Bronchopulmonary disposition of IV cefepime/taniborbactam (2-0.5 g) administered over 2 h in healthy adult subjects.

INTRODUCTION: Taniborbactam (formerly VNRX-5133) is an investigational ß-lactamase inhibitor in clinical development in combination with cefepime for the treatment of MDR Gram-negative pathogens. OBJECTIVES: To assess the safety profile and pulmonary disposition of 2-0.5 g cefepime/taniborbactam administered as a 2 h IV infusion every 8 h following three doses in healthy adult subjects. METHODS: In this Phase 1 trial, open-label study, plasma samples were collected over the last dosing interval, and subjects (n = 20) were randomized to undergo bronchoalveolar lavage (BAL) at four timepoints after the last dose. Drug concentrations in plasma (total and free as determined by protein binding), BAL fluid and alveolar macrophages (AM) were determined by LC-MS/MS, and the urea correction method was used to calculate epithelial lining fluid (ELF) drug concentrations. Pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: Mean (±SD) taniborbactam Cmax and AUC0-8 in plasma were 24.1 ±â€Š4.1 mg/L and 81.9 ±â€Š13.9 mg·h/L, respectively. Corresponding values for cefepime were 118.4 ±â€Š29.7 mg/L and 346.7 ±â€Š71.3 mg·h/L. Protein binding was 0% for taniborbactam and 22.4% for cefepime. Mean taniborbactam concentrations (mg/L) at 2, 4, 6 and 8 h were 3.9, 1.9, 1.0 and 0.3 in ELF and 12.4, 11.5, 14.3 and 14.9 in AM, with corresponding AUC0-8 ELF of 13.8 and AUC0-8 AM of 106.0 mg·h/L. Cefepime AUC0-8 ELF was 77.9 mg·h/L. No serious adverse events were observed. CONCLUSION: The observed bronchopulmonary exposures of taniborbactam and cefepime can be employed to design optimal dosing regimens for clinical trials in patients with pneumonia.

Portopulmonary hypertension: challenges in diagnosis and management.

Portopulmonary hypertension is defined as the combination of pulmonary arterial hypertension with portal hypertension and presents management complications in patients awaiting liver transplantation. The combination of these vascular disorders has a marked impact on mortality. At present the recommendations for management are limited because of the paucity of definitive clinical trials. We have reviewed the available data on prevalence, diagnosis and treatment. It is clearly time to more formally approach the study of this patient population.

An evaluation of a short chest radiograph learning intervention to evaluate internal medicine residents' ability to identify basic pathologic abnormalities and normal anatomy.

BACKGROUND: The correct interpretation of chest radiographs is an essential skill for internal medicine residents. Little formal training in radiology occurs in the graduate medical curriculum for internal medicine residents. OBJECTIVE: To assess the performance of internal medicine residents in the interpretation of chest radiographs through a 1.5-hour didactic and practical session. DESIGN: Baseline performance was assessed in the first week of a four-week rotation. An intervention was performed in the second week. Post-intervention assessment was performed in the fourth week. SETTING: A university-based internal medicine residency. PARTICIPANTS: Internal medicine residents at all levels of training. INTERVENTION: A 1.5-hour review session addressing: technique, anatomy, pathophysiology and disease pattern recognition through small group didactics. MEASUREMENTS: 38 multiple choice question assessment tool designed to assess comprehension of fundamental knowledge of chest radiograph interpretation. RESULTS: At baseline, residents were able to answer 64% of questions correctly. After the intervention, 77% of questions were answered correctly, an improvement of 13 percentage points (95% CI = 8.4 percentage points to 16.3 percentage points; P = 0.0001). No significant differences in performance were demonstrated between PGY1 and upper level residents (PGY2 and PGY3) at baseline (P = 0.11), however senior residents (PGY2 and 3) were found to perform significantly better than interns after the intervention (P = 0.002). CONCLUSIONS: Internal medicine residents perform poorly at baseline in the assessment of chest films. Interventions designed to address core competencies in chest radiograph interpretation can be efficacious in improving residents' interpretive skills. The incorporation of formal education in chest radiograph diagnostic skills into graduate medical education may be of significant benefit to internal medicine residency training.

Cerebral edema during treatment of diabetic ketoacidosis in an adult with new onset diabetes.

INTRODUCTION: Diabetic ketoacidosis (DKA) continues to be a medical emergency, in part because of a rare and devastating complication associated with its treatment, cerebral edema. In children, cerebral edema is the principal cause of mortality, but clinically significant cerebral edema in adults is rare. METHODS AND RESULTS: We report the case of a 27-year-old male (not previously known to be diabetic) who presented with a first episode of DKA complicated by the development of fatal cerebral edema despite medical treatment. CONCLUSION: The pathophysiological mechanisms for cerebral edema associated with DKA occurring in children and adults are believed to be similar and are discussed in this report. However, patients who develop cerebral edema may deteriorate rapidly, and experience with successful treatment has been limited.

Transcriptional repression of peri-implantation EMX2 expression in mammalian reproduction by HOXA10.

HOXA10 is necessary for mammalian reproduction; however, its transcriptional targets are not completely defined. EMX2, a divergent homeobox gene, is necessary for urogenital tract development. In these studies we identify and characterize the regulation of EMX2 by HOXA10. By using Northern analysis and in situ hybridization, we found that EMX2 is expressed in the adult urogenital tract in an inverse temporal pattern from HOXA10, suggestive of a negative regulatory relationship. Constitutive expression of HOXA10 diminished EMX2 mRNA, whereas blocking HOXA10 through the use of antisense resulted in high EMX2 mRNA expression. Deletional analysis of the EMX2 5' regulatory region revealed that a 150-bp element mediated transcriptional repression when cotransfected with pcDNA3.1/HOXA10 in transient-transfection assays. Binding of HOXA10 protein to this element was demonstrated by electrophoretic mobility shift assay and further localized to a consensus HOXA10 binding site within this element by DNase I footprinting. Site-directed mutagenesis abolished binding, as well as the negative transcriptional regulation. Transcriptional activation of empty spiracles, the Drosophila ortholog of EMX2, by Abdominal-B (HOXA10 ortholog) has been previously demonstrated. These findings demonstrate conservation of the transcription factor-target gene relationship, although the direction of regulation is reversed with possible evolutionary implications.

Direct regulation of beta3-integrin subunit gene expression by HOXA10 in endometrial cells.

Estrogen and progesterone regulate HOXA10 expression in the endometrium, where HOXA10 is necessary for implantation. The integrins are also involved in early embryo-endometrial interactions. Here we show that HOXA10 directly regulates beta3-integrin subunit expression in the endometrium, likely mediating the effect of sex steroids on beta3-integrin expression. beta3-Integrin expression was decreased in endometrium shown to have low HOXA10 expression. beta3-Integrin mRNA levels were increased in endometrial adenocarcinoma cells (Ishikawa) transfected with pcDNA3.1/HOXA10, and decreased in cells treated with HOXA10 antisense. Seven consensus HOXA10 binding sites were identified 5' of the beta3-integrin gene. Direct binding of HOXA10 protein to four sites was demonstrated by EMSA. Reporter gene expression increased in BT-20 cells cotransfected with pcDNA3.1/ HOXA10 and pGL3-promoter vector containing region F (encompassing all seven HOXA10 consensus sites). A 41-bp segment (Region A) showed highest affinity binding to HOXA10 protein. Increased reporter expression, equal in magnitude to that obtained with Region F, was obtained with Region A. HOXA10 protein binding within Region A was localized by deoxyribonuclease I footprinting. beta3-Integrin expression was directly up-regulated by HOXA10 through a 41-bp 5'-regulatory element. Sex steroids regulate the expression of endometrial beta3-integrin through a pathway involving HOXA10.