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.

Malignant Cerebral Ischemia in A COVID-19 Infected Patient: Case Review and Histopathological Findings.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is responsible for an unprecedented worldwide pandemic that has severely impacted the United States. As the pandemic continues, a growing body of evidence suggests that infected patients may develop significant coagulopathy with resultant thromboembolic complications including deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke. However, this data is limited and comes from recent small case series and observational studies on stroke types, mechanisms, and outcomes.1-14 Furthermore, evidence on the role of therapeutic anticoagulation in SARS-CoV-2 infected patients with elevated inflammatory markers, such as D-dimer, is also limited. We report the case of a middle-aged patient who presented with a large vessel ischemic stroke likely resulting from an underlying inflammatory response in the setting of known novel coronavirus infection (COVID-19). Histopathologic analysis of the patient's ischemic brain tissue revealed hypoxic neurons, significant edema from the underlying ischemic insult, fibrin thrombi in small vessels, and fibroid necrosis of the vascular wall without any signs of vasculature inflammation. Brain biopsy was negative for the presence of SARS-CoV-2 RNA (RT-PCR assay). Along with a growing body of literature, our case suggests that cerebrovascular thromboembolic events in COVID-19 infection may be related to acquired hypercoagulability and coagulation cascade activation due to the release of inflammatory markers and cytokines, rather than virus-induced vasculitis. Further studies to investigate the mechanism of cerebrovascular thromboembolic events and their prevention is warranted.

The enigma of fine mobile structures on the aortic surface in a patient undergoing transcatheter aortic valve replacement: a case report.

Background: The surface of the aorta generally does not show motion unless mobile atheroma, thrombi, vegetations, or intimal flaps are present. We previously described unusual mobile filamentous structures in the carotid artery. Here, we describe similar findings in the aorta and their possible cause. Case summary: An 88-year-old female with progressive exertional dyspnoea and severe aortic stenosis had a successful transcatheter aortic valve replacement (TAVR). A filamentous structure was noted on the focused pre-operative 2D transoesophageal echocardiography in the proximal descending aorta and post-TAVR as long strand-like structures attached to the thickened intimal wall with a planar component on 3D imaging. These findings were not associated with symptoms or clinical sequelae on short- and long-term follow-up. Discussion: The mobile structures that we describe are atypical for atheroma, thrombi, vegetations, and dissections in terms of their form and clinical presentation. 2D imaging showed that the filaments had focal thickening and emerged from the aortic surface. These findings suggest a relationship with the intima, perhaps from atherogenesis or injury with disruption or lifting of the intimal surface. No clinical sequelae were detected that may also relate to their position in the descending aorta and not the arch.

Modern Treatment of Pulmonary Embolism (USCDT vs MT): Results From a Real-World, Big Data Analysis (REAL-PE).

Background: Advanced therapies are increasingly utilized to treat pulmonary embolism (PE). A unique data platform allows access to electronic health record data for comparison of the safety of PE therapies. Methods: All data from Truveta (Truveta, Inc) were analyzed (16 systems, 83,612,413 patients, 535,567 with PE). All patients treated with ultrasound-assisted catheter-directed thrombolysis (USCDT) (Boston Scientific) or mechanical thrombectomy (MT) (Inari Medical) for PE were identified. The primary analysis was based on index procedures performed from January 2009 to May 2023, and contemporary analysis on those performed from January 2018 to May 2023. Bleeding was assessed via direct laboratory analysis and transfusion administration documentation. International Society for Thrombosis and Hemostasis (ISTH) and Bleeding Academic Research Consortium (BARC) 3b definitions were recreated. Multiple logistic regression analysis of major bleeding was performed. In-hospital death and median length of stay were measured. Results: For the primary analysis, 2259 patients (N = 1577 USCDT, N = 682 MT) and for the contemporary analysis 1798 patients (N = 1137 USCDT, N = 661 MT) met the criteria. Incidence of hemoglobin reduction (>2 and >5 g/dL) and transfusions received were significantly higher among MT-treated patients in both analyses, as was ISTH and BARC 3b major bleeding (primary: ISTH MT 17.3% vs USCDT 12.4% P = .002; BARC 3b MT 15.4% vs USCDT 11.8% P = .019) (contemporary: ISTH MT 17.2% vs USCDT 11.0% P = .0002; BARC 3b MT 15.4% vs USCDT 10.6% P = .002). Regression analysis demonstrated that MT is associated with major bleeding. Median length of stay, all-cause 30-day readmission and in-hospital mortality were similar between groups. Intracranial hemorrhage was more common with MT. Conclusions: Major bleeding derived from direct laboratory and transfusion data occurred more frequently with MT vs USCDT. Intracranial hemorrhage was more common among MT-treated patients. In the absence of randomized data, these results provide guidance regarding the bleeding risk and safety of strategies for advanced PE therapy.

A Rare Presentation of Nocardia pericarditis Leading to Cardiac Tamponade in an Immunocompetent Patient.

Nocardia can cause isolated disease in many parts of the body including the brain, skin, and lungs. It is also capable of causing disseminated disease. In almost all cases, Nocardia infections occur in immunocompromised hosts with depressed cell-mediated functions. We present a case of disseminated Nocardia farcinica leading to pericardial effusion and tamponade in an immunocompetent host with the only risk factor being heavy alcohol intake. Treatment relies on an accurate diagnosis. This case presentation highlights the importance of considering Nocardia infections in an alcoholic patient with a worsening clinical picture.

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.

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.

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.

Discharge patterns of patients with asthma from the emergency department: a retrospective review.

BACKGROUND: Despite evidence that specific therapies improve outcomes in patients with asthma, they are often not used. Combining several evidence-based therapies into a treatment "bundle" to be offered at the time of discharge from the emergency department, might reduce variation and potentially optimize clinical outcomes. OBJECTIVE: To assess the utilization of four evidence-based therapies for asthma by analyzing the visits of patients with acute exacerbations of asthma discharged from the emergency department. DESIGN: A retrospective chart review. SETTING: Single 650-bed inner-city hospital emergency department. PATIENTS: Two hundred and twenty six patients discharged from the emergency department after 500 acute exacerbations of asthma. MEASUREMENTS: All visits were reviewed for the presence of the four evidence-based components of asthma treatment upon discharge: follow-up referral, oral steroids, asthma education, and inhaled corticosteroids. Visits were also assessed for medications prescribed upon discharge, medication history, and patient's asthma severity based on national guidelines. RESULTS: The four components of asthma treatment were documented as follows: follow-up referral (86.2%), oral steroids (67.8%), asthma education (19.6%), and inhaled corticosteroids (16.2%). Only 3.4% of visits documented all four components in the aggregate. Twenty-three distinct combinations of medication were prescribed upon discharge. The majority of visits failed to document asthma severity. CONCLUSIONS: This retrospective chart review reveals significant variation in the discharge management of patients with asthma, specifically regarding medications prescribed. While follow-up referral was sufficiently documented, the remaining three components were not. With only 3.4% of visits containing all four components, implementing an asthma "bundle" may present an opportunity to improve outcomes in asthma management.

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.

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.