Objective: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNβ-1a) combined with methotrexate (MTX), IV methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNβ-1a monotherapy. Methods: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0–5.5, and ≥1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNβ-1a monotherapy. Participants continued weekly IFNβ-1a 30 μg IM and were randomized in a 2 × 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. Results: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNβ-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNβ neutralizing antibody titers. Conclusions: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis. ACT = Avonex Combination Trial; BPF = brain parenchymal fraction; DEXA= dual energy X-ray absorptiometry; EDSS = Expanded Disability Status Scale; GdE = gadolinium-enhancing; IFNβ-1a = interferon beta-1a; IVMP = IV methylprednisolone; MSFC = MS Functional Composite; MTX = methotrexate; N/E = new or enlarged; NAb = neutralizing antibody; OR = odds ratio; RRMS = relapsing-remitting multiple sclerosis; SENTINEL = Safety and Efficacy of Natalizumab in Combination with Interferon β-1a in Patients with Relapsing-Remitting MS.

BACKGROUND:The role of lung volume reduction surgery (LVRS) for individuals with alpha-1 antitrypsin (AAT) deficiency is unclear.METHODS:To assess the role of LVRS in individuals with severe deficiency of AAT, outcomes within the National Emphysema Treatment Trial were analyzed.RESULTS:Of 1218 randomized subjects, 16 (1.3%) had severe AAT deficiency (serum level < 80 mg/dL) and a consistent phenotype (when available). Characteristics of these 16 patients include 87.5% male; median serum AAT level, 55.5 mg/dL; age, 66 years; forced expiratory volume in 1 second (FEV1), 27% predicted; and 50% had upper-lobe-predominant emphysema. All 10 subjects randomized to LVRS underwent the procedure. Although the small number of subjects hampered statistical analysis, 2-year mortality was higher with surgery (20% versus 0%) than with medical treatment. Comparison of outcomes between the 10 AAT-deficient and the 554 AAT-replete subjects undergoing LVRS showed a greater increase in exercise capacity at 6 months in replete subjects and a trend toward lower and shorter duration FEV1 rise in deficient individuals.CONCLUSIONS:This study extends to 49 cases the published experience of LVRS in severe AAT deficiency. Although the small number of subjects precludes firm conclusions, trends of lower magnitude and duration of FEV1 rise after surgery in AAT-deficient versus AAT-replete subjects and higher mortality in deficient individuals randomized to surgery versus medical treatment suggest caution in recommending LVRS in AAT deficiency.

Background Indiscriminate antibiotic use may lead to development of antibiotic resistance. Preoperative mupirocin treatment decreases Staphylococcus aureus carriage and may reduce subsequent surgical site infection, but is unlikely to benefit noncarriers. This study was undertaken to evaluate whether avoiding mupirocin in noncarriers places them at increased risk for subsequent postoperative infection. Methods We conducted a retrospective cohort study examining incidence of postoperative infection in patients undergoing cardiac surgery at the Cleveland Clinic after introduction of a protocol of polymerase chain reaction screening for nasal S aureus carriage, and avoiding mupirocin treatment of noncarriers. Results Between August 1, 2002, and May 31, 2004, 6,334 patients were screened for nasal carriage of S aureus before undergoing cardiac surgery. There was no significant difference in infection rates between carriers and noncarriers when examining the incidence of all infections (5.6% and 5.0%; relative risk [RR] 1.11 [95% confidence interval (CI): 0.86 to 1.43]), infections caused specifically by S aureus (1.04% and 0.80%; RR 1.30 [95% CI: 0.71 to 2.39]), any surgical site infection (3.1% and 3.2%; RR 0.97 [95% CI: 0.69 to 1.36]), S aureus surgical site infection (0.82% and 0.58%; RR 1.41 [95% CI: 0.71 to 2.82]), any bloodstream infection (3.1% and 2.5%; RR 1.21 [95% CI: 0.86 to 1.71]), and S aureus bloodstream infection (0.37% and 0.48%; RR 0.77 [95% CI: 0.30 to 2.03]). Mupirocin use declined substantially after introduction of the protocol. Conclusions A strategy of targeting perioperative mupirocin treatment to carriers leads to significant reduction in mupirocin use without increasing early postoperative infectious complications in noncarriers.

The relationship between multiple sclerosis (MS) disease activity and myelin protein-induced cytokine responses over time is not elucidated. We addressed this relationship by examining longitudinal cytokine responses to myelin proteins every three months for one year in the context of gadolinium (gad)-enhancing brain lesions and of clinical relapses. The ELISPOT assay was used to determine the ex vivo cytokine production in response to nine amino acid long peptides spanning the entire proteolipid protein (PLP) and myelin basic protein (MBP) molecules in relapsing-remitting (RR) MS patients and matched healthy controls. We identified three longitudinal levels of myelin-induced cytokine secretion by adding up the positive responses for all PLP or MBP peptides obtained for five timepoints, at three-month intervals: low reactivity (<200 cumulative cytokine-secreting cells), isolated peptide reactivity (201-450 cumulative cytokine-secreting cells) and recurrent protein-wide bursts of cytokine reactivity (>451 cumulative cytokine-secreting cells). The majority of MS patients showed recurrent bursts to PLP and MBP In contrast, controls showed a more even distribution between all levels of cytokine reactivity. The majority of patients with gad-enhancing lesions showed PLP/IFN gamma and MBP/IFN gamma recurrent burst responses. This is the first longitudinal study on MS patients in which nine amino acid long myelin peptides are used to reveal the broad range of PLP- and MBP-peptide cytokine reactivity across the whole molecule of these two major myelin proteins. This study also reveals the extremely dynamic nature of the immune reactivity to numerous regions of myelin, which can fluctuate dramatically over time. Such fluctuation could hamper the efficacy of antigen-based therapies for MS.

PURPOSESubcapsular or perinephric hematoma is one of the most frequent and potentially serious complications of extracorporeal shock wave lithotripsy (SWL). We determined the incidence of and risk factors for renal hematomas following electromagnetic shock wave lithotripsy.MATERIALS AND METHODSBetween February 1999 and August 2003, 570 SWL treatments were performed using a Modulith SLX electromagnetic lithotriptor (Storz, St. Louis, Missouri). A total of 415 of these treatments in 317 patients were performed for stones in the renal pelvis or calices and these treatment episodes represent the study group reported. Treatment episodes were reviewed from a prospective institutional review board approved registry and analyzed for patient age, gender, body mass index, mean arterial pressure at induction, stone location, total number of shock waves and peak shock wave intensity.RESULTSFollowing these 415 episodes subcapsular or perinephric hematomas developed in 17 patients for an overall incidence of 4.1%. The probability of hematoma after shock wave lithotripsy increased significantly as patient age at treatment increased, such that the probability of hematoma was estimated to be 1.67 times greater for each 10-year incremental increase in patient age. None of the other variables analyzed were significantly related to the incidence of hematoma formation at the 0.05 level.CONCLUSIONSThe incidence of renal hematoma formation following electromagnetic SWL for renal calculus was 4.1%. The probability of hematoma increased significantly with increasing patient age but it was not associated with increasing mean arterial pressure at treatment. These findings are in contrast to previous reports of hematoma associated with electrohydraulic SWL. These differences may be a consequence of the smaller focal zone and higher peak pressure associated with Storz Modulith electromagnetic SWL and, just as importantly, a consequence of the difference in the manner in which blood pressure was defined.

BACKGROUND: Mathematical models have been used to describe the factors that affect cell salvage (CS) and normovolemic hemodilution (ANH). Here, the CS and ANH models were used to compare these two techniques alone or in combination with each other.STUDY DESIGN AND METHODS: Variables used for a hypothetical patient included an estimated blood volume of 5000 mL, a presurgery hematocrit (Hct) of 45 percent, and a transfusion trigger of 21 percent. The model accounts for both the effect of decreasing the Hct due to blood loss and the effect of increasing Hct due to the readministration of blood in an isovolemic patient. The efficacy of CS and ANH is defined to be the maximum allowable blood loss for a fixed blood volume and a fixed transfusion trigger.RESULTS: Comparison of CS with ANH showed that 3 units of ANH was comparable to CS when CS recovery rates ranged from 19 to 24 percent. For a patient with a blood volume of 5000 mL and a starting Hct of 40 percent, 3 units of ANH would allow for 3972 mL of blood to be lost before crossing a 21-percent transfusion trigger, whereas CS with a 125-mL bowl would allow for 7611 mL.CONCLUSION: When comparing ANH to CS, this mathematical model would suggest that CS has the potential to offer significantly greater red blood cell avoidance than does ANH; however, the combination of ANH with CS may offer allogeneic avoidance superior to either technique alone.

STUDY OBJECTIVE:To investigate the effect of intraoperative leukocyte reduction of administered blood products on the incidence of acute cellular rejection and postoperative patient outcome. DESIGN:Prospective, nonrandomized, historical control study. SETTING:Academic tertiary medical center. PATIENTS:The study group (Group 1) consisted of 30 consecutive adult patients with end-stage liver disease scheduled to undergo orthotopic liver transplantation (OLT) between 1998 and 2000. The historical control group (Group 2) consisted of 30 adult patients with end-stage liver disease matched to study group patients as closely as possible for age, gender, and etiology of liver disease who underwent OLT between 1995 and 1999. INTERVENTIONS:Group 1 patients had all intraoperative allogeneic and cell salvaged blood products leukocyte reduced before administration. Group 2 patients underwent OLT without leukocyte filtration of any administered blood products. MEASUREMENTS:Demographic data were collected for both patient groups and included age, gender, etiology of liver disease, and both intraoperative and postoperative immunosuppression. Demographic allograft donor data for both patient groups were collected and included age, gender, use of vasopressors during procurement, and cold and warm donor organ ischemic times. Outcome variables measured included incidence of acute cellular rejection, length of intensive care unit (ICU) and length of hospital stay, incidence of both graft loss and retransplantation, and mortality. MAIN RESULTS:The incidence of acute cellular rejection was 40% in Group 1 and 66.7% in Group 2 (p = 0.037). Length of ICU stay was 3.0 (2.0, 5.0) days in Group 1 and 4.0 (3.0, 6.0) days in Group 2 (p = 0.16). Length of hospital stay was 14.0 (11.0, 18.0) days in Group 1 and 18.0 (14.0, 27.0) days in Group 2 (p = 0.035). One allograft was lost in Group 2 because of primary nonfunction requiring retransplantation (p = 0.31), and three postoperative deaths occurred in Group 1 as a result of multisystem organ failure (p = 0.08). CONCLUSIONS:Coincident with leukocyte reduction of all administered blood products during OLT, an improved outcome was observed in Group 1 patients as demonstrated by both a decreased incidence of acute cellular rejection and length of hospital stay.

CONTEXT:The World Health Organization classification recommends categorizing grade 3 follicular lymphomas based on the presence of centrocytes (grade 3A) or of sheets of centroblasts (grade 3B). The clinical significance of this practice is not known. OBJECTIVE:To determine whether grade 3 follicular lymphoma subtype is associated with prognosis. DESIGN:Multi-institutional retrospective case series. MAIN OUTCOME MEASURE:Overall survival. RESULTS:Forty-five cases of grade 3 follicular lymphoma without diffuse large B-cell lymphoma were studied (35 cases of grade 3A, 10 cases of grade 3B) from 21 men and 24 women (median age, 67 years; mean age, 63.8 years; range, 26-86 years). Follow-up information from the time of diagnosis was available in all patients, with a median follow-up time of 24 months (mean, 34 months; range, 2- 115 months). Treatment information was available in 40 patients. There was no difference in age (P =.45, Wilcoxon test) or stage (P =.76, Fisher exact test) between patients with follicular lymphoma of grade 3A or grade 3B. Furthermore, the Cochran-Armitage test for trends showed no evidence that the proportion of patients with follicular lymphoma grade 3A or 3B increased or decreased with increasing stage at presentation. Kaplan-Meier analysis showed a median overall survival of 44 months from the time grade 3 follicular lymphoma was diagnosed, with no significant difference between cases diagnosed as grade 3A or grade 3B (P =.14, log-rank test). Univariable Cox proportional hazards modeling showed no evidence that an anthracycline-containing chemotherapy regimen or history of lower grade follicular lymphoma affected overall survival. CONCLUSIONS:In this retrospective series, subclassification of grade 3 follicular lymphoma into type 3A and 3B categories had limited clinical and prognostic significance. However, the study was limited by lack of statistical power. Since morphology often provides clues for progress in defining biologic differences, subtyping may still be useful, particularly in the setting of prospective clinical studies.

Objectives: Endovascular stent grafting offers a potentially less invasive option for treatment of abdominal aortic aneurysm. Clinical benefit has been demonstrated with respect to early parameters such as blood transfusion, return of gastrointestinal function, and length of hospital stay. Endovascular repair, however, has been criticized on the basis of inferior long-term outcome. Secondary procedures may be necessary to address durability issues such as migration, high-pressure endoleak, graft limb thrombosis, and degeneration of the stent-fabric structure itself, issues that may compromise the primary goal of aneurysm repair, protection from rupture. Methods: Between 1996 and 2002, 703 patients underwent endovascular treatment of infrarenal abdominal aortic aneurysm at The Cleveland Clinic Foundation. During this time, five devices were used: Ancure, AneuRx, Excluder, Talent, and Zenith. Outcome was assessed with physical examination, lower extremity arterial studies, plain abdominal radiography, and computed tomography at discharge, at 1, 6, and 12 months postoperatively, and annually thereafter. Secondary procedures were defined as any procedure, exclusive of diagnostic angiography, performed after stent graft implantation, directed at treatment of aneurysm-related events. Multivariable statistical techniques for censored data (Cox proportional hazards modeling) were used to determine baseline parameters associated with need for secondary procedures over follow-up, with calculation of hazards ratio (HR) and 95% confidence interval (CI). Results: Patient follow-up averaged 12.2 ± 11.7 months. Patient survival was 90% ± 1.4% at 1 year, 78% ± 2.6% at 2 years, and 70% ± 3.8% at 3 years. Aneurysm rupture occurred in 3 patients (0.4%), accounting for rupture risk of 1.4% over the first 2 years of follow-up (Kaplan-Meier method). Overall, 128 secondary procedures were required in 104 patients (15%), with a cumulative risk of 12% ± 1.5% at 1 year, 24% ± 2.8% at 2 years, and 35% ± 4.4% at 3 years after stent graft implantation. Among the secondary procedures, new stent grafts and extensions were placed in 34 patients (27%), embolization of endoleak was performed in 33 patients (26%), and open surgical conversion was undertaken in 11 patients (9%). Periprocedural mortality of secondary procedures was 8% overall, but was 18% for patients undergoing open surgical conversion. Multivariable modeling identified the date the procedure was performed (HR, 1.53 per 3-month period of study; CI, 1.22-1.92; P <.001) and aneurysm size (HR, 1.35 per centimeter of minor axis; CI, 1.13-1.60; P <.001) as independent predictors of need for secondary procedures. Conclusions: Current endovascular devices are associated with a relatively high rate of complications over mid-term follow-up, culminating in frequent need for secondary remedial procedures. With strict follow-up imaging compliance, however, risk for rupture and aneurysm-related death remain exceedingly low. Newer technology may achieve improved durability and a lower requirement for secondary procedures, while maintaining the minimally invasive nature of presently available devices. (J Vasc Surg 2003;37:930-7.)

BACKGROUND:An earlier randomized, controlled trial showed that weekly or as-needed (as opposed to daily) changes of in-line suction catheters were associated with substantial cost savings, without a higher rate of ventilator-associated pneumonia (VAP). To examine the impact of decreasing the frequency of in-line suction catheter changes in our medical intensive care unit, we conducted an observational study, comparing the catheter costs and frequency of VAP during (1) a control period, during which in-line suction catheters were changed daily, and (2) a treatment period, during which the catheters were changed every 7 days or sooner if needed, for mechanical failure or soilage.METHODS:All adult patients admitted to our 18-bed medical intensive care unit were evaluated for the 3-month interval 1 year prior to the practice change (May through July 1998) and for the 3 months after implementing the new policy (May through July 1999). To avoid bias related to usual seasonal variation in VAP frequency, we also determined (via medical records) the VAP rate during May through July 1997. The occurrence of VAP was ascertained by an infection control practitioner, using criteria established by the Centers for Disease Control and applied in a standard fashion. The VAP rate was calculated as the mean number of VAPs per 100 ventilator-days for each 3-month interval. Use of ventilators, humidifiers, and non-heated-wire, disposable circuits was uniform during the study, as were policies regarding humidity, temperature settings, and frequency of routine ventilator circuit changes.RESULTS:During the control period 146 patients accounted for 1,075 ventilator-days and there were 2 VAPs (0.19 VAPs per 100 ventilator-days). During the treatment period 143 patients accounted for 1,167 ventilator-days and there were no VAPs. The mean +/- SD duration of in-line suction catheter use during the treatment period was 3.8 +/- 0.8 days, and 51% of the patients had the same catheter in place for > 3 days (range 4-9 days). The actual cost of catheters used during the treatment period was lower than during the control period ($1,330 vs $6,026), predicting annual catheter cost savings of $18,782.CONCLUSIONS:We conclude that (1) a policy of weekly (vs daily) change of in-line suction catheter is associated with substantial cost savings, with no significant increase in the frequency of VAP, and (2) to the extent that these findings confirm the results of prior studies they support a policy of changing in-line suction catheters weekly rather than daily.

Background: Because the correlation between ammonia levels and the severity of hepatic encephalopathy remains controversial, we prospectively evaluated the correlation in 121 consecutive patients with cirrhosis. Methods: The diagno‐ sis of hepatic encephalopathy was based on clinical criteria, and the severity of hepatic encephalopathy was based on the West Haven Criteria for grading of mental status. Arterial and venous blood samples were obtained from each patient. Four types of ammonia measurements were analyzed: arterial and venous total ammonia, and arterial and venous partial pressure of ammonia. Spearman rank correlations (r s) were calculated. Results: Of the 121 patients, 30 (25%) had grade 0 encephalopathy (no signs or symptoms), 27 (22%) had grade 1, 23 (19%) had grade 2, 28 (23%) had grade 3, and 13 (11%) had grade 4 (the most severe signs and symptoms). Each of the four measures of ammonia increased with the severity of hepatic encephalopathy: arterial total ammonia (r s =0.61, p ≤ .001), venous total ammonia (r s =0.56, p ≤ .001), arterial partial pressure of ammonia (r s =0.55, p ≤ .001), and venous partial pressure of ammonia (r s =0.52, p≤ .001).Conclusions: Ammonia levels correlate with the severity of hepatic encephalopathy. Venous sampling is adequate for ammo‐ nia measurement. There appears to be no additional advantage of measuring the partial pressure of ammonia compared with total ammonia levels.

Background & Purpose: It has been demonstrated that analysis of ROC area can be somewhat insensitive to observed differences in discrimination compared with the Normalized Discrimination Index (NDI) and the Slope Index (SI) (MDM 1999, p524). SI has the most direct relationship to the true probability separation in predictions, but it is unaffected by the variance of predictions. We examine 3 modifications to the SI and compare them with ROC area (in terms of Somer's D) and NDI.