Discovery of a Potent and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase with Oral Anti-Inflammatory Activity

Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.     

Heartech: Another parachute looking for a landing zone in interventions for heart failure

• Maladaptive left ventricular remodeling after acute myocardial infarction is defined by increased left ventricular dimensions and is associated with poor clinical outcomes.
• Left ventricular partitioning devices mechanically reduce left ventricular dimensions and are postulated to improve symptomatic heart failure.
• In this first in human study, deployment of the Heartech LVPD was shown to be feasible without a prohibitive safety signal precluding future pivotal trials.

     

Peripheral saline contrast with Valsalva and a modified Müller's maneuver may improve detection of atrial level right‐to‐left shunts: A preliminary observation

As part of an evaluation for source of embolism, transthoracic echocardiography with peripheral saline contrast injection during normal respirations and also Valsalva release is routinely performed to evaluate for an atrial level shunt. We present a preliminary observation of addition of a modified Müller's maneuver early during the Valsalva release. The Müller's maneuver has been described to occur with sleep apnea and will increase right‐to‐left shunting through a PFO. Of 34 patients, 24 were negative for a right‐to‐left shunt with normal respiration or Valsalva release. Of these 24 patients, 8 were then positive for a shunt by addition of a modified Müller's maneuver. One additional patient could not perform the modified Müller's maneuver. This preliminary observation suggests that in patients referred to an echocardiography laboratory for evaluation of source of embolism, adding the modified Müller's maneuver to those negative for shunting during normal respirations and Valsalva release may yield an increase in right‐to‐left atrial level shunt detection.     

Usefulness of three‐dimensional echocardiography in the assessment of valvular involvement in Loeffler endocarditis

Loeffler endocarditis is a complication of hypereosinophilic syndrome resulting from eosinophilic infiltration of heart tissue. We report a case of Loeffler endocarditis in which three‐dimensional transthoracic and transesophageal echocardiography provided additional information to what was found by two‐dimensional transthoracic echocardiography alone. Our case illustrates the usefulness of combined two‐ and three‐dimensional echocardiography in the assessment of Loeffler endocarditis. In addition, a summary of the features of hypereosinophilic syndrome and Loeffler endocarditis is provided in tabular form.     

Two-dimensional transthoracic echocardiographic finding of left atrial compression resulting from blunt trauma to the thoracic spine

We present an adult female in whom two-dimensional transthoracic echocardiography demonstrated encroachment of the thoracic spine on the left atrium (LA) resulting in a very small, compressed LA cavity by a prominent thoracic spine shadow. Computed tomography (CT) scan of the chest showed compression of the LA produced by localized anterior deformation of the thoracic spine which had resulted from blunt injury to her spine following a fall from a swing several years previously.     

Periprocedural Major Bleeding Risk of Image-Guided Percutaneous Chest Tube Placement in Patients with an Elevated International Normalized Ratio

PurposeTo evaluate the incidence of major hemorrhage after image-guided percutaneous chest tube placement in patients with an abnormal international normalized ratio (INR) measured before the procedure.Materials and MethodsBetween January 2013 and September 2017, 49 image-guided percutaneous chest tubes were placed in 45 adult patients who had an elevated INR of greater than 1.6. Data collected included routine serum pre-procedure coagulation studies, indication for chest tube placement, insertion technique, size of chest tube, and presence of complications after drain placement. Major bleeding complications were defined using the Society of Interventional Radiology classification system.ResultsMean patient age was 62 years (range, 22–94 years), with median American Society of Anesthesiologists score of 4. Mean INR was 2.1 (range, 1.7–3), with 21 (43%) procedures with an INR between 1.7 and 1.9, 20 (41%) procedures with an INR between 2.0 and 2.4, and 8 (16%) procedures with an INR between 2.5 and 3.0. Computed tomography guidance was used for 27 (55%) procedures; ultrasound guidance was used for 22 (45%) procedures. Median size of chest tube was 10 Fr (range, 8–14 Fr) used in 27 (55%) procedures. No major bleeding complications were observed. There was a small, significant decrease in mean hemoglobin after the procedure (mean = 0.9g/dL; P < .0001), which correlated to increasing chest tube size (P = .0269).ConclusionsNo major bleeding complications were observed after image-guided percutaneous chest tube placement in patients with an elevated INR. Major bleeding complications in these patients may be safer than initially considered, and this study encourages the conduct of larger trials for further evaluation.