BACKGROUND: Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients with disseminated coccidioidomycosis (DCM) who lack alternative treatment options. OBJECTIVE: To evaluate olorofim effectiveness and adverse events in patients with DCM. DESIGN: Single-group, open-label, phase 2b study. (ClinicalTrials.gov: NCT03583164). SETTING: Ten U.S. sites. PARTICIPANTS: Forty-one patients with DCM and limited or no treatment options. Patients received olorofim alone or in combination with ongoing standard of care during an 84-day main treatment phase. Extended treatment was offered to patients. MEASUREMENTS: Mycoses Study Group-European Organization for Research and Treatment of Cancer (MSG-EORTC) criteria for global response based on subcategories of clinical, radiologic, and mycologic response were adjudicated by an independent data review committee (DRC) at days 42 and 84 (main treatment phase). Because the slow pace of serologic improvement in DCM limits global response to stable at best, this article focuses on patient clinical responses. Treatment-emergent adverse events (TEAEs) were compiled for both treatment phases. RESULTS: Forty-one patients with DCM were enrolled from May 2019 to August 2022. Thirty-nine (95.1%) did not have immunosuppression. Central nervous system disease was present in 30 (73.2%) patients, and 13 (43.3%) had a ventriculoperitoneal shunt with or without an Ommaya reservoir. Clinical success as adjudicated by the DRC occurred in 31 of 41 patients (75.6% [95% CI, 59.7% to 87.6%]) at day 42 and 30 of 41 patients (73.2% [CI, 57.1% to 85.8%]) at day 84. The main TEAE was hepatic biochemistry elevation in 9 of 41 patients (21.9%), which was managed by liver enzyme monitoring and dose reduction or pause in 8 patients (19.5%) and drug discontinuation in 1 patient (2.4%). LIMITATION: This was a single-group, open-label trial, but a randomized controlled trial would be preferable. CONCLUSION: Olorofim showed effectiveness in patients with DCM with limited or no therapeutic options. PRIMARY FUNDING SOURCE: F2G, Ltd.
Tuberculosis (TB) is the leading cause of infection-related mortality in the world, and cases in the United States are increasing. Prompt diagnosis, isolation, and treatment improve patient outcomes and reduce onward transmission. Screening of contacts and high-risk persons for asymptomatic TB infection and treatment of those testing positive reduces progression to disease. TB disease should be suspected in persons with compatible symptoms, risk factors, and consistent imaging. Microbiological confirmation requires an acid-fast smear, nucleic acid amplification test, and culture. Treatment, guided by drug sensitivity testing, requires multiple antibiotics given for 4 to 9 months and monitoring for drug toxicity and clinical response.
BACKGROUND:The 1959 World Health Organization (WHO) definition of anemia is widely used, but its relationship with mortality in the general adult population is uncertain. OBJECTIVE:To evaluate associations between baseline hemoglobin concentration and long-term mortality by age and sex. DESIGN:Prospective cohort study. SETTING:Population-based cohort in the United Kingdom. PARTICIPANTS:502 188 adults (median age, 58 years; 54.4% women) recruited from 2006 to 2010; hemoglobin concentration was measured in 477 876 (95.2%). Analyses were stratified by sex and age (<60 vs. ≥60 years). Median follow-up was 13.6 years. MEASUREMENTS:Hemoglobin concentration categorized relative to WHO sex-specific thresholds (men, <13.0 g/dL; women, <12.0 g/dL). Outcomes were all-cause, cardiovascular, and cancer mortality. RESULTS:All-cause mortality showed a U-shaped association with hemoglobin concentration, with lowest risk 1 to 3 g/dL above the WHO threshold. In the primary adjusted model, the 10-year standardized cumulative incidence (SCI) was 4.5% in the reference group versus 12.5% among participants more than 2 g/dL below the threshold (absolute risk difference [ARD], +8.1 percentage points; 95% CI, 6.7 to 9.4 percentage points); over the entire follow-up, the adjusted hazard ratio (HR) was 2.87 (CI, 2.54 to 3.25). Among those 0 to 1 g/dL above the threshold, the 10-year SCI was 5.3% (ARD, +0.8 percentage points; CI, 0.7 to 1.0 percentage points) and the adjusted HR was 1.18 (CI, 1.15 to 1.21). Associations were less consistent in women younger than 60 years. Patterns for cardiovascular and cancer mortality were similar at low and borderline concentrations but attenuated at higher concentrations. LIMITATION:Single baseline hemoglobin concentration measurement; predominantly White population. CONCLUSION:Mortality was lowest at hemoglobin concentrations 1 to 3 g/dL above current WHO thresholds, with higher mortality below and above this range. These hypothesis-generating findings should not define new thresholds but may inform clinical interpretation and evaluation of borderline hemoglobin concentration values. PRIMARY FUNDING SOURCE:None.
