hershey Medical Center in Hershey, PA. In total, data from 305,339 adults aged 21-90 was investigated, with 43 percent of the cohort being male, and with an average age of 50. By observing ferritin and hemoglobin levels, IDA was diagnosed retrospectively.
The team also gathered information regarding the patient's hearing. They looked separately at conductive hearing loss - due to problems with the bones of the inner ear, or SNHL - damage to the cochlea or nerve pathways passing from the inner ear to the brain, deafness, and unspecified hearing loss.
Once the data had been analyzed, the team found a relationship: SNHL and combined hearing loss (SNHL and conductive hearing loss in the same individual) were both significantly associated with IDA.
The authors conclude:

"An association exists between IDA in adults and hearing loss. The next steps are to better understand this correlation and whether promptly diagnosing and treating IDA may positively affect the overall health status of adults with hearing loss."

How does anemia influence hearing?

Why IDA might be linked to hearing loss is not yet fully understood, but there are a few potential pathways. For instance, blood supply to the inner ear via the labyrinthine artery is highly sensitive to ischemic damage (damage caused by reduced blood flow), which could certainly play a role.
Additionally, individuals with vascular disease are known to be more susceptible to sudden SNHL. Blood supply is, therefore, clearly an important factor in hearing loss.
Another potential mechanism involves myelin, a waxy substance that coats nerves and which is important for the efficient conduction of signals along nerve fibers. Reduced iron in the body causes the breakdown of lipid saturase and desaturase, both of which are important in energy production and, consequently, the production of myelin. If the myelin coating the auditory nerve is damaged, hearing could be reduced.
The next step for researchers will be to understand whether iron supplementation might positively affect hearing loss. If it can improve damaged hearing or reduce hearing loss, it could be a cost-effective way to minimize a highly prevalent and disruptive medical condition.
Learn how anemia might raise the risk of death for stroke patients.

Written by Tim Newman

Iron deficiency anemia is a frequently occurring clinical disorder. Despite the suggested association with hearing loss in the literature, cochlear sequelae of iron deficiency have yielded conflicting results in experimental studies. Auditory function was tested in iron-deficient and normal male Wistar albino rats using distortion product otoacoustic emissions and auditory brainstem response audiometry for the clarification of the opposing results in the literature. Hemoglobin, hematocrit, serum iron and albumin levels were monitored to verify iron deficiency. Although dramatic differences in weight gain and blood test parameters were noted, no significant change in auditory function due to iron deficiency was detected.

IMPORTANCE Vascular events play a big part in the development of sudden sensorineural hearing loss (SSNHL), but only those associated with sickle-cell anemia have been previously associated with SSNHL. This study demonstrates an association between SSNHL and prior iron-deficiency anemia (IDA).OBJECTIVE To evaluate the association between IDA and SSNHL using a nationwide population-based database.DESIGN, SETTING, AND PARTICIPANTS In this case-control study in Taiwan, participants with SSNHL (n = 4004) were identified, and controls (n = 12 012) were randomly selected.MAIN OUTCOMES AND MEASURES Conditional logistic regression was used to calculate the ORs (95%CIs) for IDA in participants with SSNHL vs controls.RESULTS Of the 16 016 sampled participants, 533 (3.3%) had previously been diagnosed with IDA, including 172 (4.3%) participants with SSNHL and 361 (3.0%) controls. The χ2 test revealed a significant difference (P < .001) in the prevalence of prior IDA between participants with SSNHL and controls. By conditional logistic regression, we found that the OR for previous IDA among the participants with SSNHL was 1.34 (95%CI, 1.11-1.61) (P < .01)after adjusting for monthly income, geographic region, urbanization level, and comorbidities(ie, hypertension, diabetes, hyperlipidemia, renal disease, and coronary heart disease). The significant relationship between SSNHL and prior IDA was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95%CI, 1.35-2.72) (P < .001) for the participants with SSNHL compared with controls, and the strength of this relationship decreased with age.CONCLUSIONS AND RELEVANCE There is an association between SSNHL and prior IDA.Patients with IDA, especially those younger than 60 years, should be more aggressively surveyed and managed to reduce hearing-related morbidities.

The Role of Red Blood Cells in Anemia

Red blood cells carry hemoglobin, an iron-rich protein that attaches to oxygen in the lungs and carries it to tissues throughout the body. Anemia occurs when you do not have enough red blood cells or when your red blood cells do not function properly. It is diagnosed when a blood test shows a hemoglobin value of less than 13.5 gm/dl in a man or less than 12.0 gm/dl in a woman. Normal values for children vary with age.
When you have anemia, your body lacks oxygen, so you may experience one or more of the following symptoms:

• Weakness
• Shortness of breath
• Dizziness
• Fast or irregular heartbeat
• Pounding or "whooshing" in your ears
• Headache
• Cold hands or feet
• Pale or yellow skin
• Chest pain

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Am I at Risk?

Many people are at risk for anemia because of poor diet, intestinal disorders, chronic diseases, infections, and other conditions. Women who are menstruating or pregnant and people with chronic medical conditions are most at risk for this disease. The risk of anemia increases as people grow older. People who engage in vigorous athletic activities, such as jogging or basketball, may develop anemia as a result of red blood cells breaking down in the bloodstream.
If you have any of the following chronic conditions, you might be at greater risk for developing anemia:

• Rheumatoid arthritis or other autoimmune disease
• Kidney disease
• Cancer
• Liver disease
• Thyroid disease
• Inflammatory bowel disease (Crohn disease or ulcerative colitis)

The signs and symptoms of anemia can easily be overlooked. In fact, many people do not even realize that they have anemia until it is identified in a blood test.
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Common Types of Anemia

Iron-deficiency anemia is the most common type of anemia. It happens when you do not have enough iron in your body. Iron deficiency is usually due to blood loss but may occasionally be due to poor absorption of iron. Pregnancy and childbirth consume a great deal of iron and thus can result in pregnancy-related anemia. People who have had gastric bypass surgery for weight loss or other reasons may also be iron deficient due to poor absorption.
Vitamin-deficiency anemia may result from low levels of vitamin B12 or folate (folic acid), usually due to poor dietary intake. Pernicious anemia is a condition in which vitamin B12 cannot be absorbed in the gastrointestinal tract.
Anemia and Pregnancy - Learn about the risk factors and symptoms of anemia during pregnancy.
Aplastic anemia   is a rare form of anemia that occurs when the body stops making enough red blood cells. Common causes include viral infections, exposure to toxic chemicals, drugs, and autoimmune diseases. Idiopathic aplastic anemia is the term used when the reason for low red blood cell production is not known.
Hemolytic anemia   occurs when red blood cells are broken up in the bloodstream or in the spleen. Hemolytic anemia may be due to mechanical causes (leaky heart valves or aneurysms), infections, autoimmune disorders, or congenital abnormalities in the red blood cell. Inherited abnormalities may affect the hemoglobin or the red blood cell structure or function. Examples of inherited hemolytic anemias include some types of thalassemia and low levels of enzymes such as glucose-6 phosphate dehydrogenase deficiency. The treatment will depend on the cause.
Sickle cell anemia is an inherited hemolytic anemia in which the hemoglobin protein is abnormal, causing the red blood cells to be rigid and clog the circulation because they are unable to flow through small blood vessels.
Anemia caused by other diseases   - Some diseases can affect the body's ability to make red blood cells. For example, some patients with kidney disease develop anemia because the kidneys are not making enough of the hormone erythropoietin to signal the bone marrow to make new or more red blood cells. Chemotherapy used to treat various cancers often impairs the body's ability to make new red blood cells, and anemia often results from this treatment.
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How is Anemia Treated?

The treatment for anemia depends on what causes it.
Iron-deficiency anemia is almost always due to blood loss. If you have iron-deficiency anemia, your doctor may order tests to determine if you are losing blood from your stomach or bowels. Other nutritional anemias, such as folate or B-12 deficiency, may result from poor diet or from an inability to absorb vitamins in the gastrointestinal tract. Treatment varies from changing your diet to taking dietary supplements.
If your anemia is due to a chronic disease, treatment of the underlying disease will often improve the anemia. Under some circumstances, such as chronic kidney disease, your doctor may prescribe medication such as erythropoietin injections to stimulate your bone marrow to produce more red blood cells.
Aplastic anemia occurs if your bone marrow stops producing red blood cells. Aplastic anemia may be due to primary bone marrow failure, myelodysplasia (a condition in which the bone marrow produces abnormal red blood cells that do not mature properly), or occasionally as a side effect of some medications. If you appear to have a form of aplastic anemia, your doctor may refer you to a hematologist for a bone marrow biopsy to determien the cause of the anemia. Meedications and blood transfusions may be used to treat aplastic anemia.
Hemolytic anemia occurs when red blood cells are destroyed in the blood stream. This may be due to mechanical factors (a leaky heart valve or aneurysm), infection, or an autoimmune disease. The cause can often be identified by special blood tests and by looking at the red blood cells under a microscope. The treatment will depend upon the cause and may include referral to a heart or vascular specialist, antibiotics, or drugs that suppress the immune system.
Talk with your doctor if you believe you may be at risk for anemia. Your doctor will determine your best course of treatment and, depending on your condition, may refer you to a hematologist, a doctor who specializes in blood disorders.
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Is Anemia Preventable?

While many types of anemia cannot be prevented, eating healthy foods can help you avoid both iron-and vitamin-deficiency anemia. Foods to include in your diet include those with high levels of iron (beef, dark green leafy vegetables, dried fruits, andnuts),vitamin B-12 (meat and dairy), and folic acid (citrus juices, dark green leafy vegetables, legumes, and fortified cereals). A daily multivitamin will also help prevent nutritional anemias; however, older adults should not take iron supplementsfor iron-deficiencyanemia unless instructed by their physicians.

 Iron deficiency anemia (IDA) is a blood condition in which the body fails to make enough healthy red blood cells. IDA is caused by a deficiency in iron, a mineral that acts as an important building block for red blood cell construction. It's the most common nutritional disorder in the world, affecting mostly women and children.
Who Is at Risk?
In the United States, 9 percent to 12 percent of non-Hispanic white women and close to 20 percent of black and Mexican-American women have iron deficiency anemia.
The two main causes of IDA are blood loss and low iron. Blood loss can occur from menstruation, recent major surgery or trauma or peptic ulcer disease, among other causes. Low iron may result from gastrointestinal diseases such as celiac sprue, Crohn's disease or ulcerative colitis; a diet low in iron; and history of a bariatric procedure like gastric bypass.
Pregnancy and breastfeeding increase iron requirements, so both are risk factors for IDA.
Children who drink more than 16 to 24 ounces of cow's milk a day are at an increased risk for IDA. Cow's milk can lead to blood loss by irritating the lining of the intestines and can interfere with iron absorption.
What Are the Symptoms?

Symptoms of Iron Deficiency Anemia
Fatigue	Shortness of breath
Weakness	Blue color to whites of the eyes
Irritability	Increased heart rate
Headache	Sore tongue
Pale skin	Pounding or "whooshing" sound in ears
Trouble concentrating	Lightheadedness upon standing
Brittle nails	Craving for ice or clay, called picophagia

How Is It Treated?
Treatment for IDA depends on its cause and severity and individual factors, including your age, health and medical history. Your health care professional may advise:

• taking supplemental iron, either in the form of pills or intravenous (IV) iron.
• eating more iron-rich foods, such as meats, poultry, seafood, dark leafy greens, egg yolks, legumes, oatmeal, peanut butter, raisins, prunes, apricots, soybeans, whole-wheat breads and iron-enriched bread, cereal, pasta and rice.
• in severe cases, your doctor may recommend getting a blood transfusion.

How Is It Prevented?
To prevent IDA, the best thing you can do is make sure you get sufficient iron in your diet. At times when your body requires extra iron, such as during pregnancy or breastfeeding, boost your iron intake even more with food and talk to your health care professional about iron supplements.

Anaemia and Tinnitus

Anaemia is a blood condition in which a person has a low level of haemoglobin in their blood or fewer red blood cells than normal. The most common type of anaemia is caused by iron deficiency, which results in fewer red blood cells. A low level of vitamin B12 can also cause Anaemia. Symptoms vary depending on the type of anemia you have and what causes it. The body uses iron to produce blood cells. These red blood cells store and carry oxygen around the body. If you have fewer red blood cells your body’s organs and tissues will receive less oxygen. One of the more common symptoms of anaemia is tinnitus and medical research shows a direct link between pulsatile tinnitus and iron deficient anaemia.
Diet can affect tinnitus in individuals in different ways. There is no definitive link to particular types of foods making tinnitus worse or better however there is a clear association between tinnitus and anaemia.

Pulsatile Tinnitus

Severe Anaemia caused by iron deficiency; vitamin b12 deficiency, cancer or kidney failure can cause pulsatile tinnitus. Pulsatile tinnitus resembles the sound of a heartbeat in the ear. Anaemia causes low blood viscosity, which increases blood flow. Anything that increases blood flow can cause pulsatile tinnitus. Pulsatile tinnitus can be caused by a number of other medical conditions including hyperthyroidism and sounds that are conducted into the middle ear from the carotid artery and jugular vein. This is because they run so close to the inner ear.  If tinnitus is attributed to Anaemia the severity of symptoms can reflect the level of iron deficiency. Once the cause of Anaemia is found and treatment is successful the tinnitus symptoms usually subside.

Common Anaemia Symptoms

• Fatigue
• Weakness
• Rapid Heartbeat
• Breathlessness
• Dizziness or light headedness
• Headache
• Pale Skin
• Feeling faint
• Tinnitus
• Irritability
• Low energy levels
• Weight loss
• Heart palpitations
• Loss of sex drive
• Mental confusion
• Pica
• Restless legs

Anaemia Causes

Iron Deficiency

• Poor diet
• Unbalanced vegetarian diet
• Demands of pregnancy and breastfeeding
• Menstruation
• Blood donation
• Bowel conditions – Crohn’s disease
• Non-steroidal anti-inflammatory drugs
• Endurance sports

Blood Loss

• Gastrointestinal conditions. Haemorrhoids, Gastritis, Stomach Ulcers and Gastrointestinal cancer
• Chronic Kidney Disease
• Menstruation
• Pregnancy
• Accidents and Trauma
• Angiodysplasia
• Inflammatory bowel disease
• Haematuria (blood in your urine)
• Nose bleeds
• Oesophagitis
• Non-steroidal anti-inflammatory drugs

Decreased red blood cell production

• Thalassaemia
• Vitamin B12 Deficiency
• Stem cell and bone marrow problems
• Sickle cell anaemia

Treatment for Anaemia

The main treatment for anaemia is iron supplements in tablet form or eating foods that are rich in iron.

Iron Supplement Side Effects

• Nausea
• Diarrhea
• Upset stomach
• Constipation

Iron Supplements for Meat Eaters

• Beef
• Chicken
• Clams
• Molluscs
• Mussels
• Oysters
• Sardines
• Turkey

Iron Supplements for Vegans and Vegetarians

• Legumes: Soybeans, Lentils, Lima beans, Tofu
• Grains: Brown rice, Oatmeal, Quinoa
• Nuts: Pine, Pistachio, Cashews
• Seeds: Pumpkin, Squash, Sesame
• Dried fruit: Apricots
• Whole grains, Brown rice
• Fortified breakfast cereals
• Green vegetables: Kale, watercress

When taking iron supplements

• The less you eat the better it is absorbed
• Combine non-heme iron foods with Vitamin C to increase absorption
• Take with meals and orange juice
• Keep taking for several months after you are better
• Regular iron check ups
• Drink plenty of fluids

 Question  Is iron deficiency anemia associated with hearing loss in the adult population?
Findings  In this retrospective cohort study of 305 339 young to elderly adults, iron deficiency anemia was positively associated with sensorineural hearing loss and the presence of combined hearing loss.
Meaning  Additional studies to examine how iron supplementation influences hearing status are warranted.

Abstract

Importance  Hearing loss in the US adult population is linked to hospitalization, poorer self-reported health, hypertension, diabetes, and tobacco use. Because iron deficiency anemia (IDA) is a common and easily correctable condition, further understanding of the association between IDA and all types of hearing loss in a population of US adults may help to open new possibilities for early identification and appropriate treatment.
Objective  To evaluate the association between sensorineural hearing loss (SNHL) and conductive hearing loss and IDA in adults aged 21 to 90 years in the United States.
Design, Setting, and Participants  The prevalence of IDA and hearing loss (International Classification of Diseases, Ninth Revision codes 389.1 [SNHL], 389.0 [conductive hearing loss], and 389 [combined hearing loss]) was identified in this retrospective cohort study at the Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania. Iron deficiency anemia was determined by low hemoglobin and ferritin levels for age and sex in 305 339 adults aged 21 to 90 years. Associations between hearing loss and IDA were evaluated using χ² testing, and logistic regression was used to model the risk of hearing loss among those with IDA. The study was conducted from January 1, 2011, to October 1, 2015.
Main Outcomes and Measures  Hearing loss.
Results  Of 305 339 patients in the study population, 132 551 were men (43.4%); mean (SD) age was 50.1 (18.5) years. There was a 1.6% (n = 4807) prevalence of combined hearing loss and 0.7% (n = 2274) prevalence of IDA. Both SNHL (present in 26 of 2274 individuals [1.1%] with IDA; P = .005) and combined hearing loss (present in 77 [3.4%]; P  < .001) were significantly associated with IDA. Logistic regression analysis confirmed increased odds of SNHL (adjusted odds ratio [OR], 1.82; 95% CI, 1.18-2.66) and combined hearing loss (adjusted OR, 2.41; 95% CI, 1.90-3.01) among adults with IDA, after adjusting for sex.
Conclusions and Relevance  Iron deficiency anemia was associated with SNHL and combined hearing loss in a population of adult patients. Further research is needed to better understand the potential links between IDA and hearing loss and whether screening and treatment of IDA in adults could have clinical implications in patients with hearing loss.

Introduction

In 2014, approximately 15% of adults reported difficulty with hearing, with the highest prevalence among white men.¹ Hearing loss increases with each decade of life, affecting 40% to 66% of adults older than 65 years and 80% of those older than 85 years.^2,3 Risk factors for earlier onset of adult hearing loss include hypertension, diabetes, and tobacco use.^3,4 Sudden sensorineural hearing loss (SNHL) is characterized by a rapid deterioration in hearing function that occurs in less than a 72-hour period. The mechanism is unknown, but a recent study by Chung et al⁵ found a significant association between iron deficiency anemia (IDA) and sudden SNHL (odds ratio [OR], 1.34; 95% CI, 1.11-1.61; P <  .01), which was most prominent in patients younger than 60 years. Iron deficiency anemia is a subset of anemia in which patients exhibit low hemoglobin, serum ferritin, and serum iron levels and increased soluble transferrin receptor levels. In US adults, IDA is usually a result of blood loss and often responds well to reversal of the source of blood loss and oral iron supplementation.⁶

Although the role of iron in the inner ear has not been clearly established, blood supply to this area is highly sensitive to ischemic damage. Sudden SNHL may have a vascular cause potentially exacerbated by IDA as described in a rat model of iron deficiency and sudden SNHL. This study identified defects in the cochlea, including strial atrophy⁷ and reduced spiral ganglion cells, with effects on the stereocilia of the inner and outer hair cells.^7,8 The role of iron in the vasculature and nervous system raises the possibility of its association with other common types of adult hearing loss beyond sudden SNHL. Because IDA is a common and reversible condition, further understanding of the association between IDA and all types of hearing loss in a population of US adults may open new possibilities for treatment. Thus, the objective of this study was to examine the association between IDA and SNHL, conductive hearing loss (CHL), and combined hearing loss among a cohort of adult patients aged 21 to 90 years. Based on previous reports⁵ of sudden SNHL and the mechanical component involved in CHL, the hypothesis was that IDA would demonstrate a stronger association with SNHL compared with CHL.

Methods

Study Population

We performed a retrospective cohort study using data obtained from deidentified electronic medical records from the Penn State Milton S. Hershey Medical Center in Hershey, Pennsylvania. Data were extracted using the National Institutes of Health–supported Informatics for Integrating Biology and the Bedside electronic medical records query tool.^9,10 Patients were included if they were aged 21 to 90 years with at least 1 outpatient, inpatient, or emergency department visit between January 1, 2011, and October 1, 2015. Patients with sickle cell disease (identified as at least 1 International Classification of Diseases, Ninth Revision [ICD-9] code for 282.6) were excluded owing to previous studies linking sickle cell anemia with hearing loss.^11- 17 The study was determined to be exempt by the Pennsylvania State University College of Medicine Institutional Review Board, which also waived the need for patient informed consent because deidentified data were used.

Individuals with IDA were identified based on the presence of at least 1 low serum ferritin (<12.0 ng/mL) value (to convert to picomoles per liter, multiply by 2.247) and 1 low serum hemoglobin value between January 1, 2011, and October 1, 2015. Low hemoglobin values were defined in a previous National Health and Nutritional Examination Survey (NHANES) III study by an expert panel (men: 21-49 years, <13.7 g/dL; 50-69 years, <13.3 g/dL; and ≥70 years, <12.4 g/dL; women: 21-69 years, <12.0 g/dL; ≥70 years, <11.8 g/dL [to convert to grams per liter, multiply by 10]).¹⁸

Patients were identified as having hearing loss if they had at least 1 encounter associated with 1 of the following spectra of ICD-9 codes: 389.0 (CHL), 389.1 (SNHL), or 389 (combined hearing loss). Patients meeting these criteria for hearing loss were categorized as having CHL, SNHL, or combined hearing loss. Combined hearing loss was defined as any combination of CHL, SNHL, deafness, and unspecified hearing loss. Covariates included age (21-69 and ≥70 years) and sex (male and female). Hearing loss–related ICD-9 codes may have been added by a primary care physician, otolaryngologist, or audiologist following a visit with a hearing–related symptom. Formal audiogram testing would not be required for a clinician to select 1 of these codes.

Statistical Analysis

Prevalence of IDA and hearing loss are reported. Two-sided χ² testing was performed and ORs were determined via 2 × 2 contingency tables. In addition, multivariate conditional logistic regression analysis (adjusted for sex) was performed to obtain adjusted ORs and 95% CIs. All statistical testing was performed using R, version 3.2.3 software (The R Project for Statistical Computing).

Results

Demographics

Overall, a total of 305 339 individuals aged 21 to 90 years were identified in the study population. Of these, 132 551 were men (43.4%); mean (SD) age was 50.1 (18.5) years. This cohort was identified as having at least 1 outpatient, inpatient, or emergency department visit at Penn State Hershey Medical Center from 2011 to 2015. The prevalence of IDA was 0.7% (n = 2274). Consistent with published data,¹⁹ IDA was more prevalent in women compared with men (prevalence, 1.1% vs 0.3%; P  < .001). The prevalence of combined hearing loss was 1.6% (n = 4807), and SNHL (0.7%) was more prevalent than CHL (0.2%). Iron deficiency anemia was positively associated with both SNHL (1.1%; P = .005) and the presence of combined hearing loss (3.4%; P < .001) (Table 1).

Association of IDA and Hearing Loss

After adjustment for sex, IDA remained associated with an increased odds of combined hearing loss (adjusted OR, 2.41; 95% CI, 1.90-3.01). Similarly, IDA was associated with increased odds of SNHL (adjusted OR, 1.82; 95% CI, 1.18-2.66) in the adjusted analysis (Table 2). Serum ferritin and hemoglobin are not usually tested unless the diagnosis warrants it; to account for this potential underrepresentation of individuals with IDA, a sensitivity analysis was performed using an IDA prevalence of 3% for women and 1% for men. Overall, similar results were seen, indicating increased odds of both SNHL and combined hearing loss with IDA (eTable in the Supplement).

Discussion

Our study demonstrates increased odds of hearing loss among adults aged 21 to 90 years with IDA. These findings are consistent with those of another observational study in Taiwan that identified an association between IDA and sudden SNHL most prominently in individuals younger than 60 years.⁵ Previous studies^7,8,20- 26 suggest several potential mechanisms by which IDA may affect hearing health; however, it is unknown whether early diagnosis and treatment of IDA could positively affect the overall health status of adults with hearing loss.

The cochlea is highly susceptible to ischemic damage since only the labyrinthine artery supplies blood to this area.²⁷ Iron deficiency anemia has been demonstrated to be a potential risk factor for ischemic stroke due to lower hemoglobin levels leading to impaired oxygen-carrying capacity.^20,21 Individuals with vascular disease have been shown to have a higher risk for developing sudden SNHL.^5,28- 32 Another potential vascular mechanism linking IDA and hearing loss is the increased risk of IDA in patients with reactive thrombocytosis.^22,23 Iron is a regulator of thrombopoiesis, and previous associations between blood loss and thrombocytosis have been established.^33,34 This hypothesis is further substantiated by a case report that demonstrated acute SNHL in a patient with marked thrombocytosis that was reversed after plasmapheresis.³⁵ Iron deficiency results in the degradation of lipid saturase and desaturase, impairing energy production and, consequently, myelin production.²⁴ Damage to the myelin surrounding the auditory nerve impairs conduction velocity resulting in noise-induced hearing loss,²⁵ possibly due to changes in sodium channel density.²⁶

The present study found an association between IDA and hearing loss. Iron deficiency anemia is easily treated with several months of oral iron supplementation.⁶ A study using the NHANES data from 1999-2002 found that individuals with healthier dietary habits were able to detect higher-frequency noises.³⁶ Treatment of IDA will naturally improve anemia and replenish iron stores. Iron deficiency anemia is associated with a large number of related morbidities (eg, fatigue and reduced work capacity), which are also likely to improve with treatment.^37- 56 Additional studies are needed to determine whether there is a link between iron supplementation and hearing status.

Limitations

There are limitations to this analysis that should be considered. The use of laboratory results (ie, serum ferritin and hemoglobin levels) increased the specificity of the IDA definition in our study but reduced the sensitivity. With the wide availability of laboratories not affiliated with our institution and with Informatics for Integrating Biology and the Bedside unable to include data that are not internal, the prevalence of IDA and hearing loss in this study may be falsely reduced. A sensitivity analysis was performed to address this limitation. Using an IDA prevalence of 1% for men and 3% for women, the same analyses were performed. The data remained significant, indicating that although the sensitivity of the analysis is reduced by the present methods, the positive association between IDA and hearing loss remains (eTable in the Supplement). In addition, identifying whether iron deficiency or anemia alone is associated with hearing loss is unable to be accurately performed with this analysis since hemoglobin and serum ferritin are not often tested in the general population. Therefore, distinguishing between iron deficiency, anemia, and IDA would not be definitive.

The prevalence of combined hearing loss, SNHL, and CHL was also lower than has been reported in the literature.³ An analysis using NHANES data from 2001 to 2008 reported a prevalence of 3.2% (95% CI, 1.4%-5.1%) of bilateral and unilateral hearing loss of more than 25 dB among individuals aged 20 to 29 years, increasing with each decade of life with a prevalence of 89.1% (95% CI, 86.1%-92.0%) for those 80 years or older. In contrast, this present investigation was an observational study of health care–seeking adults, and the results may not be generalizable to the rest of the US population.⁵⁷ Patients with hearing loss in this analysis were defined by ICD-9 codes; thus, there are no diagnostic values for comparison. There were likely instances in which hearing loss was not consistently coded due to human error during data entry, neglect to include the ICD-9 code for hearing loss in the patients’ medical records, or exclusion from the query due to billing before January 2011. Similarly, adjusting for potential risk factors, such as smoking status, is unable to be performed in Informatics for Integrating Biology and the Bedside owing to noninclusion in the database. Adjusting for other potential risk factors, such as diabetes and hypertension, is possible with our model, but the results would then be uninterpretable because of the high collinearity between age and these confounding comorbidities.

5 Foods Rheumatoid Arthritis Should Avoid

 

1 / 6   Eat Less of These Foods To Feel Better

It's time to kick that morning donut and coffee habit. Research shows that eating particular foods — like sugary treats and certain caffeinated beverages — may worsen rheumatoid arthritis symptoms.
There are many drugs to treat rheumatoid arthritis (RA), but don't ignore the simpler ways of reducing RA pain, like diet modification. Though the research surrounding diet and rheumatoid arthritis is still inconclusive, many doctors recommend cutting out common foods that trigger RA symptoms to see if it helps your joints.
"As of now, there is no agreed upon diet for rheumatoid arthritis, but there are some people who do seem to have food sensitivities," says Clement Michet, Jr., MD, a rheumatologist and professor at Mayo Clinic in Rochester, Minnesota. Patients may have different tolerance for various foods, so it's not possible to recommend a single diet across the board. But here are five foods commonly reported to aggravate arthritis symptoms.
 

 

2 / 6   Eat, Drink Less Dairy

Rheumatoid arthritis symptoms may flare in response to specific proteins found in dairy products. Some people with rheumatoid arthritis who report intolerance to milk have antibodies to milk proteins, Dr. Michet said. The body forms these antibodies to protect itself from what it mistakenly perceives as a harmful substance, but the antibodies attack other parts of the body in addition to the milk. Cut dairy products from your diet to see if that reduces your RA symptoms.
"Try rice, cashew, or almond milk as anti-inflammatory alternatives," says Ulka Agarwal, MD, staff psychiatrist at George Washington University in Washington, DC, who advocates a vegan diet.  Cut milk-based products from your diet to see if it helps your pain.
 

 

3 / 6   Cut Back on Meat

Changing from a meat-heavy to a vegetarian diet often improves RA symptoms. Meat consumption is associated with higher overall fat and calorie intake, which are markers for an unhealthy diet. The fats in meat are more easily metabolized into pro-inflammatory chemicals in the body, Michet says. Production of these inflammatory chemicals is good in certain circumstances like when you're fighting an infection — but they can also cause painful inflammation and swelling in spaces like your joints. Instead of eating meat exclusively, supplement your diet with plant sources of protein such as beans, lentils, and soy, Dr. Agarwal says.
 

 

4 / 6   Go Easy on Gluten

Research shows that some people with rheumatoid arthritis also have celiac disease, which is triggered by gluten. Gluten is a protein found in wheat and other grains that gives dough a chewy texture. When someone has celiac disease, eating gluten causes an immune reaction in the small intestine that can lead to bloating and diarrhea.
In some people, the inflammatory reaction may extend to the joints, which only aggravates rheumatoid arthritis symptoms. While dietary interventions for rheumatoid arthritis remain controversial, the gluten-free trend is showing some positive results, notably the easing of celiac rheumatic symptoms, according to research published in September 2016 in Autoimmunity Reviews. But before trying a gluten-free diet, get tested for celiac disease, Michet suggests.
 

 

5 / 6   Skip Refined Sugars And Sweets

While certain carbohydrates are an essential part of our diets, refined sugars and sweets are not, as much as we may enjoy them. Refined sugars, such as high fructose corn syrup, are empty calories devoid of any nutrients and detrimental to our bodies.
"It's a poison by itself," says Robert Lustig, MD, a pediatric endocrinologist and professor at the University of California, San Francisco. Cutting down on refined sugar is even more important for people with rheumatoid arthritis because it drives more chronic inflammation, something people with RA don't need. Risks for diabetes and cardiovascular disease are also high for people living with RA, and controlling blood pressure and cholesterol is crucial.
Mary Poppins was wrong, Dr. Lustig says: "Just a spoonful of sugar helps the blood pressure go up."
 

 

6 / 6   Limit Coffee And Other Caffeinated Beverages

America is powered by caffeine: Nearly 180 million people drink coffee in the United States, with 74% of the adult population partaking, according to the 2016 NCA National Coffee Drinking Trends study. The health effects of coffee are controversial, especially in regard to rheumatoid arthritis. Large population studies show conflicting results and are inconclusive. However, coffee drinking was linked to the development of anti-cyclic citrllinated protein, a specific subtype of RA, according to a study published in July 2006 in Arthritis Research & Therapy. While research is still ongoing, you may want to consider tossing that coffee mug as your own experiment.
 

There is no cure for rheumatoid arthritis. But recent discoveries indicate that remission of symptoms is more likely when treatment begins early with strong medications known as disease-modifying antirheumatic drugs (DMARDs).

Medications

The types of medications recommended by your doctor will depend on the severity of your symptoms and how long you've had rheumatoid arthritis.

• NSAIDs. Nonsteroidal anti-inflammatory drugs (NSAIDs) can relieve pain and reduce inflammation. Over-the-counter NSAIDs include ibuprofen (Advil, Motrin IB) and naproxen sodium (Aleve). Stronger NSAIDs are available by prescription. Side effects may include ringing in your ears, stomach irritation, heart problems, and liver and kidney damage.
• Steroids. Corticosteroid medications, such as prednisone, reduce inflammation and pain and slow joint damage. Side effects may include thinning of bones, weight gain and diabetes. Doctors often prescribe a corticosteroid to relieve acute symptoms, with the goal of gradually tapering off the medication.
• Disease-modifying antirheumatic drugs (DMARDs). These drugs can slow the progression of rheumatoid arthritis and save the joints and other tissues from permanent damage. Common DMARDs include methotrexate (Trexall, Otrexup, Rasuvo), leflunomide (Arava), hydroxychloroquine (Plaquenil) and sulfasalazine (Azulfidine).
  Side effects vary but may include liver damage, bone marrow suppression and severe lung infections.
  
• Biologic agents. Also known as biologic response modifiers, this newer class of DMARDs includes abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), tocilizumab (Actemra) and tofacitinib (Xeljanz).
  These drugs can target parts of the immune system that trigger inflammation that causes joint and tissue damage. These types of drugs also increase the risk of infections.
  Biologic DMARDs are usually most effective when paired with a nonbiologic DMARD, such as methotrexate.
  

Therapy

Your doctor may send you to a physical or occupational therapist who can teach you exercises to help keep your joints flexible. The therapist may also suggest new ways to do daily tasks, which will be easier on your joints. For example, if your fingers are sore, you may want to pick up an object using your forearms.
Assistive devices can make it easier to avoid stressing your painful joints. For instance, a kitchen knife equipped with a saw handle helps protect your finger and wrist joints. Certain tools, such as buttonhooks, can make it easier to get dressed. Catalogs and medical supply stores are good places to look for ideas.

Surgery

If medications fail to prevent or slow joint damage, you and your doctor may consider surgery to repair damaged joints. Surgery may help restore your ability to use your joint. It can also reduce pain and correct deformities.
Rheumatoid arthritis surgery may involve one or more of the following procedures:

• Synovectomy. Surgery to remove the inflamed synovium (lining of the joint). Synovectomy can be performed on knees, elbows, wrists, fingers and hips.
• Tendon repair. Inflammation and joint damage may cause tendons around your joint to loosen or rupture. Your surgeon may be able to repair the tendons around your joint.
• Joint fusion. Surgically fusing a joint may be recommended to stabilize or realign a joint and for pain relief when a joint replacement isn't an option.
• Total joint replacement. During joint replacement surgery, your surgeon removes the damaged parts of your joint and inserts a prosthesis made of metal and plastic.

Surgery carries a risk of bleeding, infection and pain. Discuss the benefits and risks with your doctor.

Alternative medicine

Some common complementary and alternative treatments that have shown promise for rheumatoid arthritis include:

• Fish oil. Some preliminary studies have found that fish oil supplements may reduce rheumatoid arthritis pain and stiffness. Side effects can include nausea, belching and a fishy taste in the mouth. Fish oil can interfere with medications, so check with your doctor first.
• Plant oils. The seeds of evening primrose, borage and black currant contain a type of fatty acid that may help with rheumatoid arthritis pain and morning stiffness. Side effects may include nausea, diarrhea and gas. Some plant oils can cause liver damage or interfere with medications, so check with your doctor first.
• Tai chi. This movement therapy involves gentle exercises and stretches combined with deep breathing. Many people use tai chi to relieve stress in their lives. Small studies have found that tai chi may reduce rheumatoid arthritis pain. When led by a knowledgeable instructor, tai chi is safe. But don't do any moves that cause pain.

 

Rheumatoid Arthritis Linked To Serious Mood Disorders, Cognitive Impairment

 

According to a new study of autoimmune patients, neuropsychiatric symptoms were found to be common among those with RA.

It makes sense that those who live with a chronic illness or disability may occasionally feel down or depressed about their health status.
But new research shows a stronger-than-expected link between serious neuropsychiatric symptoms and rheumatoid arthritis (RA).
The comprehensive review, published in Autoimmunity Reviews, concluded that not only can RA affect the joints and tendons as well as other organs, but it can also have some effect on the central nervous system, spine, and brain.

This goes far beyond mood swings.
"Neuropsychiatric manifestations — especially mood disorders and headache — are frequently observed in RA,” lead author Dr. Andrei Joaquim from the Department of Neurology at State University of Campinas (UNICAMP) in São Paolo, Brazil said in a statement. “It is of paramount importance for neurologists and rheumatologists to understand the nuances of neurological symptoms in RA patients for a proper diagnosis and an adequate treatment.”
Read More: A Simple Blood Test Could Predict Rheumatoid Arthritis Up to 16 Years in Advance »

Mental Health Side Effects

The researchers concluded that neurological manifestations of RA could include, but are not limited to, peripheral neuropathy (nerve pain,), migraine headaches, “brain fog,” cognitive impairment, depression, anxiety, and even seizures.
Some studies have even shown links between autism spectrum disorders and inflammatory autoimmune conditions like RA. Others have investigated the prevalence of bipolar disorder with the disease.
Many studies and articles have discussed the existence of suicidal thoughts and tendencies in patients with chronic illnesses such as RA. The UNICAMP study focused mainly on headache, depression, anxiety, and cognitive impairment.
The researchers found that headaches were the leading neuropsychiatric condition found in RA patients. However, whether these headaches were from the disease process itself, co-existing health problems, or the medications used in treatment remains unknown.

The study also showed that up to 40 percent of patients acknowledge having, or have been diagnosed with, depression. That is a higher rate than the general population. The researchers found that anywhere from 21 to 70 percent of RA patients experience anxiety.
Read More: Stem Cell Therapy a Possible Treatment for Rheumatoid Arthritis »

Impaired Cognitive Functions

The researchers also concluded that patients with RA appeared to have far higher rates of cognitive dysfunction than the general population.
This was apparent mostly in areas of visual-spatial perception and planning. However, some level of cognitive dysfunction was also observed regarding impaired functional ability, reduced quality of life, and/or poor medication compliance.
The authors of the study did acknowledge that outside factors may have played a role in cognitive dysfunction among RA patients. These include low education, low income, use of oral steroids, and increased cardiovascular disease.
The symptom “brain fog” is also commonly mentioned by rheumatologists and their patients, especially those with RA and fibromyalgia, yet the lack of mental clarity remains a mystery. Researchers have yet to determine if “brain fog” stems from the diseases, the associated fatigue, the pharmaceutical drugs used in treatment, or a culmination of all of these factors.
Perhaps the most interesting part of the review is the involvement of focal/visual disturbances, the mention of stroke and seizure, and the affectation of the spine and central nervous system.

Still the biggest question remains unanswered: What is the cause?
In many cases, it’s uncertain whether the disease is actually causing these conditions, whether the sedentary lifestyle or medications taken are a factor, and whether the patients observed would have had these neuropsychiatric or mood disorders even without a diagnosis of RA.

Symptoms

Signs and symptoms of rheumatoid arthritis may include:

• Tender, warm, swollen joints
• Joint stiffness that is usually worse in the mornings and after inactivity
• Fatigue, fever and weight loss

Early rheumatoid arthritis tends to affect your smaller joints first — particularly the joints that attach your fingers to your hands and your toes to your feet.
As the disease progresses, symptoms often spread to the wrists, knees, ankles, elbows, hips and shoulders. In most cases, symptoms occur in the same joints on both sides of your body.
About 40 percent of the people who have rheumatoid arthritis also experience signs and symptoms that don't involve the joints. Rheumatoid arthritis can affect many nonjoint structures, including:

• Skin
• Eyes
• Lungs
• Heart
• Kidneys
• Salivary glands
• Nerve tissue
• Bone marrow
• Blood vessels

Rheumatoid arthritis signs and symptoms may vary in severity and may even come and go. Periods of increased disease activity, called flares, alternate with periods of relative remission — when the swelling and pain fade or disappear. Over time, rheumatoid arthritis can cause joints to deform and shift out of place.

When to see a doctor

Make an appointment with your doctor if you have persistent discomfort and swelling in your joints.

Causes

• 
  

  Rheumatoid arthritis vs. osteoarthritis

Rheumatoid arthritis occurs when your immune system attacks the synovium — the lining of the membranes that surround your joints.
The resulting inflammation thickens the synovium, which can eventually destroy the cartilage and bone within the joint.
The tendons and ligaments that hold the joint together weaken and stretch. Gradually, the joint loses its shape and alignment.
Doctors don't know what starts this process, although a genetic component appears likely. While your genes don't actually cause rheumatoid arthritis, they can make you more susceptible to environmental factors — such as infection with certain viruses and bacteria — that may trigger the disease.

Risk factors

Factors that may increase your risk of rheumatoid arthritis include:

• Your sex. Women are more likely than men to develop rheumatoid arthritis.
• Age. Rheumatoid arthritis can occur at any age, but it most commonly begins between the ages of 40 and 60.
• Family history. If a member of your family has rheumatoid arthritis, you may have an increased risk of the disease.
• Smoking. Cigarette smoking increases your risk of developing rheumatoid arthritis, particularly if you have a genetic predisposition for developing the disease. Smoking also appears to be associated with greater disease severity.
• Environmental exposures. Although uncertain and poorly understood, some exposures such as asbestos or silica may increase the risk for developing rheumatoid arthritis. Emergency workers exposed to dust from the collapse of the World Trade Center are at higher risk of autoimmune diseases such as rheumatoid arthritis.
• Obesity. People who are overweight or obese appear to be at somewhat higher risk of developing rheumatoid arthritis, especially in women diagnosed with the disease when they were 55 or younger.

Complications

Rheumatoid arthritis increases your risk of developing:

• Osteoporosis. Rheumatoid arthritis itself, along with some medications used for treating rheumatoid arthritis, can increase your risk of osteoporosis — a condition that weakens your bones and makes them more prone to fracture.
• Rheumatoid nodules. These firm bumps of tissue most commonly form around pressure points, such as the elbows. However, these nodules can form anywhere in the body, including the lungs.
• Dry eyes and mouth. People who have rheumatoid arthritis are much more likely to experience Sjogren's syndrome, a disorder that decreases the amount of moisture in your eyes and mouth.
• Infections. The disease itself and many of the medications used to combat rheumatoid arthritis can impair the immune system, leading to increased infections.
• Abnormal body composition. The proportion of fat compared to lean mass is often higher in people who have rheumatoid arthritis, even in people who have a normal body mass index (BMI).
• Carpal tunnel syndrome. If rheumatoid arthritis affects your wrists, the inflammation can compress the nerve that serves most of your hand and fingers.
• Heart problems. Rheumatoid arthritis can increase your risk of hardened and blocked arteries, as well as inflammation of the sac that encloses your heart.
• Lung disease. People with rheumatoid arthritis have an increased risk of inflammation and scarring of the lung tissues, which can lead to progressive shortness of breath.
• Lymphoma. Rheumatoid arthritis increases the risk of lymphoma, a group of blood cancers that develop in the lymph system.

 

Maternal rheumatoid arthritis linked to childhood epilepsy

 

Rheumatoid arthritis is an autoimmune disease whereby the body's own immune system attacks the joints. New research suggests there may be a link between mothers with the autoimmune disorder and their children who develop epilepsy.

Rheumatoid arthritis in the mother may lead to childhood epilepsy, study suggests.

Rheumatoid arthritis (RA) is an autoimmune condition characterized by inflammation of the joints. It is different from osteoarthritis, which is caused by wear and tear in the joints.
RA affects up to 1.3 percent of the worldwide population, according to the Centers for Disease Control and Prevention (CDC). In the United States in 2005, 1.5 million adults over 18 years old were diagnosed with RA, and the CDC report that the numbers may currently be on the rise.
While there is no known cure for RA, one study found that 75 percent of people with RA experienced remission within the first 5 years of being diagnosed.
Epilepsy is a neurologic disorder consisting of recurrent epileptic seizures that are sometimes of unknown origin. According to the CDC, about 5.1 million people in the U.S. have been diagnosed with epilepsy or have had a seizure disorder. Of these, 2.9 million adults have active epilepsy.
Previous research has connected the presence of an autoimmune disorder in mothers with the risk that the child develops epilepsy. New research looks at the link between RA and epilepsy.

Mothers with RA linked to children with epilepsy

A new study led by Ane Lilleore Rom, Ph.D., of Copenhagen University Hospital in Denmark, examines the link between mothers with RA and the incidence of epilepsy in their children.
Researchers looked at the clinical records of almost 2 million children born in Denmark between 1977-2008. The children were then followed up for an average of 16 years. Diagnoses of RA and epilepsy were obtained from the Danish National Hospital Registry.
A total of 13,511 children from the studied cohort had mothers with RA. The number included mothers who were diagnosed with rheumatoid arthritis after their child was born, as they were considered to have "preclinical" PA.
Of these, 31,491 children, or 1.6 percent, developed epilepsy over the 16-year period.
Children whose mothers had RA at the time they were born were 90 percent more likely to develop epilepsy than children whose mothers were healthy, while children whose mothers had preclinical RA also had a 30 percent higher risk of developing epilepsy than mothers without the condition.
The study did not find any effect on whether the child would have epilepsy if the father had RA.
The researchers say the association between preclinical RA and increased epilepsy risk in offspring suggests it is likely RA itself that is to blame, rather than treatments for epilepsy.
The results also remained unchanged after adjusting for other factors, such as the baby's birth weight, the mother's age at birth, and if the mother also had epilepsy.
The results are published in Neurology - the journal of the American Academy of Neurology.

Significance of results and further research

According to Rom, previous research has already found an increased risk of epilepsy in people with autoimmune diseases that involve the brain directly, such as multiple sclerosis (MS) or autoimmune encephalitis.
"But it is new knowledge that also offspring of mothers with rheumatoid arthritis seem to have an increased risk of developing epilepsy," Rom says.
Recently, other autoimmune and inflammatory disorders have been associated with seizures and epilepsy, such as systemic lupus erythematosus, ulcerative colitis, and type 1 diabetes.

"These results suggest that changes in the environment for the fetus may play a role in the development of epilepsy. We don't know yet how this may work, but it could involve the production of maternal antibodies that could affect the unborn child."

Ane Lilleore Rom, Ph.D.

However, researchers point out that more research is needed to look into the consequences of RA treatment.
Also, the study only showed an association between the RA and epilepsy, so further research is needed to confirm causality and explain exactly how RA in the mother might affect the chances of offspring having epilepsy.
Learn about how stress increases seizures for patients with epilepsy.

Written by Ana Sandoiu

 Rheumatoid arthritis is a chronic inflammatory disorder that can affect more than just your joints. In some people, the condition also can damage a wide variety of body systems, including the skin, eyes, lungs, heart and blood vessels.
An autoimmune disorder, rheumatoid arthritis occurs when your immune system mistakenly attacks your own body's tissues.
Unlike the wear-and-tear damage of osteoarthritis, rheumatoid arthritis affects the lining of your joints, causing a painful swelling that can eventually result in bone erosion and joint deformity.
The inflammation associated with rheumatoid arthritis is what can damage other parts of the body as well. While new types of medications have improved treatment options dramatically, severe rheumatoid arthritis can still cause physical disabilities.

Mangosteen juice: Can it relieve arthritis pain?

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Can drinking mangosteen juice reduce arthritis inflammation and pain?

Answers from Brent A. Bauer, M.D.

It might. A number of laboratory and animal studies suggest that mangosteen has significant anti-inflammatory effects. And a few small-scale studies in humans indicate that the juice helps reduce blood levels of C-reactive protein (CRP). CRP is a substance associated with inflammation, which may be caused by widespread infection or disorders such as inflammatory bowel disease, lupus and rheumatoid arthritis.
But the studies that found this reduction in CRP were not conducted with people who have arthritis. And not everybody who has arthritis has elevated CRP. So at this point, while the data appears promising, it's too early to say what role mangosteen juice has in treating arthritis symptoms.
Mangosteen is a tropical fruit native to Southeast Asia. Despite its name, mangosteen is not related to the mango. The mangosteen fruit is the size and shape of a tangerine, with a thick, dark rind and creamy flesh. Mangosteen is marketed as a supplement, both as a juice and in capsule form.

20 cigarettes daily for 1 year equals 150 lung cell mutations

 

In-depth genetic research gives new insight into how smoking is capable of causing cancer in such a wide array of organs. The study provides a link between the number of cigarettes smoked and the number of mutations in tumor DNA.

Smoking is a killer; new research uncovers its modus operandi.

The negative health consequences of smoking are well known and have been heavily studied.
An estimated 6 million people die each year due to smoking-related illnesses.
If trends continue, according to the World Health Organization (WHO), there will be 1 billion tobacco-related deaths this century.
Smoking is known to cause irreparable damage in a variety of organs. It sparks mutations in DNA via a number of mechanisms.
However, it has not been clear how cancer generates so many different types of cancers in disparate body parts. To date, smoking has been associated with 17 types of cancer, but the genetic mechanisms behind this have remained hidden.
Researchers from the Wellcome Trust Sanger Institute and King's College London in the United Kingdom and the Los Alamos National Laboratory, NM, recently undertook a deep dive into the genetics of smoking-related cancers. Their results are published this week in the journal Science.
In the most detailed investigation of its type, scientists delved into the the DNA of 5,000 tumors. They compared tumors from nonsmokers with tumors from smokers and examined any genetic differences. The analysis allowed them to understand the molecular fingerprints of smoking-related DNA damage.
The researchers were able to study these mutational signatures and count the number of mutations in each tumor.

Counting tobacco-related tumor mutations

Once the data was in, the authors could measure the rate of mutations caused per cigarette smoked. They found that smoking a pack of cigarettes per day caused a predictable average number of mutations in the lungs over the course of a year.
"Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking," says first author Dr. Ludmil Alexandrov, of the Los Alamos National Laboratory,.
"With this study, we have found that people who smoke a pack a day develop an average of 150 extra mutations in their lungs every year, which explains why smokers have such a higher risk of developing lung cancer."
The team also developed a clearer picture of the effects of cigarettes on mutations in other organs. They found that a pack a day led to:

• 97 mutations in each cell in the larynx
• 39 mutations in each cell in the pharynx
• 23 mutations in each cell in the mouth
• 18 mutations in each cell in the bladder
• 6 mutations in each cell in the liver.

As mentioned previously, how mutations affect organs of the body other than lungs has been difficult to understand. This new research uncovered ways in which tobacco can develop mutations in different tissues and organs.

"Mutations caused by direct DNA damage from carcinogens in tobacco were seen mainly in organs that come into direct contact with inhaled smoke. In contrast, other cells of the body suffered only indirect damage, as tobacco smoking seems to affect key mechanisms in these cells that in turn mutate DNA."

Study co-author Prof. David Phillips, King's College London

Of the five distinct processes by which DNA is damaged by tobacco smoke, the most widespread was one already found in other nonsmoking-related cancers. The team found that smoking accelerated the speed of a cellular clock that prematurely mutates DNA.

Looking into the future of cancer research

The researchers were surprised by some of the results; smoking-related cancers are more complex than previously thought.
Prof. Sir Mike Stratton, from the Wellcome Trust Sanger Institute and joint lead author, says: "This study of smoking tells us that looking in the DNA of cancers can provide provocative new clues to how cancers develop and thus, potentially, how they can be prevented."
Medical News Today recently asked Dr. Alexandrov if they plan to carry out more research in a similar vein. He said:
"This study has shown that molecular profiling of cancer patients can be used to identify the mechanisms by which different carcinogens cause cancer. We are planning future studies to reveal the mechanisms by which other known epidemiological factors cause cancer. For example, we are currently working on elucidating the mechanisms by which obesity causes cancer.​"
When MNT asked him what research he would carry out if he was given unlimited time, money, and resources, he said: "I would molecularly profile every single cancer patient across the world to better understand the causes of cancer and use this knowledge for developing future cancer prevention strategies.​"
The current results mark a milestone along the path to understanding how smoking-related cancers negatively influence DNA. There is still much to know, but investigations such as this will steadily bring us closer to understanding and preventing cancer on a molecular level.
Learn how deadly brain cancer genes were identified.

Written by Tim Newman

 Research has found several risk factors that may increase your chances of getting lung cancer.

Smoking

Cigarette smoking is the number one risk factor for lung cancer. In the United States, cigarette smoking is linked to about 80% to 90% of lung cancers. Using other tobacco products such as cigars or pipes also increases the risk for lung cancer. Tobacco smoke is a toxic mix of more than 7,000 chemicals. Many are poisons. At least 70 are known to cause cancer in people or animals.
People who smoke cigarettes are 15 to 30 times more likely to get lung cancer or die from lung cancer than people who do not smoke. Even smoking a few cigarettes a day or smoking occasionally increases the risk of lung cancer. The more years a person smokes and the more cigarettes smoked each day, the more risk goes up.
People who quit smoking have a lower risk of lung cancer than if they had continued to smoke, but their risk is higher than the risk for people who never smoked. Quitting smoking at any age can lower the risk of lung cancer.
Cigarette smoking can cause cancer almost anywhere in the body. Cigarette smoking causes cancer of the mouth and throat, esophagus, stomach, colon, rectum, liver, pancreas, voicebox (larynx), trachea, bronchus, kidney and renal pelvis, urinary bladder, and cervix, and causes acute myeloid leukemia.

Secondhand Smoke

Smoke from other people’s cigarettes, pipes, or cigars (secondhand smoke) also causes lung cancer. When a person breathes in secondhand smoke, it is like he or she is smoking. In the United States, two out of five adults who don’t smoke and half of children are exposed to secondhand smoke, and about 7,300 people who never smoked die from lung cancer due to secondhand smoke every year.

Radon

Radon is a naturally occurring gas that comes from rocks and dirt and can get trapped in houses and buildings. It cannot be seen, tasted, or smelled. According to the U.S. Environmental Protection Agency (EPA), radon causes about 20,000 cases of lung cancer each year, making it the second leading cause of lung cancer. Nearly one out of every 15 homes in the U.S. is thought to have high radon levels. The EPA recommends testing homes for radon and using proven ways to lower high radon levels.

Other Substances

Examples of substances found at some workplaces that increase risk include asbestos, arsenic, diesel exhaust, and some forms of silica and chromium. For many of these substances, the risk of getting lung cancer is even higher for those who smoke.

Personal or Family History of Lung Cancer

If you are a lung cancer survivor, there is a risk that you may develop another lung cancer, especially if you smoke. Your risk of lung cancer may be higher if your parents, brothers or sisters, or children have had lung cancer. This could be true because they also smoke, or they live or work in the same place where they are exposed to radon and other substances that can cause lung cancer.

Radiation Therapy to the Chest

Cancer survivors who had radiation therapy to the chest are at higher risk of lung cancer.

Diet

Scientists are studying many different foods and dietary supplements to see whether they change the risk of getting lung cancer. There is much we still need to know. We do know that smokers who take beta-carotene supplements have increased risk of lung cancer.

 

Can E-Cigarettes Survive The War Against Vaping?

 

The Food and Drug Administration regulations referred to in this story as pending, came out May 5. As expected, the rules require e-cigarette makers to put all products that came on the market after February 15, 2007, through an extremely costly, retroactive pre-market application process, that will likely put thousands of vaping entrepreneurs out of business. Companies have a two-year period to comply. The regulations also ban the sale of e-cigarettes to Americans under 18.
In the winter of 2008 Jan Verleur was living on the outskirts of Prague, working on a novel about three failed Internet entrepreneurs who invest their dwindling capital in an ecstasy-smuggling ring. It wasn't exactly autobiographical, but Verleur, now 36, was writing from experience with failed ventures. His most recent had been an ambitious pornography business that lost $22 million of investors' money, including $1.6 million of his own.
One day, as he was picking up a pack of smokes at a Vietnamese convenience store, he noticed a box of e-cigarettes. He tried one, and it leaked liquid into his mouth. "The technology wasn't ready for market," he says, "but the idea struck me as amazing." Soon after, Dan Recio, his buddy and colleague in the porn business, persuaded him to return to the U.S. and take another crack at making money by satisfying a different human craving.

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The nascent e-cig market was wide open. Startup costs were low, and regulation was nonexistent. The potential payoff looked huge: Vaping seemed poised to grow into an enormous global market for a healthier product. Invented in 2003 by a Chinese pharmacist whose father had died of lung cancer, e-cigarettes use lithium-ion batteries to heat nicotine-laced liquid, turning it into a vapor that has only traces of some of the 60-plus carcinogens in cigarette smoke. At first Verleur and Recio's Miami-based company, VMR, looked to be riding a big, beautiful wave.
But the industry has shifted dramatically in the six years since Verleur and thousands of other entrepreneurs jumped in. Demand for e-cigs has turned out to be smaller than at first expected. It grew from virtually nothing a decade ago to an estimated $3.7 billion in the U.S. last year, according to ECigIntelligence, a British outfit that supplies information to the industry. But Nielsen NLSN +0.69% reports that sales in convenience stores and big retailers like Wal-Mart have started to contract, shrinking 6.2% in the 52 weeks that ended Mar. 26. Nielsen doesn't capture sales online or in America's 10,000 vape shops, but last year those channels were flat for VMR, which logged 2015 revenue of $50 million. All told, e-cig sales still pale in comparison with the $92 billion U.S. cigarette market.
Many smokers try e-cigs once and abandon them, disappointed that vapor doesn't taste or feel the same as real smoke in their mouths and throats and gives a slower nicotine hit. "There is a lot of trial and a lot of rejection," says tobacco analyst Vivien Azer, of Cowen and Company, in New York. "I'm not convinced the e-cigarette market will grow at all."
Meanwhile the forces arrayed against the many little players trying to grab a piece of that smaller-than-expected pie are daunting. Vaping entrepreneurs are up against a three-headed monster--Big Tobacco, the Food & Drug Administration and an army of antismoking zealots--which is able and more than willing to wipe them out.
Tobacco giants like Reynolds and Altria have leveraged their fat balance sheets, huge sales forces and established distribution channels to enter the e-cig market and now own the top four brands in the U.S. Vaping cognoscenti say those are inferior devices that don't really threaten Big Tobacco's core product, traditional cigarettes (the tobacco companies insist they are committed to their cigarette alternatives).

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More ominous for smaller players like Verleur: The FDA is expected to announce regulations soon that will treat e-cigs as tobacco products. If a draft rule released by the FDA in 2014 stands, thousands of e-cig products on the market will have to go through an onerous preapproval process that e-cig companies say could cost them as much as $2 million per item. (The FDA puts the figure at $330,000.) VMR, which sells mostly online and doesn't need to limit itself to what will fit in a convenience store display, offers more than 500 types of e-liquids, vaporizers and e-cig accessories, so fully complying with the new regulations will cost it anywhere from $175 million to $1 billion. Daniel Walsh, CEO of Purebacco, an e-liquid maker in Gaylord, Mich., which sells more than 200 selections, calls the impending rules "Vapocalypse."
The FDA has been egged on by antismoking groups like the American Lung Association and the Campaign for Tobacco-Free Kids, which have taken a hard line against vaping. Ignoring or minimizing the fact that millions of smokers have used e-cigs to quit or cut down, the antismoking lobby instead obsesses over the minimal health risks of vaping. They prefer that would-be quitters stick with patches and gum, which work as little as 7% of the time. Some 70% of American smokers say they want to quit, and 480,000 people died last year of smoking-related illness.
One tobacco industry consultant, who did not want to be quoted on the record for fear of irritating his powerful clients, recently remarked that the warnings against e-cigs by one prominent antismoking public health professor are "the best p.r. campaign for cigarettes going."
In an e-mailed statement, FDA spokesman Michael Felberbaum says, "The FDA's responsibility is to protect Americans from tobacco-related disease and death," insisting that the agency's objective is to learn as much as it can about e-cigs before approving them rather than put anyone out of business. Yet the proposed rules require that companies present comprehensive research findings on the impact of every product on the entire population and gauge the likelihood that ex-smokers will start vaping, a near-impossible task for small players like VMR.
Joel Nitzkin, former cochair of the Tobacco Control Task Force of the American Association of Public Health Physicians, who is now a fellow at a free-market think tank called R Street Institute, says of the FDA, "They think they're on a mission from God. The horrific part is that they're going to maintain cigarettes as the lead nicotine-delivery product in American society." What's more, he says, "they are refusing either to tell the public or allow manufacturers and vendors to tell the public about the difference in risks between e-cigarettes and tobacco cigarettes." Indeed, even if a vaping company can jump through the FDA's proposed regulatory hoops, it won't be allowed to claim its products pose less harm than traditional cigarettes.
No one suggests that e-cigs are completely safe. They deliver nicotine, which can interfere with brain development in young people, harm a developing fetus and pose risks to people with cardiovascular disease. E-cig vapor contains a dozen or so of the carcinogens found in cigarette smoke, though at very low levels. As an August 2015 report from Public Health England, an arm of the U.K.'s health service, reported last year, e-cigs are 95% safer than cigarettes. This April the Royal College of Physicians cited that figure and urged smokers to switch to vaping.
But the British evidence hasn't swayed antismoking advocates like the American Lung Association's assistant vice president of national advocacy, Erika Sward, who says she's worried that e-cig makers are marketing to kids with flavors like cotton candy, that the majority of vapers continue to smoke and that former smokers will start vaping. "Cigarettes are the nuclear option," she says. "That doesn't make conventional warfare any less deadly."
Media reports have fed the idea that e-cigs pose all sorts of dangers. In January 2015 the New England Journal of Medicine published a study that showed toxic levels of formaldehyde could be produced by a high-powered vaporizer. The report also noted that no one would ever heat e-liquid to that temperature. Likewise, when a Harvard study showed the presence of the chemical diacetyl in 75% of e-liquids, there were headlines about e-cigs causing irreversible scarring of the lungs, despite the fact that diacetyl is present in extremely low doses. The toxic chemical is hundreds of times more plentiful in traditional cigarettes.
Since Verleur started VMR, the American e-cig market has stratified into two broad segments: "cigalikes," which mimic traditional cigarettes, and "mods," which are more powerful and satisfying.
The differences are striking. Cigalikes, which include VUSE (Reynolds), MarkTen (Altria), blu (Imperial Tobacco) and Logic (JTI), are the Budweisers and Millers of the vapor market, sold in convenience stores and chain retailers. They are packaged to look like cigarettes, with a long, tubular battery making up the body, a cartridge of fluid where the filter would go and, on the tip, an LED that glows when in use. A VUSE startup kit costs $10 for a vaporizer, a battery charger and a cartridge of liquid that roughly equals a pack of cigarettes. Replacement cartridges are $6 for a pack of two.
Mods are more like craft brews. There are thousands of them, and they're typically modified to accommodate more powerful batteries, for a greater volume of vapor and a more satisfying experience. Mods are open systems, meaning that the vaper buys bottles of nicotine liquid and fills the tank herself. Most are made by mom-and-pop entrepreneurs and small companies like VMR. They sell mainly in vape shops, which stock e-liquids that cost as little as $1.20 for the equivalent of a pack of cigarettes.
Big Tobacco brands have light-years to travel before their e-cigs make anywhere near the money combustibles do. Extrapolating from Nielsen-tracked retail sales numbers, the four top brands combined were responsible for just $300 million in U.S. revenue last year, barely a rounding error in an industry where, in the same period, Reynolds alone brought in nearly $11 billion. Also e-cigs yield little if any profit. VUSE, the No. 1 brand, which Reynolds introduced in 2014, was still in the red at the end of last year. Among the reasons for the poor performance, says tobacco analyst Vivien Azer: e-cigs' relatively high manufacturing cost and heavy discounting to attract customers. By contrast, gross margins on Reynolds' traditional tobacco products were 44% last year, according to Azer. (Reynolds declines to comment except to say that it is continuing to invest in VUSE.)
At VMR, Verleur has pushed to attract both the masses and the connoisseurs, offering cigalikes, mods and multiple e-liquids in convenience stores, online and in vape shops. Unlike the Big Tobacco brands, which focus on the domestic market, a quarter of his business is overseas, where he sells in 30 countries. In December he sold a 51% stake to a Chinese company, Huabao, in exchange for entrée to a largely untapped market, where some 315 million smokers spend more than $200 billion a year on cigarettes. Controlled by billionaire Chu Lam Yiu, Huabao had $558 million in revenue last year and, at least in theory, deep enough pockets to pay for regulatory compliance back in the U.S. The company supplies tobacco flavoring to the state cigarette monopoly and already sells e-cigs to the Chinese market. Huabao paid $23 million and left Verleur in control as chairman and CEO. (The deal includes a golden parachute that he says will pay him more than $23 million should he be ousted.) The three-headed monster has hounded him into business exile .
These days Verleur shuttles back and forth between China and Florida. He lives half the year in a hotel in Shenzhen, where VMR has 60 full-time employees and contracts with 3,000 workers in two factories. The rest of the time he's in Miami, where he says he's "homeless" after splitting up with the mother of his third child. ("I'm a hard person to have a relationship with.") He sometimes sleeps in a room next to his office, making conference calls to China at 3 a.m., or stays in a company apartment nearby. He keeps a packed suitcase in the trunk of his Jeep, which is covered in shiny bronze bulletproof Kevlar. "I bought it because it looked cool," he says.
Before he hit on e-cigs, Verleur displayed a knack for sales and hit-or-miss entrepreneurship. As a freshman at Penn State, he says, he made as much as $30,000 a month selling $1,000 Cutco knife sets before dropping out. Next he got a job in Orlando with a company that sold Web-design services. Then he followed a Cuban girlfriend to Miami, where he started and shut down a series of businesses, including one that sold sales-intelligence software and another that supplied Indian tech workers to American companies. "There were times when I'd have a million-dollar year," he says, "and other times I'd lose a couple hundred grand."
Or more. In 2003 he tried to build an online venture he hoped would become "the HBO of porn." It produced its own Internet programming, including a reality show called The Brothel, at studios in Miami and Prague. He planned to sell sex toys and lingerie on the shows and to pipe live porn into hotel rooms. "If I had endless capital," he shouts over a plate of bacon-wrapped dates at a trendy Miami restaurant, music thumping, "I think we'd be the largest adult entertainment company in the world today."
When he got around to e-cigs, in 2010, he figured he'd be most successful online, where there were only a handful of poorly designed sites selling them. He and Recio invested $7,500 each, as did a third partner. Within a year VMR had moved into a ten-story glass-and-steel office building in Miami, and revenue hit $19 million. Two years later, revenue ballooned to $75 million and the head count was at 180, split among Miami, Shenzhen, a distribution center in Prague and small offices in Hamburg, London, Moscow and Hong Kong. Then came two years of declining sales and growing concerns about regulation.

Electronic cigarettes (or e-cigarettes) are battery powered devices which heat liquid (also called e-liquid) into an aerosol which is inhaled into a person’s lungs^[1]. The aerosol is often called ‘vapour’.
E-cigarettes are also called electronic nicotine delivery systems (ENDS), alternative nicotine delivery systems (ANDS), or e-cigs.
Unlike tobacco cigarettes, where the smoke from burning tobacco is inhaled, the e-cigarette user inhales an aerosol which may contain nicotine, propylene glycol and other chemicals into their lungs^[1]. Inhaling the aerosol is usually called ‘vaping’.
When e-cigarette is being used, the user inhales and exhales the vapour which may give the appearance of smoke.
E-liquids are often flavoured, with over 7,000 flavours available such as tobacco, confectionery, fruit and chocolate^[2]. They may or may not contain nicotine and may or may not be labelled as containing nicotine^[3].
E-cigarettes may be shaped and coloured to make them look like cigarettes or other tobacco products like cigars, cigarillos, pipes, hookahs or shishas. E-cigarettes are also sometimes made to look like everyday items such as pens or USB memory sticks^[3].
E-cigarettes can either be disposable or re-useable. Most devices include a battery, an airflow sensor (to activate the power from the battery), an aerosol generator (to turn the e-liquid into an aerosol) and e-liquid.

Are e-cigarettes legal in NSW?

On 25 June 2015, the NSW Parliament passed the Public Health (Tobacco) Amendment (E-cigarettes) Act 2015 to amend the Public Health (Tobacco) Act 2008. The Act was assented on 30 June 2015. The changes to the Act define e-cigarettes and e-cigarette accessories to be separate from tobacco products. The Act makes many of the provisions that apply to tobacco products also apply to e-cigarette and e-cigarette accessories.
The changes commenced in two stages.
From 1 September 2015 it is an offence:

• to sell e-cigarettes and e-cigarette accessories to minors under the age of 18
• for adults to buy e-cigarettes and e-cigarette accessories on behalf of minors
• to operate or use a vending machine that dispenses e-cigarettes and/or e-cigarette accessories on behalf of a minor.

NSW Police have the power to seize an e-cigarette that is in the possession of a person under the age of 18.
From 1 December 2015:

• it is an offence to use e-cigarettes in cars with children under the age of 16 present
• new provisions apply to the display and advertising of e-cigarettes and accessories.

The sale of e-cigarettes and e-cigarette accessories to a minor is subject to the same maximum penalty as the sale of a tobacco product to a minor:

• a penalty of $11,000 for an individual or $55,000 for a corporation; and
• for repeat offenders, a penalty of $55,000 for an individual and $110,000 for a corporation.

For more information about these new laws, read the following fact sheets:

•  Use of e-cigarettes with kids in the car is against the law
•  Ban on the display of electronic cigarettes and accessories in retail outlets and locations in which they can be sold
•  Ban on the advertising of electronic cigarettes and accessories

It is important to note that the sale of liquid nicotine, including in liquids used in e-cigarettes, is illegal under NSW Poisons legislation (Poisons and Therapeutic Goods Regulation 2008 NSW) without approval from the NSW Ministry of Health unless the product is listed or registered on the Australian Register of Therapeutic Goods.
If you see an e-cigarette or e-liquid that is labelled as containing nicotine, you can report this to NSW Health by email ecigs@doh.health.nsw.gov.au.
To find out more about the law and e-cigarettes, read  Are electronic cigarettes legal in NSW? It includes information about NSW tobacco legislation, NSW poisons legislation and national therapeutics legislation.

Are e-cigarettes and liquids safe?

To find out more about whether e-cigarettes and their liquids are safe, read  Are electronic cigarettes and liquids safe?

Can e-cigarettes help me to quit smoking?

To find out more about whether e-cigarettes can help you to quit smoking, read  Can electronic cigarettes help me to quit smoking?​​​​
The NSW Government encourages all smokers to quit smoking. You can get help from the Quitline 13 7848; a free telephone based counselling service, the iCanQuit website and your General Practitioner or pharmacist.

Public health warning

Some e-cigarettes and e-liquids which are labelled as containing no nicotine have been found upon analysis in Australia to actually contain significant quantities of nicotine. Scientific testing undertaken by the NSW Ministry of Health showed that many of the liquids used in e-cigarettes contained high levels of nicotine that, if swallowed are potentially lethal. A public health warning was released in October 2013 to raise consumer awareness of the potential risks of these products. 

Refere​nces

1. World Health Organization, Electronic nicotine delivery systems: Report by WHO. 2014.
2. Zhu, S.-H., et al., Four hundred and sixty brands of e-cigarettes and counting: implications for product regulation. Tob Control, 2014. 23 Suppl 3: p. 3-9.
3. Brown, C.J. and J.M. Cheng, Electronic cigarettes: product characterisation and design considerations. Tob Control, 2014. 23 Suppl 2: p. 4-10.