Low vitamin D levels raise anemia risk in children

Low levels of the "sunshine" vitamin D appear to increase a child's risk of anemia, according to new research led by investigators at the Johns Hopkins Children's Center. The study, published online Oct. 10 in the Journal of Pediatrics, is believed to be the first one to extensively explore the link between the two conditions in children.

The researchers caution that their results are not proof of cause and effect, but rather evidence of a complex interplay between low vitamin D levels and hemoglobin, the oxygen-binding protein in red blood cells. The investigators say several mechanisms could account for the link between vitamin D and anemia, including vitamin D's effects on red blood cell production in the bone marrow, as well as its ability to regulate immune inflammation, a known catalyst of anemia.

To capture the interaction between the two conditions, researchers studied blood samples from more than 10,400 children, tracking levels of vitamin D and hemoglobin. Vitamin D levels were consistently lower in children with low hemoglobin levels compared with their non-anemic counterparts, the researchers found. The sharpest spike in anemia risk occurred with mild vitamin D deficiency, defined as vitamin D levels below 30 nanograms per milliliter (ng/ml). Children with levels below 30 ng/ml had nearly twice the anemia risk of those with normal vitamin D levels. Severe vitamin D deficiency is defined as vitamin D levels at or below 20 ng/ml. Both mild and severe deficiency requires treatment with supplements.

When investigators looked at anemia and vitamin D by race, an interesting difference emerged. Black children had higher rates of anemia compared with white children (14 percent vs. 2 percent) and considerably lower vitamin D levels overall, but their anemia risk didn't rise until their vitamin D levels dropped far lower than those of white children. The racial difference in vitamin D levels and anemia suggests that current therapeutic targets for preventing or treating these conditions may warrant a further look, the researchers say.

"The clear racial variance we saw in our study should serve as a reminder that what we may consider a pathologically low level in some may be perfectly adequate in others, which raises some interesting questions about our current one-size-fits-all approach to treatment and supplementation," says lead investigator Meredith Atkinson, M.D., M.H.S., a pediatric kidney specialist at the Johns Hopkins Children's Center.

Untreated, chronic anemia and vitamin D deficiency can have wide-ranging health consequences, including organ damage, skeletal deformities and frequent fractures, and lead to premature osteoporosis in later life.

Long known for its role in bone development, vitamin D has recently been implicated in a wide range of disorders. Emerging evidence suggests that low vitamin D levels may play a role in the development of certain cancers and heart disease and lead to suppressed immunity, the researchers note.

Anemia, which occurs when the body doesn't have enough oxygen-carrying red blood cells, is believed to affect one in five children at some point in their lives, experts say. Several large-scale studies have found severe vitamin D deficiency in about a tenth of U.S. children, while nearly 70 percent have suboptimal levels.

"If our findings are confirmed through further research, low vitamin D levels may turn out to be a readily modifiable risk factor for anemia that we can easily tackle with supplements," says senior study investigator Jeffrey Fadrowski, M.D., M.H.S., also a pediatric kidney specialist at Johns Hopkins.

Journal Reference:

1. Meredith A. Atkinson, Michal L. Melamed, Juhi Kumar, Cindy N. Roy, Edgar R. Miller, Susan L. Furth, Jeffrey J. Fadrowski. Vitamin D, Race, and Risk for Anemia in Children. The Journal of Pediatrics, 2013; DOI: 10.1016/j.jpeds.2013.08.060

Vigilance for kidney problems key for rheumatoid arthritis patients

Rheumatoid arthritis patients are likelier than the average person to develop chronic kidney disease, and more severe inflammation in the first year of rheumatoid arthritis, corticosteroid use, high blood pressure and obesity are among the risk factors, new Mayo Clinic research shows. Physicians should test rheumatoid arthritis patients periodically for signs of kidney problems, and patients should work to keep blood pressure under control, avoid a high-salt diet, and eliminate or scale back medications damaging to the kidneys, says senior author Eric Matteson, M.D., Mayo rheumatology chair. The study is published in the American Journal of Kidney Diseases, the National Kidney Foundation journal.

Researchers studied 813 Mayo Clinic patients with rheumatoid arthritis and 813 without it. They found that over a 20-year period, people with rheumatoid arthritis have a 1 in 4 chance of developing chronic kidney disease, compared with the general population's 1-in-5 risk.

"That might not seem like a lot, but in fact that's quite a big difference, and it has important implications for the course of rheumatoid arthritis and for the management of the disease," Dr. Matteson says.

In addition, heart disease is more common in rheumatoid arthritis patients who have chronic kidney disease, he adds.

Factors contributing to a higher kidney disease risk for rheumatoid arthritis patients include use of corticosteroids such as prednisone and cortisone; a higher "sed rate" -- a blood test that measures inflammation -- in the first year of rheumatoid arthritis; obesity; hypertension; and dyslipidemia, abnormally high cholesterol in the blood, according to the study.

There are currently no medical guidelines specifically for the management of chronic kidney disease in rheumatoid arthritis, says Dr. Matteson, adding that he hopes the research will make physicians more alert to the risk of kidney disease in rheumatoid arthritis and lead to guidelines.

Dr. Matteson recommends that physicians be careful about the medications they give people with rheumatoid arthritis, to reduce the risk of medication-induced kidney disease. Rheumatoid arthritis patients should have blood tests and urine analysis once a year or more often to detect kidney problems, depending on the medications they are taking and on other conditions such as diabetes and high blood pressure they may have, he says.

"Kidney disease in patients with rheumatoid arthritis can be detected very simply, and the techniques are the same as are used in the general population," Dr. Matteson says.

To reduce their risk of developing kidney disease, patients should be attentive to their blood pressure and keep it under control, maintain a diet that isn't high in salt; avoid or reduce use of medications that are directly toxic to the kidneys; including nonsteroidal anti-inflammatory drugs; and get their rheumatoid arthritis and inflammation under as good of control as possible, he adds.

More research is planned to understand contributors to kidney disease in rheumatoid arthritis and how to intervene to reduce the risk, Dr. Matteson says.

Journal Reference:

1. LaTonya J. Hickson, Cynthia S. Crowson, Sherine E. Gabriel, James T. McCarthy, Eric L. Matteson. Development of Reduced Kidney Function in Rheumatoid Arthritis. American Journal of Kidney Diseases, 2014; 63 (2): 206 DOI: 10.1053/j.ajkd.2013.08.010

How the immune system protects children from malaria

According to a study published today in PLOS Pathogens, children who live in regions of the world where malaria is common can mount an immune response to infection with malaria parasites that may enable them to avoid repeated bouts of high fever and illness and partially control the growth of malaria parasites in their bloodstream. The findings may help researchers develop future interventions that prevent or mitigate the disease caused by the malaria parasite.

A colorized scanning electron micrograph shows a red blood cell infected with malaria parasites, which are colorized in blue. To the left are uninfected cells with a smooth red surface.

Each year, approximately 200 million cases of malaria occur worldwide, resulting in roughly 627,000 deaths (mostly children less than the age of 5 years living in sub-Saharan Africa). In 2013, 97 countries had ongoing malaria transmission, according to the World Health Organization. Unlike individuals who are newly exposed to malaria, people living in malaria-endemic regions often do not experience malaria-induced fever and manage to control par

asite numbers in the bloodstream.

To better understand why, researchers analyzed immune cells from children in Mali who are bitten by malaria-infected mosquitoes more than 100 times per year, yet experience malaria fever only two times per year on average. The scientists collected blood samples from children on three occasions: before the start of the six-month malaria season; seven days after each child had been treated for his or her first malaria fever of the season, when symptoms had cleared; and after the subsequent six-month dry season, when little to no malaria transmission occurs.

To simulate malaria infection at these time points, researchers exposed the immune cells to malaria parasites in a test tube. They found that immune cells collected before the malaria season responded by producing large amounts of molecules that cause inflammation, fever and other malaria symptoms. Conversely, cells collected after the first bout of malaria fever responded by producing molecules that control inflammation and destroy the malaria parasite.

The third set of immune cells (those taken after the dry season when there is an absence of malaria exposure) lost their ability to produce molecules that control inflammation, leaving children susceptible again to malaria fever. According to the authors, this immune response, which appears to depend on ongoing exposure to malaria parasites, may have evolved to protect young children from potentially life-threatening inflammation and unchecked parasite growth in the face of repeated malaria infections, before they acquire antibodies that reliably protect against the onset of malaria symptoms.

Journal Reference:

1. Silvia Portugal, Jacqueline Moebius, Jeff Skinner, Safiatou Doumbo, Didier Doumtabe, Younoussou Kone, Seydou Dia, Kishore Kanakabandi, Daniel E. Sturdevant, Kimmo Virtaneva, Stephen F. Porcella, Shanping Li, Ogobara K. Doumbo, Kassoum Kayentao, Aissata Ongoiba, Boubacar Traore, Peter D. Crompton. Exposure-Dependent Control of Malaria-Induced Inflammation in Children. PLoS Pathogens, 2014; 10 (4): e1004079 DOI: 10.1371/journal.ppat.1004079

Why alcoholism saps muscle strength

Muscle weakness is a common symptom of both long-time alcoholics and patients with mitochondrial disease. Now researchers have found a common link: mitochondria that are unable to self-repair. The link to self-repair provides researchers both a new way to diagnose mitochondrial disease, and a new drug target.

Mitochondria -- organelles that produce the energy needed for muscle, brain, and every other cell in the body -- repair their broken components by fusing with other mitochondria and exchanging their contents. Damaged parts are segregated for recycling and replaced with properly functioning proteins donated from healthy mitochondria.

While fusion is one major method for mitochondrial quality control in many types of cells, researchers have puzzled over the repair mechanism in skeletal muscle -- a type of tissue that relies constantly on mitochondria for power, making repair a frequent necessity. However, mitochondria are squeezed so tightly in between the packed fibers of muscle cells, that most researchers assumed that fusion among mitochondria in this tissue type was impossible.

An inkling that fusion might be important for the normal muscle function came from research on two mitochondrial diseases: Autosomal Dominant Optical Atropy (ADOA) disease, and a type of Charcot-Marie-Tooth disease (CMT). A symptom of both disease is muscle weakness and patients with both these diseases carry a mutation in one of the three genes involved in mitochondrial fusion.

To investigate whether mitochondria in the muscle could indeed fuse to regenerate, first author Veronica Eisner, Ph.D., a postdoctoral fellow at Thomas Jefferson University created a system to tag the mitochondria in skeletal muscle of rats with two different colors and then watch if they mingled. First, she created a rat model whose mitochondria expressed the color red at all times. She also genetically engineered the mitochondria in the cells to turn green when zapped with a laser, creating squares of green-shining mitochondria within the red background. To her surprise, the green mitochondria not only mingled with the red, exchanging contents, but were also able to travel to other areas where only red-colored mitochondria had been. The results were exciting in that they showed "for the first time that mitochondrial fusion occurs in muscle cells," says Dr. Eisner.

The researcher team, led by Dr. Gyorgy Hajnoczky, M.D., Ph.D., Director of Jefferson's MitoCare Center and professor in the department of Pathology, Anatomy & Cell Biology, then showed that of the mitofusin (Mfn) fusion proteins, Mfn1 was most important in skeletal muscle cells.

Once they had identified Mfn1, they were able to test whether mitochondrial fusion was the culprit in other examples of muscle weakness, such as alcoholism. One long-term symptom of alcoholism is the loss of muscle strength. The researchers showed that the Mfn1 abundance went down as much as 50 percent in rats on a regular alcohol diet-while other fusion proteins were unchanged, and that this decrease was coupled with a massive decrease in mitochondrial fusion. When Mfn1 was restored, so was the mitochondrial fusion. They also linked the decreased Mfn1 and mitochondrial fusion to increased muscle fatigue.

"That alcohol can have a specific effect on this one gene involved in mitochondrial fusion suggests that other environmental factors may also specifically alter mitochondrial fusion and repair," says Dr. Hajnoczky.

"The work provides more evidence to support the concept that fission and fusion -- or mitochondrial dynamics -- may be responsible for more than just a subset of mitochondrial diseases we know of," says Dr. Hajnoczky. "In addition, knowing the proteins involved in the process gives us the possibility of developing a drug."

Journal Reference:

1. V. Eisner et al. Mitochondrial fusion is frequent in skeletal muscle and supports excitation contraction coupling. Journal of Cell Biology, April 2014 DOI: 10.1083/jcb.201312066, 2014

The Evolving Role of HPV Testing in Cervical Cancer Screening

By Timothy Uphoff, PhD, DABMG, MLS (ASCP)

For decades, cervical cytology has been the mainstay of cervical cancer screening, but emerging evidence about the pathologic role of human papillomavirus (HPV) in cervical cancer is changing the screening landscape for this disease. As the science involving HPV advances and as guidelines from professional organizations evolve, laboratorians need to keep abreast of cervical cancer testing developments and work with clinicians to ensure appropriate test utilization.

Cervical Cytology

Widespread introduction of cervical cytology or Papanicolaou (Pap) testing in the United States during the 1950s and 1960s launched a trend of markedly reduced squamous cell cervical cancer-related mortality. Cervical cancer, once the most frequent cause of cancer death in women, now ranks 14th among cancer deaths in the U.S. (See Figure 1, p. 9) (1). Cytology-based screening aims to detect squamous cell cancers, which account for about 80% of cervical cancer. It is less useful for detecting adenocarcinomas arising from endocervical glands because these cells are less evident than ectocervix squamous cells by this method. Fortuitously, evidence shows that HPV testing is more effective than cervical cytology in detecting both adenocarcinoma and glandular cell cancers of the cervix, thereby making it a useful adjunct to cervical cytology (2).

Figure 1 Age-Adjusted U.S. Morality Rates By Cancer Site All Ages, All Races, Female, 1975-2012 Cancer sites include invasive cases only unless otherwise noted. Mortality source: US Mortality Files, National Center for Health Statistics, CDC. Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups – Census P25-1130). Regression lines are calculated using the Joinpoint Regression Program Version 4.0.3, April 2013, National Cancer Institute

HPV Testing

HPV is a common, sexually transmitted DNA virus comprised of more than 100 genotypes. In the late 1970s, Dr. Harald zur Hausen first described HPV's role in the development of cervical cancer (3). Significant evidence now exists to support a causal relationship between duration of infection with a high risk HPV genotype (HR-HPV) and development of cervical cancer (4). Early HPV infections can be recognized most often by cytology as low grade squamous intraepithelial lesions (LGSIL) or by histology as cervical intraepithelial neoplasia grade 1 (CIN 1) (5). Most such infections spontaneously resolve by host immunity, and their corresponding cellular abnormalities revert to normal.

Because HR-HPV infections are very common in young women and most women clear HPV infections within 6–12 months, the presence of HPV DNA alone does not guarantee that cervical dysplasia or cervical cancer is present or will develop in women younger than age 30. When HR-HPV infections persist, cervical pre-cancers, such as high grade squamous intraepithelial lesion (HGSIL) by cytology or cervical intraepithelial neoplasia grade 2 or 3 (CIN 2 or 3) by histology, can arise from genetic instability and clonal expansion of highly transformed cells. Later stage lesions like these are much less likely to regress (See Figure 2, p. 10). Factors leading to HPV persistence include: HPV genotype—with the greatest risk from HPV 16 and 18—increasing age, smoking, mutagens, immunosuppression, inflammation, hormones, and genetic factors. This and other evidence demonstrates that HPV testing could play an important role in cervical cancer screening.

Figure 2 Cervical Cytology Progression

In 1997, Digene received Food and Drug Administration (FDA) clearance for the Hybrid Capture HPV DNA assay as an aid in triaging women with equivocal cervical cytology. Six years later the FDA cleared Digene's Hybrid Capture 2 DNA assay (HC2) as an adjunctive screen with cervical cytology for women 30 years and older. At this point, the field of HPV test interpretation became confounded as some clinical laboratories developed real-time polymerase chain reaction tests with better analytic sensitivity than HC2 which, unfortunately, did not translate into improved prediction of cervical cancer. Many studies demonstrated that clinical cut-offs for HPV viral loads were necessary to establish levels that better predicted cervical cancer risk(6–8). Given these circumstances, HC2, as the only FDA-cleared HPV assay, served as the gold standard for cervical cancer screening until 2011 and 2012 when the FDA approved the Aptima, Cervista, and Roche HPV assays (9).

Current HPV assays differ in methodology, target, and analytic cutoffs, but are all interpreted as positive or negative for HR-HPV and carry equivalent clinical implications for most practitioners. As these newer methods are adopted more broadly, we will likely see more studies demonstrating performance characteristic differences among them. For example, a large number of studies have already demonstrated that the Aptima HPV assay has equivalent sensitivity but superior specificity to HC2 in two testing situations. The first involves reflex testing, in which cytology testing revealed atypical squamous cells of undetermined significance (ASC-US). The second concerns co-testing via cytology and HPV testing in women older than age 30 to detect ≤CIN 2 likely to indicate persistent infection and clinically significant cervical dysplasia (10–13).

This improved specificity translates into fewer false positive screening results, saving patients undue anxiety and unnecessary follow-up diagnostic procedures. Differences in the HPV target between the two assays might contribute to their different specificities. E6 and E7 mRNA, the targets of the Aptima method, are believed to be expressed at higher levels during persistent infections, while HPV DNA levels, the target of HC2, are high early in the course of HPV infection. Evidence also suggests the potential for false-negative HPV results from assays that target the L1 region of the HPV genome, since portions of this region have been shown to be lost on viral integration during persistent infections (14). A recent expert opinion paper by Tjalma and Depuydt promotes the use of an E6/E7-based assay over an L1-based method for just such reasons (15). Thus, based on assay-specific performance characteristics, we may expect to see distinct indications and outcomes put forward for each test method.

Cervical Cancer Screening Guidelines

2015 will mark the 40th anniversary of the American College of Obstetricians and Gynecologists (ACOG) having first published a technical bulletin as guidance for Pap testing (16). Screening guidelines have continually evolved since then, with various professional organizations often offering differing recommendations. By 2012 it seemed that everyone—at least in the U.S.—had come to agreement, as the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) published joint consensus guidelines for the Prevention and Early Detection of Cervical Cancer (17), followed by ACOG, which later that year released new guidelines for cervical cancer screening (See Table, p. 10) (18). These guidelines are primarily in agreement with the U.S. Preventive Services Task Force's (USPSTF) current recommendations for cervical cancer screening (19). A major development among these guidelines is that women ages 30–65 who undergo co-testing with HPV and cytology need retesting only every 5 years. These recommendations are for screening only and do not relate to other uses of cytology and HPV testing such as follow-up of patients with untreated disease, post-colposcopic, or immediate post-treatment follow-up or surveillance. These are all circumstances in which testing at more frequent intervals might be appropriate.

Summary of 2012 ACOG, ASCP, ACS, and ASCCP Cervical Cancer Screening Guidelines for Women of Average Risk
Age	Screening Recommendation	Comments
Less than 21 years	No cervical cancer screening of any kind	HPV testing should not be used for screening or ASC-US reflex in this age group.
21 - 29 years	Cytology alone primary screening every 3 years (acceptable) HPV testing with cytology ASC-US findings (preferred)	Routine HPV co-testing is not recommended in this age group. HPV testing is recommended in cases of ASC-US cytology.
30 - 65 years	HPV and cytology 'co-testing every 5 years (preferred) Cytology alone every 3 years (acceptable)	Screening by HPV testing alone is not recommended for most clinical settings.
Over 65 years	No screening following adequate history of negative prior screening	Women with history of >CIN 2 should continue screening for at least 20 years.
After hysterectomy	No screening if no previous history of >CIN 2	Continue screening (cytology) if there is history of >CIN 2 in the past 20 years or cervical cancer ever.
A more complete summary of these recommendations is available at http://www.cdc.gov/cancer/cervical/pdf/guidelines.pdf

In general, the new guidelines extend the recommended screening intervals to every 3 years for women 21–29 years undergoing cytology alone, or every 5 years for those ages 30–65 who undergo both cytology and HPV testing. There is significant evidence that the use of co-testing in the latter group allows for an extended test interval and provides better sensitivity for >CIN 3 than screening by cytology alone (20–22). The guidelines do not recommend co-testing in women 21–29 years because of the high prevalence of HPV in this age group; however, HPV testing can be useful for these patients if the cytology results identify ASC-US findings.

Screening more frequently than these recommendations not only offers no benefit but has significant risks. Both the USPSTF and ACS/ASCCP/ASCP documents state that screening more often than every 3 years causes significant harm in terms of potential short-term psychological stress, additional procedures, and assessment and treatment of transient lesions, vaginal bleeding and infection, and potential adverse pregnancy outcomes.

The new guidelines also advise no longer screening women older than age 65 if they have a documented negative screening history. The documents define adequate negative screening results as three consecutive negative cytology results or two consecutive negative co-test results within the past 10 years, with the most recent test performed within 5 years. Women with a history of ≥CIN 2 or adenocarcinoma in situ should continue screening for 20 years after spontaneous regression or appropriate management even if it extends the screening past age 65 years.
Future evidence may show that less frequent screening is appropriate for women who have received the HPV vaccine, but given the limitations of current research and the low vaccination coverage among U.S. adolescents prior to first intercourse, the screening protocol is now the same for both vaccinated and unvaccinated women.

HPV Genotyping

The major guidelines published in 2012 also introduced an emerging role for definitively identifying HPV genotypes 16 and 18, specifically in women who have discordant co-testing results with normal cytology and a positive HR-HPV result. These women can be managed by either repeat co-testing in 1 year or immediate HPV16/18 genotyping. If HPV genotyping reveals the presence of HPV 16 or 18, the patient would undergo colposcopy but if this result is negative she would undergo repeat co-testing in 1 year. The major guidelines do not denote a preference between immediate HPV genotyping and 1 year co-testing follow-up. They do specify, however, that women should not be tested for genotypes other than 16 and 18. Of note, since the guidelines were published in 2012, the FDA approved the Aptima HPV 16 18/45 Genotype Assay as a follow-up to positive HR-HPV results in ASC-US reflex and co-testing indications. Despite the guidelines' recommendations, we have seen slow adoption of HPV genotyping requests by providers at our institution thus far.

HPV as Primary Screening

The role of HPV testing in cervical cancer screening is continuing to evolve. Many studies have considered the possibility of HPV testing superseding cytology as a primary screen for cervical cancer (23–25), and there are strong proponents on each side of this debate (26, 27). A central point in this issue is the superior negative predictability of HPV tests over cervical cytology. Most recently, Ronco et al. evaluated data from four randomized controlled studies in Europe and found that HPV screening appears to offer 60–70% greater protection against invasive cervical cancer than cytology (28). In July 2013, Roche submitted a premarket approval supplement to the FDA seeking the addition of a cervical cancer primary screening indication for the company's cobas HPV test. The filing is based on evidence coming from 3-year follow-up data of the 47,000 women included in the Roche-sponsored ATHENA study (29). On March 12, FDA held a public meeting of the Microbiology Devices Panel of the Medical Devices Advisory Committee and the committee voted unanimously that the data was sufficient to prove safety and effectiveness for the Cobas HPV test for primary screening (30). FDA is not bound to abide by committee recommendations, but usually does. When an FDA-approved HPV test for primary screening becomes available in the U.S., its adoption in clinical practice certainly would lag until major guidelines endorse such a strategy and clinicians recognize its utility.

Conclusion
Debate over the best utilization of cytology and HPV testing in cervical cancer will no doubt intensify and continue for some time. It is critical that laboratorians are familiar with these methods and the evidence supporting their utility. We must inform clinicians and champion appropriate test utilization for patient care. This quote by Britain's 19th century prime minister, Benjamin Disraeli, certainly applies to cervical cancer screening: "Change is inevitable. Change is constant."

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Fixing the Problem of Mislabeled Specimens in Clinical Labs

The incidence of patient identification errors, including mislabeled and misidentified specimens, is much too high in clinical laboratories. One of the challenges laboratories face is that specimen mislabeling can occur at multiple points in the pre-analytic process (See Box, right). While these single-point weaknesses exist within an infinite set of complex and continually changing processes, a few practical steps can be taken to eliminate these errors. Some of the solutions are easy to implement and others are more costly and involved.

Specimen Labeling Problem Points

Patient misidentification at the time of collection. Incorrect barcode reads on point-of-care devices. Use of handwritten labels at any point. Labeling mix-ups immediately before or after collection. Mislabeling during laboratory accessioning, aliquoting, and post-centrifugation pour-off. Relabeling specimens that already have an existing label from another system, such as may occur in a core laboratory or a reference laboratory.

One approach—single piece flow—will be familiar to Lean practitioners. This concept has significant error-proofing potential for labeling tasks at relatively low cost. For example, to prevent errors during collection and processing, avoid having specimens from multiple patients in the active work area at the same time. Also, avoid using strips of labels from a label printer with labels for multiple patients that must be matched to specimens. Unused labels should be destroyed before proceeding to the next patient. Aliquot labels which have limited identifiers and truncated names should be avoided. If aliquoting manually, pour off and label only one specimen at a time before proceeding to the next specimen. Similarly, if using an automated aliquoting device, be sure that the label exactly duplicates the barcode label from the primary tube to facilitate error detection.

Another tool that more laboratories are using is the portable barcode scanner. These scanners read wristband barcodes at point-of-collection and work well in conjunction with portable barcode label printers or point-of-care analytical devices. However, barcode devices make more errors than commonly believed. Snyder et al. made several recommendations to improve the accuracy of barcode reading.

One of the most important actions a laboratory can take to is to implement the CLSI Standard AUTO12-A, Specimen Labels: Content and Location, Fonts, and Label Orientation. Many hospital laboratories have extensive outreach programs or serve as core laboratories for other laboratories and clinics, and most laboratories refer samples to reference labs. This requires sample relabeling, introducing another error-prone step. Often the information systems for these separate facilities differ, and the printed specimen labels have different formats and fonts. Even when specimens are not relabeled, employees must transition quickly and accurately between various fonts, formats, and identifiers. Display and layout inconsistency also leads to an increase in errors. CLSI developed the AUTO12-A standard specifically to deal with the incidence of mislabeled specimens arising from formatting inconsistencies.

Figure 1 shows samples for a fictitious patient using two versions of the label specified by the standard. One version has a vertical zone at the left end of the label which can be used as a reverse font indicator of a priority, such as STAT. The entire top line of each label is reserved for the patient name to limit any possibility of truncation of a long name. The standard, however, does have a very detailed description of a recommended rule for name truncation written in a manner that can be directly implemented in the laboratory information system (LIS) by a software engineer.

Figure 1 Examples of specimen labels that follow the CLSI Standard AUTO12-A. Used with permission from the Clinical and Laboratory Standards Institute (CLSI) www.clsi.org.

On the second line of the label, left-justified, is the secondary unique identifier used by the institution in compliance with regulatory guidelines. Right-justified on the second line are the patient’s date of birth, age, and sex. Below the barcode, left-justified, are the collection date and time. Alternatively, if the labels are printed prior to specimen collection, that space can be reserved for hand writing the collection date and time with the collector’s ID as required.

Although the standard does not specify fonts for the label, it does recommend the use of a sans serif font, because the serifs—the small tails at the tops and bottoms of characters—make characters harder to read. A minimum font size is specified and spacing is to be adequate so that adjacent characters do not touch each other, either vertically or horizontally. Often laboratories attempt to squeeze as much information as possible on the labels by decreasing font size and crowding the characters and lines closer together, which makes the content more difficult to read.

Under the standard, labels are affixed lengthwise along the tube while holding the tube by its cap or stopper with the left hand. This ensures that the vertical priority zone is on the upper end of the tube when it is held in a rack or an automation carrier so it can be easily viewed. CLSI has received preliminary indications from both CAP and the Joint Commission that the AUTO12-A standard will be referenced in inspection checklists in the coming years. Enforcing this standard will significantly improve laboratory labeling accuracy.

Figure 2 An automated camera system developed for photographing specimen tube exteriors for vision processing and optical character recognition analysis to detect possible mislabeled specimens.

Our laboratory has invented one high tech solution that we believe will bring our own error rate for mislabeled specimens to near zero and which, with further refinement, may become suitable for use on commercial automation systems. This is a robotic camera system that can lift a specimen tube from the transport carrier on our automated track, take four simultaneous photographs of the tube using four equidistantly spaced high resolution cameras, precisely stitch the four photographs into a single photograph of the entire exterior of the tube, and then use optical character recognition (OCR) to compare the patient name on the original label to the patient name in our LIS (as identified by reading the barcode on our LIS label). The description and validation of this system has recently been published. Figure 2 is a photograph of the robotic system.

One reason we developed this robotic camera system is that, although the incidence of mislabels from our specimen processing function (approximately 1/8000) is lower than the reported incidences, our objective of zero mislabeled specimens has remained elusive. We implemented the robotic system in our testing environment in October 2012. Since that time, the system has collected and analyzed some 2.4 million images and more than 300 mislabeled specimens have been detected, of which only 53% were found through our normal quality assurance processes. For the subset of specimens routed through this advanced automation, significantly fewer corrected reports have been issued.

When placed in full production, this technology offers us the prospect of meeting our objective of zero mislabeled specimens escaping the pre-analytical process, at least for that portion of our laboratory’s work that passes through the OCR analysis. As we gain more experience with this technology, we anticipate that it can be widely used, especially in higher volume settings.

FURTHER READING

1. Bonini P, Plebani M, Ceriotti F, et al. Errors in laboratory medicine. Clin Chem 2002;48:691–8.
2. Clinical and Laboratory Standards Institute (CLSI). Specimen labels: Content and location, fonts, and label orientation; approved standard. CLSI document AUTO12-A. Wayne, Pa.: CLSI 2011.
3. Grimm E, Friedberg RC, Wilkinson DS, et al. Blood bank safety practices: Mislabeled samples and wrong blood in tube – a Q-Probes analysis of 122 clinical laboratories. Arch Pathol Lab Med 2010;134:1108–15.
4. Hawker CD. Bar codes may have poorer error rates than commonly believed. Clin Chem 2010;56:1513–4.
5. Hawker CD, McCarthy W, Cleveland D, et al. Invention and validation of an automated camera system that uses optical character recognition to identify patient name mislabeled samples. Clin Chem 2014;60:463–70.
6. Snyder ML, Carter A, Jenkins K, et al. Patient misidentifications caused by errors in standard bar code technology. Clin Chem 2010;56:1554–60.
7. Valenstein PN, Raab SS, Walsh MK. Identification errors involving clinical laboratories: A College of American Pathologists Q-Probes study of patient and specimen identification errors at 120 institutions. Arch Pathol Lab Med 2006;130:1106–13.
8. Wagar EA, Stankovic AK, Raab S, et al. Specimen labeling errors: A Q-Probes analysis of 147 clinical laboratories. Arch Pathol Lab Med 2008;132:1617–22. 

source: www.aacc.org

Chowing down on watermelon could lower blood pressure, study suggests

Be sure to pick up a watermelon -- or two -- at your local grocery store. It could save your life.
A new study by Florida State University Associate Professor Arturo Figueroa, published in the American Journal of Hypertension, found that watermelon could significantly reduce blood pressure in overweight individuals both at rest and while under stress.
"The pressure on the aorta and on the heart decreased after consuming watermelon extract," Figueroa said.
The study started with a simple concept. More people die of heart attacks in cold weather because the stress of the cold temperatures causes blood pressure to increase and the heart has to work harder to pump blood into the aorta. That often leads to less blood flow to the heart.
Thus, people with obesity and high blood pressure face a higher risk for stroke or heart attack when exposed to the cold either during the winter or in rooms with low temperatures.
So, what might help their hearts?
It turned out that watermelon may be part of the answer.
Figueroa's 12-week study focused on 13 middle-aged, obese men and women who also suffered from high blood pressure. To simulate cold weather conditions, one hand of the subject was dipped into 39 degree water (or 4 degrees Celsius) while Figueroa's team took their blood pressure and other vital measurements.
Meanwhile, the group was divided into two. For the first six weeks, one group was given four grams of the amino acid L-citrulline and two grams of L-arginine per day, both from watermelon extract. The other group was given a placebo for 6 weeks.
Then, they switched for the second six weeks.
Participants also had to refrain from taking any medication for blood pressure or making any significant changes in their lifestyle, particularly related to diet and exercise, during the study.
The results showed that consuming watermelon had a positive impact on aortic blood pressure and other vascular parameters.
Notably, study participants showed improvements in blood pressure and cardiac stress while both at rest and while they were exposed to the cold water.
"That means less overload to the heart, so the heart is going to work easily during a stressful situation such as cold exposure," Figueroa said.
Figueroa has conducted multiple studies on the benefits of watermelon. In the past, he examined how it impacts post-menopausal women's arterial function and the blood pressure readings of adults with pre-hypertension.
In addition to being published in the American Journal of Hypertension, the study was also published in the US National Library of Medicine National Institutes of Health and was one of the "top new hypertensive articles" in MDLinx.

Story Source:
The above story is based on materials provided by Florida State University. Note: Materials may be edited for content and length.

Journal Reference:

1. A. Figueroa, A. Wong, R. Kalfon. Effects of Watermelon Supplementation on Aortic Hemodynamic Responses to the Cold Pressor Test in Obese Hypertensive Adults. American Journal of Hypertension, 2014; DOI: 10.1093/ajh/hpt295