Antibiotic De-Escalation Practices in the Intensive Care Unit: A Multicenter Observational Study.

BACKGROUND: There is little known about antibiotic de-escalation (ADE) practices in the intensive care unit (ICU). OBJECTIVE: The objective was to determine the proportion of patients who received ADE within 24 hours of actionable cultures and identify predictors of timely ADE. METHODS: Multicenter cohort study in ICUs of 15 hospitals in Australia and New Zealand. Adult patients were included if they were started on broad-spectrum antibiotics within 24 hours of ICU admission. The ADE was defined as switching from a broad-spectrum agent to a narrower-spectrum agent or antibiotic cessation. The primary outcome was ADE within 24 hours of an actionable culture, where ADE was possible. RESULTS: The 446 patients included in the study had a mean age of 63 ± 16 years, 60% were male, 32% were mechanically ventilated, and 19% were immunocompromised. Of these, 161 (36.1%) were not eligible for ADE and 37 (8.3%) for whom ADE within 24 hours of actionable culture could not be determined. In the remaining 248 patients, ADE occurred ≤24 hours in 60.5% (n = 150/248) after actionable cultures. In the multivariable logistic regression analysis, ADE was less likely to occur within 24 hours for patients with negative cultures (odds ratio [OR] = 0.48, 95% confidence interval [CI] = 0.25-0.92, P = 0.03). CONCLUSION AND RELEVANCE: Timely ADE may not occur in 40% of patients in the ICU and is less likely to occur in patients with negative cultures. Timely ADE can be improved, and patients with negative cultures should be targeted as part of antimicrobial stewardship efforts.

Pathways to ovarian cancer diagnosis: a qualitative study.

BACKGROUND: Ovarian cancer is often diagnosed at a late stage, when survival is poor. Qualitative narratives of patients' pathways to ovarian cancer diagnoses may identify opportunities for earlier cancer detection and, consequently, earlier stage at diagnosis. METHODS: We conducted semi-structured interviews of ovarian cancer patients and survivors (n = 14) and healthcare providers (n = 11) between 10/2019 and 10/2021. Interviews focused on the time leading up to an ovarian cancer diagnosis. Thematic analysis was conducted by two independent reviewers using a two-phase deductive and inductive coding approach. Deductive coding used a priori time intervals from the validated Model of Pathways to Treatment (MPT), including self-appraisal and management of symptoms, medical help-seeking, diagnosis, and pre-treatment. Inductive coding identified common themes within each stage of the MPT across patient and provider interviews. RESULTS: The median age at ovarian cancer diagnosis was 61.5 years (range, 29-78 years), and the majority of participants (11/14) were diagnosed with advanced-stage disease. The median time from first symptom to initiation of treatment was 2.8 months (range, 19 days to 4.7 years). The appraisal and help-seeking intervals contributed the greatest delays in time-to-diagnosis for ovarian cancer. Nonspecific symptoms, perceptions of health and aging, avoidant coping strategies, symptom embarrassment, and concerns about potential judgment from providers prolonged the appraisal and help-seeking intervals. Patients and providers also emphasized access to care, including financial access, as critical to a timely diagnosis. CONCLUSION: Interventions are urgently needed to reduce ovarian cancer morbidity and mortality. Population-level screening remains unlikely to improve ovarian cancer survival, but findings from our study suggest that developing interventions to improve self-appraisal of symptoms and reduce barriers to help-seeking could reduce time-to-diagnosis for ovarian cancer. Affordability of care and insurance may be particularly important for ovarian cancer patients diagnosed in the United States.

Emerging immune checkpoint inhibitors for the treatment of head and neck cancers.

Introduction: The benefits of immune checkpoint inhibitors (ICIs) in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have been demonstrated through multiple studies to improve overall survival (OS) with decreased side effects when compared to the standard of care (SOC) treatment regimens in place for decades, leading to the approval of two ICIs, nivolumab and pembrolizumab. There has been a subsequent influx in the development of novel immunotherapy agents for the treatment of HNSCC. Areas covered: Data for anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies in treatment of R/M HNSCC will be reviewed. Emerging immune checkpoint inhibitors as well as combined therapies in HNSCC will be discussed. The role of predictive biomarkers, HPV-status, PD-L1 expression, and challenges related to treating patients with ICIs will be summarized. Expert opinion: A shift toward ICIs as SOC for the treatment of R/M HNSCC will continue as emerging immune checkpoints and combination therapies are evaluated. Response rates are variable in this patient population underlying the importance of identifying predictive biomarkers to aid in patient selection for ICI treatment.

Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6.

Macrophage polarization plays a central role in both protective immunity and immunopathology. While the role of cytokines in driving macrophage polarization is well characterized, less is understood about the role of chemokines. The purpose of this study was to determine if CC chemokine 2 (CCL2/MCP1) could influence macrophage polarization in response to subsequent activation with cytokines and microbial products. Treatment of bone marrow-derived macrophages with CCL2 alone did not result in increased expression of either classical or alternatively-activated macrophage genes as compared to standard skewing cytokines or Toll-like receptor agonists. However, subsequent stimulation of CCL2 pre-treated macrophages with classical activation stimuli resulted in enhanced expression of genes associated with classical activation. This enhancement correlated with increased phosphorylation of ERK1/2 kinases, a decrease in expression of the ERK phosphatase Dusp6 and enhanced expression of miR-9. These results indicate that CCL2 supports the classical activation of macrophages, with miR-9 mediated down-regulation of Dusp6 and enhanced ERK-mediated signal transduction possibly mediating this enhanced pro-inflammatory gene expression.

Pathways to lung cancer diagnosis among individuals who did not receive lung cancer screening: a qualitative study.

BACKGROUND: Although early detection of lung cancer through screening is associated with better prognosis, most lung cancers are diagnosed among unscreened individuals. We therefore sought to characterize pathways to lung cancer diagnosis among unscreened individuals. METHODS: Participants were individuals with lung cancer who did not undergo asymptomatic lung cancer screening (n = 13) and healthcare providers who may be involved in the pathway to lung cancer diagnosis (n = 13). We conducted semi-structured interviews to identify themes in lung cancer patients' narratives of their cancer diagnoses and providers' personal and/or professional experiences of various pathways to lung cancer diagnoses, to identify delays in diagnosis. We audio-recorded, transcribed, and coded interviews in two stages. First, we conducted deductive coding using three time-period intervals from the Models of Pathways to Treatment framework: appraisal, help-seeking, and diagnostic (i.e., excluding pre-treatment). Second, we conducted inductive coding to identify themes within each time-period interval, and classified these themes as either barriers or facilitators to diagnosis. Coding and thematic summarization were completed independently by two separate analysts who discussed for consensus. RESULTS: Eight of the patient participants had formerly smoked, and five had never smoked. We identified eight barrier/facilitator themes within the three time-period intervals. Within the appraisal interval, the barrier theme was (1) minimization or misattribution of symptoms, and the facilitator theme was (2) acknowledgment of symptoms. Within the help-seeking interval, the barrier theme was (3) hesitancy to seek care, and the facilitator theme was (4) routine care. Within the diagnosis interval, barrier themes were (5) health system challenges, and (6) social determinants of health; and facilitator themes were (7) severe symptoms and known risk factors, and (8) self-advocacy. Many themes were interrelated, including minimization or misattribution of symptoms and hesitancy to seek care, which may collectively contribute to care and imaging delays. CONCLUSIONS: Interventions to reduce hesitancy to seek care may facilitate timely lung cancer diagnoses. More prompt referral to imaging-especially computed tomography (CT)-among symptomatic patients, along with patient self-advocacy for imaging, may reduce delays in diagnosis.