Donor-derived Coccidioides immitis fungemia in solid organ transplant recipients.

We report disseminated coccidioidomycosis in 3 transplant recipients from a donor in an endemic area found to have unrecognized meningeal coccidioidomycosis. All 3 transplant recipients presented within 3 weeks of receipt of their organ. Only 1 organ recipient survived the acute presentation of coccidioidomycosis. Serologic testing for Coccidioides immitis infection should be considered for organ donors residing in endemic areas.

Correlation of susceptibility of Cryptococcus neoformans to amphotericin B with clinical outcome.

Testing of Cryptococcus neoformans for susceptibility to antifungal drugs by standard microtiter methods has not been shown to correlate with clinical outcomes. This report describes a modified quantitative broth macrodilution susceptibility method showing a correlation with both the patient's quantitative biological response in the cerebrospinal fluid (CSF) and the survival of 85 patients treated with amphotericin B (AMB). The Spearman rank correlation between the quantitative in vitro measure of susceptibility and the quantitative measure of the number of organisms in the patient's CSF was 0.37 (P < 0.01; 95% confidence interval [95% CI], 0.20, 0.60) for the first susceptibility test replicate and 0.46 (P < 0.001; 95% CI, 0.21, 0.62) for the second susceptibility test replicate. The median in vitro estimated response (defined as the fungal burden after AMB treatment) at 1.5 mg/liter AMB for patients alive at day 14 was 5 CFU (95% CI, 3, 8), compared to 57 CFU (95% CI, 4, 832) for those who died before day 14. These exploratory results suggest that patients whose isolates show a quantitative in vitro susceptibility response below 10 CFU/ml were more likely to survive beyond day 14.

Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients.

OBJECTIVES: The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections. METHODS: A randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 h after dosing) and CSF samples were taken at baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography. RESULTS: Sixty-four treated patients had fluconazole measurements: 11 in the AmB group, 12 in the AmB+Fluc400 group and 41 in the AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated with AmB+Fluc800 (P<0.001, r=0.873) and AmB+Fluc400 (P=0.005, r=0.943). Increased serum area under the curve (AUC) appears to be associated with decreased mortality at day 70 (P=0.061, odds ratio=2.19) as well as with increased study composite endpoint success at days 42 and 70 (P=0.081, odds ratio=2.25 and 0.058, 2.89, respectively). CONCLUSION: High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear to be associated with increased survival and primary composite endpoint success.

Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease.

Cryptococcus neoformans is an uncommonly recognized cause of pneumonia in HIV-negative patients. Because of its propensity to disseminate to the meninges and other sites, a lumbar puncture is recommended for patients with pulmonary cryptococcosis, regardless of other risk factors. This study explored clinical and laboratory features to help predict which patients had pulmonary disease alone versus those who had pulmonary plus extrapulmonary disease. A retrospective chart review at 15 medical centers was performed from 1990 to 2000 of all HIV-negative patients who had pulmonary cryptococcosis. Demographic, clinical, radiographic, and laboratory features were evaluated to determine factors that differentiated those patients who had extrapulmonary disease. Among 166 patients who had pulmonary cryptococcosis, 122 had pulmonary infection only and 44 had pulmonary plus extrapulmonary (disseminated) disease. A negative serum cryptococcal antigen titer was more common in patients with pulmonary disease alone (p < 0.01). Multivariate analysis demonstrated that patients who had disseminated disease were more likely than those who only had pulmonary disease to have cirrhosis (p = 0.049), headache (p < 0.001), weight loss (p = 0.003), fever (p = 0.035), altered mental status (p < 0.001), and to be receiving high-dose corticosteroids (p = 0.008). In this large cohort of HIV-negative patients with pulmonary cryptococcosis, there were easily distinguished clinical and laboratory features among patients with pulmonary disease alone versus those with pulmonary plus extrapulmonary disease. These findings may be helpful in the evaluation of HIV-negative patients with pulmonary cryptococcosis with regard to the need for lumbar puncture or to search for disseminated disease.

Clinical trial of junction seals for the prevention of urinary catheter-associated bacteriuria.

BACKGROUND: Preconnected catheter systems with sealed junctions have been associated with reduced rates of bacteriuria and mortality. A clinical trial was undertaken to evaluate the effectiveness of a junction seal applied after catheter insertion for preventing bacteriuria and reducing mortality. METHODS: Patients undergoing transurethral catheterization at a community hospital were randomized within 24 hours of catheter insertion to receive either a tape seal applied to the catheter-drainage tubing junction or no tape seal. Catheter urine cultures and catheter care violations were monitored daily until catheter removal or patient discharge. RESULTS: Overall, 124 (13.7%) of 903 patients in the group receiving a junction seal acquired bacteriuria, compared with 125 (14.9%) of 837 patients in the control group (P = .52, odds ratio = 0.91, 95% confidence interval, 0.69 to 1.20). Multivariate analysis revealed that only female gender and lack of systemic antibiotic use independently correlated with the development of bacteriuria; neither junction treatment randomization nor disconnection of the junction was associated with bacteriuria. Survival curve analysis of patients stratified by gender and antibiotic use revealed no significant differences in the rate of bacteriuria between treatment groups. The overall mortality in the tape seal group was less than that in the control group (6.6% vs. 8.0%, respectively), but not to a statistically significant extent despite stratification by antibiotic use. CONCLUSIONS: The use of a tape seal applied to the catheter-drainage tubing junction within 24 hours of catheter insertion was not associated with significantly lower rates of bacteriuria and mortality in patients undergoing short-term catheterization.

Seronegative disseminated coccidioidomycosis in patients with HIV infection.

Serologic testing for complement-fixing antibodies to Coccidioides immitis is commonly employed to assist in the diagnosis and management of this infection, but its usefulness in an HIV-coinfected population is unknown. In this study we reviewed all the mycologically or histologically proven cases of disseminated C. immitis infection after 1982. Disseminated C. immitis and proven HIV infection were present in eight patients. We performed serum complement-fixing antibody titers on all eight patients, six of whom gave positive tests, while two patients (25%) gave repeatedly negative results despite widely disseminated disease. We conclude that histopathology and culture remain the most reliable methods for the diagnosis of disseminated coccidioidomycosis in the HIV-infected host.

Catastrophic visual loss due to Cryptococcus neoformans meningitis.

We have reviewed our experience with 17 of our own patients with cryptococcal meningitis and 32 cases from the literature. Although this complication is an uncommon event, patients with cryptococcal meningitis may develop visual loss in the absence of other ocular lesions (endophthalmitis or cryptococcomas in the visual pathway) that could explain the visual symptoms. There are 2 distinct patterns of visual loss: rapid visual loss and slow visual loss. Rapid visual loss is characterized by onset of profound visual loss over a period as short as 12 hours before or early in the course of therapy and a clinical syndrome that is strongly suggestive of optic neuritis. Direct invasion of the optic nerve by C. neoformans is demonstrated by cases in this and other reports. Slow visual loss is characterized by slow but progressive visual loss which typically begins later during therapy and may be due to the effects of increased intracranial pressure. While the initial deficit may be mild, patients with slow visual loss can progress to severe visual loss over weeks to months. The only factors that appear to predict either pattern of visual loss are the presence of papilledema, an elevated CSF opening pressure, and a positive CSF India ink preparation. In the 25 visual loss patients for whom data were available for all 3 items, 10 (40%) were positive for all 3, as opposed to only 4 of 114 (3.5%) from a reference group of cryptococcal meningitis patients without visual loss (p < 0.00001). The only therapeutic measures with any degree of consistent success were those directed at reducing intracranial pressure. When begun early and used aggressively, such therapy halted and sometimes even reversed the course of visual loss, particularly in the slow visual loss group. Corticosteroids did not appear to be of value in the small number of patients who received them.

Tuberculous meningitis in patients with and without human immunodeficiency virus infection.

OBJECTIVE: To characterize the symptoms, signs, laboratory findings, and outcome of culture-proven meningitis due to Mycobacterium tuberculosis in patients with and without human immunodeficiency virus (HIV) infection. DESIGN: Retrospective chart review. SETTING: Urban public general hospital in the United States. PATIENTS: Fifteen patients with and 16 without HIV infection. MEASUREMENTS: Demographics, symptoms, physical exam findings, serum sodium, complete blood cell count, CD4+ cell count, cerebrospinal fluid findings, imaging data, and in-hospital mortality. MAIN RESULTS: Symptoms, signs, chest radiograph appearance, cerebrospinal fluid cell counts and chemistries, and mortality were similar in both groups (p = NS). Median CD4+ cell counts were lower in HIV-infected patients (median 99/mm3, range 7 to 251, versus 384/mm3, range 171 to 724 in those without HIV infection, p = 0.007). Intracerebral mass lesions were more common in the HIV-infected group (60% versus 14% in the uninfected group, p = 0.01), although the presence of a mass did not correlate with focal neurologic deficits, altered level of consciousness, or mortality. CONCLUSION: With the exception of an increased incidence of intracerebral mass lesions in HIV-infected individuals, HIV infection appears to have little impact on the findings and in-hospital mortality of tuberculous meningitis.

Prevalence of neurosyphilis in human immunodeficiency virus-infected patients with latent syphilis.

PURPOSE: A prospective study was done to determine the prevalence of confirmed neurosyphilis (cerebrospinal fluid [CSF] Venereal Disease Research Laboratory [VDRL]-reactive) in human immunodeficiency virus (HIV)-infected patients with latent syphilis (reactive serum rapid plasma reagin [RPR] and microhemagglutination-Treponema pallidum [MHA-TP]). PATIENTS AND METHODS: All HIV-infected patients seen for their first visit at the Los Angeles County/University of Southern California Medical Center AIDS Clinic from June through December 1990 were screened for latent syphilis. Those with reactive serum RPRs and MHA-TPs who had not received recent (within 6 months) therapy for syphilis were offered diagnostic CSF sampling. RESULTS: A total of 312 patients were screened, of whom 71 (22.8%) had reactive serum RPRs and MHA-TPs. Thirty-three of these patients (47%) had diagnostic CSF sampling (26 refused lumbar puncture or were lost to follow-up; 12 had had recent therapy for syphilis and thus did not have CSF sampling). Among the 33 patients who had CSF sampling, 20 (60.6%) had normal CSF profiles (white blood cell count less than 8/mm3; protein less than 0.60 g/L; glucose greater than 2.8 mmol/L) and nonreactive CSF VDRLs. Ten of the 33 patients (30.3%) had abnormal CSF profiles and nonreactive CSF VDRLs, and three of 33 (9.1%) had reactive CSF VDRLs. CONCLUSIONS: Asymptomatic neurosyphilis was found in 9.1% of our patient population undergoing CSF sampling, giving a 1.0% prevalence of CSF VDRL-reactive neurosyphilis in the population we screened. The abnormal CSF findings may have been due to either nonreactive CSF VDRL neurosyphilis, central nervous system infection with HIV, or infection with some unrecognized agent.

Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trial Group.

PURPOSE: Amphotericin B has been the treatment of choice for disseminated histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). Oral antifungal agents would be welcome alternatives to standard treatment of disseminated histoplasmosis in less severe cases. The purpose of this study was to assess the efficacy and safety of itraconazole therapy in patients with AIDS and disseminated histoplasmosis. PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial conducted in university hospitals of the AIDS Clinical Trial Group. All patients had AIDS and first episodes of disseminated histoplasmosis. Patients with central nervous system involvement or with severe clinical manifestations were excluded. Patients were treated with itraconazole BID by mouth 300 mg for 3 days and then 200 mg BID for 12 weeks. Resolution of clinical findings, clearance of positive cultures, and drug tolerance were the main outcome measurements. A secondary objective was effect of therapy on Histoplasma capsulatum var capsulatum antigen levels. RESULTS: Of 59 evaluable patients, 50 (85%) responded to therapy. Five patients withdrew because of progressive infection, 1 died of a presumed pulmonary embolus within the first week of therapy without improvement, 2 withdrew because of toxicity, and 1 was lost to follow-up after week 2 of therapy. Patients with moderately severe clinical (fever > 39.5 degrees C or Karnofsky score < 60) or laboratory abnormalities (alkaline phosphatase > 5 times normal or albumin < 3 g/dL) at baseline tended to respond more poorly than did other patients. Resolution of complaints of fever and improvement in fatigue occurred after a median of 3 and 6 weeks, respectively, and weight gain after 2 weeks. Fungemia cleared after a median of 1 week. H capsulatum var capsulatum antigen cleared from the urine and serum at rates of 0.2 and 0.3 units per week, respectively. CONCLUSIONS: Itraconazole is safe and effective induction therapy for mild disseminated histoplasmosis in patients with AIDS, offering an alternative to amphotericin B in such cases. Patients with moderately severe or severe histoplasmosis should first be treated with amphotericin B and then may be switched to itraconazole after achieving clinical improvement.

Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group.

PURPOSE: This study assesses the efficacy and safety of fluconazole therapy in patients with acquired immunodeficiency syndrome (AIDS) and mild to moderately severe manifestations of disseminated histoplasmosis. PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial. All patients had AIDS and disseminated histoplasmosis. Patients were treated with 1,200 mg of fluconazole given by mouth once on the first day, then 600 mg once daily for 8 weeks, and those patients who improved clinically were then assigned fluconazole maintenance therapy 200 mg once daily for at least 1 year. Interim analysis revealed a high failure rate (10 of 20, 50%), causing revision of the protocol to increase the fluconazole dose to 1,600 mg given once on the first day, then 800 mg once daily, and the duration to 12 weeks for induction therapy and then 400 mg daily for 1 year for maintenance therapy. MEASUREMENTS AND MAIN RESULTS: Thirty-six of 49 patients (74%; 95% confidence interval [CI]: 59% to 85%) with mild to moderately severe clinical manifestations who entered into the revised study responded to 800 mg of fluconazole daily for 12 weeks as induction therapy. Of the seven patients who failed induction therapy because of progression of histoplasmosis, one died of the infection. Of 36 patients who entered into the maintenance phase of the study receiving 400 mg of fluconazole daily for 1 year, 11 (30.5%) relapsed, including one who died (2.8%). Two of the 49 patients (4.1%) were removed because of grade 4 adverse events, alkaline phosphatase elevation for one and aspartate aminotransferase elevation in the other. The relapse-free rate at 1 year was 53% (95% CI: 32% to 89%), prompting closure of the study. CONCLUSIONS: Fluconazole 800 mg daily is a safe and moderately effective induction therapy for mild or moderately severe disseminated histoplasmosis in patients with AIDS. On the basis of historic comparison, fluconazole 400 mg daily is less effective than itraconazole 200 to 400 mg daily or amphotericin B 50 mg given weekly as maintenance therapy to prevent relapse.

Daily meatal care for prevention of catheter-associated bacteriuria: results using frequent applications of polyantibiotic cream.

OBJECTIVE: To determine the efficacy of meatal treatment with a polyantibiotic cream in the prevention of bacteriuria during transurethral bladder catheterization. DESIGN: Randomized controlled trial. SETTING: Community teaching hospital. PATIENTS: Adult patients who underwent closed urinary catheter drainage for short and intermediate durations (two to 30 days). INTERVENTION: Polyantibiotic cream containing polymyxin B sulfate, neomycin sulfate, and gramicidin was applied to the urethral meatus-catheter interface three times daily from the first day of catheterization until bacteriuria was found. The onset of bacteriuria was defined as the day the colonizing species first achieved a colony count of greater than or equal to 1000 colonies/ml. Patients randomized to the control group received routine meatal care with cleansing of the meatal surface during daily bathing. RESULTS: Among 2,923 patients who were randomly allocated to receive either the protocol meatal care or routine care, the evaluable study population consisted of 747 patients who were nonbacteriuric and who remained catheterized for more than two days. Overall, 26 (6.8%) of 383 patients given the polyantibiotic treatment acquired bacteriuria, as compared to 37 (10.1%) of 364 patients not given this treatment (p = .167). A Cox proportional hazards regression analysis showed that, among putative risk factors including lack of meatal care, only female gender, a meatal swab culture yielding gram-negative rods or enterococci, and lack of antibiotic use during catheterization were independently associated with the development of bacteriuria. CONCLUSIONS: The adverse effect of meatal care noted in earlier studies of a disinfectant ointment applied twice daily was not found in this study of an antimicrobial preparation in a cream vehicle applied three times daily. However, the results do not support meatal care as an efficacious method to prevent catheter-associated bacteriuria in all patients.

Improved perioperative antibiotic use and reduced surgical wound infections through use of computer decision analysis.

A prospective study was performed over a two-year period to determine whether computer-generated reminders of perioperative antibiotic use could improve prescribing habits and reduce postoperative wound infections. During the first year, baseline patterns of antibiotic use and postoperative infection rates were established. During the second year, computer-generated reminders regarding perioperative antibiotic use were placed in the patient's medical record prior to surgery and patterns of antibiotic use and postoperative wound infections monitored. Hospitalized patients undergoing non-emergency surgery from June to November 1985 (3,263 patients), and from June to November 1986 (3,568) were monitored with respect to indications for perioperative antibiotic use, timing of antibiotic use and postoperative infectious complications. Perioperative antibiotic use was considered advisable for 1,621 (50%) patients in the 1985 sample and for 1,830 (51%) patients in the 1986 sample. Among these patients, antibiotics were given within two hours before the surgical incision in 638 (40%) of the 1985 sample and 1,070 (58%) of the 1986 sample (p less than 0.001). Overall, postoperative wound infections were detected in 28 (1.8%) of 1,621 patients in 1985 compared with 16 (0.9%) of 1,830 such patients in 1986 (p less than 0.03). We conclude that computer-generated reminders of perioperative antibiotic use improved prescribing habits with a concurrent decline in postoperative wound infections.

Prevention of catheter-associated bacteriuria: clinical trial of methods to block three known pathways of infection.

The simultaneous use of methods to block all three known pathways of bacterial entry into the bladders of catheterized patients has been suggested because of the limited effectiveness of individual methods that block single pathways. We conducted a randomized controlled trial to assess the prevention of bacteriuria in patients, using a three-way system that included a hydrophilic polymer-coated and preconnected sealed catheter system, daily catheter care, and disinfection of the outflow tube of the drainage bag with povidone-iodine (i.e., methods to block bacterial entry at the urethral insertion site, at the catheter drainage tube junction, and at the outflow tube). Among treated patients, 14 (4.7%) of 300 acquired bacteriuria as compared with 15 (4.9%) of 306 who did not receive the protocol treatments. Only 3 of 29 episodes of bacteriuria occurred in patients whose meatal cultures did not contain gram-negative bacilli or enterococci; thus migration of bacteria in the periurethral mucous sheath appeared to be the most common pathway by which bacteria gained entry into the bladder in this study. Catheter care and disinfection of the drainage bag outflow tube as used in this study remain unproven methods of preventing catheter-associated bacteriuria. Preconnected catheters with junction seals were used in both treated and untreated patients and, on the basis of previous studies, appear to be effective in reducing junction disconnections and bacteriuria. Therefore we conclude that the use of several simultaneous measures to prevent catheter-associated urinary infections is no more effective than the use of preconnected catheters with junction seals alone and is clearly more expensive.

Trends in infections and antibiotic usage in a community hospital.

The results of a physician-performed prevalence survey of infections and antibiotic use at the Salt Lake City LDS Hospital in 1984 were compared with results of surveys done in 1971 and 1979. The hospital census and length of stay declined in successive surveys, contributing to the changes observed. Community-acquired infections were more prevalent in 1984 than in the previous surveys, whereas hospital-acquired infections were seen with similar frequencies. Among hospital-acquired infections, lower respiratory tract and soft-tissue infections were more prevalent in 1984. Gram-negative bacilli accounted for 34% of hospital-acquired infections in 1984 versus rates of 60% or more found in the 1970s. Although the overall prevalences of antibiotic use were similar in the three surveys, the proportion attributed to cephalosporins increased from 17.5% (1971) to 49.2% (1979) and 59.1% (1984). Antibiotic prophylaxis was less frequent in 1984 (14.4%) than in 1979 (24.1%) and reversed the trend found after 1971 (11.0%). Despite extensive educational efforts since the prevalence survey of 1979, perioperative antibiotics were used for durations longer than 48 hours after surgery in 43% of the patients receiving such prophylaxis in 1984. The LDS Hospital has adopted a restrictive antibiotic formulary in part as a result of the present survey.

Identification and characterization of monoclonal antibodies reactive with bovine, caprine and ovine T-lymphocyte determinants by flow microfluorimetry.

Comparative flow microfluorimetric (FMF) analysis was used to identify and characterize 27 monoclonal antibodies (MoAbs) reactive with bovine T-lymphocytes. Determinants present on all circulating T-lymphocytes were recognized by 11 MoAbs, 8 of which blocked E rosette formation. Determinants present on only the BoCD4+ T-lymphocyte subset were detected by 9 MoAbs, while determinants restricted to the BoCD8+ T-lymphocyte subset were recognized by 7 MoAbs. Competitive labeling experiments demonstrated that determinants recognized by subset-specific MoAbs were present on BoCD4 or BoCD8 molecules. Comparative studies revealed that some determinants, both pan-T specific and subset-specific, were conserved on homologous (orthologous) molecules expressed on leukocytes from other species of ruminants. Polymorphism was evident with several determinants.

Case report: recurrent Salmonella typhi chest wall abscess associated with a pituitary macroadenoma.

An unusual manifestation of a Salmonella typhi infection is presented in a patient with a growth hormone producing tumor. Growth hormone may effect cell mediated immunity and predispose to localized or disseminated intracellular infections.

The frequency of fungal involvement in abnormal vocal cord biopsy specimens.

Finding an unsuspected fungal infection of the true vocal cord prompted a retrospective study of abnormal vocal cords received as surgical specimens. Of 30 cases initially diagnosed histologically as either inflammation or hyperkeratosis, two (in addition to the index case) contained fungal elements visible on special stains. None of the patients had systemic mycoses on examination or on follow-up. Local excision apparently cured all lesions. Fungi may cause more vocal cord lesions than previously recognized and cannot be well visualized on routine sections.

Predictors of poor clinical outcome of cryptococcal meningitis in HIV-infected patients.

The aim of this study was to identify baseline prognostic factors for poor clinical outcome of HIV-associated cryptococcal meningitis. We conducted a trial in Thailand and the USA comparing low- and high-dose concomitant use of amphotericin B and fluconazole for HIV-associated cryptococcal meningitis to amphotericin B followed by fluconazole. Subjects who were either alive and cerebrospinal fluid (CSF) culture-positive or dead were considered to have a poor outcome. At day 14, baseline characteristics associated with poor outcome included: low weight, high CSF cryptococcal antigen (CrAg) titre and low CSF white blood cell (WBC) count. At day 70, the associated baseline characteristics included: CSF CrAg titre >1:1024 and low Karnofsky performance status. Overall, consistent with published findings, low weight, high CSF CrAg titre and low CSF WBC counts at baseline were predictors for poor clinical outcome. In addition, we found that low Karnofsky performance status was predictive of poor outcome. Prompt management with appropriate antifungal therapy for this particular group of patients may improve the outcomes.