A Simple Method for Evaluating the Clinical Literature

The “PP-ICONS” approach will help you separate the clinical wheat from the chaff in mere minutes.

Robert J. Flaherty, MD

Keeping up with the latest advances in diagnosis and treatment is a challenge we all face as phycians. We need information that is both valid (that is, accurate and correct) and relevant to our patients and practices. While we have many sources of clinical information, such as CME lectures, textbooks, pharmaceutical advertising, pharmaceutical representatives and colleagues, we often turn to journal articles for the most current clinical information.

Unfortunately, a great deal of research reported in journal articles is poorly done, poorly analyzed or both, and thus is not valid. A great deal of research is also irrelevant to our patients and practices. Separating the clinical wheat from the chaff can take skills that many of us never were taught.

KEY POINTS

• Reading the abstract is often sufficient when evaluating an article using the PP-ICONS approach.
• The most relevant studies will involve outcomes that matter to patients (e.g., morbidity, mortality and cost) versus outcomes that matter to physiologists (e.g., blood pressure, blood sugar or cholesterol levels).
• Ignore the relative risk reduction, as it overstates research findings and will mislead you.

The article “Making Evidence-Based Medicine Doable in Everyday Practice” in the February 2004 issue of FPM describes several organizations that can help us. These organizations, such as the Cochrane Library, Bandolier and Clinical Evidence, develop clinical questions and then review one or more journal articles to identify the best available evidence that answers the question, with a focus on the quality of the study, the validity of the results and the relevance of the findings to everyday practice. These organizations provide a very valuable service, and the number of important clinical questions that they have studied has grown steadily over the past five years. (See “Four steps to an evidence-based answer.”)

FOUR STEPS TO AN EVIDENCE-BASED ANSWER

When faced with a clinical question, follow these steps to find an evidence-based answer:

1. Search the Web site of one of the evidence review organizations, such as Cochrane (http://www.cochrane.org/cochrane/revabstr/mainindex.htm), Bandolier (http://www.jr2.ox.ac.uk/bandolier) or Clinical Evidence (http://www.clinicalevidence.com), described in “Making Evidence-Based Medicine Doable in Everyday Practice,” FPM, February 2004, page 51. You can also search the TRIP+ Web site (http://www.tripdatabase.com), which simultaneously searches the databases of many of the review organizations. If you find a systematic review or meta-analysis by one of these organizations, you can be confident that you’ve found the best evidence available.
2. If you don’t find the information you need through step 1, search for meta-analyses and systematic reviews using the PubMed Web site (see the tutorial athttp://www.nlm.nih.gov/bsd/pubmed_tutorial/m1001.html). Most of the recent abstracts found on PubMed provide enough information for you to determine the validity and relevance of the findings. If needed, you can get a copy of the full article through your hospital library or the journal’s Web site.
3. If you cannot find a systematic review or meta-analysis on PubMed, look for a randomized controlled trial (RCT). The RCT is the “gold standard” in medical research. Case reports, cohort studies and other research methods simply are not good enough to use for making patient care decisions.
4. Once you find the article you need, use the PP-ICONS approach to evaluate its usefulness to your patient.

If you find a systematic review or meta-analysis done by one of these organizations, you can feel confident that you have found the current best evidence. However, these organizations have not asked all of the common clinical questions yet, and you will frequently be faced with finding the pertinent articles and determining for yourself whether they are valuable. This is where the PP-ICONS approach can help.

What is PP-ICONS?

When you find a systematic review, meta-analysis or randomized controlled trial while reading your clinical journals or searching PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi), you need to determine whether it is valid and relevant. There are many different ways to analyze an abstract or journal article, some more rigorous than others.1,2 I have found a simple but effective way to identify a valid or relevant article within a couple of minutes, ensuring that I can use or discard the conclusions with confidence. This approach works well on articles regarding treatment and prevention, and can also be used with articles on diagnosis and screening.

The most important information to look for when reviewing an article can be summarized by the acronym “PP-ICONS,” which stands for the following:

• Problem,
• Patient or population,
• Intervention,
• Comparison,
• Outcome,
• Number of subjects,
• Statistics.

For example, imagine that you just saw a nine-year-old patient in the office with common warts on her hands, an ideal candidate for your usual cryotherapy. Her mother had heard about treating warts with duct tape and wondered if you would recommend this treatment. You promised to call Mom back after you had a chance to investigate this rather odd treatment.

When you get a free moment, you write down your clinical question: “Is duct tape an effective treatment for warts in children?” Writing down your clinical question is useful, as it can help you clarify exactly what you are looking for. Use the PPICO parts of the acronym to help you write your clinical question; this is actually how many researchers develop their research questions.

You search Cochrane and Bandolier without success, so now you search PubMed, which returns an abstract for the following article: “Focht DR 3rd, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris (the common wart). Arch Pediatr Adolesc Med. 2002 Oct;156(10):971-974.”

You decide to apply PP-ICONS to this abstract (see “Abstract from PubMed”) to determine if the information is both valid and relevant.

ABSTRACT FROM PUBMED

Using the PP-ICONS approach, physicians can evaluate the validity and relevance of clinical articles in minutes using only the abstract, such as this one, obtained free online from PubMed,http://www.ncbi. nlm.nih.gov/entrez/query.fcgi. The author uses this abstract to evaluate the use of duct tape to treat common warts.

Problem. The first P in PP-ICONS is for “problem,” which refers to the clinical condition that was studied. From the abstract, it is clear that the researchers studied the same problem you are interested in, which is important since flat warts or genital warts may have responded differently. Obviously, if the problem studied were not sufficiently similar to your clinical problem, the results would not be relevant.

Patient or population. Next, consider the patient or population. Is the study group similar to your patient or practice? Are they primary care patients, for example, or are they patients who have been referred to a tertiary care center? Are they of a similar age and gender? In this case, the researchers studied children and young adults in outpatient clinics, which is similar to your patient population. If the patients in the study are not similar to your patient, for example if they are sicker, older, a different gender or more clinically complicated, the results might not be relevant.

Intervention. The intervention could be a diagnostic test or a treatment. Make sure the intervention is the same as what you are looking for. The patient’s mother was asking about duct tape for warts, so this is a relevant study.

Comparison. The comparison is what the intervention is tested against. It could be a different diagnostic test or another therapy, such as cryotherapy in this wart study. It could even be placebo or no treatment. Make sure the comparison fits your question. You usually use cryotherapy for common warts, so this is a relevant comparison.

Outcome. The outcome is particularly important. Many outcomes are “disease-oriented outcomes,” which are based on “disease-oriented evidence” (DOEs). DOEs usually reflect changes in physiologic parameters, such as blood pressure, blood sugar, cholesterol, etc. We have long assumed that improving the physiologic parameters of a disease will result in a better disease outcome, but that is not necessarily true. For instance, finasteride can improve urinary flow rate in prostatic hypertrophy, but it does not significantly change symptom scores.3

DOEs look at the kinds of outcomes that physiologists care about. More relevant are outcomes that patients care about, often called “patient-oriented outcomes.” These are based on “patient-oriented evidence that matters” (POEMs) and look at outcomes such as morbidity, mortality and cost. Thus, when looking at a journal article, DOEs are interesting but of questionable relevance, whereas POEMs are very interesting and very relevant. In the study on the previous page, the outcome is complete resolution of the wart, which is something your patient is interested in.

Number. The number of subjects is crucial to whether accurate statistics can be generated from the data. Too few patients in a research study may not be enough to show that a difference actually exists between the intervention and comparison groups (known as the “power” of a study). Many studies are published with less than 100 subjects, which is usually inadequate to provide reliable statistics. A good rule of thumb is 400 subjects.4 Fifty-one patients completed the wart study, which is a pretty small number to generate good statistics.

Statistics. The statistics you are interested in are few in number and easy to understand. Since statistics are frequently misused in journal articles, it is worth a few minutes to learn which to believe and which to ignore.

Relative risk reduction. It is not unusual to find a summary statement in a journal article similar to this one from an article titled “Long-Term Effects of Mammography Screening: Updated Overview of the Swedish Randomised Trials”

“There were 511 breast cancer deaths in 1,864,770 women-years in the invited groups and 584 breast cancer deaths in 1,688,440 women-years in the control groups, a significant 21 percent reduction in breast cancer mortality.”

This 21-percent statistic is the relative risk reduction (RRR), which is the percent reduction in the measured outcome between the experimental and control groups. (See “Some important statistics” for more information on calculating the RRR and other statistics.) The RRR is not a good way to compare outcomes. It amplifies small differences and makes insignificant findings appear significant, and it doesn’t reflect the baseline risk of the outcome event. Nevertheless, the RRR is very popular and will be reported in nearly every journal article, perhaps because it makes weak results look good. Think of the RRR as the “reputation reviving ratio” or the “reporter’s reason for ‘riting.” Ignore the RRR. It will mislead you. In our wart treatment example, the RRR would be (85 percent – 60 percent)/60 percent x 100 = 42 percent. The RRR could thus be interpreted as showing that duct tape is 42 percent more effective than cryotherapy in treating warts.

SOME IMPORTANT STATISTICS

Absolute risk reduction (ARR): The difference between the control group’s event rate (CER) and the experimental group’s event rate (EER).

Control event rate (CER): The proportion of patients responding to placebo or other control treatment. For example, if 25 patients are in a control group and the event being studied is observed in 15 of those patients, the control event rate would be 15/25 = 0.60.

Experimental event rate (EER): The proportion of patients responding to the experimental treatment or intervention. For example, if 26 patients are in an experimental group and the event being studied is observed in 22 of those patients, the experimental event rate would be 22/26 = 0.85.

Number needed to treat (NNT): The number of patients that must be treated to prevent one adverse outcome or for one patient to benefit. The NNT is the inverse of the ARR; NNT = 1/ARR.

Relative risk reduction (RRR): The percent reduction in events in the treated group compared to the control group event rate.

View/Print Table

	When the experimental treatment reduces the risk of a bad event:	Example: Beta-blockers to prevent deaths in high-risk patients with recent myocardial infarction:	When the experimental treatment increases the probability of a good event:	Example: Duct tape to eliminate common warts.
Relative risk reduction (RRR)	CER-EER/CER	(.66 -. 50)/.66 = .24 or 24 percent	EER-CER/CER	(.85-.60)/.60 = .42 or 42 percent
Absolute risk reduction (ARR):	CER-EER	(.66 – .50) = .16 or 16 percent	EER-CER	.85-.60 = .25 or 25 percent
Number needed to treat (NNT)	1/ARR	1/.16 = 6	1/ARR	1/.25 = 4

Absolute risk reduction. A better statistic is the absolute risk reduction (ARR), which is the difference in the outcome event rate between the control group and the experimental treated group. Thus, in our wart treatment example, the ARR is the outcome event rate (complete resolution of warts) for duct tape (85 percent) minus the outcome event rate for cryotherapy (60 percent) = 25 percent. Unlike the RRR, the ARR does not amplify small differences but shows the true difference between the experimental and control interventions. Using the ARR, it would be accurate to say that duct tape is 25-percent more effective than cryotherapy in treating warts.

Number needed to treat. The single most clinically useful statistic is the number needed to treat (NNT). The NNT is the number of patients who must be treated to prevent one adverse outcome. To think about it another way, the NNT is the number of patients who must be treated for one patient to benefit. (The rest who were treated obtained no benefit, although they still suffered the risks and costs of treatment.) In our wart therapy article, the NNT would tell us how many patients must be treated with the experimental treatment for one to benefit more than if he or she had been treated with the standard treatment.

Now this is a statistic that physicians and their patients can really appreciate! Furthermore, the NNT is easy to calculate, as it is simply the inverse of the ARR. For our wart treatment study, the NNT is 1/25 percent =1/0.25 = 4, meaning that 4 patients need to be treated with duct tape for one to benefit more than if treated by cryotherapy.

Wrapped up in this simple little statistic are some very important concepts. The NNT provides you with the likelihood that the test or treatment will benefit any individual patient, an impression of the baseline risk of the adverse event, and a sense of the cost to society. Thus, it gives perspective and hints at the “reasonableness” of a treatment. The value of this statistic has become appreciated in the last five years, and more journal articles are reporting it.

What is a reasonable NNT? In a perfect world, a treatment would have an NNT of 1, meaning that every patient would benefit from the treatment. Real life is not so kind (see “Examples of NNTs”). Clearly, an NNT of 1 is great and an NNT of 1,000 is terrible. Although it is hard to come up with firm guidelines, for primary therapies I am satisfied with an NNT of 10 or less and very pleased with an NNT less than 5. Our duct tape NNT of 4 is good, particularly since the treatment is cheap, easy and painless.

EXAMPLES OF NNTS

The number needed to treat (NNT) is one of the most useful statistics for physicians and patients. It calculates the number of patients that must be treated to prevent one adverse event or for one patient to benefit. Note that NNTs for preventive interventions will usually be higher than NNTs for treatment interventions. The lower the NNT, the better.

The following examples of NNTs are borrowed from an excellent list available through the Bandolier Web site at http://www.jr2.ox.ac.uk/bandolier/band50/b50-8.html.

View/Print Table

Therapy	NNT
Triple antibiotic therapy to eradicate H. pylori	1.1
Isosorbide dinitrate for prevention of exercise-induced angina	5
Short course of antibiotics for otitis media in children	7
Statins for secondary prevention of adverse cardiovascular outcomes	11
Statins for primary prevention of adverse cardiovascular outcomes	35
Finasteride to prevent one operation for benign prostatic hyperplasia	39
Misoprostol to prevent any gastrointestinal complication in nonsteroidal anti-inflammatory drug users	166

Note that NNTs for preventive interventions (e.g., the use of aspirin to prevent cardiac problems) will usually be higher than NNTs for treatment interventions (e.g., the use of duct tape to cure warts). Prevention groups contain both higher-risk and lower-risk individuals, so they produce bigger denominators, whereas treatment groups only contain diseased patients. Thus, an NNT for prevention of less than 20 might be particularly good.

When discussing a particular therapy, I explain the NNT to my patient. Since this statistical concept is easy to understand, it can help the patient be a more informed partner in therapeutic decisions.

You will soon start to see a similar statistic, the number needed to screen (NNS), which is the number of patients needed to screen for a particular disease for a given duration for one patient to benefit.6Although few NNSs have been calculated, they are likely to involve higher numbers, since the screening population consists of patients with and without the disease. For example, in the article on mammography screening mentioned above, the NNS was 961 for 16 years. In other words, you would need to screen 961 women for 16 years to prevent one breast cancer death.

The good news and the bad

Using PP-ICONS to assess the wart study, the problem, the patient/population, the intervention, the comparison and the outcome are all relevant to your patient. The number of subjects is on the small side, making you a little wary, but the intervention is cheap and low-risk. The statistics, particularly the NNT, are reasonable. On balance, this looks like a fair approach, so you call the patient’s mother and discuss it with her.

The PP-ICONS approach is an easy way to screen an article for validity and relevance, and the abstract often contains all of the information you need. Even the statistics can be done quickly in your head. You can apply PP-ICONS when searching for a particular article, when you come across an article in your reading, when data are presented at lectures, when a pharmaceutical representative hands you an article to support his or her pitch, and even when reading news stories describing medical breakthroughs.

Don’t be discouraged if you find that high-quality articles are rare, even in the most prestigious journals. This seems to be changing for the better, although many careers are still being built on questionable research. Nevertheless, screening articles will help you find the truth that is out there and will help you practice the best medicine. And as we become more discerning end-users of research, we might just stimulate improvements in clinical research in the process.

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Dr. Flaherty is a family physician with the Student Health Service and WWAMI Medical Program, Montana State University-Bozeman, and a clinical professor in the Department of Family Medicine, University of Washington.

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Empowering patients with genetic testing

More and more women like actress Angelina Jolie are stepping forward to undergo genetic testing for breast cancer – and for good reason.

As many as 5 percent to 10 percent of all cancers may be linked to an inherited risk, and approximately 30 percent of cancer cases occur in families with close relatives who have experienced similar cancers. Women with BRCA1 or BRCA2 gene mutations may have up to an 80 percent risk of being diagnosed with breast cancer during their lifetimes. Many other gene mutations have also been linked to hereditary cancer.

Hereditary cancer is the development of cancer due to an inherited gene mutation that has been passed from parent to child upon conception. Experts in the field of cancer genetics can help identify an individual’s risk of developing cancer and understand the options available to help manage related health issues, explained David Euhus, M.D., Professor of Surgery at UT Southwestern Medical Center and surgical oncologist at UT Southwestern’s NCI-designatedHarold C. Simmons Comprehensive Cancer Center.

“When we understand the causes of this disease and its triggers, we can empower patients to fight cancer,” said Dr. Euhus, co-director of the Mary L. Brown Breast Cancer Genetics and Risk Assessment Clinic in the Center for Breast Care at UT Southwestern.

Dr. Euhus helped develop the groundbreaking CancerGene software program that is used in more than 4,000 cancer centers throughout the world to help doctors work with patients to identify their inherited risk for breast cancer.

“Knowing that you carry a mutation in one of the BRCA genes opens up numerous options for early diagnosis and cancer prevention,” he said. “If you have been diagnosed with breast cancer recently, this information is critical for making treatment decisions.”

Clinical trials for patients with a BRCA gene mutation are available at UT Southwestern.

UT Southwestern’s genetic counselors have also partnered with FORCE, or Facing our Risk of Cancer Empowered, a support group for patients with hereditary breast cancer. This sentiment of cancer prevention is echoed through families facing hereditary breast and ovarian cancer.

One woman who recently discovered that she has a BRCA1 mutation spoke about her plans to undergo prophylactic bilateral mastectomy and removal of her ovaries. “At the end of the day, I want to do everything I can to make sure that I am here to watch my children grow up,” she said.

Dr. Euhus offered the following checklist to help individuals decide whether they should consider genetic testing for breast cancer:

• Breast cancer diagnosis before age 45
• Three or more blood relatives on the same side of the family diagnosed with breast cancer
• A family history of ovarian cancer
• A relative on either side of the family diagnosed with breast cancer before age 45
• Being of Ashkenazi Jewish heritage
• A family member who had triple negative breast cancer before age 60
• Any male in the family who has had breast cancer
• Female relatives who have had cancer in both breasts

An inherited risk for cancer also may be higher when:

• The same type of cancer occurs in multiple close relatives.
• You or a family member have a rare cancer/tumor such as a sarcoma, male breast cancer, medullary thyroid cancer, or a pheochromocytoma.
• You have a family history with a combination of breast and ovarian cancers, or colon and uterine cancers.
• You have more than 20 colon polyps.
• You or a family member have had multiple different kinds of cancer.

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tips for doing research with schools, charities and NGOs

Conducting research on children, young people and learning often requires access to and help from schools, charities or NGOs. Alicia Blum-Ross draws on both struggles and successes from previous projects with learning institutions and presents five key strategies to build meaningful and mutually beneficial relationships.

You are a busy researcher, interested in children, young people and learning. They are a (probably even busier) NGO, charity or school working with children and young people (or vice versa). Possibly an ideal match; possibly a source of stress for both.

Partnering with schools, charities, NGOs and community organisations can make or break a research project. It may be how we observe learning practices, meet young people, or learn from facilitators, teachers and organisers. But often these potential partners are at best too busy to answer emails, or at worst sceptical or downright suspicious (sometimes rightly) about academic research.

In our current and previous projects we negotiated great (and sometimes not so great) research relationships with schools, charities and NGOs. These are our top tips for successful relationships

1. Research with

Researchers increasingly emphasise the importance of working with ‘ethical symmetry’ to do researchwith their participants – including organisations – instead of research on them.

Think of these relationships as partnerships, where sometimes your research goals may be called into question. This isn’t a hurdle to be overcome, but something that can enhance your research.

2. So you think you’re busy?

Bouncing from teaching to research to committees, you may have a lot going on. But try working in a (sometimes severely) under-resourced school, arts or learning organisation, or volunteering for a community group. Now that’s busy.

Make things as easy as you can – limit the emails you send, keep them to the point, make sure any action items / deadlines are clear, and get all your research materials (consent letters, project descriptions, any ethics approvals or police checks you might need) in order before you contact anyone.

Credit: J. Baxter, CC BY-NC-SA 2.0

3. Make it worth their while

In your memoranda of understanding (MoU), spell out what they can expect from you. Can you collect evidence (quotes, photos etc.) that they could use in an evaluation report or a future funding bid? How might your research help them answer their own questions about impact? Will you be collecting any data they can use as evidence of meeting key performance indicators (KPIs)?

There is a huge burden on organisations to ‘measure outcomes’, so your partners will love it if you can help them find evidence to do this, but be careful that you aren’t compromising the point of your research or confidentiality.

You can also be helpful in smaller ways – do they need more chairs for the meeting you’re sitting in on? Do they need an extra pair of hands to serve food? Helping out builds goodwill and also gives you opportunities to get to know both staff and participants.

4. Put it in writing

Okay, we said above to keep it simple. But also make sure that everyone is on the same page about what you need / want from each other. We suggest writing a document (sometimes called an MoU) that clarifies the following:

• The aims of your research. What are you trying to find out and why? Highlight why this would be interesting to them and how they might benefit from it.

• Your source of funding.

• Your research methods. What are you going to do, and where? Will you be asking to use an empty classroom for interviews? Will you be audio-recording or taking notes? How will you inform participants of the research? How will you get consent? Are there any research activities (like participant-observation) that may impact on their programmes? Also note your policy on anonymity – will you anonymise the school/organisation or just the names of the children/young people? What about in photos or video, if you are using them?

• Relationship with the organisation. Is the organisation recruiting participants on your behalf? Do you have a specific named contact in the organisation? How will you notify them if there are any problems that are raised in your research (e.g. evidence of criminal activity, feedback on the programmes)? Clarify what you would be expected to tell them and what you would keep confidential.

• Who will see this research? To whom and how will you be disseminating your research? Academic articles or in something more public-facing? Highlight especially if you are trying to create public impact or influence policy.

5. Don’t disappear

You’ve done your fieldwork, you’re back writing up the research, and the school or community organisation seems pretty far away (although not that far away if you’re still transcribing or coding interviews!). No matter how distant you may start to feel from the research, don’t disappear – find ways of involving the site in disseminating the research, or at least in giving them access to it. They may not take you up on it, but it’s good ethical practice to at least try.

Yes, this list does place a burden on you as a researcher, and adds a few more hoops to jump through. But in our experience, making sure that you honour the time you’re given, clarify expectations, and communicate about the process and the findings is not only good for building a relationship with a partner organisation, but it will also enhance the research itself.

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Fasting: what are the health benefits and risks?

Fasting is commonly associated with the month of Ramadan. As you read this, billions of Muslims around the world are engaging in this declaration of faith that involves abstaining from food and drink from dusk until dawn. While fasting for Ramadan is down to spiritual beliefs, many of us choose to fast with the belief that it benefits our health. But does it?

In recent years, numerous studies have suggested that intermittent fasting – abstaining or reducing food and drink intake periodically – can be good for us, making it one of the most popular diet trends worldwide.One of the most well-known intermittent fasting diets is the 5:2 Fast Diet – a plan that involves eating the recommended calorie intake for 5 days a week but reducing calorie intake by 25% for the remaining 2 days – to 500 calories a day for women and 600 a day for men.According to Dr. Michael Mosley – author of The Fast Dietbooks – this eating plan can not only help people lose weight, but it offers an array of other health benefits.”Studies of intermittent fasting show that not only do people see improvements in blood pressure and their cholesterol levels, but also in their insulin sensitivity,” he adds.In June 2014, for example, Medical News Today reported on a study suggesting periodic fasting – defined in the study as 1 day of water-only fasting a week – may reduce the risk of diabetes among people at high risk for the condition.Another study, conducted by Dr. Valter Longo and colleagues from the University of Southern California (USC) in Los Angeles, found longer periods of fasting – 2-4 days – may even “reboot” the immune system, clearing out old immune cells and regenerating new ones – a process they say could protect against cell damage caused by factors such as aging and chemotherapy.But what are the mechanisms underlying the suggested health benefits of fasting?

THE POTENTIAL BENEFITS OF INTERMITTENT FASTING

Since the body is unable to get its energy from food during fasting, it dips into glucose that is stored in the liver and muscles. This begins around 8 hours after the last meal is consumed.

When the stored glucose has been used up, the body then begins to burn fat as a source of energy, which can result in weight loss.

When the body has used up glucose stores during fasting, it burns fat for energy, resulting in weight loss.

As well as aiding weight loss, Dr. Razeen Mahroof, of the University of Oxford in the UK, explains that the use of fat for energy can help preserve muscle and reduce cholesterol levels.”A detoxification process also occurs, because any toxins stored in the body’s fat are dissolved and removed from the body,” he adds, noting that after a few days of fasting, higher levels of endorphins – “feel-good” hormones – are produced in the blood, which can have a positive impact on mental well-being.As mentioned previously, the study by Dr. Longo and colleagues suggests prolonged fasting may also be effective for regenerating immune cells.

“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged,” Dr. Longo explains.

In their study, published in the journal Cell Stem Cell, the team found that repeated cycles of 2-4 days without food over a 6-month period destroyed the old and damaged immune cells in mice and generated new ones.What is more, the team found that cancer patients who fasted for 3 days prior to chemotherapy were protected against immune system damage that can be caused by the treatment, which they attribute to immune cell regeneration.”The good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting,” says Dr. Longo. “Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”With the potential health benefits of fasting widely hailed by nutritionists worldwide, it is no wonder many of us are putting our love of food to one side in order to give it a try.But intermittent fasting isn’t all bells and whistles, according to some researchers and health care professionals, and there are some people who should avoid the diet altogether.

THE HEALTH RISKS

According to the UK’s National Health Service (NHS), there are numerous health risks associated with intermittent fasting.

People who fast commonly experience dehydration, largely because their body is not getting any fluid from food. As such, it is recommended that during Ramadan, Muslims consume plenty of water prior to fasting periods. Other individuals following fasting diets should ensure they are properly hydrated during fasting periods.If you are used to having breakfast, lunch, dinner and snacks in between, fasting periods can be a major challenge. As such, fasting can increase stress levels and disrupt sleep. Dehydration, hunger or lack of sleep during a fasting period can also lead to headaches.

Fasting can also cause heartburn; lack of food leads to a reduction in stomach acid, which digests food and destroys bacteria. But smelling food or even thinking about it during fasting periods can trigger the brain into telling the stomach to produce more acid, leading to heartburn.While many nutritionists claim intermittent fasting is a good way to lose weight, some health professionals believe such a diet is ineffective for long-term weight loss.

“The appeal is that [fasting] is quick, but it is quick fluid loss, not substantial weight loss,” says Madelyn Fernstrom, PhD, of the University of Pittsburgh Medical Center’s Weight Loss Management Center. “If it’s easy off, it will come back quickly – as soon as you start eating normally again.”

“My experience has been that [this] way of eating does not produce weight loss even in the short term,” dietitian and author of Diet Simple Katherine Tallmadge told ABC News in 2013.

Some health professionals believe intermittent fasting may steer people away from healthy eating recommendations, such as eating five portions of fruits and vegetables a day. Many fear fasting may also trigger eating disorders or binge eating.In a blog for The Huffington Post last year, fitness and nutrition expert JJ Virgin wrote:

“The ‘anything goes’ mentality some experts permit during the feeding state could lead someone to overeat, creating guilt, shame, and other problems that only become worse over time. For someone with emotional or psychological eating disorders, intermittent fasting could become a convenient crutch to amplify these issues.”

While Dr. Mosely says there is no evidence to suggest the 5:2 Fast Diet is associated with eating disorders, he stresses people who have eating disorders should not engage in intermittent fasting.Other people who should not follow this diet include people who are underweight, individuals under the age of 18, pregnant women, people with type 1 diabetes and individuals recovering from surgery.

COULD WE REAP THE BENEFITS OF FASTING WITHOUT FASTING?

While intermittent fasting may have health risks, nutritionists claim it can be good for us if individuals consult with their doctors before adopting such a diet and adhere to it correctly.But could there be a way to reap the potential health benefits of fasting without actually having to fast? Dr. Longo believes so.

Earlier this week, Dr. Longo and colleagues from USC published a study in the journal Cell Metabolism revealing how a fasting-mimicking diet (FMD) triggered immune cell regeneration and extended the lifespan of mice.

What is more, on testing the diet in humans – who adhered to it for only 5 days a month for 3 months – they found it reduced a number of risk factors associated with aging, cardiovascular disease (CVD), diabetes and cancer.

Researchers say a fasting-mimicking diet could simulate the effect of fasting without the food deprivation and side effects.

The FMD is low in protein, low in unhealthy fats and high in healthy fats, according to the researchers. It stimulates markers linked to fasting, such as low glucose levels and high levels of ketone bodies, in order to mimic the effects of prolonged fasting.

Dr. Longo and colleagues say their diet could promote immune cell regeneration and longevity associated with fasting without the need for food restriction and the potential adverse effects that come with it.”Although the clinical results will require confirmation by a larger randomized trial,” they add, “the effects of FMD cycles on biomarkers/risk factors for aging, cancer, diabetes, and CVD, coupled with the very high compliance to the diet and its safety, indicate that this periodic dietary strategy has high potential to be effective in promoting human healthspan.”The team hopes that clinicians will one day have the ability to prescribe this diet to patients. “This is arguably the first non-chronic preclinically and clinically tested anti-aging and healthspan-promoting intervention shown to work and to be very feasible as a doctor or dietitian-supervised intervention,” says Dr. Longo.It may be a while before the FMD receives approval from the US Food and Drug Administration (FDA) for clinical use. First, the team needs to put the diet through a rigorous testing process.

Further research is required to gain a better understanding of the exact benefits and risks the FMD poses, and this appears to be the case with existing fasting diets. One thing is clear, however; talk to your doctor before engaging in any form of fasting.

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Revealed: how teens are using the Internet to access health information

by David McNamee

Medical News Today

Researchers from Northwestern University in Evanston, IL, report that the vast majority of teenagers turn to the Internet to learn about puberty, drugs, sex, depression and other issues. However, kids still turn to their parents first when it comes to advice on health matters.

“We found some real surprises about what teens are doing online when it comes to their health,” said Ellen Wartella, director of Northwestern’s Center on Media and Human Development and lead author of the report.”We often hear about all the negative things kids are doing online,” she continues, “but teens are using the Internet to take care of themselves and others around them. The new study underscores how important it is to make sure there is accurate, appropriate and easily accessible information available to teens, because it’s used and acted upon.”

The Northwestern team surveyed 1,156 teenagers in the US who were aged between 13 and 18 years old.

The researchers found that although 84% of teens use the Internet to find information on health concerns, 88% of respondents would not share health concerns with Facebook friends or on other social media. However, 21% of the teens said they had downloaded mobile health apps.

Thirty-two percent of respondents said that information they had found online had prompted changes of their behavior – examples cited by the authors include cutting back on soda, eating more healthily and using exercise to alleviate depression.Despite the focus on Internet delivery of health information, the teenagers reported that they get the majority of their health information from their parents:

• 55% said they get “a lot” of health information from parents
• 32% said they get a similar amount of information from health classes at school
• Health care professionals provided “a lot” of information to 29% of the teens
• The Internet was reported as the source of “a lot” of health information for just 25% of respondents.

Medical websites were responsible for providing health information to 31% of those surveyed, followed by YouTube (20%), Yahoo (11%), Facebook (9%) and Twitter (4%).

MAJORITY OF HEALTH-RELATED SEARCHES ARE FOR HOMEWORK

Any concerns that the reported scouring of the Internet is reflective of dangerous new health risks facing teenagers may be somewhat relieved by the study’s finding that the main reason teens search for health information is for school assignments – 53% of the respondents said they do this.By contrast, only 33% of teens said they used the Internet to check symptoms or attempt to diagnose an illness.

The topics most searched for by teens breaks down as follows:

• Fitness/exercise (42%)
• Diet/nutrition (36%)
• Stress and anxiety (19%)
• Sexually transmitted diseases (18%)
• Puberty (18%)
• Depression (16%)
• Sleep (16%).

What the study terms as “negative health information” was found fairly infrequently. Although 27% of teens had come across drinking games online and 25% had seen information on how to access tobacco or nicotine products, only 4% said they had seen such information often, and 23% said they had just seen it once or twice.The study reports some useful findings for online health services. For instance, half of the respondents said they usually just click on the first website that is returned in a search. And teens also pay attention to domain names – 37% said they trusted a dot-edu domain, compared with just 14% for a dot-com domain. Only 8% of teens reported using sites specifically designed for their age group, however.

“The Internet is clearly empowering teens to protect their health,” says Vicky Rideout, head of VJR Consulting in San Francisco, CA, and a co-author of the report. “But we need to make sure they are equipped with the digital literacy skills to successfully navigate this online landscape.”

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What is an Exosome?

1. Exosomes are cell-derived vesicles that are present in many and perhaps all biological fluids, including blood, urine, and cultured medium of cell cultures. The reported diameter of exosomes is between 30 and 100 nm, which is larger than LDL, but much smaller than for example, red blood cells.

We asked 10 prominent scientists to share their thoughts on science and in particular the field of exosomes research. The video-series tell the story and history of this exciting new area of research, and its impact on other research fields such as cancer and immunology. The video-series also discusses the potential future therapeutic and diagnostic applications that may come from exosome research.

Contributors:
– Xandra Breakefield, Ph.D……….. Professor, Massachusetts General Hospital
– Jan Lötvall, MD., Ph.D ………….. Professor, University of Gothenburg, President of ISEV
– Suresh Mohla, Ph.D……………… Chief (TBMB) and Division Associate Director, NIH
– Esther Nolte-‘t Hoen, Ph.D……… Senior Scientist, Utrecht University
– Michiel Pegtel, Ph.D…………….. Assistant Professor, VUmc, Amsterdam
– Graça Raposo-Benedetti, Ph.D.. Director of Research, CNRS, Institut Curie
– Phillip A. Sharp, Ph.D…………… Nobel Laureate, Professor, MIT
– Johan Skog, Ph.D……………….. CSO, Exosomes Diagnostics
– Dima Ter-Ovanesyan……………..Ph.D Student, Harvard University
– Clotilde Thery, Ph.D…………….. Director of Research, INSERM, Institut Curie, Secretary General of ISEV

Acknowledgements:
Members of the research groups of Michiel Pegtel (Cancer Center Amsterdam, VUmc), Graça Raposo-Benedetti (Structure and Membrane Compartments, CNRS, Institut Curie) and Clotilde Théry (Immunity and Cancer, INSERM, Institut Curie)

What is an Exosome?

The History and Promise of Exosomes

Exosomes in Cancer Research

Curiosity and a Passion for Science

Collaboration – the Key to Scientific Success

Exosomes – The Next Small Thing

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Drug Development

Drug

Drug development involve multiple stages. The process from start to finish can take lots of funding and time (many years). Large drug companies usually have multiple drug candidates that go through the development process at the same time. Out of the many, only a few will make it to regulatory approval and be sold to the public. This is the reason why new drug costs so much. The cost is to support this lengthy and costly process of drug development.

The process of drug development includes:

• Drug Discovery
• Pre-clinical testing
• Clinical trials
• Post market surveillance

Drug Discovery

Drug discovery is the process that new drug candidates are screened and selected. Thousands of potential small molecules, natural products, or extract are initially screened for desired therapeutic effects. For example, candidates for protease inhibitor should bind the protein protease with certain affinity, selectivity, potency, and metabolic stability. Oral stability and bioavailability should also be considered for the candidates to be made into a pill that can be swallowed. Once one or more top candidates are selected, the next step is to conduct pre-clinical testing to confirm safety, toxicity, pharmacokinetics and metabolism.

Pre-Clinical Testing

Prior to testing new drug candidate on human, extensive pre-clinical testing in animals must be done to ensure the safety of the new drug. Pre-clinical testing is also conducted to learn of any toxicity, metabolism profile, and pharmacokinetic of the new drug. Pharmacokinetic studies, commonly referred as PK studies, are conducted to learn what happens to the new drug in a living organism, from the moment it enters the body to the moment it get eliminated through urine and stool.  Pre-clinical testing also includes studying the biochemical and physiological effects of the drug on the body.  This is called Pharmacodynamics or PD studies.  PD studies aim to learn the mechanisms of drug action and the impact of drug concentration on the living organism.  From PK and PD studies, appropriate doses and dosing schemes of the new drug can be determined.

The chemical makeup of the new drug is also studied in pre-clinical testing. This includes the solubility, stability, and formulation of the new drug in different forms (capsules, tablets, aerosol, injectable, and intravenous). This portion of chemical studies is known as Chemistry, Manufacturing and Control (CMC).

In addition, other studies may include genotoxicity, carcinogenicity, and reproduction toxicity.

Clinical Trials

Once extensive pre-clinical testing showed promising results for the new drug candidate, the next step is to conduct clinical trial in human. In United States, prior to conducting clinical trial in human, an application to the FDA called Investigational New Drug (IND) application. Below is a link for FDA 21 CFR 312, the regulation that govern new drug candidate that requires IND.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

If the sponsor or drug manufacturer does not receive any objection notice from the FDA within 30 days after IND application submission and the clinical trial has been approved by the IRB, the clinical trial can start.

Clinical trials in human are often done in phases:

Phase 0 – Pharmacokinetics (PK) and Pharmacodynamics (PD)

This is first in human trial where pharmacokinetics (PK) and pharmacodynamics (PD) are studies. The number of subjects are usually very small (N = 10 to 15)

–        Pharmacokinetics (PK) studies are done similar to the PK studies described in pre-clinical testing to understand what happens to the new drug from the moment it under human body to excretion. PK studies are done to learn what the body does to the new drug.

–        Pharmacodynamics (PD) studies are opposite to the PK studies. PD studies are done to learn what the new drug does to the body.

NOTE: Phase 0 is commonly described as part of Phase I below.

Phase I – Safety

Phase I studies are often done in small number (N = 20 – 80) of healthy subject. The goal of this phase is to learn of the safety of the new drug. To avoid further complication and symptoms from underlining disease, healthy subjects are recruited into this phase. Exception to this includes oncology trials where actual disease patient may be used. Phase I studies are often done in a specialized facility or clinic where continuous monitoring of subjects can be done. These facilities or clinics are often called CPUs (Central Pharmacological Units). Side effects of the new drug are carefully recorded in phase I studies. In addition, phase I studies are often designed to test single (Single Ascending Dose) and multiple (Multiple Ascending Dose) dosage and dosing interval to learn of the range where the new drug is safe in human.

Phase II – Efficacy (Proof of Concept)

Phase II studies are done in larger number of subjects (N = 100 – 200). The population for this phase is patient with the disease where the new drug is intended to treat. Study design for phase II studies usually compares the new drug against standard care treatment and / or placebo group. Placebo is an inert substance that has no medical effect (e.g. sugar pill). The goal of phase II studies is to test for efficacy of the new drug. Additional safety information is also usually collected. Phase II studies can be done in two stages, phase IIa to compared dosing and dose regiment and phase IIb to evaluate efficacy and safety. Sometimes, phase I and phase II are done in combination to evaluate efficacy and toxicity in order to save time and cost. Since phase II studies evaluate efficacy, this phase can be referred as “Proof of Concept.” Phase II usually determine the fate of the new drug; continue to phase III if shown efficacy vs. discontinue clinical testing if shown ineffective.

Phase III – Pivotal Studies

Phase III studies are designed to obtain large enough population to show statistical evidence of efficacy and safety of the new drug. Phase III studies are often done in large number of patients with the disease the new drug is intended to treat (N = 300 – 3000). Similar to phase II, new drug in phase III studies are being compared against standard care treatment and / or placebo group. Due to the large number of patients being evaluated, phase III studies are time consuming and costly. Similar to phase II, phase III studies can be done in stages; phase IIIa to evaluate efficacy and safety and phase IIIb to evaluate additional disease indication or additional marketing claims. Due to the evaluation of efficacy and safety in large population, phase IIIa are often called “Pivotal Study.” While not required in all cases, often 2 successful phase IIIa trials are needed to show efficacy and safety to obtain regulatory approval from major regulatory bodies such as the FDA in the U.S. and EMA in European Union. Upon favorable results from these phase IIIa trials, sponsor or drug manufacturer may submit a New Drug Application (NDA) to the FDA or EMA for regulatory approval.

Phase IV – Post Marketing Surveillance

Phase IV studies are usually done after regulatory approval of the new drug. The goal of phase IV studies is to collect safety information in larger population (general population) and in longer time period (multiple years) than in phase I, II, and III trials. Phase IV studies are necessary to protect patient’s safety after regulatory approval of new drug. As safety information are collected and reported to the overseeing regulatory body, if serious side effects are found, the new drug may be restricted to certain use or it may be prohibited from being sold altogether.

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