The Value of Serum Procalcitonin Level for Differentiation of Infectious from Noninfectious Causes of Fever After Orthopaedic Surgery

Hunziker, Sabina MD; Hügle, Thomas MD; Schuchardt, Katrin MD; Groeschl, Isabelle MD; Schuetz, Philipp MD; Mueller, Beat MD; Dick, Walter MD; Eriksson, Urs MD; Trampuz, Andrej MD

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.H.01600
Scientific Articles
Abstract

Background: Early diagnosis of postoperative orthopaedic infections is important in order to rapidly initiate adequate antimicrobial therapy. There are currently no reliable diagnostic markers to differentiate infectious from noninfectious causes of postoperative fever. We investigated the value of the serum procalcitonin level in febrile patients after orthopaedic surgery.

Methods: We prospectively evaluated 103 consecutive patients with new onset of fever within ten days after orthopaedic surgery. Fever episodes were classified by two independent investigators who were blinded to procalcitonin results as infectious or noninfectious origin. White blood-cell count, C-reactive protein level, and procalcitonin level were assessed on days 0, 1, and 3 of the postoperative fever.

Results: Infection was diagnosed in forty-five (44%) of 103 patients and involved the respiratory tract (eighteen patients), urinary tract (eighteen), joints (four), surgical site (two), bloodstream (two), and soft tissues (one). Unlike C-reactive protein levels and white blood-cell counts, procalcitonin values were significantly higher in patients with infection compared with patients without infection on the day of fever onset (p = 0.04), day 1 (p = 0.07), and day 3 (p = 0.003). Receiver-operating characteristics demonstrated that procalcitonin had the highest diagnostic accuracy, with a value of 0.62, 0.62, and 0.71 on days 0, 1, and 3, respectively. In a multivariate logistic regression analysis, procalcitonin was a significant predictor for postoperative infection on days 0, 1, and 3 of fever with an odds ratio of 2.3 (95% confidence interval, 1.1 to 4.4), 2.3 (95% confidence interval, 1.1 to 5.2), and 3.3 (95% confidence interval, 1.2 to 9.0), respectively.

Conclusions: Serum procalcitonin is a helpful diagnostic marker supporting clinical and microbiological findings for more reliable differentiation of infectious from noninfectious causes of fever after orthopaedic surgery.

Level of Evidence: Diagnostic Level II. See Instructions to Authors for a complete description of levels of evidence.

Author Information

1Department of Internal Medicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland

2Department of Orthopaedic Surgery, University Hospital Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland

3Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland. E-mail address: andrej.trampuz@chuv.ch

Article Outline

Postoperative fever is common after orthopaedic and trauma surgery and can be caused by infections or noninfectious conditions1-3. Damaged tissue due to trauma and surgical intervention and the postoperative healing process can lead to the production of proinflammatory cytokines and can induce a nonspecific systemic inflammatory response syndrome4 without true infection. In addition, other factors such as hematoma in the surgical site, transfusion of blood or blood products, lung atelectasis, deep venous thrombosis, and adverse drug reactions also may provoke postoperative fever. Conventional laboratory parameters are often nonspecifically elevated after surgery and are frequently not helpful in differentiating infectious from noninfectious causes of postoperative fever.

For the diagnosis of bacterial infections, elevated serum procalcitonin has been demonstrated to have higher diagnostic accuracy than clinical findings or standard laboratory parameters, such as the white blood-cell count and serum C-reactive protein levels, in various clinical settings5-17. The value of elevated serum procalcitonin in the diagnosis of infections has been demonstrated for specific surgical settings, such as cardiac surgery after cardiopulmonary bypass, lung decortication, major neurosurgery, and abdominal surgery5,18-24. In addition, elevated procalcitonin values correlate with the adverse prognosis of patients after thoracic surgery and ventilator-associated pneumonia25,26. However, the diagnostic accuracy of procalcitonin levels to distinguish infectious from noninfectious causes of fever in patients after orthopaedic surgery is not known.

Given the high prevalence of postoperative infection and its impact on mortality and morbidity in patients undergoing orthopaedic and nonorthopaedic procedures26, a reliable marker for the diagnosis of infection would be of great importance. It would allow the initiation of empirical antimicrobial therapy rapidly in patients with an infection and avoid unnecessary antimicrobial usage in patients without an infection, thereby saving health-care costs and preventing the development of antimicrobial resistance. For serum procalcitonin, this approach has been successfully validated for respiratory tract infections6-10,27.

We therefore prospectively evaluated consecutive patients with fever after orthopaedic procedures and trauma, using a standardized diagnostic procedure to diagnose or exclude infection. We then assessed the diagnostic accuracy of standard (white blood-cell count and C-reactive protein level) and investigational (procalcitonin) laboratory parameters to distinguish fever episodes of infectious causes from those with noninfectious causes in a blinded manner. Repeated determinations of blood values were performed during the postoperative period to determine the kinetics of the inflammatory parameters.

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Materials and Methods

Study Population

The study was conducted in the Departments of Orthopaedic Surgery and Traumatology at the University Hospital Basel in Switzerland, an 800-bed tertiary health-care center. Between May 2006 and October 2007, we prospectively included consecutive hospitalized patients who were eighteen years of age or older with a new onset of fever within ten days after surgery, including fracture fixation (upper limb, lower limb, and spine) and orthopaedic procedures (joint arthroplasty, fracture stabilization, or fracture repair). Patients were screened daily for study eligibility by one of the study coordinators (S.H., T.H., K.S., and I.G.), who were internal medicine physicians in charge on the surgical ward. For this study, fever was defined as a core body (tympanic membrane) temperature of ≥38.5°C (≥101.3°F) at a single measurement or ≥38.0°C (≥100.4°F) determined at two consecutive measurements within one hour. Patients who had, or were incubating, a preexisting infection before surgery or who had a fever on the day of surgery were excluded. The local ethical committee classified this study as a quality control study and waived the need for obtaining patient informed consent.

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Standardized Diagnostic Procedure

Patients included in the study were assessed with a standardized diagnostic procedure, including full clinical examination, chest radiograph, urine sediment investigation (analysis and culture), and collection of two pairs of aerobic and anaerobic blood cultures (each pair of blood samples was harvested thirty to sixty minutes apart). Blood cultures were collected as early as possible after fever onset as part of the routine procedure. To study the kinetics of laboratory parameters, blood was collected for laboratory investigations at the onset of fever (day 0) and at one day (day 1) and three days (day 3) thereafter. In patients with a suspected respiratory tract infection, the results of sputum or tracheal secretion cultures or antigen testing for Legionella pneumophila and Streptococcus pneumoniae in the urine were collected. In patients with a suspected wound infection, a wound swab sample was obtained for microbiological testing. Patient records were prospectively abstracted with use of a standardized data-collection case report form to retrieve demographic, clinical, microbiological, radiographic, and laboratory data. All patients were followed until hospital discharge by one of the study physicians and were monitored for the occurrence of any complications including a recurrent or new infection.

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Laboratory Investigations

Laboratory analyses included the determination of the white blood-cell count, C-reactive protein level, and procalcitonin level from the routinely collected blood samples. C-reactive protein concentrations were determined by an enzyme immunoassay (EMIT; Merck Diagnostica, Zurich, Switzerland) having a detection limit of <5 mg/dL. Procalcitonin was determined with use of a rapid ultrasensitive immunoluminometric assay with an assay turnaround time of less than twenty minutes and a functional detection limit of 0.06 ng/mL (KRYPTOR; B.R.A.H.M.S., Hennigsdorf, Germany). Blood cultures were processed with use of an automated colorimetric detection system (BacT/ALERT; bioMérieux, Durham, North Carolina)28.

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Definitions

On the basis of the diagnostic procedures, patients were prospectively assessed and febrile episodes were independently classified by the physician in charge on the ward and by a senior infectious diseases consultant. Classification of febrile episodes was done after collection of all diagnostic information and was based on clinical judgment, routine laboratory results including the C-reactive protein level and white blood-cell count measurements, and definitions of nosocomial infections according to the Centers for Disease Control and Prevention29. In brief, pneumonia was defined as the presence of (1) at least one respiratory symptom (cough, sputum production, dyspnea, tachypnea, or pleuritic pain) and at least one finding during auscultation (rales or crepitation), or (2) one sign of infection (a core body temperature of >38.0°C, shivering, or a white blood-cell count of >10 × 109/L or <4 × 109/L) and a new infiltrate on a chest radiograph; urinary tract infection was defined as (1) substantial leukocyturia (>10 white blood cells per visual field on microscopy of sediment per high-power field) or (2) substantial bacteriuria (>105 bacteria per milliliter of urine). Surgical site infection was defined as microbiologically proven superficial incisional, deep incisional, or organ and/or space infection; prosthetic joint infection was defined as the presence of (1) visible purulence, (2) acute inflammation on histopathological analysis, (3) a sinus track, or (4) microbial growth in synovial fluid or periprosthetic tissue; and bloodstream infection was defined as growth of relevant bacteria in blood cultures. Both investigators were blinded to each other and blinded to the procalcitonin values. Patients were classified as having (1) a fever of infectious origin or (2) a fever of noninfectious origin. In case of disagreement between the two specialists, a consensus by a third independent physician was reached, and the most likely (“best guess”) diagnosis was presumed. On the basis of this classification, empirical or targeted (if the pathogen was isolated) antimicrobial therapy was prescribed for patients with a fever of infectious origin.

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Statistical Methods

To evaluate differences between groups, the unpaired Student t test or the Mann-Whitney U test for continuous variables and the chi-square or Fisher exact test for categorical variables was used, as appropriate. If the C-reactive protein or procalcitonin level was not detectable, a value equal to the detection limit for the respective assay was assigned. To compare the diagnostic value of individual laboratory markers to diagnose infectious and noninfectious fever, we performed a logistic regression analysis and report odds ratios (i.e., the ratio of the probability that an event will occur compared with the probability that the event will not occur). Further, we calculated a receiver-operating characteristic analysis and report sensitivity (the proportion of actual positives that are correctly identified as such, i.e., the percentage of patients with infectious fever who are identified as having an infection) and specificity (the proportion of negatives that are correctly identified, i.e., the percentage of patients with a noninfectious fever who are identified as not having an infection) of procalcitonin at different cutoff points30. The area under the receiver-operating characteristic curve was the overall performance measure of the accuracy of the laboratory parameter to distinguish patients with infectious fevers from those with noninfectious fevers. A p value of <0.05 (for a two-sided test) was considered significant.

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Source of Funding

This study was supported by the Swiss National Science Foundation (#3200B0-112547/1), Stanley Thomas Johnson Foundation, and Gebert Rüf Stiftung.

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Results

A total of 103 patients who were febrile, with a median age of seventy-seven years (range, nineteen to ninety-seven years; interquartile range, sixty-one to eighty-five years), were included in this study; forty-five (44%) were men. A local or systemic infection was diagnosed in forty-five patients (44%), and these febrile episodes were classified as infectious, whereas no infection could be found in fifty-eight patients (56%) and these febrile episodes were classified as noninfectious (Table I). The most common surgical procedures were insertion of a dynamic hip screw (thirty-four patients) and hip arthroplasty (twenty-eight), followed by knee or foot surgery (sixteen) and spine surgery (twelve).

The median tympanic membrane temperature at the onset of fever was 38.4°C in both groups, and the course of fever during the following three days did not differ between groups. Fever tended to occur earlier with regard to the surgical procedure in patients without infection compared with patients with infection (median postoperative day 2 compared with day 3, p = 0.06).

Patients with infection had involvement of the lung (eighteen), urinary tract (eighteen), prosthetic joint (four), surgical site (two), bloodstream (two), or soft tissues (one). Causative microorganisms were found in the blood in four patients (Staphylococcus aureus [two patients], Escherichia coli [one], and Streptococcus pneumoniae [one]), in intraoperative specimens in three patients (Staphylococcus aureus [three patients]), and in urine in seventeen patients (Escherichia coli [sixteen], Klebsiella species [two]; both strains were found in one patient). In twenty-one patients, no microorganisms were identified. In most patients with noninfectious fever, a definite cause of the fever could not be established. However, presumed causes were postoperative fever due to a prolonged and complicated operative procedure (seven patients), adverse drug reaction (four), gout or underlying rheumatologic disease (four), and fever due to resorption of a large hematoma (three).

In the forty-five patients with an infectious cause of the fever, forty-four (98%) received antibiotic therapy including amoxicillin-clavulanic acid (eighteen patients), a cephalosporin (nine), a quinolone (eleven), sulfamethoxazole-trimethoprim (three), or broad-spectrum antibiotics (three). In the fifty-eight patients with a noninfectious fever, seven (12%) received antibiotics including sulfamethoxazole-trimethoprim (three), a cephalosporin (two), a quinolone (one), or amoxicillin-clavulanic acid (one).

Table II shows the laboratory parameters in patients with postoperative fever of infectious origin and those with a fever of noninfectious origin. Overall, at the onset of fever (day 0), the patients showed normal median white blood-cell count values (8.9 × 109/L) but increased median concentrations of C-reactive protein (147 mg/L) and procalcitonin (0.28 ng/mL). The areas under the receiver-operating characteristic curve for the diagnosis of an underlying infection on days 0, 1, and 3 were 0.62, 0.57, and 0.53, respectively, on the basis of the white blood-cell count and 0.56, 0.59, and 0.56, respectively, on the basis of the C-reactive protein level. Procalcitonin level showed the highest diagnostic accuracy, with an area under the receiver-operating characteristic curve of 0.62, 0.62, and 0.71 on days 0, 1, and 3.

As demonstrated in Figures 1-A, 1-B, and 1-C, on all three postoperative days, the white blood-cell count and C-reactive protein level were similar for both groups, with exception of the white blood-cell count on day 0, which was higher in patients with an infectious fever. In contrast, procalcitonin values were consistently higher in patients with infection compared with those without infection on day 0 (p = 0.04), day 1 (p = 0.07), and day 3 (p = 0.003).

Table III shows sensitivity, specificity, and positive and negative likelihood ratios of procalcitonin values at different cutoff values on days 0, 1, and 3, respectively.

In a univariate logistic regression analysis, only procalcitonin values, but not C-reactive protein level and white blood-cell count values, were significant predictors for underlying infection on all postoperative days, with odds ratios of 2.1 (95% confidence interval, 1.1 to 4.1) on day 0, 2.2 (95% confidence interval, 1.0 to 4.75) on day 1, and 3.4 (95% confidence interval, 1.3 to 9.1) on day 3. When the postoperative time point of fever onset was added in a multivariate regression model, procalcitonin concentrations were still independent predictors for underlying infection, with odds ratios of 2.3 (95% confidence interval, 1.1 to 4.4; p = 0.02), 2.3 (95% confidence interval, 1.1 to 5.2; p = 0.04), and 3.3 (95% confidence interval, 1.2 to 9.0; p = 0.02) on days 0, 1, and 3, respectively. Again, C-reactive protein levels and white blood-cell counts did not significantly correlate in the multivariate analysis with underlying infection (data not shown). Additionally, we investigated whether relative changes in the concentration of procalcitonin, C-reactive protein level, and white blood-cell count among the different postoperative days rather than absolute values had a better diagnostic potential to differentiate infectious from noninfectious fever. The relative decrease of procalcitonin in patients with an infectious fever was significantly more pronounced compared with that in patients with a noninfectious fever, but the overall diagnostic accuracy of relative procalcitonin changes as assessed in receiver-operating characteristic analysis was not as high compared with absolute values. For C-reactive protein level and white blood-cell count, no significant difference was detected between groups (data not shown).

Table IV shows procalcitonin values for various types of infection, namely respiratory tract infections, urinary tract infections, and other infections including joint infection (four patients), wound infection (two), primary bloodstream infection (two), and cellulitis (one). Procalcitonin values at the fever onset were lower in patients with respiratory and urinary tract infections than in patients with other infections, particularly in the four patients with positive blood cultures (the mean concentration of procalcitonin was 1.8, 0.91, and 1.37 on days 0, 1, and 3, respectively).

Procalcitonin concentrations correlated negatively with the onset of fever after surgery in patients with noninfectious fever (correlation coefficient R2 = 0.82; p < 0.0001), whereas no correlation was found for patients with an infectious fever (correlation coefficient R2 = 0.03; p = 0.86) (Figs. 2-A and 2-B).

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Discussion

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Figure. No caption a...

This study demonstrates that a single serum procalcitonin level has moderate diagnostic accuracy in predicting underlying infection in patients with a new onset of fever during the early period after orthopaedic surgery. The course of procalcitonin levels is different in a fever of infectious origin compared with fever of noninfectious origin, and thus diagnostic. Commonly used blood markers such as white blood-cell count and C-reactive protein levels were similar for all patients and were not at all helpful in discriminating between true infection and the nonspecific systemic inflammatory response due to surgical stress and/or underlying trauma.

Infections in the postoperative course after orthopaedic surgery can lead to prolonged hospitalization, increased morbidity and mortality, and high costs1-3. Timely administration of adequate antibiotic therapy is an important factor to reduce morbidity and mortality in patients with postoperative infections, and thus a thorough clinical examination and diagnostic workup is mandatory. In patients with a new onset of fever after an orthopaedic procedure, various laboratory parameters are frequently used in the routine setting to differentiate infectious from noninfectious causes. However, parameters such as C-reactive protein level and white blood-cell count may be misleading since they are increased in all patients in the postoperative period and are not specific for underlying infection; therefore, they are of limited clinical utility. A fracture itself and the inflammatory reaction caused by the fracture surgery may stimulate the production of cytokines, leading to a nonspecific increase of these commonly used markers of inflammation. Thus, there is an unmet need for specific markers of infection after surgical procedures. Only one small study has addressed the procalcitonin kinetics in twenty-one patients after surgery for a peritrochanteric hip fracture31. The authors concluded that procalcitonin was less affected by the orthopaedic procedure and thus was superior to other infection parameters. Our study confirms in a larger cohort of patients after various orthopaedic procedures that procalcitonin distinguishes infectious from noninfectious causes of fever more reliably than C-reactive protein level and white blood-cell count.

The exact mechanisms underlying procalcitonin induction during or after surgery are unknown. Infection and bacterial endotoxins are stimuli for the induction of procalcitonin32. Endotoxin liberation or bacterial translocation within the intestine to various degrees has been reported after different types of surgery33. However, in vitro and in vivo data have shown that a number of other stimuli may also induce procalcitonin by promoting different proinflammatory cytokines. On a transcriptional level, a stimulatory effect on messenger RNA (mRNA) production of procalcitonin has been reported for different proinflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, which may be upregulated as a result of fractures, tissue damage, and the surgical procedure5,32,34,35. Thus, there is a broad range of possible stimuli that might contribute to procalcitonin induction after orthopaedic surgery. The nonspecific induction of procalcitonin production by trauma or tissue injury, however, seems to be lower compared with a specific induction by bacterial infections. The return of procalcitonin levels to normal within a few days after an uncomplicated postoperative course can be explained by the physiological half-life of procalcitonin of eighteen to twenty-four hours in the absence of further inducing stimuli for procalcitonin production35. Since the present study was limited to the evaluation of the clinical usefulness of procalcitonin, we did not evaluate other cytokines that could help to better understand these mechanisms.

We used receiver-operating characteristic curves evaluating the sensitivities and specificities at any given procalcitonin cutoff point to compare the accuracy of procalcitonin to diagnose infection in patients with postoperative febrile episodes. The findings of this study are consistent with reports from other surgical settings showing a nonspecific procalcitonin increase in patients postoperatively, depending on the extent of surgical stress and inflammation18-22. Thus, it is important to recognize that so-called normal procalcitonin values in patients after surgery are not within the normal range for healthy subjects, and cutoff ranges must be adapted accordingly. At a cutoff of 0.1 ng/mL, procalcitonin had a reasonable sensitivity of between 85% and 91% to exclude an infection (Table III). Conversely, in patients with procalcitonin concentrations above the cutoff of 0.5 ng/mL, the likelihood for underlying bacterial infection was high, especially when this increase persisted for more than two days. In this context, the course of procalcitonin values over time rather than a single value should be considered to diagnose an infectious etiology. Our study suggests that, in patients who are febrile with procalcitonin values of <0.1 ng/mL, antibiotics can be initially withheld if no obvious clinical focus of infection is present and the patient is in good general health. However, these patients should be reassessed the next day with a thorough clinical examination and repeat blood analysis. In contrast, in patients with procalcitonin values of >0.5 ng/mL, a rapid initiation of antibiotics may be warranted. The use of an algorithm for patients with respiratory tract infections, in which the initiation or continuation of antibiotics was discouraged if procalcitonin was <0.1 ng/mL or ≤0.25 ng/mL, respectively, and was encouraged if procalcitonin was >0.5 ng/mL or >0.25 ng/mL, has been shown to markedly reduce the initiation and duration of antibiotic therapy6-9,27.

In accordance with other studies, C-reactive protein concentrations were increased about twentyfold to fortyfold in all patients after surgery, and levels remained high throughout the three-day observation period18-22. In a previous study, procalcitonin kinetics were studied in a cohort of patients undergoing elective cardiac surgery18. The investigators reported that, in the presence of fever, procalcitonin was a reliable marker for infection and more relevant than C-reactive protein for the diagnosis of postoperative infection. In the postoperative course following major neurosurgery, procalcitonin levels, in contrast to C-reactive protein level and white blood-cell count, showed a less pronounced nonspecific increase21. Similarly, in patients who underwent major cancer surgery, elevated procalcitonin and IL-6 levels were reported to be early markers of postoperative sepsis when associated with systemic inflammatory response syndrome, whereas C-reactive protein levels were not36. The routine use of C-reactive protein to diagnose infection in patients presenting with fever after surgery is motivated by its low cost and easy availability and by historical practice rather than on the basis of the evidence. However, the reliability of C-reactive protein is hampered by a protracted response with late peak levels and a low specificity in patients with systemic inflammatory response syndrome, whereas procalcitonin is more specific for distinguishing infectious from noninfectious febrile episodes.

With an observational design and a moderate sample size, this pilot study has limitations and requires validation in a larger population. As a consequence of the limited power of this study, the confidence intervals of our receiver-operating characteristic analysis overlap considerably. Therefore, we refrained from performing additional subgroup analyses on the various surgical procedures or types of infections. Importantly, because of multiple comparisons performed in the analysis of this study, p values in the range of 0.01 to 0.05 should be viewed cautiously, given the attendant higher risk of a chance association. However, the clinical and diagnostic workup and the blood sampling of patients were standardized, and the investigators were blinded with respect to procalcitonin results. We used the clinical evaluation of the patients based on a comprehensive diagnostic and microbiological workup and the assessment by an infectious diseases consultant as our diagnostic “gold standard,” which remains at present the best available method to establish the presence or absence of an infectious disease37,38. Only interventional studies, in which antibiotic therapy is guided on the basis of predefined procalcitonin cutoff ranges, have the potential to resolve this dilemma11. In this context, our results regarding the procalcitonin kinetics in patients without an infection and the sensitivity and specificity of procalcitonin at various cutoff values and on different postoperative days are of importance to the rational design of potential future interventional studies. These studies should not only address the safety and efficacy of serum procalcitonin levels for antibiotic stewardship but also should establish cost-effectiveness by considering the costs of procalcitonin measurement (US$10 to $30 per sample) and the potential savings in the consumption of other health-care resources. Additionally, it would be interesting to investigate the time course of other cytokines and biomarkers (e.g., IL-6) following other surgical procedures.

Infection is far too complex a process to be reliably diagnosed by means of a specific cutoff value for any single biomarker, particularly in patients who have recently undergone operative procedures. However, this study demonstrates that the likelihood for a bacterial infection in patients presenting with fever in the postoperative course increases gradually with increasing serum levels of procalcitonin. As an adjunct to clinical and microbiological parameters, serum procalcitonin levels may serve as a diagnostic surrogate marker for helping to differentiate infectious from noninfectious causes of early postoperative fever after orthopaedic procedures. Early identification of patients with postoperative infections is of great importance in order to establish effective antibiotic therapy. Conversely, procalcitonin may help us to avoid unnecessary antimicrobial treatment in patients with noninfectious causes of fever.

NOTE: The authors thank the nursing staff and the surgeons of the Departments of Orthopaedic Surgery and Traumatology for their continuous support during the study.

1 Investigation performed at the Departments of Orthopaedic Surgery and Traumatology, University Hospital Basel, Basel, Switzerland

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Swiss National Science Foundation (3200B0-112547/1), Stanley Thomas Johnson Foundation, and Gebert Rüf Stiftung. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

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