Comparing practices to prevent infectious diseases transmission among Veterans Affairs and Nonveterans Affairs hospitals: Results from a national survey in the United States.

Our national cross-sectional survey of United States hospitals found greater implementation of contact precautions for multidrug-resistant organisms and a higher percentage reporting the use of supplemental no-touch disinfection devices among Veterans Affairs (VA) versus non-VA hospitals. Nationally coordinated infection prevention initiatives within the VA could account for these practice differences.

RSV Infection in Older Adults.

This JAMA Patient Page describes respiratory syncytial virus (RSV) and its symptoms, risk factors, and preventive measures.

Impact of Metagenomic Next-Generation Sequencing of Plasma Cell-free DNA Testing in the Management of Patients With Suspected Infectious Diseases.

Metagenomic next-generation sequencing (mNGS) of cell-free DNA is an emerging modality for the diagnosis of infectious diseases, but studies on its clinical utility are limited. We conducted a retrospective single-center study including all patients who had plasma mNGS sent at the University of Michigan between 1 January 2021 and 25 July 2022. Test results were assessed for clinical impact. A total of 71 tests were sent on 69 patients; the mean ± SD age was 52 ± 19 years; and 35% of patients were immunocompromised. Forty-five (63%) mNGS test results were positive and 14 (31%) had clinical impact-from starting new antimicrobials (n = 7), discontinuing antimicrobials (n = 4), or changing antimicrobial duration (n = 2) or by affecting surgical decision making (n = 1). Twenty-six (37%) mNGS test results were negative and only 4 (15%) were impactful, leading to discontinuation of antimicrobials. Overall, just 25% of mNGS tests were clinically relevant. There was no significant difference in the proportion of tests that were clinically relevant between negative and positive results (P = .16) or if patients were immunocompromised (P = .57). Plasma mNGS was most frequently impactful (in 50% of patients) when included in the diagnostic workup of cardiovascular infection but less impactful in other clinical syndromes, including fever of unknown origin and pulmonary infection. Our findings underscore the need to further study this testing modality, particularly with prospective research including negative controls, before it is considered for widespread use.

What US hospitals are doing to prevent common device-associated infections during the coronavirus disease 2019 (COVID-19) pandemic: Results from a national survey in the United States.

OBJECTIVE: The ways that device-associated infection prevention practices changed during the coronavirus disease 2019 (COVID-19) pandemic remain unknown. We collected data mid-pandemic to assess the use of several infection prevention practices and for comparison with historical data. DESIGN: Repeated cross-sectional survey. SETTING: US acute-care hospitals. PARTICIPANTS: Infection preventionists. METHODS: We surveyed infection preventionists from a national random sample of 881 US acute-care hospitals in 2021 to estimate the current use of practices to prevent catheter-associated urinary tract infection (CAUTI), central line-associated bloodstream infection (CLABSI), and ventilator-associated events (VAE). We compared the 2021 results with those from surveys occurring every 4 years since 2005. RESULTS: The 2021 survey response rate was 47%; previous survey response rates ranged from 59% to 72%. Regular use of most practices to prevent CLABSI (chlorhexidine gluconate for site antisepsis, 99.0%, and maximum sterile barrier precautions, 98.7%) and VAE (semirecumbent positioning, 93.4%, and sedation vacation, 85.8%) continued to increase or plateaued in 2021. Conversely, use of several CAUTI prevention practices (portable bladder ultrasound scanner, 65.6%; catheter reminders or nurse-initiated discontinuation, 66.3%; and intermittent catheterization, 37.3%) was lower in 2021, with a significant decrease for some practices compared to 2017 (P ≤ .02 for all comparisons). In 2021, 42.1% of hospitals reported regular use of the newer external urinary collection devices for women. CONCLUSIONS: Although regular use of CLABSI and VAE preventive practices continued to increase (or plateaued), use of several CAUTI preventive practices decreased during the COVID-19 pandemic. Structural issues relating to care during the pandemic may have contributed to a decrease in device-associated infection prevention practices.

Blastomycosis: A Review of Mycological and Clinical Aspects.

Blastomycosis is caused by a thermally dimorphic fungus that thrives in moist acidic soil. Blastomyces dermatitidis is the species responsible for most infections in North America and is especially common in areas around the Great Lakes, the St. Lawrence Seaway, and in several south-central and southeastern United States. Other Blastomyces species have more recently been discovered to cause disease in distinct geographic regions around the world. Infection almost always occurs following inhalation of conidia produced in the mold phase. Acute pulmonary infection ranges from asymptomatic to typical community-acquired pneumonia; more chronic forms of pulmonary infection can present as mass-like lesions or cavitary pneumonia. Infrequently, pulmonary infection can progress to acute respiratory distress syndrome that is associated with a high mortality rate. After initial pulmonary infection, hematogenous dissemination of the yeast form of Blastomyces is common. Most often this is manifested by cutaneous lesions, but osteoarticular, genitourinary, and central nervous system (CNS) involvement also occurs. The diagnosis of blastomycosis can be made by growth of the mold phase of Blastomyces spp. in culture or by histopathological identification of the distinctive features of the yeast form in tissues. Detection of cell wall antigens of Blastomyces in urine or serum provides a rapid method for a probable diagnosis of blastomycosis, but cross-reactivity with other endemic mycoses commonly occurs. Treatment of severe pulmonary or disseminated blastomycosis and CNS blastomycosis initially is with a lipid formulation of amphotericin B. After improvement, therapy can be changed to an oral azole, almost always itraconazole. With mild to moderate pulmonary or disseminated blastomycosis, oral itraconazole treatment is recommended.

SARS-CoV-2 Anti-Spike IgG Antibody and ACE2 Receptor Binding Inhibition Levels among Breakthrough Stage Veteran Patients.

SARS-CoV-2 mRNA vaccines have been critical to curbing pandemic COVID-19; however, a major shortcoming has been the inability to assess levels of protection after vaccination. This study assessed serologic status of breakthrough infections in vaccinated patients at a Veterans Administration medical center from June through December 2021 during a SARS-CoV-2 delta variant wave. Breakthrough occurred mostly beyond 150 days after two-dose vaccination with a mean of 239 days. Anti-SARS-CoV-2 spike (S) IgG levels were low at 0 to 2 days postsymptoms but increased in subjects presenting thereafter. Population measurements of anti-S IgG and angiotensin converting enzyme-2 receptor (ACE2-R) binding inhibition among uninfected, vaccinated patients suggested immune decay occurred after 150 days with 62% having anti-S IgG levels at or below 1,000 AU comparable with breakthrough patients at 0 to 2 days postsymptom onset. In contrast, vaccination after resolved infection conferred robust enduring anti-S IgG levels (5,000 to >50,000 AU) with >90% ACE2-R binding inhibition. However, monoclonal antibody (MAb)-treated patients did not benefit from their prior infection suggesting impaired establishment of B cell memory. Analysis of boosted patients confirmed the benefit of a third vaccine dose with most having anti-S IgG levels above 5,000 AU with >90% ACE2-R binding inhibition, but a subset had levels <5,000 AU. Anti-S IgG levels >5,000 AU were associated with >90% ACE2-R binding inhibition and no documented breakthrough infections, whereas levels falling below 5,000 AU and approaching 1,000 AU were associated with breakthrough infections. Thus, quantitative antibody measurements may provide a means to guide vaccination intervals for the individual. IMPORTANCE Currently, clinicians have no guidance for the serologic assessment of SARS-Cov-2 postvaccination status regarding protection and risk of infection. Vaccination and boosters are administered blindly without evaluation of need or outcome at the individual level. The recent development of automated quantitative assays for anti-SARS-CoV-2 spike protein IgG antibodies permits accurate measurement of humoral immunity in standardized units. Clinical studies, such as reported here, will help establish protective antibody levels allowing identification and targeted management of poor vaccine responders and vaccinated subjects undergoing immune decay.

Infectious complications after second allogeneic hematopoietic cell transplant in adult patients with hematological malignancies.

We conducted a retrospective review of the infectious complications and outcomes over a 2-year follow-up period of adult patients who received a second allogeneic hematopoietic cell transplant (2nd allo-HCT) during a five-year period at two cancer centers in Michigan. Sixty patients, of whom 44 (73%) had acute leukemia or myelodysplastic syndrome, were studied. The majority (n = 37,62%) received a 2nd allo-HCT because of relapsed leukemia. Infection episodes after the 2nd allo-HCT totaled 112. Bacteria were identified in 76 episodes, the majority of which occurred pre-engraftment. The most common infecting organisms were Enterococcus species and Clostridioides difficile. Viral infections, predominantly cytomegalovirus, accounted for 59 infection episodes and occurred mostly in pre-engraftment and early post-engraftment periods. There were 16 proven/probable fungal infections, of which 9 were invasive aspergillosis or candidiasis. Mortality was 45% (n = 27) at one year and 65% (n = 39) at 2 years after transplant, and 16 deaths (41%) were due to infection. Of those 16 infection deaths, 8 were bacterial, 4 fungal, 2 both bacterial and fungal, and 2 viral. Failure to engraft neutrophils or platelets was significantly associated with decreased survival, p < 0.0001 and p < 0.001, respectively. Infections are common after a 2nd allo-HCT and are associated with a high mortality rate.

Invasive Fungal Disease in Patients with Newly Diagnosed Acute Myeloid Leukemia.

This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014-2019. Patients had primary AML (n = 148, 59%); antecedent myelodysplastic syndrome (n = 76, 30%), or secondary AML (n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis (n = 6), fusariosis (n = 3), and mucomycosis (n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018-1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585-22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients.

BACKGROUND: Few options are available for cytomegalovirus (CMV) treatment in transplant recipients resistant, refractory, or intolerant to approved agents. Letermovir (LET) is approved for prophylaxis in hematopoietic cell transplant (HCT) recipients, but little is known about efficacy in CMV infection. We conducted an observational study to determine the patterns of use and outcome of LET treatment of CMV infection in transplant recipients. METHODS: Patients who received LET for treatment of CMV infection were identified at 13 transplant centers. Demographic and outcome data were collected. RESULTS: Twenty-seven solid organ and 21 HCT recipients (one dual) from 13 medical centers were included. Forty-five of 47 (94%) were treated with other agents prior to LET, and 57% had a history of prior CMV disease. Seventy-seven percent were intolerant to other antivirals; 32% were started on LET because of resistance concerns. Among 37 patients with viral load < 1000 international units (IU)/ml at LET initiation, two experienced >1 log rise in viral load by week 12, and no deaths were attributed to CMV. Ten patients had viral load > 1000 IU/ml at LET initiation, and six of 10 (60%) had a CMV viral load < 1000 IU/ml at completion of therapy or last known value. LET was discontinued in two patients for an adverse event. CONCLUSIONS: Patients treated with LET with viral load < 1000 IU/ml had good virologic outcomes. Outcomes were mixed when LET was initiated at higher viral loads. Further studies on combination therapy or alternative LET dosing are needed.

COVID-19-Associated Pulmonary Aspergillosis at an Academic Medical Center in the Midwestern United States.

Pulmonary aspergillosis has been reported at high rates in patients with coronavirus disease 2019 (COVID-19) and is associated with high morbidity and mortality. We retrospectively assessed all patients admitted to an intensive care unit during the early COVID-19 surge (3/17/20-5/10/20) at our medical center in the midwestern USA for the presence of COVID-19-associated pulmonary aspergillosis (CAPA). Patients were not routinely screened for CAPA; diagnostic work-up for fungal infections was pursued when clinically indicated. Among 256 patients admitted to the ICU with severe COVID-19, 188 (73%) were intubated and 62 (24%) ultimately expired within 30 days of admission to the ICU. Only three patients (1%) were found to have CAPA; diagnosis was made by tracheal aspirate cultures in two cases and by bronchoalveolar lavage fluid Aspergillus galactomannan in one case. None of the patients who developed CAPA had classic risk factors for invasive fungal infection. The occurrence of CAPA was much lower than that reported at other centers, likely reflecting the local epidemiology.

Evaluation of targeted versus universal prophylaxis for the prevention of invasive fungal infections following lung transplantation.

BACKGROUND: Antifungal prophylaxis to prevent invasive fungal infections (IFI) is widely used following lung transplantation, but the optimal strategy remains unclear. We compared universal with targeted antifungal prophylaxis for effectiveness in preventing IFI. METHODS: Adult patients who underwent lung transplantation at the University of Michigan from /1 July 2014-31 December 2017 were studied for 18 months post-transplant. Universal prophylaxis consisted of itraconazole with or without inhaled liposomal amphotericin B. Using specific criteria, targeted prophylaxis was given with voriconazole for patients at risk for invasive pulmonary aspergillosis (IPA) and with fluconazole or micafungin for patients at risk for invasive candidiasis. Risk factors, occurrence of proven/probable IFI, and mortality were analyzed for the two prophylaxis cohorts. RESULTS: Of 105 lung transplant recipients, 84 (80%) received a double lung transplant, and 38 (36%) of patients underwent transplant for pulmonary fibrosis. Fifty-nine (56%) patients received universal antifungal prophylaxis, and 46 (44%), targeted antifungal prophylaxis. Among 20 proven/probable IFI, there were 14 IPA, 4 invasive candidiasis, 1 cryptococcosis, and 1 deep sternal mold infection. Six (10%) IFI occurred in the universal prophylaxis cohort and 14 (30%) in the targeted prophylaxis cohort. Five of 6 (83%) IFI in the universal prophylaxis cohort, compared with 9/14 (64%) in the targeted prophylaxis cohort, were IPA Candida infections occurred only in the targeted prophylaxis cohort. The development of IFI was more likely in the targeted prophylaxis cohort than the universal prophylaxis cohort, HR = 4.32 (1.51-12.38), P = .0064. CONCLUSIONS: Universal antifungal prophylaxis appears to be more effective than targeted antifungal prophylaxis for prevention of IFI after lung transplant.

Performance of Aspergillus Galactomannan Lateral Flow Assay on Bronchoalveolar Lavage Fluid for the Diagnosis of Invasive Pulmonary Aspergillosis.

Background: Several newly developed biomarker tests for invasive pulmonary aspergillosis (IPA) have been developed, including the IMMY Aspergillus galactomannan lateral flow assay (Aspergillus GM-LFA) evaluated in this study. Methods: Twenty patients with proven/probable IPA (EORTC/MSGERC criteria) were matched by age and underlying disease with 20 patients without IPA. Bronchoalveolar lavage fluid (BALF) was analyzed in duplicate using the Aspergillus GM-LFA. Results were read visually by two blinded observers, and the optical density index (ODI) was obtained digitally with a cube reader. Results: Using a cutoff of ≥0.5 ODI, the Aspergillus GM-LFA had a sensitivity of 40%, specificity of 80%, positive predictive value (PPV) of 67% and negative predictive value (NPV) of 57%. When the cutoff was increased to ≥1.0 ODI, sensitivity remained at 40%, specificity rose to 95%, PPV was 89%, and NPV was 61%. Excellent agreement was found when duplicate samples were read either visually (κ = 1) or with the cube reader (κ = 0.89). Correlation of results obtained by visual inspection and those obtained using the cube reader was excellent (κ = 0.82). Conclusion: The Aspergillus GM-LFA had poor sensitivity but excellent specificity for proven/probable IPA in BALF. The assay was easy to interpret, and there was high concordance between results obtained visually and with a cube reader.

Diagnostic Performance of Bronchoalveolar Lavage (1,3)-ß-d-Glucan Assay for Pneumocystis jirovecii Pneumonia.

We evaluated the performance of the (1,3)-ß-d-glucan (BDG) assay on bronchoalveolar lavage fluid (BALF) as a possible aid to the diagnosis of Pneumocystis jirovecii pneumonia. BALF samples from 18 patients with well-characterized proven, probable, and possible Pneumocystis pneumonia and 18 well-matched controls were tested. We found that the best test performance was observed with a cut-off value of 128 pg/mL; receiver operating characteristic/area under the curve (ROC/AUC) was 0.70 (95% CI 0.52-0.87). Sensitivity and specificity were 78% and 56%, respectively; positive predictive value was 64%, and negative predictive value was 71%. The low specificity that we noted limits the utility of BALF BDG as a diagnostic tool for Pneumocystis pneumonia.

Performance of the (1,3)-Beta-D-Glucan Assay on Bronchoalveolar Lavage Fluid for the Diagnosis of Invasive Pulmonary Aspergillosis.

Detection of (1,3)-beta-D-glucan (BDG), a component of the cell wall of many fungi, was studied in bronchoalveolar lavage fluid (BALF) as a possible aid for the diagnosis of proven/probable invasive pulmonary aspergillosis (IPA). BDG was measured on stored BALF from 13 patients with EORTC/MSGERC defined proven/probable IPA and 26 matched control patients without IPA. The median BALF BDG was 80 pg/mL (range < 45-8240 pg/mL) in the IPA cohort and 148 pg/mL (range < 45-5460 pg/mL) in the non-IPA cohort. Using a positive cutoff of ≥ 80 pg/mL, sensitivity was 54% and specificity was 38%. Higher cutoff values led to improvement in specificity but a dramatic decrease in sensitivity. ROC/AUC analysis was unable to identify an optimal cutoff value at which test performance was enhanced: AUC 0.43, 95% CI 0.24-0.63. When the BDG assay was performed on BALF, neither sensitivity nor specificity was sufficient for use in the diagnosis of IPA.

Breakthrough Invasive Fungal Infections in Patients with Acute Myeloid Leukemia.

OBJECTIVES: We sought to determine the occurrence, risk factors, effect of antifungal prophylaxis, and outcomes of invasive fungal infections (IFIs) in patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: We performed a retrospective analysis of all adult patients admitted to the University of Michigan Health System for AML over a 3-year period from 2010 to 2013. We determined comorbidities, hematopoietic cell transplant (HCT) status, antifungal prophylaxis, proven and probable IFI, and outcomes at 12 weeks after initiation of appropriate antifungal therapy. RESULTS: Of 333 patients in our cohort, 116 of whom had received a HCT, 98 (29%) developed an IFI. Of the 30 (9%) patients who had a proven or probable IFI, 18 had breakthrough infection while on micafungin (n = 5), voriconazole (n = 4), posaconazole (n = 5), or fluconazole (n = 4). Breakthrough IFIs were due to Aspergillus species (n = 11), other molds (n = 4), and Candida species (n = 3). Factors associated with breakthrough IFI were prolonged severe neutropenia (p = .05) and having received tacrolimus (p = .04). Antifungal therapy was successful in 7 of the 18 (39%) patients with breakthrough IFI and 8 of the 12 (67%) patients with non-breakthrough IFI, p = .13. Mortality at 12 weeks was 27%, 5 with breakthrough IFI and 3 with non-breakthrough IFI and was associated with prolonged severe neutropenia, p = .04. CONCLUSIONS: Patients with AML remain at risk for IFI despite the use of several different antifungal agents for prophylaxis. Mortality remains high in patients with AML who develop IFI.

Current and New Perspectives in the Diagnosis of Blastomycosis and Histoplasmosis.

The diagnosis of blastomycosis and histoplasmosis can be difficult for clinicians who rarely see infections caused by these environmentally restricted dimorphic fungi. Historically, the diagnosis of blastomycosis has been established by culture and sometimes by histopathologic identification. Currently, antigen detection in urine and serum has been shown to aid in the rapid diagnosis of blastomycosis, and newer antibody assays are likely to contribute to our diagnostic capability in the near future. The gold standard for the diagnosis of histoplasmosis has been culture of the organism from involved tissues, aided in some patients by histopathological verification of the typical yeast forms in tissues. Antigen detection has contributed greatly to the ability of clinicians to rapidly establish the diagnosis of histoplasmosis, especially in severely ill and immunocompromised patients, and antibody testing for Histoplasma capsulatum provides important adjunctive diagnostic capability for several forms of both acute and chronic histoplasmosis. For both of these endemic mycoses, novel molecular tests are under active investigation, but remain available in only a few reference laboratories. In this review, we provide a synopsis of diagnostic test options that aid in establishing whether a patient has blastomycosis or histoplasmosis.

Clinical application of Aspergillus lateral flow device in bronchoalveolar lavage fluid of patients with classic risk factors for invasive pulmonary aspergillosis.

BACKGROUND: The diagnosis of invasive pulmonary aspergillosis (IPA) remains challenging. We evaluated the performance characteristics of a newly formatted Aspergillus lateral flow test, AspLFD, in bronchoalveolar lavage (BAL) fluid from patients with classic risk factors for IPA. METHODS: Prospectively banked BAL samples from 14 patients with proven or probable IPA defined by EORTC/MSG criteria and 28 BAL samples from age-matched high-risk patients without IPA were tested with AspLFD according to manufacturer's directions. Results were read by two independent observers, and test performance was calculated. RESULTS: Age, gender and underlying risk factors, except for neutropenia and haematological malignancy, were similar between IPA cases and controls. Seven patients (50%) in the IPA group received a mould-active agent within 5 days prior to bronchoscopy compared with only three patients (11%) in the control group, P = .004. Of 14 patients with proven/probable IPA, AspLFD was positive in 3 and negative in 9; two tests yielded invalid results. All 28 control patients had a negative AspLFD test. AspLFD showed low sensitivity (25%, 95% CI: 5.5% to 57.2%), but high specificity (100%. (95% CI: 87.7% to 100%). CONCLUSIONS: A positive AspLFD test in BAL fluid of patients with classic risk factors for IPA could be useful to support the diagnosis of proven/probable IPA because of its high specificity. However, as a stand-alone test for IPA, the use of AspLFD is limited by low sensitivity.

Treatment Failure of Isavuconazole in a Patient with Cryptococcosis.

Isavuconazole is a broad-spectrum azole that is FDA-approved for the treatment of aspergillosis and mucormycosis; data on the use of isavuconazole for the treatment and prevention of other invasive fungal infections are limited. Here, we report a patient with pulmonary cryptococcosis treated with isavuconazole who experienced progression to disseminated infection with Cryptococcus while on isavuconazole. Caution is advised when using isavuconazole in situations where there is a paucity of data to recommend its use.

Infectious Complications After Umbilical Cord Blood Transplantation for Hematological Malignancy.

BACKGROUND: Umbilical cord blood transplant (UCBT) is used for patients who do not have a matched donor, but engraftment often takes longer than with a standard allogeneic transplant, likely increasing the risk for infection. We characterized specific infections and outcomes in adults undergoing UCBT at our 2 centers. METHODS: All adults who underwent UCBT between January 1, 2006 and December 31, 2015 were included. Infectious episodes from 6 months before to 2 years after UCBT were reviewed. RESULTS: Fifty-seven patients underwent UCBT; 47 had neutrophil engraftment. A total of 179 infectious episodes occurred in 55 patients, 73 (41%) within 30 days post-UCBT. Viruses caused 85 (47%) infections. Cytomegalovirus caused 32 infectious episodes and was most common from day 30 to 100. Human herpesvirus 6 occurred in 28 episodes, was most common within 30 days, and caused 1 death. Bacteria were responsible for 82 (46%) infections, most commonly bacteremias due to Staphylococcus spp, Enterococcus spp, and Enterobacteriaceae. Of 11 invasive fungal infections, 9 were aspergillosis, 4 of which were fatal. Overall mortality was 56% in the first year. Thirteen deaths were from infection; 11 occurred in the first 100 days and 7 in the first 30 days post-UCBT. Of 10 patients who never engrafted, 9 died, 6 from infection, within 100 days post-UCBT. CONCLUSIONS: Infectious complications were common after UCBT, especially in the first 30 days. Deaths from viral infections were fewer than expected. Delayed engraftment and nonengraftment continue to convey increased risk for fatal bacterial and fungal infections post-UCBT.