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Clinical Laboratories and Pathology Groups

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Clinical Laboratories and Pathology Groups

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Researchers at Emory University School of Medicine Develop Technology That Makes Urine Fluorescent When Transplanted Organs Are Rejected

This new technology could replace needle biopsies and allow physicians to detect rejection of transplanted organs earlier, saving patients’ lives

Anatomic pathologists may be reading fewer biopsy reports for patients with organ transplants in the future. That’s thanks to a new technology that may be more sensitive to and capable of detecting organ rejection earlier than traditional needle biopsies.

When clinicians can detect organ transplant rejection earlier, patients survive longer. Unfortunately, extensive organ damage may have already occurred by the time rejection is detected through a traditional needle biopsy. This led a group of researchers at Emory University School of Medicine to search for a better method for detecting organ rejection in patients with transplants.

The Emory researchers describe the method and technology they devised in a paper published in Nature Biomedical Engineering, titled, “Non-Invasive Early Detection of Acute Transplant Rejection Via Nanosensors of Granzyme B Activity.” The new technology could make it easier for clinicians to detect when a patient’s body is rejecting a transplanted organ at an earlier time than traditional methods.

This technology also provides a running measure of processes, so clinicians have more powerful tools for deciding on the most appropriate dosage of immunosuppressant drugs.

“Right now, most tests are aimed at organ dysfunction, and sometimes they don’t signal there is a problem until organ function is below 50 percent,” Andrew Adams, MD, PhD Co-Principal Investigator and an Associate Professor of Surgery at Emory University School of Medicine, in a Georgia Institute of Technology news release.

How the Technology Works

The method that Adams and his colleagues tested involves the detection of granzyme B, a serine protease often found in the granules of natural killer cells (NK cells) and cytotoxic T cells. “Before any organ damage can happen, T cells have to produce granzyme B, which is why this is an early detection method,” said Gabe Kwong, PhD, Assistant Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, in the news release.

The new technology is made up of sensor nanoparticles in the shape of a ball with iron oxide in the middle. Amino acids stick out of the ball like bristles. Each amino acid has a fluorescent molecule attached to the tip.

The nanoparticles are injected into the patient. Their size prevents them from gathering in the patient’s tissue or from being flushed out through the kidneys. They are designed to accumulate in the tissue of the transplanted organ.

If the T cells in the transplanted organ begin to produce granzyme B, the amino acids break away from the nanoparticles, releasing the fluorescent molecules attached to their tips. Those molecules are small enough to be processed through the kidneys and can be detected in the patient’s urine.

Pathologists Play Crucial Role on Transplant Teams

Anatomical pathologists (histopathologists in the UK) are key members of transplant teams for many reasons, including their ability to assess biopsies. The current method for detecting organ transplant rejection involves needle biopsies. It is considered the gold standard.

However, according to a paper published in the International Journal of Organ Transplantation Medicine: “Although imaging studies and laboratory findings are important and helpful in monitoring of the transplanted liver, in many circumstances they are not sensitive enough. For conditions such as rejection of the transplant, liver histology remains the gold-standard test for the diagnosis of allograft dysfunction. Therefore, histopathologic assessments of allograft liver biopsies have an important role in managing patients who have undergone liver transplantation.”

There are two main problems with needle biopsies. The first, as mentioned above, is that they don’t always catch the rejection soon enough. The second is that the needle may cause damage to the transplanted organ.

“The biggest risk of a biopsy is bleeding and injury to the transplanted organ,” noted Andrew Adams, MD, PhD (above), Co-Principal Investigator and an Associate Professor of Surgery at Emory University School of Medicine, in the Georgia Tech news release. “Then there’s the possibility of infection. You’re also just taking a tiny fraction of the transplanted organ to determine what’s going on with the whole organ, and you may miss rejection or misdiagnose it because the needle didn’t hit the right spot,” he added.

And, according to Kwong, even though biopsies are the gold standard, the results represent one moment in time. “The biopsy is not predictive. It’s a static snapshot. It’s like looking at a photo of people in mid-jump. You don’t know if they’re on their way up or on their way down. With a biopsy, you don’t know whether rejection is progressing or regressing.”

Future Directions of Emory’s Research

The research conducted by Adams and Kwong, et al, is in its early stages, and the new technology they created won’t be ready to be used on patients for some time. Nevertheless, there’s reason to be excited.

Nanoparticles are not nearly as invasive as a needle biopsy. Thus, risk of infection or damaging the transplanted organ is much lower. And Emory’s technology would allow for much earlier detection, as well as giving clinicians a better way to adjust the dose of immunosuppressant drugs the patient takes.

“Adjusting the dose is very difficult but very important because heavy immunosuppression increases occurrence of infections and patients who receive it also get cancer more often,” said Kwong. The new technology provides a method of measuring biological activity rates, which would give clinicians a clearer picture of what’s happening.

The Emory team’s plan is to enhance the new sensors to detect at least one other major cause of transplant rejection—antibodies. When a patient’s body rejects a transplanted organ, it produces antibodies to neutralize what it sees as a foreign entity.

“Antibodies kill their target cells through similar types of enzymes. In the future, we envision a single sensor to detect both types of rejection,” said Kwong.

Adams adds, “This method could be adapted to tease out multiple problems like rejection, infection, or injury to the transplanted organ. The treatments for all of those are different, so we could select the proper treatment or combination of treatments and also use the test to measure how effective treatment is.”

This line of research at Emory University demonstrates how expanding knowledge in a variety of fields can be combined in new ways. As this happens, medical laboratories not only get new biomarkers that can be clinically useful without the need for invasive procedures like needle biopsies, but these same biomarkers can guide the selection of more effective therapies.

—Dava Stewart

Related Information:

Non-Invasive Early Detection of Acute Transplant Rejection Via Nanosensors of Granzyme B Activity

Role of Histopathologist in Liver Transplantation

Urine Test Detects Organ Transplant Rejection, Could Replace Needle Biopsies

Potential New Clinical Laboratory Urine Test for TB Could Speed Up Diagnosis and Treatment of Disease That Kills 1.7 Million People Each Year

Public health agencies and physicians would gain access to accurate, rapid dip-stick test that could give results similar to a pregnancy test Tuberculosis is a major killer that ranks alongside HIV/AIDS as a leading cause of death worldwide. This deadly disease takes the lives of more than a million people each year. And, unfortunately, traditional medical laboratory testing using X-rays, blood/skin/sputum specimens, or the new molecular diagnostic systems can be time consuming and expensive....

UK Physician Develops Unique Collection System for Clinical Laboratories and Pathology Groups Designed to Improve Quality of Urine Specimens

National Health Service estimates 73% of 65-million urine specimens collected annually in the UK are contaminated

Wanting to know why so many female patients that present with urinary tract infections (UTIs) require repeat appointments, Dr. Vincent Forte, a family GP and forensic physician who worked for the National Health Service (NHS) for 26 years, began investigating. He determined that the standard urine specimen collection cup is primarily the cause of poor-quality medical laboratory test results.

Forte realized that the method of collecting the specimens was largely to blame, with the required “start-aim-start” midstream collection technique required by traditional polypropylene specimen cups at the root of the problem.

That realization led to the development of a unique “midstream” urine collection device that eliminates the problem of first-void urine contaminating samples, according to a blog post on the Royal Society for the encouragement of Arts, Manufactures and Commerce (RSA) website written by Forte Medical of London’s Founding Director and Chief Executive Officer Giovanna Forte, Vincent Forte’s sister.

65-million Specimens Deemed Unreliable

Healthcare professionals, whether working in clinical laboratories and anatomic pathology groups or hospitals and out-patient clinics, often are among the first to notice when gaps in the quality or integrity of medical laboratory test results exist. However, in this case, it was a general practice physician rather than a medical laboratorian or in vitro diagnostics (IVD) manufacturer that set out to solve the problem of poor urine specimen collection, which The Daily Telegraph reports results in 73% of the 65-million urine specimens collected annually by the NHS being unreliable. That’s 47.5-million unreliable medical laboratory specimens collected and tested yearly in the United Kingdom.

Accurate Urine Collection Brings Billions in Savings

Vincent Forte concluded that the quality gap in urine specimen collection for his female patients was preventing accurate first-time analysis, diagnosis, and targeted treatment. In 2001, he set out to re-engineer urine collection cups. His first design—“a simple flushable paper funnel, which rejected first-flow urine, collected midstream, and ejected the remainder”—established the underlying design principle behind the patented Peezy Midstream product, Giovanna Forte stated in the RSA blog post.

Giovanna Forte noted that the first version of the device, marketed in 2010, was a “funnel formed by flat-sheet film, with a unique container-acceptor,” with overflow duct and incorporating a compressed sponge that rejects the first 8-10 ml of urine. While the product was well received, Forte says the selling price was too expensive to meet the NHS requirement for cost savings. By 2012, the product evolved into an injected-modeled design, which cut production costs by 50%. By 2014, the ergonomically designed funnel was improved to incorporate the two most common urine collection tubes.

In a Forte Medical presentation, Giovanna Forte predicted that accurate urine collection could result in a £1.2-billion (US $1.56-billion) savings to the NHS.

A Design Week article described the testing process for developing the midstream specimen collection device as “similar to launching a website in beta,” with initial testing resulting in changes such as the creation of a flatter, rounder handle to make the product easier to hold.

“Within the NHS, I was allowed to attend clinics where evaluations were taking place and speak directly to the patients. This allowed me to find out what they thought of everything from instructions for use to the collection system itself,” Vincent Forte stated in the Design Week article. “All the information was fed back into our design engineers, who proposed an improved product made more simply at a lower price.”

The patented Peezy Midstream urine collection system rejects the first (often contaminated) 8-10 ml of urine, isolating and capturing the important midstream and rejecting the rest of the urine into the toilet. The product claims 98.5% accurate urine specimen collection and would improve the accuracy and reliability of the medical laboratory tests performed on urine samples collected with this device. (Photo copyright: Forte Medical.)

Today, Forte Medical offers two midstream urine collection devices used by both men and women:

1.     Peezy Midstream PE40, which collects urine into a traditional 30ml universal container; and

2.     Peezy Midstream PE50, which collects urine into a lab-friendly 10ml primary tube designed to fit in laboratory analyzers.

“This simple solution … took 10 years and £2.6-million [US $3.38-million] to get right. It was achieved not by a multinational with deep pockets, but by a startup funded largely by friends, family, and a handful of angel investors, along with the goodwill of design and manufacturing partners,” Vincent Forte stated in the RSA blog post.

Specimen Capture Methods Lead to Careless Infection Control

In an article published on News Medical, an online, open-access medical information provider, Giovanna Forte points out another flaw in traditional urine collection systems.

“Thrusting one’s hands willingly into our own urine is hardly common practice. That we are expected to do so in order to capture an important specimen essential to diagnosis hardly chimes with the concept of modern medicine and leads to pretty shabby infection control by any standards,” she stated.

The Peezy Midstream is a Medicines and Healthcare Products Regulatory Agency (MHRA) approved product in the UK, and is FDA listed in the United States. As a Class 1 “Container, Specimen Mailer and Storage, Non-Sterile” device, the Peezy Midstream is “510(k) exempt” and did not require FDA review before being marketed in this country.

Still to come are clinical trials and papers in peer-reviewed medical journals that support the function of this medical device to improve patient care. It is notable, though, that the National Health System in the UK is collaborating with Forte Medical in certain ways to determine how the device can improve patient care. Dark Daily would like to hear from any medical laboratories in the UK and USA that are using this device when urine specimens are collected.

—Andrea Downing Peck

Related Information:

Liquid Gold: Urine Is the Unsung Hero of Modern Medicine and Health Economy

Peezy Mid-Stream Urine (MSU) Usability Study Results Report

What Is a Mid-Stream Urine Sample and Why Do Healthcare Professionals Request Them?

The Peezy: The Tale of an Award-Winning, Rapid-Prototyped, User-Developed Design

How Design Integrity Can Save Lies in Essential Basic Medicine

Point-of Care Urine Drug Test Kits Used by Rehabilitation Programs in Canada and US to Help Drug Users Detect the Presence of Fentanyl in Their Heroin and Opiate Drugs

A legal, supervised injection site (SIS) affiliated with Vancouver Coastal Health found 86% of drugs tested with strips contained fentanyl when tested with these medical lab test kits

Here’s an unexpected application of point-of-care testing (POCT) that may surprise pathologists and medical laboratory leaders. In a sort of “guerilla-warfare” street experiment that applies diagnostic technologies to a problem, the manager of a needle-exchange program in the Bronx has been helping heroin and other opioid users discover if a product they are about to ingest is contaminated by handing out test strips designed for testing urine.

The addicts participating in these special programs use the POCT urine test strips to test their drugs for the presence of fentanyl, a powerful synthetic opioid analgesic similar to morphine that can increase the potency of opioids to lethal levels. Rehab program directors adopted this approach to help prevent overdoses and deaths among drug users.

Reducing Overdoses with Test Strip Handouts

Opioids such as morphine are often prescribed to cancer or surgery patients to treat severe pain. However, according to a National Institute on Drug Abuse (NIDA) fact sheet, fentanyl is “50 to 100 times more potent than morphine.” When fentanyl is mixed with heroin or cocaine and sold on the streets, the potent mix can be deadly, NIDA explained.

Test strips ordered from Canada designed to check patients’ urine for fentanyl are being used by St. Ann’s Corner of Harm Reduction (St. Ann’s) in the Bronx, New York. The strips are being used to check drug users’ syringes for fentanyl, according to a National Public Radio Shots article. The idea is to inform drug users of what they have in hand and possibly encourage them to choose not to take the drug, use less, or slow things down, Shots reported.

“If you’re doing dope, we’ll give you a test strip so you can test and see if there’s fentanyl,” stated Van Asher, Data Manager at St. Ann’s, in the Shots article.

Whether an unlicensed individual distributing test strips to drug users violates state or federal regulations was not broached in the Shots article.

St. Ann’s gives out about 15 strips a day each costing $1, Shots noted. St. Ann’s staff is sharing data collected on the encounters with the Centers for Disease Control and Prevention (CDC) and with New York health departments.

Finding Fentanyl with Test Strips in Canada

St. Ann’s isn’t the first to use urine test strips for drug checking. Vancouver Coastal Health (VCH) in British Columbia, Canada, launched a pilot program for drug-checking in 2016 at its Insite facility.

Insite is a supervised injection site (SIS). It opened its doors in 2003 and operates under a constitutional exemption to Canada’s Controlled Drugs and Substances Act.

At Insite’s “supervised injection site” facility (above) in Vancouver, British Columbia, drug users can “legally” inject illegal drugs. Directors of this program have adapted point-of-care urine test kits typically used in medical laboratory testing to allow drug users to test their heroin and opiate drugs for the presence of fentanyl. The goal is to reduce overdoses and deaths from users unknowingly ingesting fentanyl. (Photo copyright: CBCNews.)


Insite began to test drugs for the presence of fentanyl in the fall of 2016. Data from 173 tests performed in July and August found that 86% of drugs tested contained fentanyl, noted a VCH news release.

“These initial results confirm our suspicion that the local drug supply is overwhelmingly contaminated with fentanyl. We’re hoping this information can help people who use drugs,” stated Mark Lysyshyn, MD, MPH, VCH Medical Health Officer and Professor of Medicine at University of British Columbia.

The test works when the client dilutes the substance with a few drops of water. A positive or negative result for fentanyl is revealed within seconds.

The test strip used by Insite was designed to check for fentanyl in urine, not for checking drugs, noted the VCH statement. Insite intends to review the pilot program test data and decide whether to continue testing services after the pilot program concludes.

Alexander Walley, MD, Director of the Addiction Medicine Fellowship Program and Assistant Professor of Medicine at Boston Medical Center, stated the test may aid users’ decision-making.

“Even when they know they’re going to be positive for fentanyl, the experience of somebody testing their drugs and seeing that it’s fentanyl has an impact. It really encourages them to use more safely,” he stated in the Shots article.

Overdose Deaths Due to Fentanyl in America

A CBC News, Manitoba, article called the death rate due to fentanyl ingestion a “Canada-wide disaster.” However, the problem is significant in the US as well.

Death rates from synthetic opioids, including fentanyl, rose more than 72% from 2014 to 2015 in the US, according to the CDC.

In New York City, fentanyl is increasingly being linked to overdoses. In 2016, nearly half (44%) of drug deaths involved drugs mixed with fentanyl. That’s a 16% increase over 2015, according to a NYC Health press release.

A report from the Tennessee Department of Health noted that 1,451 people died from drug overdose in 2015. That’s a state record. Deaths associated with fentanyl rose significantly from 69 in 2014 to 174 in 2015, the report noted.

How Fentanyl Works and Why It Is Dangerous

Here are some fentanyl facts from the NIDA:

  • Fentanyl works by binding to opioid receptors located in areas of the brain that control pain and emotions;
  • People may experience side effects such as euphoria, drowsiness, nausea, confusion, addiction, respiratory arrest, unconsciousness, coma, and death;
  • Increased risk of overdose exists when drug users are unaware a drug they are ingesting contains fentanyl.

Clinical laboratory directors and pathology groups nationwide might want to follow the progress of test strip services at St. Ann’s Corner and Insite’s SIS. This twist on traditional POCT—using urine test strips to look for the presence of fentanyl in substances—could aid their own communities achieve public awareness, change behaviors, and save lives.

—Donna Marie Pocius

Related Information:

An Experiment Helps Heroin Users Test Their Street Drugs for Fentanyl

86% of Drugs Checked at Insite Contain Fentanyl

Fentanyl Deaths Are a Canada-wide Disaster

5 New Supervised Injections Sites Coming to Fight Vancouver’s Fentanyl Overdose Crisis

1,451 Tennesseans Die from Drug Overdoses in 2015

State Data Confirms Overdose Deaths Primarily White Opioid Users

British Scientists Develop Urine Test that Can Quickly Reveal Health of a Person’s Eating Habits and Might Create New Markets for Clinical Laboratories

Since most patients do not accurately report what they eat, a new medical laboratory test could provide doctors and researchers with the ‘first independent indicator of the quality of a person’s diet’

It may soon be possible to measure the health of a person’s diet by use of a 5-minute diagnostic test recently developed by British scientists. The test can reveal the facts about how well a person eats and has the potential to find clinical value among medical professionals and in clinical laboratories.

What adds to the interest in this test is the widespread incidence of obesity in most developed nations around the world. It would be a useful tool for medical professionals who have wanted better ways to manage this health problem. (more…)