How Is Gout Distinguished From Pseudogout Using A Microscope With A Polarizing Filter?
Arthritis Rheumatol. Author manuscript; available in PMC 2017 Jul 1.
Published in final edited class as:
PMCID: PMC4992577
NIHMSID: NIHMS810204
A Point-of-Care Raman Spectroscopy–Based Device for the Diagnosis of Gout and Pseudogout
Comparing With the Clinical Standard Microscopy
Bolan Li
aneCase Western Reserve University, Cleveland, Ohio
Nora G. Singer
2MetroHealth Medical Middle and Instance Western Reserve University, Cleveland, Ohio
Yener N. Yeni
threeHenry Ford Hospital, Detroit, Michigan
Donard Grand. Haggins
iiiHenry Ford Hospital, Detroit, Michigan
Emma Barnboym
ivMetroHealth Medical Center, Cleveland, Ohio
Daniel Oravec
3Henry Ford Infirmary, Detroit, Michigan
Steven Lewis
2MetroHealth Medical Eye and Case Western Reserve University, Cleveland, Ohio
Ozan Akkus
1Instance Western Reserve University, Cleveland, Ohio
Abstruse
Objective
To demonstrate the usefulness of a novel medical device based on Raman spectroscopy for the rapid point-of-care diagnosis of gout and pseudogout.
Methods
A shoebox-sized point-of-care Raman spectroscopy (POCRS) device was developed for utilise in the diagnosis of gout and pseudogout. The device included a disposable syringe microfiltration kit to collect arthropathic crystals from synovial fluid and a customized automated Raman spectroscopy system to chemically identify crystal species. Diagnosis according to the findings of POCRS was compared with the clinical standard diagnosis based on compensated polarized light microscopy (CPLM) of synovial fluid aspirates collected from symptomatic patients (n = 174). Kappa coefficients were used to measure the agreement between POCRS and CPLM findings.
Results
Overall, POCRS and CPLM results were consequent in 89.seven% of samples (156 of 174). For the diagnosis of gout, the kappa coefficient for POCRS and CPLM was 0.84 (95% confidence interval [95% CI] 0.75–0.94). For the diagnosis of pseudogout, the kappa coefficient for POCRS and CPLM was 0.61 (95% CI 0.42–0.81).
Conclusion
Kappa coefficients indicated that there was excellent agreement between POCRS and CPLM for the diagnosis of gout, with good agreement for the diagnosis of pseudogout. The POCRS device holds the potential to standardize and expedite the fourth dimension to clinical diagnosis of gout and pseudogout, peculiarly in settings where certified operators trained for CPLM analysis are not available.
Crystal-associated arthritis is caused past an inflammatory response to micron-sized crystals deposited in joint spaces and soft tissues. Monosodium urate monohydrate (MSU) crystals (involved in gout) and calcium pyrophosphate dihydrate (CPPD) crystals (involved in pseudogout) are the 2 most ofttimes observed crystals and were clinically characterized decades agone (one–6). Gout affects viii.3 million Americans (7), and pseudogout affects equally much as 3% of the population in the age range of 60–70 years, according to the American College of Rheumatology. The prevalence of chondrocalcinosis (i.e., deposition of CPPD crystals in the soft tissues of the articulation) increases exponentially with age (8). The estimated overall cost of gout in the United states is in the tens of billions of dollars and is comparable to the cost of other chronic conditions, such equally Parkinson's illness or migraine (9).
Gout and pseudogout ordinarily share common symptoms with other forms of arthritis. Compensated polarized light microscopy (CPLM) of synovial aspirates is the standard clinical method used in the diagnosis of gout and pseudogout. While CPLM is sensitive and specific in the hands of a skilled technician, CPLM may carry an boilerplate false-negative rate of equally much as 30% depending on the operator (ten–12). As such, experienced operators in Clinical Laboratory Improvement Amendments (CLIA)–certified laboratories are essential for the successful diagnosis by CPLM findings. Withal, many clinical settings may lack such operators in real-time, or the clinical schedules may not allow for the coordination of sample transfer for CPLM. Therefore, many gout patients are diagnosed presumptively, based on symptoms, in the primary care setting (xiii), where the bulk of gout cases are diagnosed and managed (14,fifteen).
In addition to CPLM, other approaches have been used to diagnose the presence of gout and pseudogout. Serum urate analysis is associated with unsatisfactory sensitivity (57–67%) and specificity (78–92%) values (16–18). In comparisons of ultrasound and radiography in the diagnosis of gout, Rettenbacher et al (19) establish ultrasound to be more sensitive (96% versus 31%) simply less specific (73% versus 93%) than radiography. Filippou et al (20) reported the diagnosis of pseudogout by ultrasound to have a sensitivity of 86.vii% and a specificity of 96%. These studies had relatively low number of patients, and CPLM was accustomed as the gold standard. Every bit with CPLM, successful diagnosis past ultrasound requires adept technicians.
Raman spectroscopy is a chemical analysis technique that is 100% specific for fingerprinting species based on the identification of chemical bonds unique to each material. Raman spectroscopy has been used in several studies (21–23) to identify crystals in synovial fluid, simply costly and bulky laboratory-grade instruments were used, which limits the applicability of this technique in the clinic. Contempo work from our laboratory addressed these challenges past developing an automated, shoebox-sized point-of-care Raman spectroscopy (POCRS) device for apply in the diagnosis of gout and pseudogout from synovial aspirates (24). The aim of the present report was to demonstrate the usefulness of the POCRS device in the diagnosis of gout and pseudogout, and to investigate the diagnostic agreement betwixt POCRS and CPLM findings in a large clinical sample set.
MATERIALS AND METHODS
Synovial fluid samples
A total of 174 synovial fluid samples were collected: 114 from MetroHealth Medical Center and 60 from Henry Ford Hospital. Samples were obtained from patients who presented with symptomatic arthritis requiring clinically indicated joint aspiration and/or intra-articular joint injection. A recent corticosteroid injection was non an exclusion criterion. Adult patients were included without regard to sexual practice or race. The age range of the patients was 18–88 years. Both sexes were comparably represented, with 48.3% men and 51.7% women in the population.
The study was approved by the Institutional Review Boards of the respective institutions. All patients gave their consent for study.
CPLM and POCRS
Synovial fluid samples were separated into 2 aliquots, 1 of which was sent to the clinical pathology laboratory for crystal identification by CPLM, and the other was placed in a sealed sterile container. As part of the normal handling course in these patients, CPLM analyses were conducted by experts (rheumatologists or pathologists with >20 years' experience) in CLIA-certified laboratories at both institutions. Samples were stored at −80°C until their delivery in dry ice via overnight shipment to Case Western Reserve Academy (CWRU) for the POCRS analysis. Samples were and so stored at −xx°C in a freezer at CWRU until they were used for the POCRS analysis. There was a single freeze–thaw cycle prior to the POCRS analysis.
POCRS consisted of two major steps (Figure i). Kickoff, a disposable syringe–microfiltration stride was performed, which included a brief digestion and dilution to collect and concentrate crystals for Raman spectroscopic analysis. 2nd, a Raman spectroscopy step was performed, in which a shoebox-sized optoelectromechanical system was customized for conducting an automated Raman spectroscopic analysis to identify crystal species, as detailed in a previous publication from our group (24).
Point-of-intendance Raman spectroscopy (POCRS). The POCRS arrangement consists of 2 parts: a syringe microfiltration kit for isolating and collecting arthritic crystals from synovial fluid (a–c) and a shoebox-sized optoelectromechanical system for acquiring diagnostic signals (d and e). To utilize the organization, synovial fluid is loaded in a glass vial with digestive enzymes (a). After 30 minutes of digestion at 40°C, the uric acid–supplemented buffer (b) is used to dilute the digested synovial fluid. Post-obit dilution, the synovial fluid is transferred into a standard syringe (c) and pushed through the disposable microfiltration cartridge for crystal collection. Later microfiltration, the cartridge is direct inserted into the optoelectromechanical organisation (d) for diagnostic betoken acquisition (e).
Brief digestion of hyaluronic acid and inflammatory organic debris was essential for isolating crystals from synovial fluid via microfiltration. The digestion solution independent 1 mg/ml of hyaluronidase (item no. H3506; Sigma), 2 mg/ml of proteinase Chiliad (particular no. P2308; Sigma), and 0.five% (volume/weight) of sodium dodecyl sulfate (particular L3771; Sigma). Following xxx minutes of incubation at 40°C, the digested fluid was so diluted by adding uric acrid–supplemented buffer at a volume ratio of 2-to-i. Uric acid supplement was used to forestall MSU crystals from dissolving, and dilution helped to facilitate the microfiltration process by thinning the digested synovial fluid. Uric acid was added into 1× phosphate buffered saline at a concentration of 60 μ1000/ml, and the solution was filtered using a 0.2-μm filter. Dissolution of uric acid was confirmed by cantankerous-polarized imaging at loftier magnification. Previous enquiry from our grouping (24) demonstrated that this pretreatment procedure, including the digestion and the uric acid supplementary buffer, preserves the crystals, as confirmed by the lack of pregnant departure between crystal counts performed before versus later treatment. It was also affirmed that artifactual nucleation of crystals from the buffer does not occur.
The digested synovial fluid was transferred to a standard syringe mounted with a customized disposable microfiltration cartridge (24) and was pushed through the cartridge for crystal collection. Via the microfiltration stride, crystals were retained inside a circular spot of ~900 μm in diameter on a filter membrane in the cartridge. Following microfiltration, the cartridge was directly inserted into the optoelectromechanical system for acquiring Raman signals from thirty sampling points distributed over the filtrate spot. MSU and CPPD crystals were detected based on the presence of signature Raman peaks at 631 cm−1 (25) and 1,050 cm−1 (26), respectively. Indicate acquisition was fully automated and was completed inside xv minutes. The crystal concentration was estimated according to our previous strategy, based on the scale curves established previously (24).
Data management
Written report data were collected and managed using REDCap electronic data capture tools hosted at MetroHealth Medical Center (27). REDCap (Research Electronic Data Capture) is a secure, web-based awarding designed to support data capture for enquiry studies, providing: 1) an intuitive interface for validated data entry, 2) inspect trails for tracking data manipulation and export procedures, three) automated export procedures for seamless data downloads to mutual statistical packages, and iv) procedures for importing information from external sources.
Statistical assay
The laboratory personnel at CWRU who were conducting the POCRS were blinded with regard to the outcome of the CPLM findings at the 2 hospitals and vice versa. Both the CPLM and POCRS results were aggregated and analyzed past a biostatistician (SL, a member of the Center for Health Care Inquiry and Policy at Metro-Health Medical Center), who measured the agreement between POCRS and CPLM in the diagnosis of gout and pseudogout, respectively (28). The kappa coefficient is a measure of understanding between ii methods that assumes values from 0 to 1, where 0 represents understanding just by chance and 1 represents perfect agreement. Generally, kappa coefficients are rated as <0.twenty, which indicates poor understanding, 0.21–0.xl fair, 0.41–0.60 moderate, 0.61–0.fourscore proficient, and 0.81–1.00 excellent agreement (28). The sample size of 174 subjects provided 0.96 power value when using the kappa coefficient to measure the charge per unit of understanding betwixt POCRS and CPLM.
RESULTS
Typical Raman spectra of affirmed gout and pseudogout samples demonstrated peaks associated with MSU (631 cm−i) and CPPD (ane,050 cm−1) crystals, respectively, and samples which did non announced to include crystals were devoid of such peaks (Figure two). The MSU crystal concentration as measured by POCRS varied from 0.1 μgrand/ml to 84.3 μthou/ml, with an average of ix.0 μyard/ml, and the CPPD crystal concentration ranged from 2.5 μchiliad/ml to 109.0 μthou/ml, with an average of 19.2 μg/ml (Figure three).
Raman peaks associated with monosodium urate monohydrate (MSU; 631 cm−1) and calcium pyrophosphate dihydrate (CPPD; i,050 cm−1) crystals. Raman peaks associated with MSU and CPPD crystals are presented in the spectra of samples from patients with confirmed gout and pseudogout, respectively. No crystal-associated peak was observed in the spectra of crystal-free synovial fluid samples. Spectra for constructed pure MSU and CPPD crystals are included equally references. Fluorescence background and filter membrane–associated peaks were removed from these spectra.
Concentrations of monosodium urate monohydrate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals, as measured by bespeak-of-care Raman spectroscopy. Each symbol represents a single sample.
The CPLM and POCRS findings were consistent for 89.7% of the samples analyzed (156 of 174). For 18 samples, the diagnosis by POCRS and CPLM findings showed discrepancies (Table 1). Past CPLM, 44 samples indicated gout and 12 indicated pseudogout. By POCRS, 36 samples had MSU crystals and 20 samples had CPPD crystals. POCRS, simply not CPLM, showed two samples with coexistent MSU and CPPD crystals (Tabular array 2).
Tabular array 1
Diagnostic results of 18 samples with inconsistent findings between CPLM and POCRS*
| ID no. | CPLM event | POCRS effect |
|---|---|---|
| 4 | X | CPPD |
| 7 | 10 | CPPD |
| nine | X | CPPD |
| 32 | X | MSU |
| 36 | MSU | X |
| 43 | Ten | CPPD |
| threescore | MSU | 10 |
| 64 | MSU | CPPD |
| 67 | MSU | CPPD |
| 88 | X | CPPD |
| 102 | MSU | X |
| 118 | MSU | X |
| 122 | X | CPPD |
| 146 | MSU | Ten |
| 148 | MSU | X |
| 159 | X | CPPD |
| 162 | X | MSU |
| 172 | CPPD | X |
Table two
Number of samples plant to be positive on CPLM and POCRS*
| POCRS result | CPLM result | |
|---|---|---|
| Gout (MSU crystals) | 36 | 44 |
| Pseudogout (CPPD crystals) | 20 | 12 |
| Both gout and pseudogout | two | 0 |
| Total | 58 | 56 |
For the diagnosis of gout, both CPLM and POCRS showed that 128 samples lacked MSU crystals and 36 samples independent MSU crystals. However, 2 samples identified by POCRS as existence positive for MSU crystals were missed past CPLM, and 8 samples identified by CPLM as being positive for MSU crystals were missed past POCRS (Table 3).
Table iii
Comparison of CPLM and POCRS results for the diagnosis of gout and pseudogout*
| CPLM negative | CPLM positive | Full | |
|---|---|---|---|
| Gout (MSU crystals) | |||
| POCRS negative | 128 | 8 | 136 |
| POCRS positive | 2 | 36 | 38 |
| Total | 130 | 44 | 174 |
| Pseudogout (CPPD crystals) | |||
| POCRS negative | 151 | 1 | 152 |
| POCRS positive | xi | eleven | 22 |
| Total | 162 | 12 | 174 |
For the diagnosis of pseudogout, CPLM and POCRS showed 151 negative samples and 11 positive samples. Yet, 11 samples identified past POCRS as being CPPD crystal–positive were missed by CPLM, and 1 sample identified by CPLM as being CPPD crystal–positive was missed by POCRS (Table 3).
In detecting MSU crystals, the kappa coefficient for POCRS and CPLM was 0.84 (95% confidence interval [95% CI] 0.75–0.94). In detecting CPPD crystals, the kappa coefficient for both analyses was 0.61 (95% CI 0.42–0.81). Kappa coefficients indicated that POCRS and CPLM had excellent understanding for the diagnosis of gout, and expert agreement for the diagnosis of pseudogout (28).
DISCUSSION
This work demonstrated the usefulness of a novel medical device (POCRS) based on Raman spectroscopy for use in the point-of-care diagnosis of gout and pseudogout. Our clinical study of 174 samples indicated that POCRS was comparable to the clinically accustomed method of CPLM in detecting MSU and CPPD crystals. Information technology must be emphasized that the POCRS method identifies the type of crystals, and this data alone would not constitute a conclusive diagnosis of gout or pseudogout. The diagnoses of gout and pseudogout remain clinical diagnoses only are highly contingent on the identification of MSU and CPPD crystals, respectively, in synovial aspirates from inflammatory joints. Information technology must as well exist emphasized that we practice non propose POCRS as a replacement or alternative to CPLM. Rather, POCRS tin be used in settings where time and resources are limited or no CLIA-certified staff is available to perform CPLM. In some situations, POCRS can also exist used in conjunction with CPLM, every bit when there is ambiguity in identifying the type of crystal microscopically. Our results and those published in the literature (29–31) signal such ambiguity to exist for CPPD crystals, which appear to evade detection past CPLM. Therefore, use of methods such equally POCRS would help to mitigate this shortcoming.
In the electric current written report, we refrained from deriving a sensitivity value for POCRS or CPLM because there is no gold standard method that gives a 100% accurate diagnosis. Therefore, the focus was placed on reporting the extent of the agreement between the 2 methods by using the kappa coefficient as the measure of understanding. Kappa coefficients indicated excellent agreement and practiced understanding, respectively, between CPLM and POCRS in identifying the presence of MSU and CPPD crystals, suggesting that most samples for which gout or pseudogout is diagnosed via CPLM can besides exist diagnosed by POCRS findings.
The apply of CPLM to analyze synovial fluid is highly dependent on the skill and experience of the operator in identifying negatively (MSU) and/or positively (CPPD) birefringent crystals, forth with the respective crystal morphologies (10,xi,32–34). Diagnoses of the aforementioned sample set by unlike personnel frequently vary (xi). When crystal sizes are pocket-size, birefringence is weak or absent, and crystal concentrations are low, it becomes difficult for the operators to make decisive judgments of the crystal species.
Although CPLM is used equally the routine approach by rheumatologists to aid in the clinical diagnosis of gout and pseudogout, appropriate personnel and facilities are frequently unavailable in urgent care centers, emergency departments, and local community healthcare settings, where patients usually nowadays with astute symptoms. Doctors may take to plough to symptom-based criteria to reach a presumptive diagnosis, which carries a high fake-negative rate (13). Gout is therefore misdiagnosed and undertreated in such settings. Failure to find and place MSU and/or CPPD crystals in a timely and correct style may result in suboptimal management of crystal-induced arthritis, which may include the use of inappropriate medications. Inaccurate diagnosis of gout besides results in potentially avoidable hospital admissions due to diagnostic uncertainty. A point-of-intendance automated device would enable aspirate-based diagnosis in healthcare settings that lack trained operators, and it may likewise reduce the healthcare costs associated with avoidable hospital admissions.
The coexistence of MSU and CPPD crystals in synovial fluid has previously been reported in studies of cytocentrifugation analyses (35). In our sample set, CPLM was unable to identify whatsoever samples with both MSU and CPPD crystals. POCRS indicated the combined presence of MSU and CPPD crystals simultaneously in samples no. 14 and no. 145. Due to its subjectivity, physicians reporting results of CPLM may be reluctant to diagnose both gout and pseudogout unless the sample is laden with both types of crystals. Different CPLM, POCRS is objective, and it clearly confirmed the coexistence of MSU and CPPD crystals, which could change the course of treatment in such patients.
To the best of our cognition, at that place is no study that formally provides any applicable quantitative measurement of MSU and CPPD crystal concentrations in the diagnosis of gout and pseudogout. POCRS, as demonstrated in this work, was able to guess the crystal concentration based on the Raman betoken intensity. The crystal concentration in synovial fluid may be an indicator for tracing the efficacy of gout and pseudogout medications.
The limit of detection of POCRS is defined by the amount of crystals retained in the cartridge and less so by the volume of the synovial fluid. An aliquot of 0.1 ml of synovial fluid that is heavily laden with crystals may provide a Raman signal, whereas 10 ml of synovial fluid that is absent of crystals would non. In this study, the smallest volume of clinical synovial fluid in a sample was ~0.5 ml. The estimated concentrations in this study were mostly consistent with the anecdotally reported clinical ranges between 10 μg/ml and 100 μg/ml (32); nevertheless, our Raman assay past POCRS also identified patients with crystal concentrations in the range of 0.1–10 μk/ml. The detection limit of POCRS was favorably positioned for identifying most crystal specimens collected in the clinic.
For samples with greater amounts of MSU crystals, POCRS and CPLM had skilful agreement. Notwithstanding, the 2 methods differed when the samples had lower concentrations of crystals. POCRS was not able to detect MSU crystals if the crystal concentration was below the threshold of 0.1 μg/ml (24). CPLM tin can identify MSU crystals fifty-fifty when a unmarried crystal is detectable in the sample. Therefore, CPLM may be more sensitive than POCRS in situations when crystal concentration is exceedingly low.
The performance of CPLM in the diagnosis of pseudogout seemed to exist unsatisfactory, such that many samples that were positively identified as containing CPPD crystals by POCRS were not so identified by CPLM. The challenges of identifying CPPD crystals microscopically accept previously been shown (29): the weak birefringence of CPPD crystals makes it harder to notice them during identification by cantankerous-polarized imaging techniques. Furthermore, CPPD crystals may exist much smaller than can be detected at magnifications used by CPLM. However, the strong Raman characteristic peak of CPPD crystals enable their identification by Raman analysis.
In this report, the analyses of clinical synovial samples were conducted subsequently a single freeze–thaw cycle. Several studies demonstrated freezing not to affect crystal morphology or corporeality (36–38); however, it is unclear whether these reports employ to samples where crystal concentrations are extremely low (e.thou., <0.1 μg/ml). This limitation would non be applicable to Raman assay at the bespeak of care, because it would be practical to synovial fluid freshly nerveless in a clinical context.
Basic calcium phosphate (BCP) crystals were not observed, either by POCRS or CPLM, in any of the samples included in this report. BCP provides strong Raman signals (39) and would be detectable past POCRS if they had been present in sufficient quantity in the filtrate. There may be diverse reasons for the lack of BCP crystals. BCP crystals may accept dissolved during the sample preparation procedure. They are known to be of small size, and they may likewise have been lost during the filtration process. The concentrations of BCP crystals in these samples may take been below the detection limit of the electric current setup. It is besides possible that this patient population may not be decumbent to the development of BCP crystals. Previous studies have shown the abundance of BCP crystals in the joints of patients with advanced osteoarthritis, patients scheduled for joint replacement, and in aged patients (40,41). While osteoarthritis was present in some of the patients in our written report, about of the patients underwent aspiration because of suspected gout.
The POCRS concept holds translational hope for the futurity. The device is a collection of several dozen optical, digital, and mechanical components that tin be feasibly integrated using off-the-shelf components. While research-grade Raman systems tin cost in excess of $100,000, the cost of components for integrating POCRS was ~$10,000. The amass price of sample preparation reagents and the microfiltration cartridge is in the range of ~$ten. In a clinical setting, the clinic would procure ane device and then ane sample kit per patient. Sample preparation for POCRS consists of iii steps: digestion, dilution, and microfiltration, which takes ~1 hour (24). The majority of this fourth dimension is devoted to the digestion step (<45 minutes). Otherwise, the actual sample-treatment time is minimal (<5 minutes).
In summary, an innovative, clinically applicable Raman device was developed for the rapid detection of MSU and CPPD crystals. Assay of clinically collected samples demonstrated that POCRS findings were in full general agreement with CPLM findings over the entire pool of samples. POCRS could be used to assist guide the initiation of targeted outpatient therapy and potentially reduce the need for inpatient admission in patients with articulation effusion, in whom diagnosis might otherwise be uncertain. This could potentially amend the use of inpatient resources every bit well as the overall quality of patient care.
Acknowledgments
The authors thank Stanley Ballou, Marina Magrey, Sobia Hassan, Muhammad Khan, Cheung Yue, Ingrid Cobb, Sonia Manocha, Uzma Syeda, Zohair Abbas, Maria Antonelli, and Bassam Alhaddad at MetroHealth Medical Center and Bernard Rubin at Henry Ford Health System for identifying and recruiting the patients and collecting the clinical samples.
The contents of this commodity are solely the responsibility of the authors and practice not necessarily represent the official views of the National Institutes of Wellness, the National Plant of Arthritis and Musculoskeletal and Pare Diseases, or the National Center for Advancing Translational Sciences.
Supported by the NIH (National Constitute of Arthritis and Musculoskeletal and Skin Diseases grant R01-AR-057812 [OA]) and past the Clinical and Translational Science Collaborative of Cleveland and its Clinical Research Unit Cadre based at MetroHealth Medical Center, which receive support from the National Middle for Advancing Translational Sciences (grant UL1-TR-000439) and the NIH Road-map for Medical Research.
Footnotes
Drs. Li and Akkus are coinventors on patent no. WO2014201088 A1 for the engineering science concerning methods and devices for the diagnosis of particles in biologic fluids.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for of import intellectual content, and all authors approved the final version to be published. Dr. Akkus had full admission to all of the data in the study and takes responsibility for the integrity of the data and the accurateness of the data assay.
Study formulation and blueprint. Li, Vocaliser, Yeni, Haggins, Akkus.
Acquisition of data. Li, Vocalist, Yeni, Haggins, Barnboym, Oravec, Lewis.
Assay and interpretation of data. Li, Lewis, Akkus.
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How Is Gout Distinguished From Pseudogout Using A Microscope With A Polarizing Filter?,
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992577/
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