Autism - Hyperbaric Oxygen Chamber Therapy

Hyperbaric Oxygen Chamber Therapy and Autism - Recently, hyperbaric oxygen therapy (HBOT) has increased in popularity as a treatment for autism.

Numerous studies document oxidative stress and inflammation in individuals with autism; both of these conditions have demonstrated improvement with hyperbaric oxygen therapy, along with enhancement of neurological function and cognitive performance.

In this study, children with autism were treated with hyperbaric oxygen therapy at atmospheric pressures and oxygen concentrations in current use for this condition. Changes in markers of oxidative stress and inflammation were measured. The children were evaluated to determine clinical effects and safety.

In some studies, the use of oxygen appears to enhance neurological function. For instance, in a double-blind, placebo-controlled, cross-over study, oxygen administration in healthy young adults, when compared to room air, was demonstrated to enhance cognitive performance, including improved performance on attention, reaction times, and word recall. (Psychopharmacology (Berl) 1998, 138(1):27-33).

Additionally, in elderly patients, hyperbaric oxygen therapy (HBOT) at 2.5 atm and 100% oxygen, when compared to a control group, improved cognitive function, including memory. (N Engl J Med 1969, 281(14):753-757).

Because of these outcomes, some investigators have used HBOT to treat certain neurological disorders, including chronic and traumatic brain injury, as well as fetal alcohol syndrome, and clinical improvements in these patients have been observed.

Hyperbaric oxygen therapy for children is generally regarded as safe, even at pressures of 2.0 atm for 2 hours per day. However, to our knowledge, the safety of HBOT for autistic children has not been previously studied; a review of MEDLINE indicates that there are no prospective studies on the use of hyperbaric oxygen therapy for autism.

Yet, there are anecdotal reports of clinical improvements in autistic children with hyperbaric therapy that have been reported by some physicians.

For instance, Heuser et al. treated a four year old child with autism using hyperbaric therapy at 1.3 atm and 24% oxygen and reported “striking improvement in behaviour including memory and cognitive functions” after only ten sessions.

This child also had marked improvement of cerebral hypoperfusion as measured by pre-hyperbaric and post-hyperbaric Single Photon Emission Computed Tomography (SPECT) scans.

Another case series suggested that hyperbaric therapy at 1.3 atm led to clinical improvements in six autistic children. (Med Hypotheses 2006, 67(2):216-228).

However, the effects of hyperbaric oxygen therapy on oxidative stress in autistic individuals are unknown. To our knowledge, there have been no studies performed which examine the role of hyperbaric oxygen therapy on oxidative stress in autistic children.

This present study examined hyperbaric therapy at the low and the high ends of the ranges of atmospheric pressures and oxygen concentrations currently employed in individuals with autism: 1.3 atm and 24% oxygen, and 1.5 atm and 100% oxygen.

This study had several objectives. First, since increased oxidative stress is found in some autistic children, the effects of hyperbaric oxygen therapy (HBOT) on oxidative stress markers before and after 40 hyperbaric treatments were measured. Second, evidence of increased inflammation is found in many autistic individuals.

HBOT is also known to have anti-inflammatory effects; therefore, the impact of hyperbaric oxygen therapy on an inflammatory marker (C-reactive protein) was measured.

Third, since the efficacy of hyperbaric oxygen therapy in autism has not been previously evaluated, this current open-label pilot study (without a placebo control group) examined the changes in clinical symptoms, as rated by parents or caregivers, after treatment with hyperbaric oxygen therapy.

Finally, the safety of HBOT, used at 1.3 and 1.5 atm, was evaluated in autistic children.

Eighteen children with autism, ages 3-16 years, underwent 40 hyperbaric sessions of 45 minutes duration each at either 1.5 atmospheres (atm) and 100% oxygen, or at 1.3 atm and 24% oxygen.

Measurements of C-reactive protein (CRP) and markers of oxidative stress, including plasma oxidized glutathione, were assessed by fasting blood draws collected before and after the 40 treatments. Changes in clinical symptoms, as rated by parents, were also assessed. The children were closely monitored for potential adverse effects.

This prospective open-label pilot study in children with autism indicates, as measured by changes in plasma oxidized glutathione, that hyperbaric oxygen therapy ranging from 1.3 to 1.5 atm and 24% to 100% oxygen was not significantly associated with increased intracellular oxidative stress.

The use of therapies to raise glutathione levels and lower oxidative stress before beginning hyperbaric oxygen therapy in individuals with autism appears prudent.

Among children with high initial C-reactive protein, hyperbaric therapy led to a large improvement in CRP levels; this suggests that inflammation in these children improved with treatment.

Parental observations support anecdotal accounts of improvement in several domains of autism.

Note: A report on CBS4 in Denver quoted Dr. Daniel Rossignol, the principal researcher of this study, as saying: "We've had more language, sometimes had new words, that type of thing, or (patients have) started putting more words into sentences. We also found improvements in cognition, which means their ability to think, focus ... that type of thing."

Related Articles:

Signs of Autism in Infants – Parents See Signs Long Before Professionals

References:

Extracted and adapted from: The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: an open-label pilot study. BMC Pediatrics 2007, 7:36 doi:10.1186/1471-2431-7-36.
© 2007 Rossignol et al., licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).

http://cbs4denver.com/health/local_story_223173252.html

Disclaimer: The information contained in this article is presented for information purposes only and is in no way intended to replace professional medical care or attention by a qualified practitioner. It cannot and should not be used as a basis for diagnosis or choice of treatment.

Signs of Autism in Infants – Parents See Signs Long Before Professionals

Signs of Autism in Infants – Parents See Signs Long Before Professionals: Parents notice signs of autism spectrum disorders in infants as early as 6 months of age, but diagnosis of children with autism spectrum disorders is generally not until the age 3 or 4 years.

Parents notice signs of autism spectrum disorders in infants as early as 6 months of age, but diagnosis of children with autism spectrum disorders is generally not until the age 3 or 4 years.

According to researchers at the Department of Psychology, Virginia Tech, in the United States, most children with autism spectrum disorders were diagnosed at age 3 or later. The average age of autism diagnosis was 4 years and 10 months.

Research in the United States found that parents noticed symptoms of autism as early as 6 months of age, but diagnosis was not until age 3 or 4 years. (Nova Biomedical Books 2004:103-123).

A study in the United Kingdom found that the average age of diagnosis of a child with autism spectrum disorder was 6 years, even though most families felt that something was wrong with their child at 18 months and sought medical attention when their child was 2 years old. (Neurology 2000, 55:468-479).

Others have found that the average delay between when a parent first seeks help and the time of autism diagnosis is 4 years. (Developmental Medicine and Child Neurology 1999, 41:834-839 and Autism 1997, 1:135-162).

It has been suggested that parents are often correct about concerns with their child’s development and symptoms of autism can frequently be seen before 12 months of age. So, it is significant that families are often aware of atypical development long before a diagnosis is established.

Paediatricians and family practitioners are usually the first healthcare providers that a family contacts for children under 5 years old, which is the critical age for a diagnosis of autism spectrum disorders.

Some possible reasons for a delay in diagnosis are that professionals may be concerned about the strong emotional reaction of parents when they are told that their child has autism, fear of negative consequences from labelling the child, and hope that the symptoms will reverse.

Furthermore, some medical providers in Queensland believe they have less adequate training than needed for assessing autism spectrum disorders. (Journal of Paediatrics and Child Health 2005, 41:413-419).

Another problem that can arise in the diagnostic process involves providing caregivers with accurate information about autism spectrum disorders and related treatment options at the time of diagnosis.

A study in France found when parents express concerns about autism spectrum disorders to paediatricians, the paediatricians often trivialized the disorders because of lack of knowledge about them. (Educational Psychology in Practice 1998, 14:109-117).

Other research indicated that 4th year medical students performed poorly on questions in a survey about the causation, IQ profiles, prognosis and treatment of autism. (Autism 2001, 5:127-133).

The authors of this study (see reference below) concluded:

In sum, we found that 1) most children with autism spectrum disorders were diagnosed at age 3 or later, 2) a substantial minority of diagnosing professionals (18%) provided no further information about autism spectrum disorders, and 3) caregivers reported turning to the media, conferences, or other parents to learn more about autism spectrum disorders.

We found that developmental paediatricians were most likely to diagnose at earlier ages and provide families with additional information, and that Autism was associated with earlier diagnoses than other autism spectrum disorders.

Our findings suggest, but do not prove, that paediatricians with specialized training make earlier diagnoses and are more likely to provide additional information to caregivers.

Reference:

Extracted and adapted from:

Rachel A Rhoades, Angela Scarpa, Brenda Salley. The importance of physician knowledge of autism spectrum disorder: results of a parent survey. BMC Pediatrics 2007, 7:37 doi:10.1186/1471-2431-7-37.
© 2007 Rhoades et al., licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License.(http://creativecommons.org/licenses/by/2.0)

Women With Depression During Pregnancy – Part 3

The women who have had anxiety and depression during pregnancy talk about their experiences.

Women in this study accounted for their experiences of depression in terms of symptoms, the events and circumstances that they perceived contributed to their depression, and the steps that they took to address their depression.

They told of an inability to function, an overwhelming anxiety, an inability to organize their thoughts, and trouble making decisions: tasks that “normally seemed easy, seemed huge” so that “getting through the day was horrendous”.

Overwhelmed and exhausted, the women confront their depression, and in the circumstance of their pregnancy, the depression was conceived as threatening to themselves, to their developing baby, and to their ability to mother the coming baby.

The problems confronting women in this study were a loss of control, an altered perception of self, and doubts about their maternal ability. The basic process for these women was becoming the best mom that I can.

From the women's perspective, becoming the best mom that I can was the process of “doing everything I could” to implement control over the perceived threat to their pregnancy and their ability to care for the baby after birth.

What the women do to regain control and reground the self, and how they do it, is juxtaposed with what they perceive to be the optimum situation for the developing fetus and 'soon-to-be' baby. They search relentlessly to find the most acceptable answer; they reflect upon the self, acknowledge the problem, and embark upon a journey to “put things into place before I have the baby”.

This process consists of four major categories:

Traveling into despair (causal conditions).

Conceiving the threat (phenomena).

Confronting and confining the threat (actions)

Regrounding self and regaining control (consequences).

Causal conditions of phenomena - Traveling into despair.

The conceptual category of traveling into despair describes the women’s experiences as symptoms of depression invaded their lives. Symptoms occurred at different stages of pregnancy for each woman; however, all described arriving at a point where they could not envisage themselves being any lower.

They used phrases such as: “traveling down into blackness”, “downward spiral”, “wandering around in a blur”, “constant state of despair,” “downhill”, “teetering”, “going crazy”, “falling apart”, “crash and burn” “sliding into a depression”, “into the pit of hell”, and “over the edge”.

The five properties that comprised traveling into despair were: Irrational emotions, Inability to function, Invasive thoughts, Pervasive anxiety, and Social withdrawal.

Irrational emotions
Women spoke of frequent episodes of sadness, anxiety, irritability, anger, crying, and worry which led to feelings of “low self-worth, low self-esteem” and guilt. They were at a loss to understand or to explain their emotions which seemed to occur for no apparent reason and often without warning.

One woman reported “just tears so close to the surface that anything would, I would just fall apart, and not just, it's not that sad, but it's almost irrational.” (#7) (Note: As mentioned in Part 1, confidentiality was maintained by assigning each participant a code number).

Inability to function
The inability to function invaded every aspect of their lives. From the simplest of activities such as personal hygiene to the more complex tasks required in the performance of the work-day role, inside and outside the home, the women told of impaired performance. One woman, who had an older child, told of her inability to care for her son, “I felt bad because I wasn’t at a point where I could take care of him how I usually take care of him.” (#3)

Invasive thoughts
Some women spoke of being unable to imagine their baby or imagining the baby “as this thing growing inside of me”. A number of women had what they described as invasive thoughts:

Like, I had a thought of a woman stabbing me in my stomach when I was pregnant, you know. A woman that I saw in the elevator one day, you know, so, those weird passive thoughts. (#16)

Many women spoke of the fear of losing their mind or going crazy, and, while none attempted suicide, some had thoughts of suicide due to the intense pain their feelings were causing:

I wasn’t planning to kill myself, or I hadn’t thought of ways to do it, but I just wished every single day that I was dead, you know, I didn’t want to live. (#21)

Pervasive anxiety
Many of the women were anxious; they felt that something bad might happen but were at a loss to explain this feeling.

It’s hard to explain this anxiety, because it’s like something horrible is wrong, like something horrible happened to you. But nothing horrible happened to me. I don’t know how to explain it. The anxiety was always there.

Social withdrawal
Women withdrew from their world as they had known it. They did not maintain old friendships, nor did they establish new connections. Instead, they retreated into their homes which one woman described as becoming a “hermit”. For some, interaction with others served only to highlight the intensity of their misery. Perhaps most illuminating was the following statement:

Even going to the [baby] showers is withdrawal, you know,balloons, and happy, and presents and friends, and nothing but people wanting to smile at you and you're just standing there like miserable, for no reason you can put your finger on. (#20)

Part 4 will be published soon - The women try to make sense of their feelings and are unable to do so.

Related articles:

Dealing with Depression during Pregnancy – Part 1

Depression During Pregnancy – Part 2

Depressed? Drink Tea

The researchers were Heather Bennett, Heather Boon, Sarah Romans and Paul Grootendorst. The above is a partially modified reproduction of their research. Also their references have been omitted for ease of reading.

Reference:

Bennett HA, Boon HS, Romans SE, Grootendorst P. Becoming the best mom that I can: women's experiences of managing depression during pregnancy – a qualitative study. BMC Women's Health 2007, 7:13 (11 September 2007). © 2007 Bennett et al., licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Long Term Use of ADHD Drugs Ineffective - Are you paying attention?

Long Term Use of ADHD Drugs Ineffective - Are you paying attention? - In some of my earlier articles I warned about ADHD drugs and their possible side-effects. Now, a study called the Multimodal Treatment Study of Children with ADHD, concluded that over the long term, ADHD drugs such as Concerta and Ritalin have no evident benefit for children.

When the cure is worse than the sickness

According to a recent BBC News article, the findings by an influential US study also suggested long-term use of drugs for the treatment of ADHD could stunt children's growth.

Really? I wrote an article on this some time back.

The aforementioned study of children with ADHD has been monitoring the treatment of 600 children across the US since the 1990s. Now, after longer-term analysis, the report's co-author, Professor William Pelham of the University of Buffalo, said: "I think that we exaggerated the beneficial impact of medication in the first study.” (BBC NEWS 12/11/2007).

Medical News Today reported that Professor Pelham said that it had been thought that kids would have better outcomes if they were medicated for longer - however, it is not the case, there were no beneficial effects at all. Pelham said: "In the short run they will help the child behave better, in the long run it won't. And that information should be made very clear to parents." (Medical News Today 12/11/2007).

I can't sum it up any better than Professor Pelham who said that behavioral therapy and a simple diet of Omega-3 may help a child as a first move.

Omega-3? Why didn’t I think of that! Try reading ADHD: Fish oil increases attention, reduces hyperactivity, restlessness and impulsivity.

While you are at it you may want to read the following:

ADHD Medications Stunt Growth

ADHD Drugs: Liver Injury, Heart Attack and Stroke

ADHD Improved When Tonsils Removed

ADHD – Is your child deficient in magnesium?

ADHD Ritalin - Depression and Brain Damage

ADHD Drug Treatment and Hallucinations

Is Starting a New Exercise Program Your New Years Resolution?

Is Starting a New Exercise Program Your New Years Resolution? - Struggling with your New Year's resolution to attend aerobics class five times a week, or run two miles a day?

A Kansas State University professor says if you haven't been active, and you are beginning a new exercise program, take it slow and start out by adding activities you enjoy.

"I think you have to get away from the idea that you have to go and start a structured exercise program because it's the new year," said David Dzewaltowski, head of K-State's kinesiology department.

"Fifty percent of those who start an exercise program drop out within the first few weeks. A few stay eight weeks or so, but after six months most people drop out of those programs. And the reason they drop out is because they try to start an activity they think is the best thing for them to do."

Dzewaltowski says a much better strategy is to find something you like to do that happens to include activity. However, the catch is that the lower the intensity, the longer you have to do it.

"An hour's worth of gardening, depending on how hard you're gardening, may be equivalent to a 20-minute walk," said Dzewaltowski. "So you can get rid of exercise by working real hard three days a week, or by just building activity throughout the day and increasing your active lifestyle."
"If you are starting an exercise program and you haven't been active, I would recommend during the winter months to start increasing your activity and do more things that you enjoy," Dzewaltowski said, "whether that is walking outside, going to the mall and doing more walking, or taking the stairs more often."

Find an activity that fits into your lifestyle that you can do for 30 minutes most days of the week, Dzewaltowski added. "You could break that 30 minutes up so you're doing 10-minute walks or 10-minute sessions of exercise in your house -- those sorts of things."

Dzewaltowski cites the Centers for Disease Control and the surgeon general's recent report advocating moderate activity for 30 minutes on most days of the week.

"This means getting out and moving, maybe with brisk walking for 30 minutes on most days of the week," he said. "And if you are already doing that, it would be important to add a vigorous exercise session three days a week, and try to reach your target heart rate."

Used with permission.
Photo courtesy of USDA, ARS

The Benefits of Beta Carotene & Lutein – From Cancer to Macular Degeneration

The Benefits of Beta Carotene & Lutein – From Cancer to Macular Degeneration - Carotenoids are fat-soluble pigments responsible for many of the colorful hues of plant leaves, fruits, and flowers.

They also act as biological antioxidants, protecting cells and tissues from damage caused by naturally occurring oxygen free radicals in the body. And they’ve been linked to enhancing immune system function, protecting from sunburn, and inhibiting development of certain cancers.

Beta-carotene and lutein are two important carotenoids. Not only does beta-carotene give carrots their orange color, it may also be an important means of lessening the vitamin A deficiency prevalent in much of the world.

Lutein, a major yellow pigment in corn and leafy green vegetables, is believed to protect the human retina’s macular region, reducing risk of the macular degeneration responsible for the most common age-related blindness.

Using isotopes to tag carotenoids in kale, a food especially rich in nutrients, researchers have increased their understanding of how the human body absorbs and uses carotenoids from a whole food and how efficiently the body uses beta-carotene to form vitamin A.

The work was reported in the Journal of Lipid Research.

Source: USDA, Agricultural Research Service. Beverly A. Clevidence, USDA-ARS Diet and Human Performance Laboratory, Beltsville, Maryland; phone (301) 504-8367. Photo courtesy of USDA, Agricultural Research Service. Used with permission.

Related articles:

Natural vitamin E has roughly twice the availability of synthetic vitamin E

Vitamin E – Cancer, Alzheimer’s and Heart Disease - Alpha or Gamma?

Depression During Pregnancy – Part 2

Depression During Pregnancy - The potential side effect of many drugs having the ability to cause defects in a developing fetus and the behavioral impact of antidepressant use on the infant.

Despite the rapidly increasing quantitative literature on the clinical outcomes of maternal depression, little is known about pregnant women’s subjective experiences of depression. A review of the literature failed to reveal any publications exploring women’s experiences, feelings and perceptions of depression during pregnancy.

This is surprising given recent findings that major depressive disorder MDD is a leading cause of disease burden for women, the extensive exploration of women’s experiences of postpartum depression (PPD), and the current emphasis on disability due to mental health.

Given the intense concerns of women and their healthcare providers over possible teratogenicity (potential side effect of many drugs having the ability to cause defects in a developing fetus) and the behavioral impact of antidepressant use on the infant, the treatment experience of depression during pregnancy is likely to differ substantively from that of postpartum depression.

Furthermore, it has been suggested that there may be a “different biologic basis or vulnerability” to depression in pregnancy than in the postpartum resulting in different symptom profiles. Although existing qualitative literature exploring postpartum depression may have some relevance to the experience of depression in the prenatal period, there may also be differences between the two reproductive phases and extrapolation from one to the other is risky.

The aim of this research was to explore women’s experiences of depression during pregnancy and to develop a theoretical model for the processes they used to manage their depression. It is concerned with the women’s personal experiences, how they make sense of those experiences, and how those meanings relate to their management of the disorder.

Understanding how the women view this disorder and its management has the potential to provide fresh perspectives for the delivery of care.

To understand the process of managing prenatal depression there must be an appreciation of the women’s experiences, comprehension of their understandings of the world in which they live, and an understanding of their moral judgments. Symbolic interactionists believe: 1) That objects have meaning only through people’s interactions with them in the environment, 2) That the meanings people have for things develops through social interaction, and 3) That those meanings are handled and modified by a constant and ongoing interpretive process by individuals.

Thus, symbolic interactionism provides a useful framework within which to study depression, a disorder “deeply connected with individual and collective interpretations”.

Data about the woman’s experiences of depression were collected through individual, in-depth, semi-structured, audio-taped interviews. Women were invited to propose the time and location of the meeting so that they would feel more empowered in the interaction encouraging them to share their experiences. Sixteen women elected to be interviewed in their own homes, the remaining three women were interviewed in a private room at the hospital.

Each interview began with the question “Can you tell me what it was like for you being depressed while you were pregnant”. This broad question served to “break the ice” leading to conversation that provided information on the woman’s views about depression, labelling, stigma, incidents contributing to her depression, her symptoms, the influence of depression on her relationships, her coping strategies, her experiences of help-seeking, and her feelings and beliefs about counselling and the use of antidepressants.

While the goal of the study was to obtain information in all areas, individual experiences of each woman dictated how much time was spent discussing each topic. Questions were asked to validate the women’s experiences and encourage them to show how they had reached particular conclusions. The final question was “Is there anything that we haven’t talked about that you would like to tell me or that you think I should know?”

To gain an awareness of the experiences described by the women, taped interviews were listened to immediately following each interview. The first four interviews were transcribed verbatim by Heather Bennett and the remainder by a professional medical transcriptionist. Heather Bennett verified, and corrected where necessary, all transcripts against the recordings.

Each transcript was read multiple times to gain familiarity with its content, to identify conceptual categories within the interview data, and to examine relationships between those categories.

Interview guide - core and probe questions, asked in semi-structured interviews, that pertain to the women’s depression experiences.

Can you tell me what it was like for you being depressed while you were pregnant?

• How did the depression affect your everyday life?
  
• What affect did it have on your relationships with your partner, children, family, friends or work colleagues?
  
• How did you make sense of the symptoms that you were experiencing?
  
• How would you describe the process of becoming aware that what you were feeling may have been depression?

Where there any events that you think contributed to your depressed mood?

• Did you experience any other issues like troubles with your job, money, or with family or friends at that time?


• How did those events contribute to your depression?

Before you went to see the doctor, what did you do about your mood and how you were feeling?

• Did you seek help or support from anyone? Was the support provided by that person helpful?


• What else did you do to cope with your mood? Did anyone comment on the way you were coping?


• What do you think would have helped you cope with your depression?

How did you make the decision to seek professional help for your mood?

• Did you have any concerns about going to your doctor about your mood?


• What were your expectations of the doctor?

What type of help did your doctor suggest for your depression?

• Did you take medication or have counseling for your mood while you were pregnant?


• How did you make that decision about that? Who or what information helped you make that decision?


• How hard was that decision?


• How did you feel about the way that your doctor helped you to manage/treat your mood?


• Did you wish that your doctor had managed/treated your depression differently?

How did you feel when you got the diagnosis of depression?

• What did that mean to you?


• Did you tell anyone? Who? Why/why not?


• How did you cope with this ‘label’?


• How did you change when you got the diagnosis of depression?

How has your mood been since the birth of your baby?

• How did your mood affect your attachment with your baby?


• How did your mood affect your sense of yourself as a mother?

Is there anything else that you would like to tell me or that I should know?

Part 3 will be published soon.

Related articles:

Dealing with Depression during Pregnancy – Part 1
Depressed? Drink Tea

The researchers were Heather Bennett, Heather Boon, Sarah Romans and Paul Grootendorst. The above is a partially modified reproduction of their research. Also their references have been omitted for ease of reading.

Reference:
Bennett HA, Boon HS, Romans SE, Grootendorst P. Becoming the best mom that I can: women's experiences of managing depression during pregnancy – a qualitative study. BMC Women's Health 2007, 7:13 (11 September 2007). © 2007 Bennett et al., licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.