Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.

BACKGROUND: In the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI). METHODS: ISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections >National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. RESULTS: Procedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) and secondary (3.48% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI than after no MI using the primary (adjusted HR, 3.38 [95% CI, 2.03-5.61]; P<0.001) or secondary MI definition (adjusted HR, 3.52 [2.11-5.88]; P<0.001). CONCLUSIONS: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and with the use of the secondary MI definition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

The use of balloon dilation in revision sinus surgery.

BACKGROUND: Recent studies have demonstrated a dramatic increase in the use of balloon sinus dilation (BSD) in the United States. However, the use of BSD specifically in revision sinus surgery has not been investigated. This study addresses the question of how BSD is utilized as a tool in revision sinus surgery. METHODS: Data from MarketScan (Truven Health) over a 5-year period (2012-2016) were analyzed. Patients who underwent a sinus procedure with a minimum of 2 years of follow-up were included. RESULTS: A total of 62,304 patients met inclusion criteria; 6847 (10.99%) underwent revision. Age >55 years, the South geographical region, and medical comorbidities increased the odds of revision on multivariate analysis. For patients undergoing revision, BSD was used 11%, 21%, and 13% of the time for revisions of the maxillary, frontal, and sphenoid sinuses, respectively. For a sinus that underwent revision after an initial BSD, a repeat BSD was done close to 40% of the time. CONCLUSION: BSD is used frequently in the revision setting, especially for the frontal sinus and for patients who had already undergone an initial BSD. Our findings highlight the prevalent role of BSD in revision surgery and the need to evaluate such practices.

A pathway to value-based care of chronic rhinosinusitis using a claims database.

OBJECTIVE: To construct a comprehensive picture of the typical chronic rhinosinusitis (CRS) patient in the United States including the demographics, comorbidities, and geographic prevalence. The study will also identify the diagnostic and treatment regimens, their cost, and pattern of use for both medically and surgically managed patients. STUDY DESIGN: Historical cohort study utilizing private and public payer databases. METHODS: Medical claims data from the Truven Health MarketScan Research Databases from the years 2010 to 2012 for patients with acute rhinosinusitis (ARS) and CRS 18 and older were analyzed. RESULTS: There were 54 million unique patients in the databases from 2010 to 2012. Approximately 8 million had at least one diagnosis of ARS and 298,337 had a diagnosis of CRS. Females represented 63.7% of patients with ARS and 59.4% with CRS. Medicare patients represented 6.7% of the ARS population and 10.2% of the CRS population. The mean cost of a CRS episode for those commercially insured was $1024 and $762 in Medicare. CRS patients underwent diagnostic procedures including diagnostic endoscopy (55.1%), cultures (23.6%), sinus CT scan (82.1%) and MRI (0.2%). Endoscopic sinus surgery (ESS) was performed on 14.4% of those patients with CRS. Change in frequency of medication use from the 6 months prior to ESS to the 6 months post-ESS yielded a reduction in total costs of 34.2% or $3.9 M. The most commonly operated sinuses (with or without septoplasty on same day as ESS) were the maxillary (94%/76.1%); followed by ethmoid (82.1%/66.6%); frontal (38.8%/35.1%); and sphenoid (28.5%/28.1%). In total, 16.6% had one sinus operated on, 39.1% had two, 24.6% had three, and 18.7% had four sinuses operated on. CONCLUSIONS: This data paints a much clearer understanding of the current medical and surgical management. This study confirms the previously described "value proposition" for the surgical management of those CRS patients refractory to medical management. LEVEL OF EVIDENCE: 4.

Balloon Catheter Dilation of the Sinuses: A 2011-2014 MarketScan Analysis.

OBJECTIVE: This study uses a large national claims-based database to analyze recent practice patterns related to balloon catheter dilation (BCD) of the sinuses. STUDY DESIGN: Retrospective study. SETTING: Academic. SUBJECTS AND METHODS: Patients with chronic rhinosinusitis (CRS) undergoing BCD and functional endoscopic sinus surgery (FESS) from 2011 to 2014 were identified in Truven Health MarketScan Databases with codes from the International Classification of Diseases, Ninth Revision, Clinical Modification and Current Procedural Terminology, Fourth Edition. Prevalence of CRS and frequency of sinus procedures were trended over the study period. Information related to site of service, demographics, and comorbidities was analyzed. RESULTS: Although the prevalence of CRS and sinus procedures remained stable over the study period, there was a consistent increase in the annual number of BCD procedures performed in the office. Among BCD procedures, multisinus dilation had the largest increase. A higher proportion of patients undergoing BCD were women, aged ≥65 years, and from the South. There was a higher prevalence of headache disorder and allergic rhinitis in the BCD group, as compared with the FESS and hybrid groups. CONCLUSION: BCD, especially in the office, has risen in popularity since the introduction of Current Procedural Terminology codes in 2011. This study reveals significant differences in demographics and comorbidities between patients undergoing BCD and those undergoing FESS. Such disparities may highlight the need for better-defined indications for use of this technology.

Determinants of Variation in Pneumonia Rates After Coronary Artery Bypass Grafting.

BACKGROUND: Although conventional wisdom suggests that differences in patient risk profiles drive variability in postoperative pneumonia rates after coronary artery bypass grafting (CABG), this teaching has yet to be empirically tested. We determined to what extent patient risk factors account for hospital variation in pneumonia rates. METHODS: We studied 324,085 patients undergoing CABG between July 1, 2011, and December 31, 2013, across 998 hospitals using The Society of Thoracic Surgeons Adult Cardiac Database. We developed 5 models to estimate our incremental ability to explain hospital variation in pneumonia rates. Model 1 contained patient demographic characteristics and admission status, while Model 2 added patient risk factors. Model 3 added measures of pulmonary function, Model 4 added measures of cardiac anatomy and function and medications, and Model 5 further added measures of intraoperative and postoperative care. RESULTS: Although 9,175 patients (2.83%) experienced pneumonia, the median estimated distribution of pneumonia rates across hospitals was 2.5% (25th to 75th percentile: 1.5% to 4.0%). Wide variability in pneumonia rates was evident, with some hospitals having rates more than 6 times higher than others (10th to 90th percentile: 1.0% to 6.1%). Among all five models, Model 2 accounted for the most variability at 4.24%. In total, 2.05% of hospital variation in pneumonia rates was explained collectively by traditional patient factors, leaving 97.95% of variation unexplained. CONCLUSIONS: Our findings suggest that patient risk profiles only account for a fraction of hospital variation in pneumonia rates; enhanced understanding of other contributory factors (eg, processes of care) is required to lessen the likelihood of such nosocomial infections.

Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans.

We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5ß1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5ß1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.

National Database Analysis of Single-Level versus Multilevel Sleep Surgery.

Objective Recent evidence suggests that multilevel sleep surgery improves outcomes when compared with palate surgery alone for most patients. The study objective was to compare demographic and outcomes data for palate surgery (uvulopalatopharyngoplasty [UPPP]) alone versus multilevel surgery through a national insurance claims database. Study Design Retrospective cohort study. Setting National insurance claims database. Subjects and Methods An adult cohort undergoing single-level UPPP versus UPPP with nasal and/or tongue/hypopharyngeal surgery was identified in the Truven Health Analytics MarketScan Research Databases for the years 2010 through 2012. Demographic and outcomes data were assessed at short-term (≤14 days), intermediate (15-60 days), and long-term (61-183 days) intervals via a multivariate regression model adjusted for age, sex, geographic region, insurance type, and the Charlson-Deyo comorbidity score. The primary long-term complication considered was positive airway pressure (PAP) equipment supply, implying possible treatment failure. Results The cohort included 14,633 patients: 7559 (51.6%), UPPP alone; 5219 (35.7%), UPPP + nasal surgery; 1164 (7.95%), UPPP + tongue/hypopharyngeal surgery; and 691 (4.7%), UPPP + nasal + tongue/hypopharyngeal surgery. Demographic data were similar among the groups. UPPP alone had lower rates of postoperative bleeding than UPPP + tongue/hypopharyngeal surgery (4.31% vs 6.19%, P = .004). Multivariate modeling indicated that the addition of either nasal surgery (odds ratio = 1.21, 95% CI = 1.10-1.34, P < .001) or tongue/hypopharyngeal surgery (odds ratio = 1.15, 95% CI = 1.00-1.32, P = .048) to UPPP was associated with increased odds of postoperative continuous positive airway pressure. Conclusions UPPP alone is currently the predominant form of sleep surgery in the United States. Multilevel surgery had greater odds of postoperative bleeding and positive airway pressure equipment supply than UPPP alone. Dedicated studies formally evaluating single- versus multilevel sleep surgery and the impact of possible surgeon/patient selection bias should be a priority.

Nonadherence to Guideline Recommendations for Tympanostomy Tube Insertion in Children Based on Mega-database Claims Analysis.

Objective To estimate the nonadherence rate of pressure equalization (tympanostomy) tube (PET) placement in the preceding 3-year period before release of the 2013 American Academy of Otolaryngology-Head and Neck Surgery Foundation clinical practice guideline (CPG). Study Design Analysis of the Truven Health MarketScan Research Databases (2010-2012). Subjects and Methods Medical claims data from 2010 to 2012 were analyzed. Children aged ≤12 years with otitis media (OM)-related diagnoses were identified. Adherence and nonadherence rates for OM and PET placement were analyzed through administrative codes extrapolated from the key action statements (KASs) of the CPG. KASs were aggregated to estimate the overall nonadherence and determine areas for quality improvement. Results A total of 9,726,411 visits with OM-associated codes among 3,710,730 children were identified: 2.9% (80,451 of 3,239,700) were considered nonadherent to KAS 1 because a code for PET placement occurred with a first episode of OM with effusion <3 months; 52.1% (14,534 of 27,913) underwent PET placement for OM with effusion of >3 months and had a concurrent hearing loss code. For those without hearing loss who underwent PET placement, 48.3% (52,921 of 109,583) had a diagnosis code indicating risk for speech, language, or learning problems. For each KAS, we found heterogeneity of computed nonadherence rates by region, age, and season. Conclusion Before guideline dissemination, we found low to moderate rates of nonadherence to guideline recommendation. Deeper analysis of mega-databases could provide better insights for measurement of guideline adherence. The expansion of administrative and clinical databases provides a unique opportunity to investigate the impact of CPGs.

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome.

AIMS: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00699998.

Chronic obstructive pulmonary disease in patients with atrial fibrillation: Insights from the ARISTOTLE trial.

BACKGROUND: Comorbid chronic obstructive pulmonary disease (COPD) is associated with poor outcomes among patients with cardiovascular disease. The risks of stroke and mortality associated with COPD among patients with atrial fibrillation are not well understood. METHODS: We analyzed patients from ARISTOTLE, a randomized trial of 18,201 patients with atrial fibrillation comparing the effects of apixaban versus warfarin on the risk of stroke or systemic embolism. Using Cox proportional hazards models, we assessed the associations between comorbid COPD and risk of stroke or systemic embolism and of mortality, adjusting for treatment allocation, smoking history and other risk factors. RESULTS: COPD was present in 1950 (10.8%) of 18,134 patients with data on pulmonary disease history. After multivariable adjustment, COPD was not associated with risk of stroke or systemic embolism (adjusted HR 0.85 [95% CI 0.60, 1.21], p=0.356). However, COPD was associated with a higher risk of all-cause mortality (adjusted HR 1.60 [95% CI 1.36, 1.88], p<0.001) and both cardiovascular and non-cardiovascular mortality. The benefit of apixaban over warfarin on stroke or systemic embolism was consistent among patients with and without COPD (HR 0.92 [95% CI 0.52, 1.63] versus 0.78 [95% CI 0.65, 0.95], interaction p=0.617). CONCLUSIONS: COPD was independently associated with increased risk of cardiovascular and non-cardiovascular mortality among patients with atrial fibrillation, but was not associated with risk of stroke or systemic embolism. The effect of apixaban on stroke or systemic embolism in COPD patients was consistent with its effect in the overall trial population.

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and Chronic Obstructive Pulmonary Disease: An Analysis From the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) experiencing acute coronary syndromes (ACS) are at high risk for clinical events. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor versus clopidogrel reduced the primary endpoint of death from vascular causes, myocardial infarction, or stroke after ACS, but increased the incidence of dyspnea, which may lead clinicians to withhold ticagrelor from COPD patients. METHODS AND RESULTS: In 18 624 patients with ACS randomized to treatment with ticagrelor or clopidogrel, history of COPD was recorded in 1085 (5.8%). At 1 year, the primary endpoint occurred in 17.7% of patients with COPD versus 10.4% in those without COPD (P<0.001). The 1-year event rate for the primary endpoint in COPD patients treated with ticagrelor versus clopidogrel was 14.8% versus 20.6% (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.54 to 0.97), for death from any cause 8.4% versus 12.4% (HR=0.70; 95% CI: 0.47 to 1.04), and for PLATO-defined major bleeding rates at 1 year 14.6% versus 16.6% (HR=0.85; 95% CI: 0.61 to 1.17). Dyspnea occurred more frequently with ticagrelor (26.1% vs. 16.3%; HR=1.71; 95% CI: 1.28 to 2.30). There was no differential increase in the relative risk of dyspnea compared to non-COPD patients (HR=1.85). No COPD status-by-treatment interactions were found, showing consistency with the main trial results. CONCLUSIONS: In this post-hoc analysis, COPD patients experienced high rates of ischemic events. Ticagrelor versus clopidogrel reduced and substantially decreased the absolute risk of ischemic events (5.8%) in COPD patients, without increasing overall major bleeding events. The benefit-risk profile supports the use of ticagrelor in patients with ACS and concomitant COPD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Long-term outcomes for women versus men with unstable angina/non-ST-segment elevation myocardial infarction managed medically without revascularization: insights from the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes trial.

BACKGROUND: Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin. METHODS: Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 [39%]) and men (n = 5,676 [61%]) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or <60 kg) versus clopidogrel 75 mg/d. Sex-specific differences in 30-day platelet reactivity were analyzed in 2,564 (27%) patients participating in a platelet function substudy. RESULTS: Compared with men, women were older, weighed less, were less likely to have prior myocardial infarction or revascularization, and had lower baseline creatinine clearance and hemoglobin level values. Rates of the composite of cardiovascular death/myocardial infarction/stroke (20.2% vs 19.1%; P = .56), all-cause mortality (12.2% vs 11.7%; P = .88), and Global Use of Strategies to Open Occluded Arteries severe/life-threatening/moderate bleeding (3.8% vs 2.8%; P = .74) through 30 months were similar in women versus men. After adjustment, women had significantly lower risk for ischemic outcomes and all-cause mortality. There were no sex-specific, treatment-related differences in 30-day platelet reactivity. CONCLUSIONS: Long-term ischemic and bleeding outcomes in medically managed ACS patients were similar for women versus men, as was treatment-related platelet reactivity. Women had a higher baseline risk profile and, after adjustment, significantly lower risk of the primary composite end point and all-cause death through 30 months.

Exposure to mitochondrial genotoxins and dopaminergic neurodegeneration in Caenorhabditis elegans.

Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC) that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration, but also support non mtDNA-mediated mechanisms.

Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis.

Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus -infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.