Monthly Archives: May 2017

May 29, 2017 CRISPR-associated protein Cas9 (white) from Staphylococcus aureus based on Protein Database ID 5AXW. Credit: Thomas Splettstoesser (Wikipedia, CC BY-SA 4.0)

As CRISPR-Cas9 starts to move into clinical trials, a new study published in Nature Methods has found that the gene-editing technology can introduce hundreds of unintended mutations into the genome.

"We feel it's critical that the scientific community consider the potential hazards of all off-target mutations caused by CRISPR, including single nucleotide mutations and mutations in non-coding regions of the genome," says co-author Stephen Tsang, MD, PhD, the Laszlo T. Bito Associate Professor of Ophthalmology and associate professor of pathology and cell biology at Columbia University Medical Center and in Columbia's Institute of Genomic Medicine and the Institute of Human Nutrition.

CRISPR-Cas9 editing technologyby virtue of its speed and unprecedented precisionhas been a boon for scientists trying to understand the role of genes in disease. The technique has also raised hope for more powerful gene therapies that can delete or repair flawed genes, not just add new genes.

The first clinical trial to deploy CRISPR is now underway in China, and a U.S. trial is slated to start next year. But even though CRISPR can precisely target specific stretches of DNA, it sometimes hits other parts of the genome. Most studies that search for these off-target mutations use computer algorithms to identify areas most likely to be affected and then examine those areas for deletions and insertions.

"These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals," says co-author Alexander Bassuk, MD, PhD, professor of pediatrics at the University of Iowa.

In the new study, the researchers sequenced the entire genome of mice that had undergone CRISPR gene editing in the team's previous study and looked for all mutations, including those that only altered a single nucleotide.

The researchers determined that CRISPR had successfully corrected a gene that causes blindness, but Kellie Schaefer, a PhD student in the lab of Vinit Mahajan, MD, PhD, associate professor of ophthalmology at Stanford University, and co-author of the study, found that the genomes of two independent gene therapy recipients had sustained more than 1,500 single-nucleotide mutations and more than 100 larger deletions and insertions. None of these DNA mutations were predicted by computer algorithms that are widely used by researchers to look for off-target effects.

"Researchers who aren't using whole genome sequencing to find off-target effects may be missing potentially important mutations," Dr. Tsang says. "Even a single nucleotide change can have a huge impact."

Dr. Bassuk says the researchers didn't notice anything obviously wrong with their animals. "We're still upbeat about CRISPR," says Dr. Mahajan. "We're physicians, and we know that every new therapy has some potential side effectsbut we need to be aware of what they are."

Researchers are currently working to improve the components of the CRISPR systemits gene-cutting enzyme and the RNA that guides the enzyme to the right geneto increase the efficiency of editing.

"We hope our findings will encourage others to use whole-genome sequencing as a method to determine all the off-target effects of their CRISPR techniques and study different versions for the safest, most accurate editing," Dr. Tsang says.

The paper is titled, "Unexpected mutations after CRISPR-Cas9 editing in vivo." Additional authors are Kellie A. Schafer (Stanford University), Wen-Hsuan Wu (Columbia University Medical Center), and Diana G. Colgan (Iowa).

Explore further: Accurate DNA misspelling correction method

More information: Unexpected mutations after CRISPR-Cas9 editing in vivo, Nature Methods (2017).

Researchers at the Institute of Basic Science (IBS) proved the accuracy of a recently developed gene editing method. This works as "DNA scissors" designed to identify and substitute just one nucleotide among the 3 billion. ...

A team from the Center for Genome Engineering, within the Institute for Basic Research (IBS), succeeded in editing two genes that contribute to the fat contents of soybean oil using the new CRISPR-Cpf1 technology: an alternative ...

Researchers from Memorial Sloan Kettering Cancer Center (MSK) have harnessed the power of CRISPR/Cas9 to create more-potent chimeric antigen receptor (CAR) T cells that enhance tumor rejection in mice. The unexpected findings, ...

The IBS research team (Center for Genome Engineering) has successfully confirmed that CRISPR-Cas9 has accurate on-target effects in human cells, through joint research with the Seoul National University College of Medicine ...

A team of researchers at Western University is playing with molecular-Lego by adding an engineered enzyme to the revolutionary new gene-editing tool, CRISPR/Cas9. Their study, published today in the Proceedings of the National ...

Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

Princeton researchers have developed a way to place onto surfaces special coatings that chemically "communicate" with bacteria, telling them what to do. The coatings, which could be useful in inhibiting or promoting bacterial ...

A research group at the University of Helsinki discovered the fastest event of speciation in any marine vertebrate when studying flounders in an international research collaboration project. This finding has an important ...

(Phys.org)A team of researchers affiliated with several institutions in China has dated rice material excavated from a dig site in South China's Zhejiang province back to approximately 9,400 years ago. In their paper published ...

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If a person has 3 months to live and they use crispr/cas9 to cure the cancer, and it works, what is the worst than can happen to him?

I'm not a biologist, so no idea how conceivable or absurd that idea might be. But then there's the whole thing with the Tasmanian devils. Anyway, you asked about worst cases, and that is one possible thing that people who are against this might be thinking.

Open a door, find 12 new doors. Like the knowledge that carbon nanos caused cancer but the powers-that-be decided we should use it any way because it was so convenient.

We are so screwed! This is worse than the advent of nuclear weapons.

this might cause regulated interests to think twice before deploying this for profit. It will not help us at all against weaponized CRISPR, though...

Crispr is the only way the human race will survive. Without it the machines rule. With crispr the human race increases everyone's IQ 10 fold. The vary smartest of us say "be very afraid of AI". Musk likened AI to a devil in a bottle. It's the 2nd level of our most brilliant people that can't see the danger AI poses. Raise everyone's IQ by 10X and we will make much better decisions and solve the current world's problems overnight.

Meatbrains are passe which is why we are so intent on replacing them.

Watch Forbidden Planet to see what happens when you mix intelligence with the need to survive to procreate.

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Excerpt from:
CRISPR gene editing can cause hundreds of unintended mutations - Phys.Org

Xconomy Boulder/Denver

The randomized controlled trial has long been held up as the gold standard for testing new drugs. But the nations top drug evaluator, Janet Woodcock, believes they arent necessary for all new experimental treatments. Randomized trials are long, expensive to run, and ultimately produce limited answers, she said at a medical conference last week.

The ability to use genetic information to classify patients and match them to potential therapies opens up new possibilities for evaluating drugs. As these capabilities increase, Woodcock says, the FDA should adjust its approach to reviewing drugs.

People have been very happy with the use of the traditional standard randomized controlled trial, Woodcock said last Thursday at the Precision Medicine World Conference at Duke University. People know how to interpret that evidence. Yet that may not be appropriate for some of these diseases.

The FDA has shown such flexibility with two recent approvals based on better genetic insights. Last week, the FDA approved Mercks (NYSE: MRK) cancer drug pembrolizumab (Keytruda) for all solid tumors with a specific genetic signature, regardless of where in the body the cancer started. That decision came days after the regulator expanded use of Vertex Pharmaceuticals (NASDAQ: VRTX) cystic fibrosis drug, ivacaftor (Kalydeco), so more patients with a particular genetic mutations could get treatment. The additional approvals for both drugs did not require the companies to conduct more randomized controlled trials. Woodcock described the approvals as landmarks for precision medicine.

Pembrolizumab was already approved to treat cancers of the skin, lung, and bladder, among others. The data supporting the latest approval for the Kenilworth, NJ-based companys drug came from open-label basket trials that simultaneously tested pembrolizumab on a variety of tumors that all share a specific genetic alteration. Patients were selected for the studies based on genetic tests that identified that signature, a predictor of whether they would respond to the Merck therapy. The FDAs ruling was an accelerated approval, meaning Merck must gather additional evidence to confirm the earlier studies. Woodcock said that this type of flexible approach is particularly important for diseases that have no treatment alternatives.

Genetic information has also played a role in the development and approval of Vertexs cystic fibrosis drug, ivacaftor. The drug was initially approved to treat patients who have specific mutations that indicate they would respond to the drug. On May 17, the FDA expanded the approval from 10 mutations to 33. Woodcock said the FDA based this decision on several factors, but the main evidence was a laboratory test that showed the drug could also help CF patients with more gene mutations. Woodcock said that this decision opens a pathway for drugs in cystic fibrosis and other diseases that have similar signs and symptoms. After a drug is first approved, a drugmaker could get additional approvals for additional patient subsets by using the lab test, rather than conducting a randomized clinical trial for each group.

The FDA and drug companies have been talking about adding new approaches to clinical trials for years, and that effort is now getting a nudge forward under federal law. Among the provisions of the wide-ranging 21st Century Cures Act, signed into law last year, are requirements that the FDA hold public hearings and issue guidance to help drug companies use new clinical trial designs to test their drugs. The law also calls on the FDA to use real-world evidence to support applications for new uses of already approved drugs. (Regulatory Affairs has a good breakdown of what the new federal law means for the FDA.)

Woodcock didnt reference the Cures Act in her remarks. But she said that for some drugs, different trial designs are warranted. Platform trials might be useful to evaluate multiple drugs and drug combinations simultaneously, with the ability to adjust the studies on the fly by adding or dropping arms. This flexibility allows Next Page

Frank Vinluan is editor of Xconomy Raleigh-Durham, based in Research Triangle Park. You can reach him at fvinluan [at] xconomy.com

The rest is here:
Woodcock: New Approvals Show FDA is Adapting to Precision Medicine - Xconomy

The oncologist was blunt: Stefanie Johos colon cancer was raging out of control and there was nothing more she could do. Flanked by her parents and sister, the 23-year-old felt something wet on her shoulder. She looked up to see her father weeping.

I felt dead inside, utterly demoralized, ready to be done, Joho remembers.

But her younger sister couldnt accept that. When the family got back to Johos apartment in New Yorks Flatiron district, Jess opened her laptop and began searching frantically for clinical trials, using medical words shed heard but not fully understood. An hour later, she came into her sisters room and showed her what shed found. Im not letting you give up, she told Stefanie. This is not the end.

That search led to a contact at Johns Hopkins University, and a few days later, Joho got a call from a cancer geneticist co-leading a study there. Get down here as fast as you can! Luis Diaz said. We are having tremendous success with patients like you.

What followed is an illuminating tale of how one womans intersection with experimental research helped open a new frontier in cancer treatment with approval of a drug that, for the first time, capitalizes on a genetic feature in a tumor rather than on the diseases location in the body.

The breakthrough, made official last week by the Food and Drug Administration, immediately could benefit some patients with certain kinds of advanced cancer that arent responding to chemotherapy. Each should be tested for that genetic signature, scientists stress.

These are people facing death sentences, said Hopkins geneticist Bert Vogelstein. This treatment might keep some of them in remission for a long time.

In August 2014, Joho stumbled into Hopkins for her first infusion of the immunotherapy drug Keytruda. She was in agony from a malignant mass in her midsection, and even with the copious amounts of oxycodone she was swallowing, she needed a new fentanyl patch on her arm every 48 hours. Yet within just days, the excruciating back pain had eased. Then an unfamiliar sensation hunger returned. She burst into tears when she realized what it was.

As months went by, her tumor shrank and ultimately disappeared. She stopped treatment this past August, free from all signs of disease.

[Negotiating cancer: Tips from one whos done it ]

The small trial in Baltimore was pivotal, and not only for the young marketing professional. It showed that immunotherapy could attack colon and other cancers thought to be unstoppable. The key was their tumors genetic defect, known as mismatch repair (MMR) deficiency akin to a missing spell-check on their DNA. As the DNA copies itself, the abnormality prevents any errors from being fixed. In the cancer cells, that means huge numbers of mutations that are good targets for immunotherapy.

The treatment approach isnt a panacea, however. The glitch under scrutiny which can arise spontaneously or be inherited is found in just 4percent of cancers overall. But bore in on a few specific types, and the scenario changes dramatically. The problem occurs in up to 20percent of colon cancers and about 40percent of endometrial malignancies cancer in the lining of the uterus.

In the United States, researchers estimate that initially about 15,000 people with the defect may be helped by this immunotherapy. That number is likely to rise sharply as doctors begin using it earlier on eligible patients.

Joho was among the first.

***

Even before Joho got sick, cancer had cast a long shadow on her family. Her mother has Lynch syndrome, a hereditary disorder that sharply raises the risk of certain cancers, and since 2003, Priscilla Joho has suffered colon cancer, uterine cancer and squamous cell carcinoma of the skin.

Stefanies older sister, Vanessa, had already tested positive for Lynch syndrome, and Stefanie planned to get tested when she turned 25. But at 22, several months after she graduated from New York University, she began feeling unusually tired. She blamed the fatigue on her demanding job. Her primary-care physician, aware of her mothers medical history, ordered a colonoscopy.

When Joho woke up from the procedure, the gastroenterologist looked like a ghost, she said. A subsequent CT scan revealed a very large tumor in her colon. Shed definitely inherited Lynch syndrome.

She underwent surgery in January 2013 at Philadelphias Fox Chase Cancer Center, where her mother had been treated. The news was good: The cancer didnt appear to have spread, so she could skip chemotherapy and follow up with scans every three months.

[More than two-thirds of cancer mutations are due to random DNA copying errors, study says]

By August of that year, though, Joho started having relentless back pain. Tests detected the invasive tumor in her abdomen. Another operation, and now she started chemo. Once again, in spring 2014, the cancer roared back. Her doctors in New York, where she now was living, switched to a more aggressive chemo regimen.

This thing is going to kill me, Joho remembered thinking. It was eating me alive.

She made it to Jesss college graduation in Vermont that May. Midsummer, her oncologist confessed he was out of options. As he left the examining room, he mentioned offhandedly that some interesting work was going on in immunotherapy. But when Joho met with a hospital immunologist, that doctor told her no suitable trials were available.

Joho began planning to move to her parents home in suburban Philadelphia: I thought, Im dying, and Id like to breathe fresh air and be around the green and the trees.

Her younger sister wasnt ready for her to give up. Jess searched for clinical trials, typing in immunotherapy and other terms shed heard the doctors use. Up popped a trial at Hopkins, where doctors were testing a drug called pembrolizumab.

***

Pembro is part of a class of new medications called checkpoint inhibitors that disable the brakes that keep the immune system from attacking tumors. In September 2014, the treatment was approved by the FDA for advanced melanoma and marketed as Keytruda. The medication made headlines in 2015 when it helped treat former president Jimmy Carter for melanoma that had spread to his brain and liver. It later was cleared for several other malignancies.

Yet researchers still dont know why immunotherapy, once hailed as a game changer, works in only a minority of patients. Figuring that out is important for clinical as well as financial reasons. Keytruda, for example, costs about $150,000 a year.

By the time Joho arrived at Hopkins, the trial had been underway for a year. While an earlier study had shown a similar immunotherapy drug to be effective for a significant proportion of patients with advanced melanoma or lung or kidney cancer, checkpoint inhibitors werent making headway with colon cancer. A single patient out of 20 had responded in a couple of trials.

Why did some tumors shrink and others didnt? What was different about the single colon cancer patient who benefited?

Drew Pardoll, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Hopkins, and top researcher Suzanne L. Topalian took the unusual step of consulting with the cancer geneticists who worked one floor up.

This was the first date in what became the marriage of cancer genetics and cancer immunology, Pardoll said.

[A consumers guide to the hottest field in cancer treatments immunotherapy]

In a brainstorming session, the geneticists were quick to offer their theories. They suggested that the melanoma and lung cancer patients had done best because those cancers have lots of mutations, a consequence of exposure to sunlight and cigarette smoke. The mutations produce proteins recognized by the immune system as foreign and ripe for attack, and the drug boosts the systems response.

And that one colon-cancer patient? As Vogelstein recalls, We all said in unison, He must have MMR deficiency! because such a genetic glitch would spawn even more mutations. The abnormality was a familiar subject to Vogelstein, who in the 1990s had co-discovered its role in the development of colon cancer. But the immunologists hadnt thought of it.

When the patients tumor tissue was tested, it was indeed positive for the defect.

The researchers decided to run a small trial, led by Hopkins immunologist Dung Le and geneticist Diaz, to determine whether the defect could predict a patients response to immunotherapy. The pharmaceutical company Merck provided its still-experimental drug pembrolizumab. Three groups of volunteers were recruited: 10 colon cancer patients whose tumors had the genetic problem; 18 colon cancer patients without it; and 7 patients with other malignancies with the defect.

The first results, published in 2015 in the New England Journal of Medicine, were striking. Four out of the 10 colon cancer patients with the defect and 5 out of the other 7cancer patients with the abnormality responded to the drug. In the remaining group, nothing. Since then, updated numbers have reinforced that a high proportion of patients with the genetic feature benefit from the drug, often for a lengthy period. Other trials by pharmaceutical companies have shown similar results.

The Hopkins investigators found that tumors with the defect had, on average, 1,700 mutations, compared with only 70 for tumors without the problem. That confirmed the theory that high numbers of mutations make it more likely the immune system will recognize and attack cancer if it gets assistance from immunotherapy.

The studies were the foundation of the FDAs decision on Tuesday to green-light Keytruda to treat cancers such as Johos, meaning malignancies with certain molecular characteristics. This first-ever site-agnostic approval by the agency signals an emerging field of precision immunotherapy, Pardoll said, one in which genetic details are used to anticipate who will respond to treatments.

***

For Joho, now 27 and living in suburban Philadelphia, the hard lesson from the past few years is clear: The cancer field is changing so rapidly that patients cant rely on their doctors to find them the best treatments. Oncologists can barely keep up, she said. My sister found a trial I was a perfect candidate for, and my doctors didnt even know it existed.

Her first several weeks on the trial were rough, with an early hospitalization after she cut back too quickly on her fentanyl and went into withdrawal. She still has some lasting side effects today joint pain in her knees, minor nausea and fatigue but they are manageable.

I have had to adapt to some new limits, she acknowledged. But I still feel better than I have in five years.

The FDAs decision last week was an emotional moment. Diaz, now at Memorial Sloan Kettering Cancer Center in New York, immediately texted her. We did it! he exulted.

I got chills all over my body, Joho said. To think that I was at the end of the road, with no options, and then to be part of such a change.

Her experience has prompted her to drop plans to go back into marketing. Now she wants to help patients navigate the new cancer landscape. Become an expert on your cancer is her message. Dont be passive. She encourages patients to try clinical trials.

As a cancer survivor with Lynch syndrome, Joho will be closely watched; if she relapses, she is likely to be treated again with immunotherapy. And if her mother relapses, Keytruda might now be her best chance.

Coming out the other side, I feel really lucky, Joho said. Shes also grateful for something else: A few years ago, her sister Jess was tested for the disorder that has so affected their family. She was negative.

See the article here:
'This is not the end': Using immunotherapy and a genetic glitch to give cancer patients hope - Washington Post

May 29, 2017

Urinary incontinence in women is common, with almost 50% of adult women experiencing leakage at least occasionally. Genetic or heritable factors are known to contribute to half of all cases, but until now studies had failed to identify the genetic variants associated with the condition. Speaking at the annual conference of the European Society of Human Genetics today (Monday), Dr Rufus Cartwright, MD, a visiting researcher in the Department of Epidemiology and Biostatistics, Imperial College, London, UK, will say that his team's investigations hold out the promise that drugs already used for the treatment of other conditions can help affected women combat this distressing problem.

Pelvic floor disorders, including urinary incontinence, but also faecal incontinence and pelvic organ prolapse, have a devastating effect on quality of life. Most commonly they occur after childbirth, or at menopause, though some women report incontinence dating from childhood. Of the 25% who are affected sufficiently for it to affect their daily lives, most suffer from stress incontinence - the loss of small amounts of urine associated with laughing, coughing, sneezing, exercising or other movements that increase pressure on the bladder. Isolated urgency incontinence - where a sudden pressing need to urinate causes the leakage of urine - affects only around 5% of women, and 5-10% have a combination of both forms.

"25% of adult women will experience incontinence severe enough to impact on their quality of life," says Dr Cartwright. "Finding a genetic cause and a potential treatment route is therefore a priority."

The researchers undertook a genome-wide association study (GWAS) in just under 9,000 women from three groups in Finland and the UK, confirming their findings in six further studies. Genome-wide association studies work by scanning markers across the complete sets of DNA of large numbers of people in order to find genetic variants associated with a particular disease.

Analysis of the study data yielded a risk locus for urinary incontinence close to the endothelin gene, known to be involved in the ability of the bladder to contract. Drugs that work on the endothelin pathway are already used in the treatment of pulmonary hypertension and Raynaud's syndrome, a condition where spasm of the arteries causes reduced blood flow, most usually to the fingers.

"Previous studies had failed to confirm any genetic causes for incontinence. Although I was always hopeful that we would find something significant, there were major challenges involved in finding enough women to participate, and then collecting the information about incontinence. It has taken more than five years of work, and has only been possible thanks to the existence of high quality cohort studies with participants who were keen to help," says Dr Cartwright.

Current treatment for urinary incontinence in women includes pelvic floor and bladder training, advice on lifestyle changes (for example, reducing fluid intake and losing weight), drugs to reduce bladder contraction, and surgery.

However, as the number of identified risk variants for urinary incontinence grows, there will be potential to introduce genetic screening for the condition, and improve advice to pregnant women about the likely risks of incontinence in order that they may make an informed choice about delivery method. "We know that a caesarean section offers substantial protection from incontinence. However, across Europe there are efforts to reduce caesarean section rates, and establishing such a screening programme during pregnancy may run against current political objectives in many maternity care systems.

"Clearly this will need further debate and an analysis, not just of the cost to healthcare systems, but also of the benefit to women who may be spared the distress of urinary incontinence," Dr Cartwright will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle, United Kingdom, said: "This work reveals the first links between urinary incontinence and genetic factors. It provides important insight into the biological mechanisms for incontinence and suggests the potential of identifying women at risk."

Explore further: Urinary incontinence is common also in women who have not given birth

Women who have not given birth often end up under the radar for research on urinary incontinence. In a study of this group, however, one in five women over 45 years say they experience this type of incontinence.

According to a study published in the distinguished journal PLOS ONE, urinary incontinence symptoms in middle-aged woman are linked to lower levels of exercise. Involuntary urinary incontinence symptoms can discourage sufferers ...

(HealthDay)Effective treatment options exist for women with urinary incontinence that don't involve medication or surgery, according to new guidelines from the American College of Physicians.

A new study indicates that the benefits of duloxetine, a drug used in Europe to treat stress incontinence in women, do not outweigh the harms. The article is published in CMAJ (Canadian Medical Association Journal).

For millions of women, childbirth is a somewhat daunting yet thoroughly rewarding process. In the western world, many years of medical research and professional experience mean that women have access to expert care before, ...

Women are more likely to experience urinary incontinence, prolapse and faecal incontinence 20 years after one vaginal delivery rather than one caesarean section, finds new research published in a thesis from Sahlgrenska Academy, ...

The frightening spread of antibiotic-resistant superbugs threatens to return medicine to the pre-antibiotic era, with the return of deadly infectious diseases long thought vanquished.

The anxiety over antibiotic-resistant superbugs, which are responsible for 23,000 deaths a year in the United States, is likely to grow in California, following the recent discovery by UCLA researchers of high levels of antibiotic-resistant ...

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It's one of the most common immune-mediated diseases in the U.S., causing red, patchy and scaly marks on the skin. Yet the 1 to 2 percent of the population who have psoriasis are still left to wonder why.

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New genomic analysis promises benefit in female urinary incontinence - Medical Xpress