Assessing the Reliability of Commercially Available Point of Care in Various Clinical Fields

Updated and precise molecular diagnostics are essential in disease identification, treatment and management. Conventional technologies are limited to laboratories, which are expensive, require moderate to great volumes of biological fluids and generally create great discomfort among patients. This review discusses some key features of commercially available point of care (POC) devices, such as time to provide results, accuracy and imprecision, in several medical and veterinary fields. We searched Pubmed/Medline using the keywords “point” “of” “care” “device”, selected papers from 1984 to 2019 on the basis of their content and summarized the features in tables.Fast turnaround time and overall good reliability, in terms of accuracy and imprecision, were observed for most of POCs included in the research.POC devices are particularly useful for clinicians since they hold the potential to deliver rapid and accurate results in an inexpensive and less invasive way with an overall improvement of patients' quality of life in terms of time spent at the point-of-care and sample volume withdrawn. These features gain great relevance also in the veterinary practice, where patients’ compliance is generally poor, available sample volumes are quite far from the human ones and analysis costs are higher.


INTRODUCTION
The point-of-care (POC) is generally used outside the central laboratory to facilitate the patient's faster diagnosis and treatment. It is one of the innovations that impact potentially on the quality and rapidity of care, as well as on system redesign of a more patient-centred care approach [1,2]. POCs are commercially available either as small bench-top analyzers or as hand-held devices. The latter are used by patients for homecare and by healthcare professionals. If, on one hand, laboratory results can take from several hours to few days, on the other hand, POCs reduce analysis time from hours to few seconds, therefore, gaining relevant importance especially in emergency conditions (Table 1).
To evaluate a safe and reliable POC, it is important to consider its sensitivity (the percentage of true positive results), specificity (percentage of true negative results) and positive

MATERIALS AND METHODS
The aim of this review was to provide the actual status of point of care (POC) devices highlighting some key features, such as time to result, accuracy and imprecision, in several medical fields including ematobiochemistry, cardiology, infectious disease, andrology and gynecology, toxicology, oncology, genetics, dentistry ophthalmology ultrasology and even veterinary medicine.
We searched Pubmed/Medline and other external sources using the keywords "point of care device". Selected papers from 1984 to 2019 were chosen on the basis of their content and included. Moreover, some technical data were also downloaded from website of the POC's manufacturer.

Ematobiochemistry
Rapid evaluation of blood parameters, in particular, glucose, electrolyte and metabolic parameters, gained even more attention in the last years due to the wide diffusion of POC devices also among non-laboratory trained individuals including patients themselves [5,6]. Most of these devices are based on a photometric method, share an overall high degree of accuracy and are characterized by a rapid turnaround time of test results providing them an edge over conventional central laboratory analyzers (Table 1).

Diabetes
Glucose meters are used worldwide providing fast analysis of blood glucose, glycated hemoglobin, β-hydroxybutyrate, TSH and free T4 levels, allowing the management of hypoglycemic and hyperglycemic disorders [115]. They mainly rely on an electrochemically-based measurement test, which reduced the time-to-result from minutes to few seconds requiring blood volumes as little as few microliters [116]. Besides the need to monitor glycemia to reduce morbidity and mortality, the primary requirement of clinicians is the reliability of glucose meters (inaccuracy and imprecision remain fundamental) even in the presence of interfering substances including but not limited to ascorbate, hematocrit and maltose [117]. Despite the presence of many other factors able to undermine the accuracy of such devices, the degree of precision reached by current POCs is very high, although their handling should be generally left to a well-trained staff ( Table  2) [118].

Cardiology
The need for enabling a rapid assessment of patients with chest discomfort, both in an ambulance and emergency rooms, as well as the management of bleeding and clotting risks and myocardial infarction prevention led to a rapid increase in technological advancements of POC devices [155]. Among cardiac biomarkers, cardiac troponins gained great relevance with respect to creatine kinase [156,157]. B-Type Natriuretic Peptide has been successfully used to discriminate between heart failure symptoms and shortness of breath due to pulmonary causes [158], nevertheless also high sensitivity creactive protein, D-dimer, myoglobin and N-terminal pro-Btype natriuretic peptide are also assessed [159].

Viral Infections
Infectious diseases require an accurate and rapid diagnosis in order to limit the spread of infection. Their management mainly relies on the identification of the cause of the infection and on the initiation of a therapy to control host reaction against infection. In clinical practice, the time required to reach the final diagnosis generally exceeds 24 hours leading to unnecessary sufferings and even deaths. In the last few years, nucleic acid-based testing for infectious diseases have become particularly useful in those situations where fast turnaround times are required and centralized laboratories are overloaded. Moreover, conventional instruments are PCR-based, are limited to well-trained hospital staff and are expensive [174]. In the case of HIV infection, enumeration of CD4 lymphocytes accomplished by POCs is a pivotal diagnostic tool for initiating therapy and monitoring its efficacy, thus decentralizing the laboratories and providing results during the course of the patient visit [175]. Implementation of rapid HIV POCs may improve the prevention of such diseases by increasing testing uptake rates, timely diagnosis and access to treatment, and consequently reducing the further virus transmission ( Table 5).

Bacterial Infections
Among bacterial infections, syphilis is one of the most commonly worldwide occurring infection since it can be sexually and congenitally transmitted, with more than 6 million of new cases yearly [243,244].

Assessing the Reliability of Commercially
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Fertility and Pregnancy
Infertility phenomenon affects 10-15% of couples and usually male factors account approximately half of the cases. Due to the difficulty in diagnose of male subfertility on the basis of only sperm count, simple diagnostic sperm tests have been marketed to allow men to monitor their sperm concentration, motility but also the testosterone concentration [114,284]. As to the female counterpart, self-tests of pregnancy are increasing due to women's preferences for confidentiality, accessibility of the test tool and rapid results [285,286] (Table 7)

Drug of Abuse
Drug abuse either recreational or in competitive sports is considered a significant social problem worldwide. In the last few years, many tests using alternative specimens for drug analysis have been developed in several formats, ranging dipsticks to cup devices, cards or plastic cassettes. Current POCs are immunoassay-based and can discriminate from one class to multiple classes of drugs, i.e., cannabinoids and cocaine and amphetamines. These provide a line or color when the drug of interest is at or above the defined threshold and can utilize paper, thin-layer, or gas chromatography methods. It is crucial for users to understand the strengths, weaknesses, and limitations of these devices to facilitate accurate interpretation of results in order to avoid false-positive results due to crossreactivity with foods, over-the-counter preparations or commonly prescribed drugs. This latter condition is exacerbated in the case of POC manufacturers who use misleading nomenclature. Among possible available samples saliva is a good candidate being a noninvasive way to evaluate the presence of a drug ( Table 8).

Cancer
Cancer is considered as the second cause of death in the world, with prostate and breast cancer as the most common type of cancers in men and women, respectively (326). Most of the diagnostics tests are based on ELISA technique but unfortunately provide protein markers levels that correspond to advanced stages of the disease. Thus, cancer biomarkers-based POCs are of fundamental importance to diagnose, monitor but also to provide a prognostic approach and treatment of the disease ( Table 9).  cannabis, amphetamines, cocaine, opioids 10 minutes CV = 1.7 -13.1% r = 0.99 (THC = tetrahydrocannabinol; PCP = phencyclidine; MDMA = methylenedioxymethamphetamine; METH = methamphetamine; TCAs = tricyclic antidepressants; BZD = benzodiazepines).  [341][342][343] Pyruvate kinase isoenzyme 120 minutes CV = 4.5 -6.1% r = 0.96

Genetics
Traditional DNA tests are used to detect genotypes related to a heritable disease or phenotype of interest for clinical purposes. These methods generally require days to weeks before results are available, thus limiting the clinical practice in different circumstances, whereas POC, employ sophisticated techniques able to identify variations in the genetic sequence requiring a time ranging from few minutes to few hours (Table  10).

Dentistry
One of the challenges in dentistry is the rapid management of diseases such as chronic periodontitis, generally caused by Porphyromonas gingivalis, the rapid detection of which is important for an effective treatment [357,358]. In this sense, a novel immunochromatographic device for the rapid detection and quantification of Porphyromonas gingivalis in subgingival plaque has been recently developed [359,360]. Also, ultrasonology has now acquired great relevance in dentistry, particularly in those situations where computed tomography may prove hazardous, such as pediatric patients, where a rapid identification of mandibular fractures may rule out the necessity for operative management [361]. An updated overview of commercially available POC in dentistry is given below ( Table 11).

Ophthalmology
Eye injuries and ocular complications frequently occur in emergency department visits, convenient care appointments or primary care evaluations requiring specific training and expert knowledge of ophthalmic diagnostic equipment, which generally are of high costs and are not portable. This latter feature results in problems in case of serious ocular injuries present outside the ophthalmology office. Seidel Test is conventionally used to evaluate the integrity of the anterior globe in trauma patients and the wound severity in postoperative patients. This test is based on a subjective and not standardized outcome due to the different amount of pressure and technique used by clinicians. Other devices used to aid in the diagnosis of eye injuries include X-ray, computed tomography, ultrasound and magnetic resonance imaging that are expensive and restricted to hospital settings due to their size and cost. The OcuCheck Biosensor ™ is considered a valid alternative to the subjective Seidel Test providing an objective, rapid (5 minutes) and reliable result of ascorbic acid concentration within the ocular tear film, as a surrogate biomarker of anterior scleral or corneal wound integrity with a good accuracy degree (r = 0.89) [363].

Ultrasonology
In the last 50 years, ultrasonography has become an integral part in many medicinal fields and ongoing technological advancements led to a rapid diffusion of POC ultrasound devices among medical wards, emergency rooms, intensive care units and outpatient clinics; due to high performance, reduced size and low costs ( Table 12).

POCs in Veterinary Practice
Feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) are the two most common viruses in cats associated with significant morbidity [377]. One of the key challenges of POCT manufacturers is to identify infected cats, and beyond ELISA and other immunochromatographic tests, new in-house tests for FIV and FeLV diagnosis have been introduced to the market. Besides these two viruses, group A rotaviruses, parvovirus and influenza virus tests have also been successfully used in other species including dogs and horses. Moreover, biochemical parameters of POC devices, such as bilirubin, ketones, creatinine, hemoglobin, glucose, leucocytes, nitrites, specific weight, pH, proteins, urobilinogen, lactate, Ca i and Mg i , have been investigated for other species including cow and cattle. The turnaround time of result of veterinary POC devices is generally below 20 minutes with an overall high degree of accuracy, providing the veterinarian with a good chance to clearly diagnose the disease, to the clients the possibility to save money and to the animals to minimize the discomfort and the sample volume required ( Table 13).

CONCLUSION
POC devices are revolutionizing clinical and veterinary practice providing rapid test results in different clinical settings, located outside the human and veterinary hospital environment such as physician or vet office and pharmacy. POC technology is particularly helpful in the pre-analytical phase, reducing misidentification of patients and specimen, sample handling, transport and storage, but also in the postanalytical phase, limiting excessive turnaround time. The advancements in POCs have generally improved the quality of care, the health outcomes, and the affordability of the tests.
The use of POC by clinical personnel might have a positive impact on health-care by identifying patients at risk who need to be referred to the next level of care for an accurate diagnosis and treatment, involving patients in their own care, addressing therapeutic issues with the patients once the results are obtained and designing the disease management programs based on a POC device. Another key element of POC is connectivity, related to the possibility to link laboratory and hospital information systems with electronic the patient records. With the advent of the POCT1-A2 standard, it has now become possible to improve devices, data concentrators, and clinical information systems' interoperability and communication [395]. Although there are many challenges related to the implementation of POCT1-A2 protocol in a POC, a framework-based approach has been shown to standardize implementation across devices with consequent ease of maintenance and a return on investment for POC vendors.
However, besides the growing need for connectivity of POC, the regulatory pressure for digitalization of all medical records and patient outcomes, led to another critical issue: the cybersecurity of such records. This latter becomes particularly critical among interconnected devices or through external interfaces (i.e. USB or Ethernet cables), with possible lifethreatening consequences for patients. In fact, FDA imposed a serious vigilance to POC manufacturers in order to minimize the risk of cybersecurity threats by constantly monitoring, evaluating and updating their devices [396].
Since POC outcomes depend on the operator's expertise, training and routine updating are crucial to reduce errors [397]. Moreover, when used appropriately, POC devices are invaluable tools for patients but also for animal care, offering a rapid delivery of results and also allowing a reduction in costs due to: 1) Decreased facility costs [398], 2) Decreased maintenance costs [398], 3) Decreased waiting time [399], 4) Decreased hospitalization [399], 5) Decreased screening time [399] and 6) Improved home care delivery [398].
Nanotechnology-based devices have revolutionized the concept of accuracy in diagnosis and therapy by integrating nanomaterials and biosensors, thus consequently minimizing costs and time to provide results.

CONSENT FOR PUBLICATION
Not applicable.

FUNDING
None.