Meropenem PK/PD Variability and Renal Function: “We Go Together”

Background: Meropenem is a carbapenem antibiotic widely employed for serious bacterial infections. Therapeutic drug monitoring (TDM) is a strategy to optimize dosing, especially in critically ill patients. This study aims to show how TDM influences the management of meropenem in a real-life setting, not limited to intensive care units. Methods: From December 2021 to February 2022, we retrospectively analyzed 195 meropenem serum concentrations (Css). We characterized patients according to meropenem exposure, focusing on the renal function impact. Results: A total of 36% (n = 51) of the overall observed patients (n = 144) were in the therapeutic range (8–16 mg/L), whereas 64% (n = 93) required a meropenem dose modification (37 patients (26%) underexposed; 53 (38%) overexposed). We found a strong relationship between renal function and meropenem concentrations (correlation coefficient = −0.7; p-value < 0.001). We observed different dose-normalized meropenem exposure (Css/D) among renal-impaired (severe and moderate), normal, and hyperfiltrating patients, with a median (interquartile range) of 13.1 (10.9–20.2), 7.9 (6.1–9.5), 3.8 (2.6–6.0), and 2.4 (1.6–2.7), respectively (p-value < 0.001). Conclusions: Meropenem TDM in clinical practice allows modification of dosing in patients inadequately exposed to meropenem to maximize antibiotic efficacy and minimize the risk of antibiotic resistance, especially in renal alterations despite standard dose adaptations

Wave effect in gravitational lensing by a cosmic string

The wave effect in the gravitational lensing phenomenon by a straight cosmic string is investigated. The interference pattern is expressed in terms of a simple formula. We demonstrate that modulations of the interfered wave amplitude can be a unique signature of the wave effect. We briefly mention a possible chance of detecting the wave effect in future gravitational wave observatories.Comment: 4 pages, 1 figur

[Pathology of chronic obstructive pulmonary disease]

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lung characterized by poorly reversible airflow limitation. It is not a unique disease entity but rather a complex of conditions which include emphysema, chronic bronchitis and, sometimes, asthma. Moreover, COPD is a progressive disease often associated with exacerbations. Cigarette smoking, which is the most important risk factor for the development of COPD, induces pathological changes involving lung parenchyma, peripheral airways and central airways. Since lung parenchyma and peripheral airways are the sites responsible for airflow limitation and central airways are the main site of mucus hypersecretion, pathological changes in these compartments may be relevant in the development of COPD

Bronchoalveolar lavage in infants with recurrent lower respiratory symptoms

Background: Few data are available about the inflammatory cytokine profile of bronchoalveolar lavage (BAL) from young children with frequent wheeze. The first aim was to investigate the BAL cellular and cytokine profiles in infants with recurrent lower respiratory symptoms in whom bronchoscopy was indicated for clinical symptom evaluation. The second aim was to relate the BAL results with the histological findings of the endobronchial carina biopsies. Methods: Thirty-nine infants (median age 0.9 years) underwent lung function testing by whole-body plethysmography prior to the bronchoscopy. The BAL differential cell counts and cytokine levels were quantified. These findings were compared with the histological findings of the endobronchial carina biopsies. Results: The differential cytology reflected mainly that described for healthy infants with lymphocyte counts at the upper range level. A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement membrane was found. Detectable levels of pro-inflammatory cytokine proteins IL-1 beta, IL-17A, IL-18, IL-23, and IL-33 were found, whereas levels of Th2-type cytokine proteins were low. Frequent wheeze was the only clinical characteristic significantly related to detectable combined pro-inflammatory cytokine profile. Lung function did not correlate with any cytokine. Conclusions: A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement thickness was found. Detectable production of pro-inflammatory cytokines associated positively with frequent wheeze.Peer reviewe

Clinical impact of body mass index on palbociclib treatment outcomes and effect on exposure

The impact of body mass index (BMI) on treatment outcomes in patients with cancer is gaining increasing attention given the limited data available. The aim of this study was to investigate the contribution of BMI on the safety and efficacy profile of palbociclib in 134 patients with metastatic luminal-like breast cancer treated with palbociclib and endocrine therapy (ET). Normal-weight and underweight patients (BMI<25) were compared with overweight and obese (BMI≥25). Detailed clinical and demographic data were collected. Patients with a BMI<25 had a higher incidence of relevant-hematologic toxicities (p = 0.001), dose reduction events (p = 0.003), and tolerated lower dose intensities (p = 0.023) compared to patients with a BMI≥25. In addition, patients with a BMI<25 had significantly shorter progression-free survival (log-rank p = 0.0332). A significant difference was observed in the subgroup of patients for whom systemic palbociclib concentrations were available: patients with a BMI<25 had a 25% higher median minimum plasma concentrations (Cmin) compared to BMI≥25. This study provides compelling evidence for a clinically relevant contribution of BMI in discriminating a group of patients who experienced multiple toxicities that appeared to affect treatment adherence and lead to poorer survival. BMI could become a valuable tool for personalizing the starting dose of palbociclib to improve its safety and efficacy

α1-Antitrypsin Polymerizes in Alveolar Macrophages of Smokers With and Without α1-Antitrypsin Deficiency

BACKGROUND: The deficiency of α1-antitrypsin (AAT) is secondary to misfolding and polymerization of the abnormal Z-AAT in liver cells and is associated with lung emphysema. Alveolar macrophages (AM) produce AAT, however it is not known if Z-AAT can polymerize in AM, further decreasing lung AAT and promoting lung inflammation. AIMS: To investigate if AAT polymerizes in human AM and to study the possible relation between polymerization and degree of lung inflammation. METHODS: Immunohistochemical analysis with 2C1 monoclonal antibody specific for polymerized AAT was performed in sections of: 9 lungs from individuals with AAT deficiency (AATD) and severe COPD, 35 smokers with normal AAT levels of which 24 with severe COPD and 11 without COPD, and 13 non-smokers. AM positive for AAT polymers were counted and expressed as percentage of total AM in lung. RESULTS: AAT polymerization was detected in [27(4-67)%] of AM from individuals with AATD but also in AM from smokers with normal AAT with [24(0-70)%] and without [24(0-60)%] COPD, but not in AM from non-smokers [0(0-1.5)%] (p<0.0001). The percentage of AM with polymerized AAT correlated with pack-years smoked (r=0.53,p=0.0001), FEV1/FVC (r=-0.41,p=0.005), Small Airways Disease (r=0.44,p=0.004), number of CD8+T-cells and neutrophils in alveolar walls (r=0.51,p=0.002; r=0.31,p=0.05 respectively). CONCLUSIONS: Polymerization of AAT in alveolar macrophages occurs in lungs of individuals with AATD but also in smokers with normal AAT levels with or without COPD. Our findings highlight the similarities in the pathophysiology of COPD in individuals with and without AATD, adding a potentially important step to the mechanism of COPD