Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.

The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K.

Evaluating chemical venous thromboembolism prophylaxis in trauma patients at a single Australian center.

Purpose: Trauma patients are at an elevated risk of developing venous thromboembolism (VTE), with the subsequent mortality in patients requiring intensive care unit admission ranging from 25% to 38%. There remains significant variability in clinical practice related to VTE prophylaxis in trauma patients due to the frequent presence of contraindications impacting the timing and consistency of application. This study aimed to assess the effectiveness of the current practice of chemical VTE prophylaxis in trauma patients at a single Australian center.

Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties.

The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC < 25 nM).

Surgical treatment of shoulder instability in active-duty service members with subcritical glenoid bone loss: Bankart vs. Latarjet.

Introduction: Subcritical bone loss has been identified as a risk factor for potentially inferior outcomes following typical arthroscopic soft tissue repair. One alternative that has been presented as an option for patients with bone loss is the Latarjet, an ipsilateral coracoid transfer to the anteroinferior glenoid. The purpose of this study is to compare the outcomes between the arthroscopic Bankart repair and the open Latarjet for the treatment of anterior shoulder instability in patients with subcritical bone loss.

Can obese patients undergo simultaneous bilateral total knee arthroplasty without an increased risk of perioperative complications?

Simultaneous bilateral total knee arthroplasty (simBTKA) remains controversial, especially in obese patients. Therefore, this retrospective study compared six month perioperative complications in 313 simBTKA patients. Comparison groups included 139 non-obese patients (BMI < 30), 61 obese patients (BMI = 30-35) and 48 severely obese patients (BMI > 35).

Epidemiology and outcomes of obese critically ill patients in Australia and New Zealand.

Objective: The apparent survival benefit of being overweight or obese in critically ill patients (the obesity paradox) remains controversial. Our aim is to report on the epidemiology and outcomes of obesity within a large heterogenous critically ill adult population.

Design: Retrospective observational cohort study.

Early perioperative complication rates and subsidence with the Tribute short cementless, tapered stem in primary total hip arthroplasty.

This study examined early perioperative complications and subsidence following total hip arthroplasty (THA) with a short femoral stem. A retrospective review of 207 consecutive patients (247 hips) having undergone THA via the direct anterior approach produced only six perioperative complications: two intraoperative fractures, three perioperative femur fractures and one dislocation. Subsidence greater than 5 mm was observed in four hips but subsidence did not progress greater than 3 mm at the latest follow-up.

Management of Cerebellar Tonsillar Herniation following Lumbar Puncture in Idiopathic Intracranial Hypertension.

Lumbar puncture is performed routinely for diagnostic and therapeutic purposes in idiopathic intracranial hypertension, despite lumbar puncture being classically contraindicated in the setting of raised intracranial pressure. We report the case of a 30-year-old female with known idiopathic intracranial hypertension who had cerebellar tonsillar herniation following therapeutic lumbar puncture. Management followed guidelines regarding treatment of traumatic intracranial hypertension, including rescue decompressive craniectomy.