Pharmacy automation

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Pharmacy automation involves the mechanical processes of handling and distributing medications. Any pharmacy task may be involved, including counting small objects (e.g., tablets, capsules); measuring and mixing powders and liquids for compounding; tracking and updating customer information in databases (e.g., personally identifiable information (PII), medical history, drug interaction risk detection); and inventory management. This article focuses on the changes that have taken place in the local, or community pharmacy since the 1960s.

Contents

History

Common disk-shaped tablets FlattenedRoundPills.jpg
Common disk-shaped tablets
Manually counting individual pills on a tray Dispensing pills, Guantanamo.jpg
Manually counting individual pills on a tray

Dispensing medications in a community pharmacy before the 1970s was a time-consuming operation. The pharmacist dispensed prescriptions in tablet or capsule form with a simple tray and spatula. Many new medications were developed by pharmaceutical manufacturers at an ever-increasing pace, and medications prices were rising steeply. A typical community pharmacist was working longer hours and often forced to hire staff to handle increased workloads which resulted in less time to focus on safety issues. These additional factors led to use of a machine to count medications. [1]

The original electronic portable digital tablet counting technology was invented in Manchester, England between 1967 and 1970 by the brothers John and Frank Kirby.

I had the original idea of how the machine would work and it was my patent, but it was a joint effort getting it to work in a saleable form. It was 3 years of very hard work. I had originally studied heavy electrical engineering before changing over to Medical School and qualifying as a Medical Doctor in 1968. In fact I was Senior House (Casualty) Officer (A&E or ER) in 1970 at North Manchester General Hospital when I filed the patent. I must have been the only hospital doctor in Britain with an oscilloscope, a soldering iron and a drawing board in his room in the Doctors' Residence. The housekeepers were bemused by all the wires. Frank originally trained as a Banker but quit to take a job with a local electronics firm during the development. He died in 1987, a terrible loss. [Extract from personal communication received in March 2010 from John Kirby.]

Frank and John Kirby and their associate Rodney Lester were pioneers in pharmacy automation and small-object counting technology. In 1967, the Kirbys invented a portable digital tablet counter to count tablets and capsules.[ citation needed ] With Lester they formed a limited company. In 1970, their invention was patented and put into production in Oldham, England. The tablet counter aided the pharmacy industry with time-consuming manual counting of drug prescriptions.

A counting machine consistently counted medications accurately and quickly. This aspect of pharmacy automation was quickly adopted, and innovations emerged every decade to aid the pharmacy industry to deliver medications quickly, safely, and economically. Modern pharmacies have many new options to improve their workflow by using the new technology, and can choose intelligently from the many options available. [2]

Chronology

First early 1971 model counter KL7.jpg
First early 1971 model counter

On 1 January 1971 commercial production of the first portable digital tablet counters in the World began. John Kirby had filed U.K. Patent number GB1358378(A) on 8 September 1970 [3] and U.S. patent number 3789194 on 9 August 1971. [4] These early electronic counters were designed to help pharmacies replace the common (but often inaccurate) practice of counting medications by hand.

Second generation late 1970s model Kirby Lester KL8 Tablet Counter.jpg
Second generation late 1970s model

In 1975, the digital technology was exported to America. In early 1980 a dedicated research, development and production facility was built in Oldham, England at a cost of £500,000. Between 1982 and 1983, two separate development facilities had been created. In America, overseen by Rodney Lester; and in England, overseen by the Kirby brothers. In 1987, Frank Kirby died. In 1989, John Kirby moved his UK facility to Devon, England. [5]

A simple to operate machine had been developed to accurately and quickly count prescription medications. Technology improvements soon resulted in a more compact model. The price of such equipment in 1980 was around £1,300. This substantial investment in new technology was a major financial consideration, but the pharmacy community considered the use of a counting machine as a superior method compared to hand-counting medications. These early devices became known as tablet counter, capsule counter, pill counter, or drug counter.

The new counting technology replaced manual methods in many industries such as, vitamin and diet supplement manufacturing. Technicians needed a small, affordable device to count and bottle medications. In England and America, the 1980s and 1990s saw new the development of high-speed machines for counting and bottle filling, Like their pharmacy-based counterparts, these industrial units were designed to be fast and simple to operate, yet remain small and cost effective. [6]

Counter and prepackaging device Kirby Lester KL25 tablet counter & prepackaging device.jpg
Counter and prepackaging device

In America, in the late 1990s/early 2000s a new type of tablet counter appeared. It was simple to use, compact, inexpensive, and had good counting accuracy. At the turn of the millennium technical advances allowed the design of counters with a software verification system. With an onboard computer, displaying photo images of medications to assist the pharmacist or pharmacy technician to verify that the correct medication was being dispensed. In addition, a database for storing all prescriptions that were counted on the device. [7]

Between September 2005 and May 2007, an American company undertook major financial investment, [8] and relocated. This move added extra space for product research and development facility (R&D). It allowed the opportunity to develop new advanced technology products that met the pharmacy's needs for simple, accurate, and cost-effective ways to dispense prescriptions safely. [9]

Pictured here is an early American type of integrated counter and packaging device. This machine was a third generation step in the evolution of pharmacy automated devices. Later models held pre-counted containers of commonly-prescribed medications.[ citation needed ]

Global variations

Tablets in a blister pack Risperdal tablets.jpg
Tablets in a blister pack

In the EU member states legislation was introduced in 1998 which had a major effect on UK Pharmacy operations. It effectively prohibited the use of tablet counters for counting and dispensing bulk packaged tablets. Both usage and sales of the machines in the UK declined rapidly as a result of the introduction of blister packaging for medicines. [10]

Current state of the industry

A tablet counter has become a standard in more than 30,000 sites in 35 countries (as of 2010) (including many non-pharmacy sites, such as manufacturing facilities that use a counting machine as a check for small items). [11]

During the 1990s through 2012, numerous new pharmacy automation products came to market. During this timeframe, counting technologies, robotics, workflow management software, and interactive voice recognition (IVR) systems for retail (both chain and independent), outpatient, government, and closed-door pharmacies (mail order and central fill) were all introduced. Additionally, the concept of scalability - of migrating from an entry-level product to the next level of automation (e.g., counting technology to robotics) - was introduced and subsequently launched a new product line in 1997.

Pharmacists everywhere are making the switch to automation for its increased speed, greater accuracy, and better security. [12] As the industry evolves and customer expectations grow, automation is becoming less of a luxury and more of a necessity. Especially for independent pharmacies, automation is now a means of keeping up with the competition of large chain pharmacies.

Technological changes and design improvements

Constant developments in technology make the dispensing of prescription medications safer, more accurate and more efficient.

Computer interfaced model counter Kirby Lester KL30 pharmacy automation counting & verification system.jpg
Computer interfaced model counter

In America, in 2008, "next-generation" counting and verification systems were introduced. Based on the counting technology employed in preceding models, later machines included the ability to help the pharmacy operate more effectively. Equipped with a new computer interface to a pharmacy management system, with workflow and inventory software. It also included "checks and balances" to ensure the technician and pharmacist were dispensing the correct medication for each patient. This is something that is important to keep reported correctly when dealing with controlled substances like narcotics. This was a step forward to verify all 100% of prescriptions that were dispensed by pharmacy staff.

Hands-free automated model counter Kirby Lester KL60 fully-automated dispensing system.jpg
Hands-free automated model counter

In America, in 2009, further advanced counters were designed that included the ability to dispense hands-free – a feature that many operators had desired. This allowed pharmacies to automate their most commonly dispensed medications via calibrated cassettes. Thirty of a pharmacy's common medications would now be dispensed automatically. Another new model doubled that throughput via an enclosed robotic mechanism. Robotics had been employed in pharmacies since the mid-1990s, but later machines dispense and label filled patient vials in a comparatively tiny space (about nine square feet of floor space). These newer technologies allowed pharmacy staff to confidently dispense hundreds of prescriptions per day and still be able to manage the many functions of a busy community pharmacy. This would increase the number of patients that are able to be served each day.

Other pharmacy-dispensing concerns besides counting

Explaining medication usage to the patient US Navy 060823-N-6501M-114 U.S. Navy Lt. Cmdr. Sheron Zellous of San Diego, explains to an Indonesian assistant the proper use of the medications being dispensed.jpg
Explaining medication usage to the patient

The primary purpose of a tablet counter (also known as a pill counter or drug counter) is to accurately count prescription medications in tablet or capsule form to aid the requirement for patient medication safety, to increase efficiency and reduce costs for the typical pharmacy. Newer versions of this counting device include advanced software to continue to improve safety for the patient who is receiving the prescription, ensuring that the pharmacy staff dispense the right medication at correct dosage strength for the right patient. (see also medication safety). Today's pharmacy industry recognizes the need for heightened vigilance against medication errors across the entire spectrum. A wealth of research has been conducted regarding the prevalence of medication errors and the ability of technology to decrease or eliminate such errors. (See the March 2003 landmark study by Auburn University's Center for Pharmacy Operations and Designs). [13] Prescription dispensing safety and accuracy in the pharmacy are an essential part of ensuring the right patient gets the right medication at the right dosage. A trend in pharmacy is to place a greater reliance on technology and pharmacy automation to minimize the chance of human error and speed up the process of dispensing. Pharmacy management generally sees technology as a solution to industry challenges like staffing shortages, prescription volume increases, long and hectic work hours and complicated insurance reimbursement procedures. Pharmacies employ advanced technologies that help to handle an ever-escalating number of prescriptions, while making dispensing safer and more precise.

Cross-contamination

Perhaps the most controversial debate surrounding the use of pharmacy automated tablet counters is the impact of cross-contamination. Automated tablet-counting machines (sometimes better known as "pill counters") are designed to sort, count, and dispense drugs at high speeds for quick counting transactions. When more than one drug is exposed to the same surface, leaving seemingly unnoticeable traces of residues, the issue of cross-contamination arises. While one tablet is unlikely to leave enough residues to cause harm to a future patient, the risk of contamination increases sevenfold as the machine processes thousands of varying pills throughout the course of a day. A typical pharmacy may on average process under 100 scripts per day, while other larger dispensaries can accommodate a few hundred scripts in that amount of time.

Thoroughly cleaning pharmacy automated tablet counters is recommended to prevent the chance of cross-contamination. This method is widely preached by manufacturers of these machines, but is not always easily followed. Performing an efficient cleaning of an automated tablet counter significantly increases the amount of time spent on counts by users. Many critics argue that these problems can easily be prevented by taking the proper precautions and following all cleaning procedures, but the increase in time spent makes it hard to justify such an investment. USP<800> Compliance concerning pharmacy automation is an evolving topic.https://www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare The National Institute for Occupational Safety and Health (NIOSH) considers a drug to be hazardous if it exhibits one or more of the following characteristics in humans or animals: carcinogenicity, teratogenicity or developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity, or structure and toxicity profiles of new drugs that mimic existing hazardous drugs. Specialty pharmacies that stock and dispense medications on the NIOSH list of Hazardous Drugs must follow strict standards. Community pharmacies typically handle a small number of Hazardous Drugs; therefore, using pharmacy automation for Hazardous Drugs generally follows this guideline: pharmacy staff use an exception tray and spatula to count any Hazardous Drug, and decontaminate the tray and spatula immediately following. Pharmacy robots should not store any Hazardous Drugs for chance of pill-grinding and dust-generation. All other medications dispensed in the pharmacy that are not Hazardous Drugs can be counted with pharmacy automation safely if the manufacturer's cleaning directions are followed.

Future development

Remote tablet counter / dispenser RemoteDispensing Med-Canister.jpg
Remote tablet counter / dispenser
Remote dispensing unit RemoteDispensing Unit.jpg
Remote dispensing unit

Various companies are currently developing a range of remote tablet counters, verification systems and pharmacy automation components to improve the accuracy, safety, speed and efficiency of medication dispensing. Products that are used in retail, mail order, hospital outpatient and specialty pharmacies as well as industrial settings such as manufacturing and component factories. These advanced systems will continue to provide accurate counting without the need for adjustment or calibration when counting in different production environments.

Pictured here is a modern (2010) remote controlled tablet hopper mechanism for use with bulk packaged individual tablets or capsules. In the UK these items are more suited to Hospital Pharmacies, where the issue of E.U. blister packaging regulations relating to medicine packaging does not apply. Also pictured is another version of an automated machine that does not allow unauthorised interference to the internal store of drugs. (A useful security feature in a large pharmacy with public access.)

Repackaging process and stability data

The transient or definitive displacement of the solid oral form from the original atmosphere to enter a repackaging process, sometimes automated, is likely to play a primary role in the pharmaceutical controversy in some countries. However, the solid oral dose is to be repackaged in materials with defined quality. Considering these data, a review of the literature for determination of conditions for repackaged drug stability according to different international guidelines is presented by F Lagrange. [14]

See also

Related Research Articles

<span class="mw-page-title-main">Medication</span> Substance used to diagnose, cure, treat, or prevent disease

A medication is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and relies on the science of pharmacology for continual advancement and on pharmacy for appropriate management.

<span class="mw-page-title-main">Over-the-counter drug</span> Medication available without a prescription

Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescription. In many countries, OTC drugs are selected by a regulatory agency to ensure that they contain ingredients that are safe and effective when used without a physician's care. OTC drugs are usually regulated according to their active pharmaceutical ingredient (API) rather than final products. By regulating APIs instead of specific drug formulations, governments allow manufacturers the freedom to formulate ingredients, or combinations of ingredients, into proprietary mixtures.

<span class="mw-page-title-main">Pharmacy</span> Clinical health science

Pharmacy is the science and practice of discovering, producing, preparing, dispensing, reviewing and monitoring medications, aiming to ensure the safe, effective, and affordable use of medicines. It is a miscellaneous science as it links health sciences with pharmaceutical sciences and natural sciences. The professional practice is becoming more clinically oriented as most of the drugs are now manufactured by pharmaceutical industries. Based on the setting, pharmacy practice is either classified as community or institutional pharmacy. Providing direct patient care in the community of institutional pharmacies is considered clinical pharmacy.

<span class="mw-page-title-main">Medical prescription</span> Health-care communication from a physician to a pharmacist

A prescription, often abbreviated ℞ or Rx, is a formal communication from a physician or other registered healthcare professional to a pharmacist, authorizing them to dispense a specific prescription drug for a specific patient. Historically, it was a physician's instruction to an apothecary listing the materials to be compounded into a treatment—the symbol ℞ comes from the first word of a medieval prescription, Latin recipere, that gave the list of the materials to be compounded.

<span class="mw-page-title-main">Prescription drug</span> Medication legally requiring a medical prescription before it can be dispensed

A prescription drug is a pharmaceutical drug that is permitted to be dispensed only to those with a medical prescription. In contrast, over-the-counter drugs can be obtained without a prescription. The reason for this difference in substance control is the potential scope of misuse, from drug abuse to practicing medicine without a license and without sufficient education. Different jurisdictions have different definitions of what constitutes a prescription drug.

The Pharmaceutical Benefits Scheme (PBS) is a program of the Australian Government that subsidises prescription medication for Australian citizens and permanent residents, as well as international visitors covered by a reciprocal health care agreement. The PBS is separate to the Medicare Benefits Schedule, a list of health care services that can be claimed under Medicare, Australia's universal health care insurance scheme.

<span class="mw-page-title-main">Pill splitting</span>

Pill-splitting refers to the practice of splitting a tablet or pill to provide a lower dose of the active ingredient, or to obtain multiple smaller doses, either to reduce cost or because the pills available provide a larger dose than required. Many pills that are suitable for splitting come pre-scored so that they may easily be halved.

<span class="mw-page-title-main">Compounding</span> Preparation of a custom medication

In the field of pharmacy, compounding is preparation of custom medications to fit unique needs of patients that cannot be met with mass-produced products. This may be done, for example, to provide medication in a form easier for a given patient to ingest, or to avoid a non-active ingredient a patient is allergic to, or to provide an exact dose that isn't otherwise available. This kind of patient-specific compounding, according to a prescriber's specifications, is referred to as "traditional" compounding. The nature of patient need for such customization can range from absolute necessity to individual optimality to even preference.

A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for an FDC product, although the latter is more precise if in fact referring to a mass-produced product having a predetermined combination of drugs and respective dosages. And it should also be distinguished from the term "combination product" in medical contexts, which without further specification can refer to products that combine different types of medical products—such as device/drug combinations as opposed to drug/drug combinations. When a combination drug product is a "pill", then it may also be a kind of "polypill" or combopill.

<span class="mw-page-title-main">Codeine</span> Opiate and prodrug of morphine used to treat pain

Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, Papaver somniferum. It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Evidence does not support its use for acute cough suppression in children or adults. In Europe, it is not recommended as a cough medicine in those under 12 years of age. It is generally taken by mouth. It typically starts working after half an hour, with maximum effect at two hours. Its effects last for about four to six hours. Codeine exhibits abuse potential similar to other opioid medications, including a risk of habituation and overdose.

<span class="mw-page-title-main">Pharmacy (shop)</span> Shop that provides pharmaceutical drugs

A pharmacy is a retail shop which provides pharmaceutical drugs, among other products. At the pharmacy, a pharmacist oversees the fulfillment of medical prescriptions and is available to counsel patients about prescription and over-the-counter drugs or about health problems and wellness issues. A typical pharmacy would be in the commercial area of a community.

<span class="mw-page-title-main">Remote dispensing</span>

Remote dispensing is used in health care environments to describe the use of automated systems to dispense prescription medications without an on-site pharmacist. This practice is most common in long-term care facilities and correctional institutions that do not find it practical to operate a full-service in-house pharmacy.

<span class="mw-page-title-main">Pill organizer</span> Container for medications

A pill organiser, pill container, dosette box, pillcase or pillbox is a multicompartment compliance aid for storing scheduled doses of medications. Pill organisers usually have square-shaped compartments for each day of the week, although other more compact and discreet versions have come to market, including cylindrical and pen-shaped cases. Some organisers have sections corresponding to times of the day. Pill organisers are viewed as a way to prevent or reduce medication errors on the part of the patient, though evidence of effectiveness is not strong and they have been linked to medication errors.

<span class="mw-page-title-main">Drug packaging</span> Packaging for pharmaceutical preparations

Drug packaging is process of packing pharmaceutical preparations for distribution, and the physical packaging in which they are stored. It involves all of the operations from production through drug distribution channels to the end consumer.

An automated dispensing cabinet (ADC), also called a unit-based cabinet (UBC), automated dispensing device (ADD), or automated dispensing machine (ADM), is a computerized medicine cabinet for hospitals and healthcare settings. ADCs allow medications to be stored and dispensed near the point of care while controlling and tracking drug distribution.

<span class="mw-page-title-main">Poison Prevention Packaging Act of 1970</span> US law

The Poison Prevention Packaging Act of 1970 (PPPA); was signed into law by U.S. President Richard Nixon on December 30, 1970. It was enacted by the 91st United States Congress. This law required the use of child-resistant packaging for prescription drugs, over-the-counter (OTC) drugs, household chemicals, and other hazardous materials that could be considered dangerous for children.

<span class="mw-page-title-main">Telepharmacy</span> Pharmacy care by telecommunication

Telepharmacy is the delivery of pharmaceutical care via telecommunications to patients in locations where they may not have direct contact with a pharmacist. It is an instance of the wider phenomenon of telemedicine, as implemented in the field of pharmacy. Telepharmacy services include drug therapy monitoring, patient counseling, prior authorization and refill authorization for prescription drugs, and monitoring of formulary compliance with the aid of teleconferencing or videoconferencing. Remote dispensing of medications by automated packaging and labeling systems can also be thought of as an instance of telepharmacy. Telepharmacy services can be delivered at retail pharmacy sites or through hospitals, nursing homes, or other medical care facilities.

ScripTalk is an audible medication label technology designed to give access to individuals who are blind, visually impaired, or print impaired. It consists of a device and a microchip attached to the bottom of a prescription drug bottle. The label information is encoded on a Radio-frequency identification (RFID) electronic label (microchip) using the ScriptAbility software by a pharmacist and placed on the prescription package. ScripTalk prescription labels were introduced in the early 2000s. As of 2020, the technology was applied through the United States and Canada.

Omnicell, Inc. is an American multinational healthcare technology company headquartered in Fort Worth, Texas. It manufactures automated systems for medication management in hospitals and other healthcare settings, and medication adherence packaging and patient engagement software used by retail pharmacies. Its products are sold under the brand names Omnicell and EnlivenHealth.

Autonomous pharmacy is an approach to medication management that seeks to create a more automated and data-driven process for medication inventory and dispensing. The main concept behind autonomous pharmacy is to use technology in place of manual medication processes in order to help healthcare providers reduce medication errors, decrease costs and save staff time. Autonomous pharmacy may use a combination of hardware, software and technology-enabled services to allow pharmacists to more effectively manage medication dispersal.

References

  1. ↑ Melissa Elder (January 2008). "Pharmacy Automation: Technologies and Global Markets BCC00098". Report. Business Communications Company Research. Archived from the original on 9 August 2011. Retrieved 4 June 2021.
  2. ↑ Christopher J Thomsen (9 November 2004). "Pharmacy Automation-Practical Technology Solutions for the Pharmacy" (PDF). Business briefing : US Pharmacy review 2004. The Thompson Group. Archived from the original (PDF) on 3 March 2016. Retrieved 5 March 2010.
  3. ↑ John Kirby Filed 8 September 1970 (3 July 1974). "Patent 1358378". COUNTING MACHINES - Patent GB1358378(A). DTI Data Networks LLC. Retrieved 18 March 2010.{{cite web}}: CS1 maint: numeric names: authors list (link)
  4. ↑ United States Patent Office (29 January 1974). "Patent 3789194". RELATING TO COUNTING MACHINES. Freepatentsonline.com. Retrieved 6 March 2010.
  5. ↑ Jordans Business Information Services (2008). "Basic company details for KIRBY DEVON LIMITED". Jordans Ltd. Retrieved 6 March 2010.{{cite web}}: |author= has generic name (help)
  6. ↑ Liz Parks (November–December 2003). "Market Survey of Pharmacy Technology and Automation in Retail and Outpatient Pharmacy" (PDF). Retail Pharmacy Management. The Thomsen group. Archived from the original (PDF) on 3 March 2016. Retrieved 6 March 2010.
  7. ↑ "An Efficiency Analysis of the Kirby Lester KL16df Automatic Tablet and Capsule Counting System" (PDF). Pharmacy Automation. The ThomsenGroup Inc. 2004. Archived from the original (PDF) on 3 March 2016. Retrieved 5 March 2010.
  8. ↑ "American Capital exited its investment in Kirby Lester, LLC in the third quarter of 2007". American Capital Limited. 19 September 2005. Archived from the original on 21 July 2012. Retrieved 12 March 2010.
  9. ↑ Kevin Welch (November–December 2009). "Looking Ahead: What's Coming in 2010". Pharmacy Delivery Technology – A Primer. Computer Talk for the Pharmacist. Archived from the original on 24 March 2010. Retrieved 5 March 2010.
  10. ↑ "Labels, patient information leaflets and packaging for medicines". The Medicines and Healthcare products Regulatory Agency (MHRA). 2010. Archived from the original on 11 January 2010. Retrieved 8 March 2010.
  11. ↑ Melissa Elder (March 2008). "Pharmacy Automation: Technologies and Global Markets IAS026A". BCC Research. Retrieved 6 March 2010.
  12. ↑ Chilcott, Meghann. "The Growing Trend of Pharmacy Automation". Forbes. Retrieved 23 October 2019.
  13. ↑ Flynn EA, Barker KN, Carnahan BJ (2003). "National observational study of prescription dispensing accuracy and safety in 50 pharmacies". Journal of the American Pharmaceutical Association. 43 (2): 191–200. doi:10.1331/108658003321480731. PMID   12688437.
  14. ↑ Lagrange F (November 2010). "[Current perspectives on the repackaging and stability of solid oral doses]". Ann Pharm Fr. 68 (6): 332–58. doi:10.1016/j.pharma.2010.08.003. PMID   21073993.
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