AAHKS SYMPOSIUM: Rising to Meet the Threat Posed by PJI
Routine Use of Antibiotic Loaded Bone Cement in Primary TKA
READ THE EVIDENCE
Against ALBC Routine Use
Pro ALBC Routine Use
The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria
ICM Philly: 2018 International Consensus Meeting for Periprosthetic Joint Infection (PJI)
ARTICLES & DATA
- Pseudomonas Prosthetic Joint Infections: A Review of 102 Episodes
Background: The outcome of patients with Pseudomonas prosthetic joint infection (PS PJI) has not been well studied. The aim of this retrospective cohort study was to assess the outcome of patients with Pseudomonas PJI and to review risk factors associated with failure of therapy.
Methods: Between 1/1969 and 12/2012, 102 episodes of PS PJI in 91 patients were identified.
Results: The mean age at the time of diagnosis was 67.4 years; forty three percent had knee involvement. Over 40 percent had either diabetes mellitus or a history of gastrointestinal or genitourinary surgery. Nearly half (48 out of 102 episodes) received aminoglycoside monotherapy, while 25% received an anti-pseudomonal cephalosporin. The 2-year cumulative survival free from failure was 69% (95% CI, 56%-82%). Patients treated with resection arthroplasty, two-stage exchange, and debridement with implant retention had a 2-year cumulative survival free from failure of 80% (95% CI, 66%-95%), 83% (95% CI, 60%-100%), and 26% (95% CI, 23%-29%) respectively (P=0.0001).
Conclusions: PS PJI’s are associated with a high failure rate. Patients treated with debridement and implant retention had a worse outcome.
- Intraoperative chlorhexidine irrigation to prevent infection in total hip and knee arthroplasty
Background: Surgical site irrigation during total hip (THA) and total knee (TKA) arthroplasty is a routine practice among orthopaedic surgeons to prevent periprosthetic joint infection. The purpose of this study was to evaluate the effect of chlorhexidine gluconate (CHG) irrigation on infection rates following THA and TKA.
Methods: Arthroplasties performed before September 2014 served as controls. THA performed before September 2014 (N = 253) underwent intraoperative irrigation with 0.9% saline followed by a 2-minute soak with <2% dilute povidone-iodine. TKA (N = 411) patients underwent only intraoperative saline irrigation. After October 2014, all patients (248 TKA and 138 THA) received intraoperative irrigation with 0.9% saline and periodic 0.05% CHG solution followed by a final 1-minute soak in CHG with immediate closure afterward.
Results: In this 2:1 comparison of consecutive patients, there were no differences in patient demographics between the 2 groups. No difference was noted in wound healing concerns subjectively, and no statistically significant association in nonsurgical site infections, superficial surgical site infection, and deep surgical site infection rates between the 2 groups (nonsurgical site infections [THA: P = .244, TKA: P = .125]; superficial surgical site infection [THA: P = .555, TKA: P = .913]; and deep surgical site infection [THA: P = .302, TKA: P = .534]).
Conclusions: We were unable to discern a difference in infection rates between chlorhexidine irrigation and our prior protocols using dilute Betadine for THA and 0.9% saline for TKA. The theoretic advantages of dilute CHG retention during closure appear to be safe without infectious concerns.
- Implementing Evidence-Based Practice to Reduce Infections Following Arthroplasty
Surgical site infections can have a devastating effect on a patient’s morbidity impacting their quality of life and productivity in society. Financial burdens are placed on healthcare organizations because of surgical site infections as well. Evidence has shown that it is a worthwhile endeavor to implement a practice to screen and treat patients who are nasal carriers of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. Implementing evidence-based practices to combat surgical site infections can help ensure quality healthcare, while producing best possible patient outcomes; however, getting evidence to the bedside can be a challenge. The Johns Hopkins nursing evidence-based practice model is designed to help nurses translate evidence into practice. This article describes the steps one community hospital took to implement an evidence-based practice using the Johns Hopkins model to decrease the likelihood of methicillin-resistant Staphylococcus aureus surgical site infections in patients undergoing total knee arthroplasty and total hip arthroplasty.
- International Consensus Meeting: 2017 Congress
Periprosthetic joint infection (PJI), with its disastrous implications, continues to challenge the orthopaedic community. Practicing orthopaedic surgeons continue to invest efforts to minimize surgical site infection (SSI). Although high-level evidence may support some of these practices, many are based on little to no scientific foundation. This results in wide variation across the globe for prevention and management of PJI. To address this, The International Consensus Meeting on Periprosthetic Joint Infection was organized. Delegates from disciplines including orthopaedic surgery, infectious disease, and many others participated. The process of generating the consensus has spanned 10 months. Over 3,500 relevant publications were evaluated by 400 delegates from 60 countries and numerous societies. This consensus document has been developed using the Delphi method under the leadership of Dr. Cats-Baril, a world-renowned expert in consensus development. The consensus process was designed to include many participants, allow participation in multiple forums, and provide a comprehensive review of the literature. Covered topics included the following: mitigation and education on comorbidities associated with increased SSI/PJI, perioperative skin preparation, perioperative antibiotics, operative environment, blood conservation, prosthesis selection, diagnosis of PJI, wound management, spacers, irrigation and debridement, antibiotic treatment and timing of reimplantation, one-stage versus two-stage exchange arthroplasty, management of fungal or atypical PJI, oral antibiotic therapy, and prevention of late PJI. Every consensus statement has undergone careful scrutiny by both subject matter experts and generalists to ensure that its implementation will indeed lead to improvement of care for patients. Based on this process, the following consensus statements were developed.
- Risk Factors for Infection after Knee Arthroplasty. A register-based analysis of 43,149 cases
BACKGROUND: Clinical studies have revealed a number of important risk factors for postoperative infection following total knee arthroplasty. Because of the small numbers of cases in those studies, there is a risk of obtaining false-negative results in statistical analyses. The purpose of the present study was to determine the risk factors for infection following primary and revision knee replacement in a large register-based series.
METHODS: A total of 43,149 primary and revision knee arthroplasties, registered in the Finnish Arthroplasty Register, were followed for a median of three years. The Finnish Arthroplasty Register and the Finnish Hospital Discharge Register were searched for surgical interventions that were performed for the treatment of deep postoperative infections. Cox regression analysis with any reoperation performed for the treatment of infection as the end point was performed to determine the risk factors for this adverse outcome.
RESULTS: Three hundred and eighty-seven reoperations were performed because of infection. Both partial and complete revision total knee arthroplasty increased the risk of infection as compared with the risk following primary knee replacement. Male patients, patients with seropositive rheumatoid arthritis or with a previous fracture around the knee, and patients with constrained and hinged prostheses had increased rates of infection after primary arthroplasty. Wound-related complications increased the risk of deep infection. The rate of septic failure was lower after unicondylar than after total condylar primary knee arthroplasty, but the difference was not significant. The combination of parenteral antibiotic prophylaxis and prosthetic fixation with antibiotic-impregnated cement protected against septic failure, especially after revision knee arthroplasty. Following revision total knee arthroplasty, diagnosis and prosthesis type had no effect, but previous revision for the treatment of infection and wound-healing problems predisposed to repeat revision for the treatment of infection.
CONCLUSIONS: There was an increased risk of deep postoperative infection in male patients and in patients with rheumatoid arthritis or a fracture around the knee as the underlying diagnosis for knee replacement. The results of the present study suggest that the infection rate is similar after partial revision and complete revision total knee arthroplasties. Combining intravenous antibiotic prophylaxis with antibiotic-impregnated cement seems advisable in revision arthroplasty.
- Properties of Bone Cement: Antibiotic-Loaded Cement
In this chapter an overview is given about the rationale for antibiotic-loaded bone cement as a drug delivery system. The characteristics of antibiotic release, the suitability of various antibiotics for admixing and the clinical application and impact are described.
- In Vitro Elution Characteristics of Commercially and Noncommercially Prepared Antibiotic PMMA Beads
The successful treatment of osteomyelitis with commercially prepared gentamicin-polymethylmethacrylate (PMMA) (Septopal) beads and surgical debridement has led to the use of this technique in the United States. However, commercially prepared gentamicin-PMMA beads are not currently available to orthopedic surgeons in the United States. Therefore, these surgeons commonly manufacture their own antibiotic-containing cement beads in the operating room at the time of surgery. There is little data that compare the antibiotic elution characteristics of such preparations to commercially prepared gentamicin-PMMA beads. This study compares the measured amount of antibiotic elution of either gentamicin or tobramycin from laboratory manufactured Zimmer, Simplex, or Palacos beads to commercially prepared gentamicin-PMMA (Septopal) beads. During a 30-day study period, commercially prepared gentamicin-PMMA beads eluted more total antibiotic and maintain higher concentrations than did antibiotic acrylic composites manufactured in the authors’ laboratory.
- In Vitro Comparison between Commercially and Manually Mixed Antibiotic-Loaded Bone Cements
PURPOSE: The purpose of this study is the evaluation of the differences and, eventually, of the advantages or disadvantages of manual formulations with respect to industrial ones.
METHODS: Medical-grade bone cements (Palacos R® and Palacos LV®), based on poly-methyl methacrylate (PMMA) and used clinically in several cemented prosthetic devices were manually enriched with gentamicin sulphate during preparation and then compared with a commercially-available, antibiotic-loaded cement (Palacos R+G®) by means of an in vitro antibacterial test (inhibition zone evaluation). The purpose of this study was to evaluate the differences and advantages or disadvantages, if any, of manual formulations compared to commercial ones. The use of a different antibiotic (vancomycin) alone or in addition to gentamicin-containing bone cements was also considered.
RESULTS AND CONCLUSION: The commercial formulation produces an inhibition zone that is a bit larger and more regular than the manually mixed preparation. The vancomycin halo is smaller but clearer than the gentamicin halo. The addition of vancomycin to gentamicin-containing bone cements does not significantly increase the halo dimensions but could be an interesting strategy in the prevention of multiple and resistant infections.
- The Effect of Mixing on Gentamicin Release from Polymethlmethacrylate Bone Cements
We compared the release of gentamicin from 6 different commercially available, antibiotic-loaded PMMA bone cements used for vacuum- and hand-mixed cement using a Cemvac vacuum mixing system. We also measured the release of gentamicin after manual addition of the antibiotic to different commercial, unloaded bone cements after hand-mixing. The porosity of cements was reduced in all vacuum-mixed cements, as compared with hand-mixed cements, concurrent with a statistically significant reduction (3 of 6) or increase (1 of 6) in the total amounts of gentamicin released. The total gentamicin release was studied in 3 of the brands after manual addition and mixing of the antibiotics. We found that the release of antibiotics was lower than in samples made from industrial mixing. In conclusion, the manual addition and mixing of gentamicin in PMMA bone cements leads to a lower release of antibiotics than that in corresponding commercially available antibiotic-loaded cements, while vacuum-mixing only leads to a minor reduction in antibiotic release, as compared to hand-mixing.
- Premixed Antibiotic Bone Cement: an In Vitro Comparison of Antimicrobial Efficacy
After Food and Drug Administration (FDA) approval of premixed antibiotic bone cements (polymethylmethacrylate [PMMA]), these products are being used with increasing frequency during revision and primary hip and knee arthroplasties. To date, no studies have compared the antimicrobial efficacy of more than 2 products directly. Using a 7-day modified Kirby-Bauer assay, we assessed the in vitro antibacterial properties of 5 FDA-approved, commercially available antibiotic PMMAs. Significant differences in antimicrobial activity were noted among the antibiotic PMMA products included in this investigation. Antibacterial activity of all products tested was greatest on day 1 and rapidly diminished thereafter. Results of this investigation suggest that the antibacterial efficacies of premixed antibiotic PMMA products are not equivalent.
- Vacuum-Mixing Significantly Changes Antibiotic Elution Characteristics of Commercially Available Antibiotic-Impregnated Bone Cement
BACKGROUND: Evidence-based medicine indicates the use of antibiotic-impregnated polymethylmethacrylate bone cement during hip and knee replacement reduces the rate of prosthetic joint infection. In the United States, so-called off-label use of antibiotic-impregnated polymethylmethacrylate for primary joint replacement is increasing and multiple antibiotic-containing polymethylmethacrylate products are commercially available. However, there are sparse published data comparing the antibiotic elution characteristics of these bone cement products and the effect that vacuum-mixing has on antibiotic elution from these products. This study compares the antibiotic elution characteristics of six commercially available antibiotic polymethylmethacrylate formulations mixed under atmospheric pressure and vacuum conditions.
METHODS: The antibiotic-impregnated polymethylmethacrylate products were mixed with use of a commonly employed intraoperative technique at atmospheric pressure and clinically relevant vacuum conditions. A standard Kirby-Bauer bioassay technique was subsequently used to quantify antibiotic elution from the products. An international infectious disease database was mined to determine antibiotic susceptibility of common bacteria causing prosthetic joint infection and to define the gentamicin concentration above which optimal antibiotic efficacy begins for these organisms. Statistical analyses incorporating the above susceptibility data were performed to compare antibiotic elution (1) among products mixed at atmospheric pressure, (2) among vacuum-mixed products, and (3) between atmospheric and vacuum-mixing for each individual product.
RESULTS: Comparisons of antibiotic-loaded polymethylmethacrylate products mixed at atmospheric pressure indicated that significant antibiotic elution differences exist among the products. Comparisons of vacuum-mixed antibiotic-loaded polymethylmethacrylate products indicated that significant antibiotic elution differences exist among the products. When mixing under atmospheric pressure was compared with vacuum-mixing for each individual antibiotic polymethylmethacrylate product, vacuum-mixing significantly increased the clinically relevant cumulative antibiotic elution from three products but significantly decreased antibiotic elution from three other products.
CONCLUSIONS: The method by which antibiotic-containing polymethylmethacrylate products are prepared significantly affects their antibiotic elution characteristics. The effect of vacuum-mixing on antibiotic elution is product-specific.
- Routine Use of Antibiotic Laden Bone Cement for Primary Total Knee Arthroplasty: Impact on Infection Microbial Patterns and Resistance Profiles
Antibiotic-laden bone cement (ALBC) is used in primary arthroplasties throughout Europe. In North America, ALBC is only FDA approved for revision arthroplasty after periprosthetic joint infection (PJI). No article has evaluated whether infecting microbial profile and resistance has changed with the introduction of ALBC. We hypothesized that prophylactic use of ALBC in primary total knee arthroplasty (TKA) has not had a significant impact on infecting pathogens, and antibiotic resistance profiles. A retrospective cohort analysis was conducted of all PJI patients undergoing primary TKA and total hip arthroplasty (THA) between January 2000 and January 2009. No significant change in the patterns of infecting PJI pathogens, and no notable increase in percentage resistance was found among organisms grown from patients with PJI that had received prophylactic antibiotic-loaded cement in their primary joint arthroplasty. Early findings suggest that routine prophylactic use of ALBC has not led to changes in infecting pathogen profile, nor has led to the emergence of antimicrobial resistance at our institution.
- Risk Stratified Usage of Antibiotic-Loaded Bone Cement for Primary Total Knee Arthroplasty: Short Term Infection Outcomes with a Standardized Cement Protocol
Efficacy of antibiotic cement (ALBC) in primary knee arthroplasty (pTKA) has been debated. The study’s purpose was to examine efficacy of ALBC versus plain cement (PBC) in preventing infection in high-risk patients undergoing pTKA. 3292 consecutive pTKAs were divided into three cohorts: (1) patients receiving only PBC, (2) patients receiving only ALBC, and (3) only high-risk patients receiving ALBC. Cohorts’ infections were compared. The 30-day infection rates for cohorts 1, 2, 3 were 0.29%, 0.20%, and 0.13% respectively. 6-month rates were 0.39%, 0.54% and 0.38%. 1-year rates were 0.78%, 0.61%, and 0.64%. Differences in infection rates at all time intervals were not statistically significant. The study supports that even judicious risk-stratified usage of ALBC may not confer added benefit in decreasing infection at one year.
- Risk Factors Associated with Surgical Site Infection in 30491 Primary Total Hip Replacements
We examined patient and surgical factors associated with deep surgical site infection (SSI) following total hip replacement (THR) in a large integrated healthcare system. A retrospective review of a cohort of primary THRs performed between 2001 and 2009 was conducted. Patient characteristics, surgical details, surgeon and hospital volumes, and SSIs were identified using the Kaiser Permanente Total Joint Replacement Registry (TJRR). Proportional-hazard regression models were used to assess risk factors for SSI. The study cohort consisted of 30,491 THRs, of which 17,474 (57%) were performed on women. The mean age of the patients in the whole series was 65.5 years (13 to 97; SD 11.8) and the mean body mass index was 29.3 kg/m(2) (15 to 67; SD 5.9). The incidence of SSI was 0.51% (155 of 30,491). Patient factors associated with SSI included female gender, obesity, and American Society of Anesthesiologists (ASA) score ≥ 3. Age, diagnosis, diabetes and race were not associated with SSI. The only surgical factor associated with SSI was a bilateral procedure. Surgeon and hospital volumes, use of antibiotic-laden cement, fixation method, laminar flow, body exhaust suits, surgical approach and fellowship training were not associated with risk of SSI. A comprehensive infection surveillance system, combined with a TJRR, identified patient and surgical factors associated with SSI. Obesity and chronic medical conditions should be addressed prior to THR. The finding of increased SSI risk with bilateral THR requires further investigation.
- Is the Commercial Antibiotic-Loaded Bone Cement Useful in Prophylactic and Cost Saving After Knee and Hip Joint Arthroplasty? The Transatlantic Paradox.
BACKGROUND: The use of antibiotic-loaded bone cement (ALBC) has proven to be effective in preventing periprosthetic infection (PPI) after total hip (THA) and knee arthroplasty (TKA). However, the economic benefit of using ALBC routinely remains controversial.
METHODS: A total of 2518 patients subjected to THA, partial hip arthroplasty, and TKA between 2009 and 2012 were identified in our prospectively collected registry. Two groups were defined: before (2009-2010) and after the introduction of ALBC (2011-2012). The risks of PPI associated with each type of surgery in each group were determined and compared. Patients subjected to THA without cemented implants were used as controls, and possible bias associated with changes in infection rate during the study period and other variables were controlled. The costs of the use of ALBC were calculated, along with the savings per case of PPI avoided. The minimum follow-up for discarding PPI was 2 years.
RESULTS: Following the introduction of ALBC, a global decrease of 57% was observed in the risk of PPI (P = .001). By type of surgery, the decrease was 60.6% in the case of TKA (P = .019) and 72.6% in the case of cemented hip arthroplasty (partial and total; P = .009). No decrease in infection rate was noted in uncemented hip arthroplasty (P = .42). The total saving associated with the use of ALBC was €1,123,846 (€992 per patient): €440,412 after TKA (€801 per patient) and €686,644 after cemented hip arthroplasty (€2672 per patient).
CONCLUSION: The use of ALBC has been found to be effective in preventing PPI after TKA and hip arthroplasty, with a favorable cost-efficiency profile using standardized cost and infection rates in our setting.
- Prophylactic Use of Antibiotic-Loaded Bone Cement in Primary Total Knee Replacement
Despite significant advances in intraoperative antimicrobial procedures, deep infection remains the most devastating complication following total joint arthroplasty. Clinical studies’ results and safety profile of antibiotic-loaded bone cement are discussed in this review. Antibiotic bone cement prophylaxis is a safe and effective strategy in reducing the risk of deep infection following primary total joint arthroplasty.
- Local Antibiotic Therapy for Severe Open Fractures
We reviewed 1085 consecutive compound limb fractures treated in 914 patients at the University of Louisville over a nine-year period. Of these fractures, 240 (group 1) received only systemic antibiotic prophylaxis and 845 (group 2) were managed by the supplementary local use of aminoglycoside-polymethylmethacrylate (PMMA) beads. There were no significant differences in age, gender, fracture type, fracture location or follow-up between the two groups. All had copious wound irrigation, meticulous debridement and skeletal stabilisation, but wound management and the use of local antibiotic depended on the surgeon’s individual preference and there was no randomisation. In group 1 there was an overall infection rate of 12% as against 3.7% in group 2 (p < 0.001). Both acute infection and local osteomyelitis showed a decreased incidence in group 2, but this was statistically significant only in Gustilo type-IIIB and type-IIIC fractures for acute infection, and only in type-II and type-IIIB fractures for chronic osteomyelitis. Our review suggests that the adjuvant use of local antibiotic-laden PMMA beads may reduce the incidence of infection in severe compound fractures.
- Antibiotic-loaded bone cement reduces risk of infections in primary total knee arthroplasty? A systematic review
PURPOSE: Antibiotic-loaded bone cement has been widely used for the treatment of infected knee replacement, but its routine use in primary TKA remains controversial. The aim of this systematic review was to analyze the literature about the antimicrobial efficacy and safety of antibiotic-loaded bone cement for its prophylactic use in primary TKA.
METHODS: A detailed and systematic search of the Pubmed, Medline, Cochrane Reviews and Google Scholar databases had been performed using the keyword “total knee arthroplasty” “total knee replacement” “total knee prosthesis” and “antibiotic-loaded bone cement” with no limit regarding the year of publication. We used modified Coleman scoring methodology (mCMS) to identify scientifically sound articles in a reproducible format. The review was limited to the English-language articles.
RESULTS: Six articles met inclusion criteria. In total, 6318 arthroplasties were included in our study. 3217 of these arthroplasties received antibiotic-loaded bone cement and 3101 arthroplasties served as the control. There was no statistical difference between the two groups in terms of the incidence of deep or superficial surgical site infection. The average mCMS score was 67.6, indicating good methodological quality in the included studies.
CONCLUSIONS: Present review did not reveal any significant difference in terms of rate of deep or superficial surgical site infection in patients receiving antibiotic-loaded bone cement compared with the control (plain bone cement) during primary TKA. The clinical relevance of this study was that the use of antibiotic-loaded bone cement did not significantly reduce the risk of infection in primary TKA.
LEVEL OF EVIDENCE: III
- The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria
The introduction of the Musculoskeletal Infection Society (MSIS) criteria for periprosthetic
joint infection (PJI) in 2011 resulted in improvements in diagnostic confidence and research collaboration.
The emergence ofnewdiagnostic tests and the lessonswe have learned from the past 7 years using the MSIS
definition, prompted us to develop an evidence-based and validated updated version of the criteria.
Methods: Thismulti-institutional studyof patientsundergoingrevisiontotal joint arthroplastywas conducted
at 3 academic centers. For the development of the newdiagnostic criteria, PJI and aseptic patient cohortswere
stringently defined: PJI cases were defined using only major criteria from the MSIS definition (n ¼ 684) and
aseptic cases underwent one-stage revision for a noninfective indication and did not fail within 2 years (n ¼
820). Serum C-reactive protein (CRP), D-dimer, erythrocyte sedimentation rate were investigated, as well as
synovial white blood cell count, polymorphonuclear percentage, leukocyte esterase, alpha-defensin, and synovial
CRP. Intraoperative findings included frozen section, presence of purulence, and isolation of a pathogen
by culture.A stepwise approach using randomforest analysis andmultivariate regressionwasused to generate
relativeweights for each diagnosticmarker. Preoperative and intraoperative definitionswere created based on
beta coefficients. The new definition was then validated on an external cohort of 222 patients with PJI who
subsequently failed with reinfection and 200 aseptic patients. The performance of the new criteria was
compared to the established MSIS and the prior International ConsensusMeeting definitions.
Results: Two positive cultures or the presence of a sinus tract were considered as major criteria and
diagnostic of PJI. The calculated weights of an elevated serum CRP (>1mg/dL), D-dimer (>860 ng/mL), and
erythrocyte sedimentation rate (>30 mm/h) were 2, 2, and 1 points, respectively. Furthermore, elevated
synovial fluid white blood cell count (>3000 cells/mL), alpha-defensin (signal-to-cutoff ratio >1), leukocyte
esterase (þþ), polymorphonuclear percentage (>80%), and synovial CRP (>6.9 mg/L) received 3, 3, 3, 2, and
1 points, respectively. Patients with an aggregate score of greater than or equal to 6 were considered
infected, while a score between 2 and 5 required the inclusion of intraoperative findings for confirming or
refuting the diagnosis. Intraoperative findings of positive histology, purulence, and single positive culture
were assigned 3, 3, and 2 points, respectively. Combined with the preoperative score, a total of greater than
or equal to 6was considered infected, a score between 4 and 5was inconclusive, and a score of 3 or lesswas
not infected. The new criteria demonstrated a higher sensitivity of 97.7% compared to the MSIS (79.3%) and
International Consensus Meeting definition (86.9%), with a similar specificity of 99.5%.
Conclusion: This study offers an evidence-based definition for diagnosing hip and knee PJI, which has
shown excellent performance on formal external validation.