The Challenge of Intermediate-Risk Pulmonary Embolism.

BACKGROUND: Intermediate-risk pulmonary embolism is a common disease that is associated with significant morbidity and mortality; however, a standardized treatment protocol is not well-established. AREAS OF UNCERTAINTY: Treatments available for intermediate-risk pulmonary embolisms include anticoagulation, systemic thrombolytics, catheter-directed therapies, surgical embolectomy, and extracorporeal membrane oxygenation. Despite these options, there is no clear consensus on the optimal indication and timing of these interventions. THERAPEUTIC ADVANCES: Anticoagulation remains the cornerstone of treatment for pulmonary embolism; however, over the past 2 decades, there have been advances in the safety and efficacy of catheter-directed therapies. For massive pulmonary embolism, systemic thrombolytics and, sometimes, surgical thrombectomy are considered first-line treatments. Patients with intermediate-risk pulmonary embolism are at high risk of clinical deterioration; however, it is unclear whether anticoagulation alone is sufficient. The optimal treatment of intermediate-risk pulmonary embolism in the setting of hemodynamic stability with right heart strain present is not well-defined. Therapies such as catheter-directed thrombolysis and suction thrombectomy are being investigated given their potential to offload right ventricular strain. Several studies have recently evaluated catheter-directed thrombolysis and embolectomies and demonstrated the efficacy and safety of these interventions. Here, we review the literature on the management of intermediate-risk pulmonary embolisms and the evidence behind those interventions. CONCLUSIONS: There are many treatments available in the management of intermediate-risk pulmonary embolism. Although the current literature does not favor 1 treatment as superior, multiple studies have shown growing data to support catheter-directed therapies as potential options for these patients. Multidisciplinary pulmonary embolism response teams remain a key feature in improving the selection of advanced therapies and optimization of care.

Implementation of Novel Lipid Therapies in a Refractory Heterozygous Familial Hypercholesterolemia Patient With Atherosclerotic Disease.

Compound heterozygous familial hypercholesterolemia patients are phenotypically similar to homozygous familial hypercholesterolemia patients, present with significant elevations of low-density lipoprotein cholesterol, and are at risk of cardiovascular disease. Although new treatment options are emerging, the stepwise approach to the use of different therapies has not been well described. (Level of Difficulty: Intermediate.).

Discovery of Small-Molecule Antibiotics against a Unique tRNA-Mediated Regulation of Transcription in Gram-Positive Bacteria.

The emergence of multidrug-resistant bacteria necessitates the identification of unique targets of intervention and compounds that inhibit their function. Gram-positive bacteria use a well-conserved tRNA-responsive transcriptional regulatory element in mRNAs, known as the T-box, to regulate the transcription of multiple operons that control amino acid metabolism. T-box regulatory elements are found only in the 5'-untranslated region (UTR) of mRNAs of Gram-positive bacteria, not Gram-negative bacteria or the human host. Using the structure of the 5'UTR sequence of the Bacillus subtilis tyrosyl-tRNA synthetase mRNA T-box as a model, in silico docking of 305 000 small compounds initially yielded 700 as potential binders that could inhibit the binding of the tRNA ligand. A single family of compounds inhibited the growth of Gram-positive bacteria, but not Gram-negative bacteria, including drug-resistant clinical isolates at minimum inhibitory concentrations (MIC 16-64 µg mL-1 ). Resistance developed at an extremely low mutational frequency (1.21×10-10 ). At 4 µg mL-1 , the parent compound PKZ18 significantly inhibited in vivo transcription of glycyl-tRNA synthetase mRNA. PKZ18 also inhibited in vivo translation of the S. aureus threonyl-tRNA synthetase protein. PKZ18 bound to the Specifier Loop in vitro (Kd ≈24 µm). Its core chemistry necessary for antibacterial activity has been identified. These findings support the T-box regulatory mechanism as a new target for antibiotic discovery that may impede the emergence of resistance.