Simplifying Access to Targeted Protein Degraders via Nickel Electrocatalytic Cross-Coupling.

C-C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial α-bromoglutarimide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi-step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.

Using an artificial intelligence software improves emergency medicine physician intracranial haemorrhage detection to radiologist levels.

BACKGROUND: Tools to increase the turnaround speed and accuracy of imaging reports could positively influence ED logistics. The Caire ICH is an artificial intelligence (AI) software developed for ED physicians to recognise intracranial haemorrhages (ICHs) on non-contrast enhanced cranial CT scans to manage the clinical care of these patients in a timelier fashion. METHODS: A dataset of 532 non-contrast cranial CT scans was reviewed by five board-certified emergency physicians (EPs) with an average of 14.8 years of practice experience. The scans were labelled in random order for the presence or absence of an ICH. If an ICH was detected, the reader further labelled all subtypes present (ie, epidural, subdural, subarachnoid, intraparenchymal and/or intraventricular haemorrhage). After a washout period, the five EPs reviewed again the scans individually with the assistance of Caire ICH. The mean accuracy of the EP readings with AI assistance was compared with the mean accuracy of three general radiologists reading the films individually. The final diagnosis (ie, ground truth) was adjudicated by a consensus of the radiologists after their individual readings. RESULTS: Mean EP reader accuracy significantly increased by 6.20% (95% CI for the difference 5.10%-7.29%; p=0.0092) when using Caire ICH to detect an ICH. Mean accuracy of the EP cohort in detecting an ICH using Caire ICH was found to be more accurate than the radiologist cohort prior to discussion; this difference, however, was not statistically significant. CONCLUSION: The Caire ICH software significantly improved the accuracy and sensitivity of detecting an ICH by the EP to a level comparable to general radiologists. Further prospective research with larger numbers will be needed to understand the impact of Caire ICH on ED logistics and patient outcomes.

Bone Tumor Risk Stratification and Management System: A Consensus Guideline from the ACR Bone Reporting and Data System Committee.

The assessment and subsequent management of a potentially neoplastic bone lesion seen at diagnostic radiography is often complicated by diagnostic uncertainty and inconsistent management recommendations. Appropriate clinical management should be directed by risk of malignancy. Herein, the ACR-sponsored Bone Reporting and Data System (Bone-RADS) Committee, consisting of academic leaders in the fields of musculoskeletal oncology imaging and orthopedic oncology, presents the novel Bone-RADS scoring system to aid in risk assignment and provide risk-aligned management suggestions. When viewed in the proper clinical context, a newly identified bone lesion can be risk stratified as having very low, low, intermediate, or high risk of malignancy. Radiographic features predictive of risk are reviewed include margination, pattern of periosteal reaction, depth of endosteal erosion, pathological fracture, and extra-osseous soft tissue mass. Other radiographic features predictive of histopathology are also briefly discussed. To apply the Bone-RADS scoring system to a potentially neoplastic bone lesion, radiographic features predictive of risk are each given a point value. Point values are summed to yield a point total, which can be translated to a Bone-RADS score (1-4) with corresponding risk assignment (very low, low, intermediate, high). For each score, evidence-based and best practice consensus management suggestions are outlined. Examples of each Bone-RADS scores are presented, and a standardized diagnostic radiography report template is provided.

Deep Learning System Boosts Radiologist Detection of Intracranial Hemorrhage.

BACKGROUND: Intracranial hemorrhage (ICH) requires emergent medical treatment for positive outcomes. While previous artificial intelligence (AI) solutions achieved rapid diagnostics, none were shown to improve the performance of radiologists in detecting ICHs. Here, we show that the Caire ICH artificial intelligence system enhances a radiologist's ICH diagnosis performance. METHODS: A dataset of non-contrast-enhanced axial cranial computed tomography (CT) scans (n=532) were labeled for the presence or absence of an ICH. If an ICH was detected, its ICH subtype was identified. After a washout period, the three radiologists reviewed the same dataset with the assistance of the Caire ICH system. Performance was measured with respect to reader agreement, accuracy, sensitivity, and specificity when compared to the ground truth, defined as reader consensus. RESULTS: Caire ICH improved the inter-reader agreement on average by 5.76% in a dataset with an ICH prevalence of 74.3%. Further, radiologists using Caire ICH detected an average of 18 more ICHs and significantly increased their accuracy by 6.15%, their sensitivity by 4.6%, and their specificity by 10.62%. The Caire ICH system also improved the radiologist's ability to accurately identify the ICH subtypes present. CONCLUSION: The Caire ICH device significantly improves the performance of a cohort of radiologists. Such a device has the potential to be a tool that can improve patient outcomes and reduce misdiagnosis of ICH.

Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties.

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.

Structural and Thermal Characterization of Halogenated Azidopyridines: Under-Reported Synthons for Medicinal Chemistry.

Owing to their participation in Click reactions, bifunctional azides are valuable intermediates in the preparation of medicines and biochemical tool compounds. Despite the privileged nature of pyridines among pharmaceutical scaffolds, reports of the synthesis and characterization of azidopyridines bearing a halogen substituent for further elaboration are almost completely unknown in the literature. As azidopyridines carry nearly equal numbers of nitrogen and carbon atoms, we hypothesized that safety concerns limited the application of these useful bifunctional building blocks in medicinal and biological chemistry. To address this concern, we prepared and characterized nine azidopyridines bearing a single fluorine, chlorine, or bromine atom. All were examined by differential scanning calorimetry (DSC), in which they demonstrated exotherms of 228-326 kJ/mol and onset temperatures between 119 and 135 °C. Selected azidopyridines were advanced to mechanical stress testing, in which impact sensitivity was noted for one regioisomer of C5H3FN4. The utility of these versatile intermediates was demonstrated through their use in a variety of Click reactions and the diversification of the halogen handles.

Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.

We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.

Developmental hip dysplasia and hip ultrasound frequency in a large American payer database.

Developmental dysplasia of the hip (DDH) is an important contributor to musculoskeletal morbidity, but effective strategies to screen for DDH remain controversial. The current utilization of hip ultrasound (US) screening for DDH in the United States is not defined. This study utilized Optum's de-identified Clinformatics® Data Mart, a large commercial and Medicare Advantage claims database. The frequency of DDH and hip US utilization was estimated using billing data on an average of 2.9 million relevant beneficiaries included annually from 2007 through 2017. A total of 6806 DDH cases were identified with an average annual prevalence of 1.7 per 1000 infants, which was stable during the study period. Girls were more likely to be screened and diagnosed with DDH, comprising 72% of DDH cases with an OR of 2.55 (95% CI 2.42-2.69), p < 0.001. Hip US screening was employed in 0.9% of the infant population on average but increased substantially from 2007 (0.4%) to 2017 (2.2%). Most common billing diagnoses included hip deformity (27.4%), breech delivery (20.4%), and physical exam abnormality (17.7%). The average imaging costs per patient for all screened children was $108.94. Insurance claims reflect the current American practice of selective hip US with relative adherence to American Academy of Pediatrics guidelines based on reported diagnoses. While hip US utilization increased during the study period, prevalence of DDH diagnoses did not increase. Our results suggest that expansion of hip US screening may not effectively increase DDH detection although further investigation is needed to ascertain optimal screening strategies to improve patient outcomes.

Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.

We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.

Establishing a magnetic resonance safety program.

Establishing a magnetic resonance (MR) safety program is crucial to ensuring the safe MR imaging of pediatric patients. The organizational structure includes a core safety council and broader safety committee comprising all key stakeholders. These groups work in synchrony to establish a strong culture of safety; create and maintain policies and procedures; implement device regulations for entry into the MR setting; construct MR safety zones; address intraoperative MR concerns; guarantee safe scanning parameters, including complying with specific absorption rate limitations; adhere to national regulatory body guidelines; and ensure appropriate communication among all parties in the MR environment. Perspectives on the duties of the safety council members provide important insight into the organization of program oversite. Ultimately, the collective dedication and vigilance of all MR staff are crucial to the success of a safety program.

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1.

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.

Progression of Plaque Burden of Intracranial Atherosclerotic Plaque Predicts Recurrent Stroke/Transient Ischemic Attack: A Pilot Follow-Up Study Using Higher-Resolution MRI.

BACKGROUND: Patients with intracranial atherosclerotic disease (ICAD) have a high frequency of stroke recurrence. However, there has been little investigation into the prognostic value of higher-resolution magnetic resonance imaging (HR-MRI). PURPOSE: To investigate the use of intracranial atherosclerotic plaques features in predicting risk of recurrent cerebrovascular ischemic events using HR-MRI. STUDY TYPE: Prospective. POPULATION: Fifty-eight patients with acute/subacute stroke (N = 46) or transient ischemic attack (N = 12). FIELD STRENGTH/SEQUENCE: A 3.0 T, 3D time-of-flight gradient echo sequence and T1- and T2-weighted fast spin echo sequences with 0.31 x 0.39 mm2 in-plane resolution, twice (with >3 months between scans) following the initial event. ASSESSMENT: Patients were also followed clinically for recurrent ischemic events for up to 48 months or until a subsequent event occurred. The degree of stenosis, plaque burden (PB), minimal lumen area (MLA), and contrast enhancement ratio were assessed at each scanning session and the percentage change of each over time was calculated. STATISTICAL TESTS: Univariable and multivariable Cox regression analyses were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for predicting recurrent events. RESULTS: The mean time interval between baseline and follow-up MRI scans was 6.2 ± 4.1 months. After the second MRI scan, 20.7% of patients (N = 12) had experienced ipsilateral recurrent TIA/stroke within 10.9 ± 9.2 months. Univariable analyses showed that baseline triglyceride, percentage change of PB, and progression of PB were significantly associated with recurrent events (all P < 0.05). Multivariable Cox regression indicated that progression of PB (HR, 6.293; 95% CI, 1.620-24.444; P < 0.05) was a significant independent imaging feature for recurrent ischemic events. DATA CONCLUSION: Progression of PB was independently associated with recurrent ischemic cerebrovascular events. HR-MRI may help risk stratification of patients at risk of recurrent stroke. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 4.

Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor.

BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy. METHODS: Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo. RESULTS: CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease. CONCLUSION: CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.

Lipoblastoma: computed tomographic and magnetic resonance imaging features correlate with tumor behavior and pathology.

BACKGROUND: Lipoblastoma is a rare benign neoplasm of immature fat cells in children. Imaging appearances are frequently complex, sometimes simulating liposarcoma. OBJECTIVE: To characterize features of lipoblastoma on MRI and CT in comparison with recurrence risk. MATERIALS AND METHODS: We identified cases via retrospective review of histopathology-proven lipoblastoma cases in a large referral database and a pediatric medical center. Two radiologists scored CT and MRI on the basis of lesion features. RESULTS: We included a total of 56 children (32 boys and 24 girls) with a mean age of 2.6 years (range 0.1-13 years). Extremity lesions were most common (27%), followed by neck (19%), gluteal region (18%), chest (14%) and mesentery (14%). Children most commonly presented with painless masses (73%), followed by dyspnea (9%), distension (9%) and pain (7%). Non-adipose soft-tissue components were identified on CT and MRI in 78% of cases. Significant (moderate or marked) septations were noted in 59% and enhancement in 35%. Compartmental invasion was present in 43% of cases. Of paraspinal cases, 38% involved the neural foramina or central canal. Lesion complexity did not significantly correlate with age. Recurrence was observed in 9% of cases and was significantly correlated with compartmental invasion (correlation: 0.303, P=0.009) and septation complexity (correlation: 0.227, P=0.038) on initial imaging. CONCLUSION: Although lipoblastoma is a fat-containing entity, many lesions demonstrate marked complexity and local infiltration that resemble liposarcoma, which is exceedingly rare in younger children. Compartmental invasion and thicker septations appear to confer greater risk of recurrence following resection.

Optimizing Radiology Reading Room Design: The Eudaimonia Radiology Machine.

Physical and mental stressors on radiologists can result in burnout. Although current efforts seek to target the issues of burnout and stress for radiologists, the impact of their physical workspace is often overlooked. By combining evidence-based design, human factors, and the architectural concept of the Eudaimonia Machine, we have developed a redesign of the radiology reading room that aims to create an optimal workspace for the radiologist. Informed by classical principles of well-being and contemporary work theory, Eudaimonia integrates concerns for individual wellness and efficiency to create an environment that fosters productivity. This layout arranges a work environment into purposeful spaces, each hosting tasks of varying degrees of intensity. The improved design addresses the radiologist's work requirements while also alleviating cognitive and physical stress, fatigue, and burnout. This new layout organizes the reading room into separate areas, each with a distinct purpose intended to support the range of radiologists' work, from consultation with other health care providers to reading images without interruption. The scientific principles that undergird evidence-based design and human factors considerations ensure that the Eudaimonia Radiology Machine is best suited to support the work of the radiologists and the entire radiology department.

Diagnostic journey and impact of enzyme replacement therapy for mucopolysaccharidosis IVA: a sibling control study.

BACKGROUND: Mucopolysaccharidosis (MPS) IVA, also known as Morquio A syndrome, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase. Early recognition, diagnosis, and treatment of this progressive, multisystem disease by enzyme replacement therapy (ERT) can lead to improved outcomes and reduced mortality. METHODS: This report documents the diagnostic journey and treatment with ERT of three siblings with MPS IVA. Clinical outcome measures included growth, endurance, imaging, cardiac, respiratory, ophthalmology, and laboratory evaluations. RESULTS: Three siblings, diagnosed at 14.7, 10.1, and 3.2 years of age, demonstrated clinical improvement with weekly infusions of 2.0 mg/kg elosulfase alfa (Vimizim®, BioMarin Pharmaceutical, Novato, CA, USA). Patient 1 (oldest sibling) and Patient 2 (middle sibling) experienced a diagnostic delay of 8 years 7 months and 4 years after symptom onset, respectively. All three patients demonstrated improvements in growth, 6-min walk distance, joint range of motion, and respiratory function after 30 months of ERT. The treatment was well tolerated without any adverse events. CONCLUSIONS: This case series highlights the importance of early recognition of the clinical and imaging findings that are initially subtle in MPS IVA. Early treatment with ERT is necessary to slow irreversible disease progression and improve patient outcomes. The oldest sibling experienced improvements in mobility despite severe symptoms resulting from a late diagnosis. When evaluating patients with skeletal anomalies, imaging multiple body regions is recommended. When findings such as anterior beaking of vertebrae or bilateral femoral head dysplasia are present, MPS IVA should be included in the differential diagnosis. Newborn screening must be considered for early detection, accurate diagnosis, and initiation of treatment to reduce morbidity.

Wall enhancement on black-blood MRI is independently associated with symptomatic status of unruptured intracranial saccular aneurysm.

OBJECTIVE: This study aims to investigate whether aneurysm wall enhancement (AWE) is independently associated with symptomatic status of unruptured intracranial aneurysms (UIAs). METHODS: One hundred thirty-nine consecutive patients (67 male, mean age 58 ± 11 years) with 79 symptomatic and 87 asymptomatic UIAs were imaged using black-blood MRI pre- and post-gadolinium contrast administration and 3D DSA. Symptoms related to aneurysms were identified including cranial nerve deficits and headache. AWE grade and area were characterized, and aneurysm size was measured on DSA. Multivariate binary logistic regression analysis was used to identify factors associated with symptoms. Further subgroup analysis was performed for aneurysms size < 10 mm. RESULTS: Symptomatic UIAs had significantly larger aneurysm size (11.2 ± 6.2 mm vs. 6.4 ± 3.3 mm), enhancement grade (1.3 ± 0.6 vs. 0.4 ± 0.6), enhancement area (2.0 ± 0.9 vs. 0.4 ± 0.7), and higher prevalence of thick enhancement (39% vs. 3%) compared with asymptomatic UIAs, all p < 0.001. In multivariate analysis, only AWE area (odds ratio [OR] 6.9, 95% confidence interval [4.0, 11.7]) was independently associated with symptoms. AWE area had an area under curve (AUC) value of 0.888, with 72.2% sensitivity and 92.0% specificity for symptoms, which was superior to aneurysm size (AUC of 0.771, with 75.9% sensitivity and 65.5% specificity). In the subgroup analysis of aneurysms smaller than 10 mm (n = 118), AWE area (OR, 7.0, p < 0.001) remained the only independent risk factor associated with symptoms. CONCLUSIONS: Larger AWE area is independently associated with symptomatic UIAs, which may provide additional value to guide UIA management and improve patient outcomes. KEY POINTS: • Symptomatic intracranial aneurysms are larger and more often demonstrate significant wall enhancement than asymptomatic aneurysms. • Larger wall enhancement area is independently associated with symptomatic intracranial aneurysm.

Solitary long-bone epiphyseal lesions in children: radiologic-pathological correlation and epidemiology.

BACKGROUND: Solitary epiphyseal lesions are rare and present with nonspecific imaging features. Knowledge regarding etiologies of pediatric epiphyseal lesions is limited to small studies. OBJECTIVE: The purpose of this study was to determine the relative incidence of pathologies affecting the pediatric epiphysis based on biopsy-proven cases with imaging. MATERIALS AND METHODS: We conducted a retrospective review of imaging studies including the terms "biopsy" or "resection" and entities known to affect the epiphysis and cross-referenced these with pathology reports, recording the relevant clinical data. Two radiologists performed comprehensive imaging review and recorded relevant features. RESULTS: Forty-nine children and adolescents met inclusion criteria. The long-bone epiphyseal lesion etiologies included chondroblastoma (n=22, 45%), nonspecific nonmalignant pathology (n=11, 22%), osteomyelitis (n=9, 18%), lymphoma (n=2, 4%) and 1 case of each of aneurysmal bone cyst, chondrosarcoma, enchondroma, hemangioendothelioma, and non-Langerhans cell histiocytosis. Median age was 13.1 years old (range 1.5-18.6 years). We performed comparative analysis of the two most common lesions in our series, chondroblastoma and osteomyelitis. Chondroblastoma was significantly more likely to be peripherally located (94% vs. 33%, P=0.002) and to demonstrate a discrete T1-weighted hypointense rim (94% vs. 33%, P=0.002); there were no significant differences in enhancement or intrinsic signal properties. Children with chondroblastoma were older (15.1 years vs. 7.3 years, P=0.001), and chondroblastoma lesions were significantly larger, with mean maximum lesion diameter of 25 mm (interquartile range [IQR] 20-30) vs. 12 mm (IQR 11-18) (P=0.001) and lesion volumes of 4.4 mL (IQR 2.4-7.9) vs. 0.4 mL (IQR 0.2-1.4) (P=0.01). CONCLUSION: This study reports the relative frequency of pathology of pediatric solitary epiphyseal lesions and describes several features that might assist in differentiating between chondroblastoma and osteomyelitis.