Empiric antibiotic regimens in adults with non-ventilator-associated hospital-acquired pneumonia: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The optimal empiric antibiotic regimen for non-ventilator-associated hospital-acquired pneumonia (HAP) is uncertain. OBJECTIVES: To compare the effectiveness and safety of alternative empiric antibiotic regimens in HAP using a network meta-analysis. DATA SOURCES: Medline, EMBASE, Cochrane CENTRAL, Web of Science, and CINAHL from database inception to July 06, 2023. STUDY ELIGIBILITY CRITERIA: RCTs. PARTICIPANTS: Adults with clinical suspicion of HAP. INTERVENTIONS: Any empiric antibiotic regimen vs. another, placebo, or no treatment. ASSESSMENT OF RISK OF BIAS: Paired reviewers independently assessed risk of bias using a modified Cochrane tool for assessing risk of bias in randomized trials. METHODS OF DATA SYNTHESIS: Paired reviewers independently extracted data on trial and patient characteristics, antibiotic regimens, and outcomes of interest. We conducted frequentist random-effects network meta-analyses for treatment failure and all-cause mortality and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Thirty-nine RCTs proved eligible. Thirty RCTs involving 4807 participants found low certainty evidence that piperacillin-tazobactam (RR compared to all cephalosporins: 0.65; 95% CI: 0.42, 1.01) and carbapenems (RR compared to all cephalosporins: 0.77; 95% CI: 0.53, 1.11) might be among the most effective in reducing treatment failure. The findings were robust to the secondary analysis comparing piperacillin-tazobactam vs. antipseudomonal cephalosporins or antipseudomonal carbapenems vs. antipseudomonal cephalosporins. Eleven RCTs involving 2531 participants found low certainty evidence that ceftazidime and linezolid combination may not be convincingly different from cephalosporin alone in reducing all-cause mortality. Evidence on other antibiotic regimens is very uncertain. Data on other patient-important outcomes including adverse events was sparse, and we did not perform network or pairwise meta-analysis. CONCLUSIONS: For empiric antibiotic therapy of adults with HAP, piperacillin-tazobactam might be among the most effective in reducing treatment failure. Empiric methicillin-resistant Staphylococcus aureus coverage may not exert additional benefit in reducing mortality. REGISTRATION: PROSPERO (CRD 42022297224).

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

MRI Assessment of Cerebral Blood Flow in Nonhospitalized Adults Who Self-Isolated Due to COVID-19.

BACKGROUND: Neurological symptoms associated with coronavirus disease 2019 (COVID-19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post-COVID-19 timeframe. PURPOSE: To determine whether adults who experienced flu-like symptoms due to COVID-19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu-like symptoms but tested negative for COVID-19. STUDY TYPE: Prospective observational. POPULATION: A total of 39 adults who previously self-isolated at home due to COVID-19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu-like symptoms but had a negative COVID-19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis). FIELD STRENGTH AND SEQUENCES: A 3.0 T; T1-weighted magnetization-prepared rapid gradient and echo-planar turbo gradient-spin echo arterial spin labeling sequences. ASSESSMENT: Arterial spin labeling was used to estimate CBF. A self-reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID-19 and control groups and between those with (n = 11) and without self-reported ongoing fatigue (n = 28) within the COVID-19 group. STATISTICAL TESTS: Between-group and within-group comparisons of CBF were performed in a voxel-wise manner, controlling for age and sex, at a family-wise error rate of 0.05. RESULTS: Relative to controls, the COVID-19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t-statistic = 5.21). Within the COVID-19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self-reported on-going fatigue. DATA CONCLUSION: These cross-sectional data revealed regional CBF decreases in the COVID-19 group, suggesting the relevance of brain physiology in the post-COVID-19 timeframe. This research may help elucidate the heterogeneous symptoms of the post-COVID-19 condition. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.

Associations of white matter hyperintensities with networks of gray matter blood flow and volume in midlife adults: A coronary artery risk development in young adults magnetic resonance imaging substudy.

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.