Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers.

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC < 1 nM and > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4.

Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.

We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-]quinazolin-5(7)-one SMARCA bromodomain binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines.

Obstetric outcomes among rural parturients across US urban and rural hospitals.

Introduction: The objective of this study is to evaluate severe maternal morbidity (SMM) of rural parturients delivering at rural compared to urban hospitals in the US.

Methods: We identified patients aged 18-40 years in a multi-institutional claims database who lived in a rural ZIP code and delivered at a rural or urban hospital between October-December of 2015 and October-December of 2022. The primary outcome was SMM, and the secondary outcome was SMM exclusive of blood transfusions.

Nitinol Staple Use in Primary Arthrodesis of Lisfranc Fracture-Dislocations.

Background: Primary arthrodesis of Lisfranc fracture-dislocations is a reliable treatment option, yet concerns remain about nonunion. Nitinol staple use has recently proliferated in midfoot arthrodesis. The purpose of this study is to examine the union rate of primary arthrodesis of acute Lisfranc fracture-dislocations treated with nitinol staples compared with traditional plate-and-screw fixation.

DRL-GAN: A Hybrid Approach for Binary and Multiclass Network Intrusion Detection.

Our increasingly connected world continues to face an ever-growing number of network-based attacks. An Intrusion Detection System (IDS) is an essential security technology used for detecting these attacks. Although numerous Machine Learning-based IDSs have been proposed for the detection of malicious network traffic, the majority have difficulty properly detecting and classifying the more uncommon attack types.

Effectiveness and Safety of Retreatment with Lu-DOTATATE in Patients with Progressive Neuroendocrine Tumors: A Retrospective Real-World Study in the United States.

Advanced neuroendocrine tumors (NETs) are associated with a poor prognosis. A regimen of 4 cycles of Lu-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients with advanced NETs. To the best of our knowledge, this is the first study in the United States to evaluate the effectiveness and safety of additional cycles of Lu-DOTATATE therapy in patients with progressive NETs.

Strategies for successful integration of work from home faculty in an academic radiology department.

Academic radiology departments have added increasing numbers of entirely remote "work-from-home" or hybrid faculty. This change has presented both an opportunity to recruit and retain faculty as well as a set of challenges to maintaining the full academic mission and educational environment. In this article we describe our experience with creating a remote faculty position and the key elements that we believe made it successful.

Impact of group medical visits on patient engagement and quality of life.

Background: Group medical visits (GMV) effectively improve patient care and outcomes through interactive education, increased patient contact, and facilitated social support. This quality improvement research examined if patient activation and quality of life correlate with weight, blood pressure (BP), and hemoglobin A1c (A1C) through GMV interventions.

Methods: Participants were enrolled in GMV Lighten Up for weight management or GMV Diabetes.

Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.

Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype.

SSR white paper: guidelines for utilization and performance of direct MR arthrography.

Objective: Direct magnetic resonance arthrography (dMRA) is often considered the most accurate imaging modality for the evaluation of intra-articular structures, but utilization and performance vary widely without consensus. The purpose of this white paper is to develop consensus recommendations on behalf of the Society of Skeletal Radiology (SSR) based on published literature and expert opinion.

Materials And Methods: The Standards and Guidelines Committee of the SSR identified guidelines for utilization and performance of dMRA as an important topic for study and invited all SSR members with expertise and interest to volunteer for the white paper panel.

An exploration of the personal experiences of digital forensics analysts who work with child sexual abuse material on a daily basis: "you cannot unsee the darker side of life".

Introduction: Digital forensics analysts are a specialist group of police officers who are involved in investigating cases of online child sexual exploitation and abuse (CSEA), and identifying and classifying child sexual abuse material (CSAM) according to levels of severity, respectively. The existing literature that has examined this phenomenon suggests that this group of police officers are at greater risk of psychological harm as a result of being exposed to CSAM, and that working with this type of material has the potential to significantly affect their mental health and wellbeing.

Methods: The study presented here used Interpretative Phenomenological Analysis (IPA) to explore digital forensics analysts' personal experiences of working in this role, and with CSAM, on a daily basis, as well as how they feel this has impacted on them, and how they manage this.

Factors Influencing Admission Decisions in Skilled Nursing Facilities: Retrospective Quantitative Study.

Background: Occupancy rates within skilled nursing facilities (SNFs) in the United States have reached a record low. Understanding drivers of occupancy, including admission decisions, is critical for assessing the recovery of the long-term care sector as a whole. We provide the first comprehensive analysis of financial, clinical, and operational factors that impact whether a patient referral to an SNF is accepted or denied, using a large health informatics database.

Cost Analysis and Reimbursement of Weightbearing Computed Tomography.

Background: Weightbearing computed tomography (WBCT) is becoming a valuable tool in the evaluation of foot and ankle pathology. Currently, cost analyses of WBCT scanners in private practice are lacking in the literature. This study evaluated the costs of acquisition, utilization, and reimbursements for a WBCT at a tertiary referral center, information of particular interest to practices considering obtaining such equipment.

Radiographic assessment of acute vs chronic vertebral compression fractures.

Purpose: Distinguishing between acute and chronic vertebral compression fractures typically requires advanced imaging techniques such as magnetic resonance imaging (MRI). Recognizing specific radiographic findings associated with fracture acuity may improve the accuracy of radiographic assessment.

Methods: Patients with compression fractures that had both radiographic and MRI studies of the lumbar spine within a 30-day time frame were retrospectively reviewed.

The effect of virtual interviews on the musculoskeletal radiology fellowship match.

Objective: Resulting from the COVID-19 pandemic, a virtual interview format was adopted in lieu of in-person interviews for fellowship recruitment. The purpose of this study is to analyze the potential effect that virtual interviews have on musculoskeletal radiology fellowship match results and collect opinions of the process.

Materials And Methods: An anonymous survey was sent to 87 listed US-based musculoskeletal radiology fellowship directors, who were asked for their 2019-2020 and 2020-2021 match data: fellowship positions, interviewees, ranked interviewees, and matched ranks.

Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1.

Recent evidence suggests that deletion of STUB1─a pivotal negative regulator of interferon-γ sensing─may potentially clear malignant cells. However, current studies rely primarily on genetic approaches, as pharmacological inhibitors of STUB1 are lacking. Identifying a tool compound will be a step toward validating the target in a broader therapeutic sense.

MR Imaging of Knee Cartilage Injury and Repair Surgeries.

Cartilage injuries are common and may predispose to early accelerated osteoarthritis. Magnetic resonance (MR) imaging is critical in the detection and characterization of acute and chronic cartilage injuries. Several surgical approaches including microfracture, osteochondral allografting, autologous osteochondral transfer system, and autologous chondrocyte implantation have been developed to treat cartilage lesions.

Healthcare provider and medical student impressions of vaccine hesitancy in Romania.

Objectives: Vaccine hesitancy, including vaccination delay and refusal, threatens gains made to improve global health. Recent outbreaks of measles attributed to lower vaccination rates and the COVID-19 pandemic have added urgency to the need for current and future healthcare providers to effectively identify and address barriers to vaccination.

Study Design: Cross-sectional interviews and online surveys.

Analysis of Complement Gene Expression, Clinical Associations, and Biodistribution of Complement Proteins in the Synovium of Early Rheumatoid Arthritis Patients Reveals Unique Pathophysiologic Features.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and inflammation. The finding of autoantibodies in seropositive RA suggests that complement system activation might play a pathophysiologic role due to the local presence of immune complexes in the joints. Our first objective was to explore the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR (disease activity score in 28 joints for erythrocyte sedimentation rate) and complement system gene expression, both in the synovium and in blood.

Multifrequency electromagnetic geophysical tools for evaluating the hydrologic conditions and performance of evapotranspiration barriers.

Surface barriers are designed to isolate subsurface contaminants for 1000 years or longer, functionally limiting water infiltration and removing the driving force for contaminant transport to groundwater. Cost-effective monitoring is challenging because of the long design life for surface barriers, spatial limitations and finite lifetime of in situ sensors, and performance metrics related to drainage. Hence, ground-penetrating radar (GPR) and electromagnetic induction (EMI) tools were evaluated for use in performance monitoring of surface barriers.

Mass-Like Fat at the Medial Midfoot: A Common Pseudolesion.

Fatty masses are common and may be encountered in the foot and ankle. In some cases, normal subcutaneous fat may be mistaken for a discrete mass. The aim of this study was to evaluate the common finding of prominent subcutaneous fat at the medial midfoot resembling a lipoma and to determine the prevalence of this pseudolesion by applying a series of potential size cutoff criteria.

Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action.

Human Arginase 1 (hArg1) is a metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea, and modulates T-cell-mediated immune response. Arginase-targeted therapies have been pursued across several disease areas including immunology, oncology, nervous system dysfunction, and cardiovascular dysfunction and diseases. Currently, all published hArg1 inhibitors are small molecules usually less than 350 Da in size.