Validating the safety of low-dose CTPA in pregnancy: results from the OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) Study.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of pregnancy-related mortality. CT pulmonary angiogram (CTPA) is the first-line advanced imaging modality for suspected PE in pregnancy at institutes offering low-dose techniques; however, a protocol balancing safety with low dose remains undefined. The wide range of CTPA doses reported in pregnancy suggests a lack of confidence in implementing low-dose techniques in this group. PURPOSE: To define and validate the safety, radiation dose and image quality of a low-dose CTPA protocol optimised for pregnancy. MATERIALS AND METHODS: The OPTICA study is a prospective observational study. Pregnant study participants with suspected PE underwent the same CTPA protocol between May 2018 and February 2022. The primary outcome, CTPA safety, was judged by the reference standard; the 3-month incidence of venous thromboembolism (VTE) in study participants with a negative index CTPA. Secondary outcomes defined radiation dose and image quality. Absorbed breast, maternal effective and fetal doses were estimated by Monte-Carlo simulation on gestation-matched phantoms. Image quality was assessed by signal-to-noise and contrast-to-noise ratios and a Likert score for pulmonary arterial enhancement. RESULTS: A total of 116 CTPAs were performed in 113 pregnant women of which 16 CTPAs were excluded. PE was diagnosed on 1 CTPA and out-ruled in 99. The incidence of recurrent symptomatic VTE was 0.0% (one-sided 95% CI, 2.66%) at follow-up. The mean absorbed breast dose was 2.9 ± 2.1mGy, uterine/fetal dose was 0.1 ± 0.2mGy and maternal effective dose was 1.4 ± 0.9mSv. Signal-to-noise ratio (SNR) was 11.9 ± 3.7. Contrast-to-noise ratio (CNR) was 10.4 ± 3.5. CONCLUSION: The OPTICA CTPA protocol safely excluded PE in pregnant women across all trimesters, with low fetal and maternal radiation. CLINICAL RELEVANCE: OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) is the first prospective study to define the achievable radiation dose, image-quality and safety of a low-dose CT pulmonary angiogram protocol optimised for pregnancy (NCT04179487). It provides the current benchmark for safe and achievable CT pulmonary angiogram doses in the pregnant population. KEY POINTS: • Despite the increased use of CT pulmonary angiogram in pregnancy, an optimised low-dose protocol has not been defined and reported doses in pregnancy continue to vary widely. • The OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) study prospectively defines the achievable dose, image quality and safety of a low-dose CT pulmonary angiogram protocol using widely available technology. • OPTICA provides a benchmark for safe and achievable CT pulmonary angiogram doses in the pregnant population.

Complications in image-guided musculoskeletal injections.

Complications in musculoskeletal interventions are rare and where they do occur tend to be minor, and often short-lived or self-limiting. Nonetheless, the potential for significant complications exists, and a thorough understanding of both the mechanisms which contribute and the manner in which they may clinically present is of critical importance for all musculoskeletal radiologists involved in performing procedures, both to mitigate against the occurrence of complications and to aid rapid recognition. The purpose of this review is to analyse the relevant literature to establish the frequency with which complications occur following musculoskeletal intervention. Furthermore, we highlight some of the more commonly discussed and feared complications in musculoskeletal intervention, such as the risk of infection, potential deleterious articular consequences including accelerated joint destruction and the poorly understood and often underestimated systemic effects of locally injected corticosteroids. We also consider both extremely rare but emergent scenarios such as anaphylactic reactions to medications, and much more common but less significant complications such as post-procedural pain. We suggest that meticulous attention to detail including strict adherence to aseptic technique and precise needle placement may reduce the frequency with which complications occur.

The Evolving Roles of MRI and Ultrasound in First-Line Imaging of Rotator Cuff Injuries.

Rotator cuff tears are the most likely source of shoulder pain in adults and may cause protracted disability. Management of rotator cuff tears is associated with considerable costs. Accurate diagnosis can guide surgical planning and help achieve a favorable clinical outcome. Although radiography remains the initial imaging test for shoulder injury, the roles of MRI and ultrasound (US) as first-line imaging after radiography are evolving. This article leverages current literature and the practical experience of subspecialty musculoskeletal radiologists from different institutions in describing a practical approach to imaging rotator cuff pathology. Both MRI and US are accurate for identifying rotator cuff tears, but each has advantages and shortcomings. As both modalities currently represent reasonable first-line approaches, considerable practice variation has evolved. Given the low cost of US, imagers should strive to optimize the quality of shoulder US examinations and to build referrer confidence in this modality. The roles of direct CT and MR arthrography as well as imaging evaluation of the postoperative rotator cuff are also considered. Through careful selection among the available imaging modalities and optimal performance and interpretation of such examinations, radiologists can positively contribute to the diagnosis and treatment of patients with rotator cuff injuries.

Complications in image-guided musculoskeletal injections.

OBJECTIVE: To establish the incidence and define the nature of complications occurring following image-guided musculoskeletal injections at our institution. MATERIALS AND METHODS: All patients undergoing image-guided musculoskeletal injection during the study period (16/3/2016 to 24/01/2020) were included. Departmental records were reviewed to identify all patients describing possible complications following injection, what therapy was required (if any) and what the outcome was. No patients were excluded. Complications were classified as minor or major. Injections were categorised as follows: cervical spine, lumbar facet joint, lumbar nerve root, caudal epidural and 'other'. The complication rate for each individual category of procedure was compared with the combined complication rate for all other categories by constructing contingency tables and using Fisher's exact test. RESULTS: A total of 8226 patients underwent image-guided musculoskeletal injections within the study period. Exactly 100 patients were identified as having reported a complication, producing an overall complication rate of 1.2%. One complication was categorised as 'major', with the patient requiring expedited surgery. The remainder (99 patients) were categorised as having experienced minor complications. The incidence of complications after 'other' injections was significantly greater than for other categories of injection (1.86%, p = 0.028). There was no significant difference in the complication rate for cervical spine (0.93%, p = 0.257), lumbar nerve root (0.85%, p = 0.401), lumbar facet joint (0.67%, p = 0.326) or caudal epidural (1.29%, p = 0.687) injections. 'Other' injections were subsequently further sub-categorised by anatomical site and imaging modality used. Glenohumeral (2.97%, p = 0.0361) and sacro-iliac (3.51%, p = 0.0498) joint injections were associated with a significantly increased risk of complications. There was no difference in the incidence of complications with fluoroscopic or ultrasound guidance. CONCLUSION: In conclusion, image-guided musculoskeletal injections are safe and well-tolerated procedures. Complications are rare, occurring in just 1.2% of patients. 99% of complications are minor, either not requiring intervention or resolving with simple supportive treatment.

Annulation reaction enables the identification of an exocyclic amide tricyclic chemotype as retinoic acid Receptor-Related orphan receptor gamma (RORγ/RORc) inverse agonists.

RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.

Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization.

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.

Whole-body MRI of bone marrow: A review.

Technical advances in the last two decades have allowed rapid, high-resolution whole-body magnetic resonance imaging (WBMRI). MRI allows unparalleled visualization and detail in the imaging of bone marrow and surrounding soft tissues. The properties of nuclear magnetic resonance allow superb characterization of bone marrow constituents. WBMRI allows superb characterization of the different types of bone marrow and their natural evolution during the life cycle. Diffusion-weighted WBMRI is an exciting development that adds functional information to anatomical detail. The mainstay of WBMRI for bone marrow abnormalities to date has centered upon staging multiple myeloma and other hematologic bone marrow conditions, and as a valuable tool in quantifying skeletal metastases. Increasingly, WBMRI is being utilized in a variety of additional malignant and nonmalignant conditions. Due to the absence of ionizing radiation, WBMRI represents a valuable screening tool in areas such as malignant transformation in hereditary multifocal exostoses or for the development of ischemic marrow insult in at-risk patients. An additional novel area of use includes postmortem WBMRI for characterization of skeletal injuries. This article provides a state-of-the-art and current review of WBMRI of the bone marrow and highlights potential future areas of development. Level of Evidence: 5 Technical Efficacy Stage: 3 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2019;50:1687-1701.

Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity.

The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.

Role of Musculoskeletal Radiology in Modern Sports Medicine.

Musculoskeletal radiology's role in the recent and continued evolution of sports medicine is an exciting and expanding one. In this article we explore a variety of the ways that musculoskeletal radiology contributes to current practices in modern sports medicine, discussing advances across a variety of imaging modalities in the care of both elite athletes and so-called weekend warriors. We describe the technical and ethical factors pertaining to image-guided therapeutic intervention in athletes and speculate on the potential for future developments in the role of imaging in deciding when an athlete may return to participation. We also explore the recent shift to the delivery of imaging facilities at sporting events and in stadiums.

Therapeutic Intervention in Musculoskeletal Radiology: Current Practice and Future Directions.

Over the last several decades, the volume and range of therapeutic musculoskeletal (MSK) interventions that radiologists can offer their patients has dramatically increased. With new materials and improving imaging modalities, as well as significant investment in research, the field of MSK interventional radiologic intervention will likely continue to expand. In this article, we summarize the range of interventions currently available to the MSK radiologist. We also seek to explore new and emerging techniques that may become commonplace in the near future while considering the challenges that may lie ahead in the field of MSK radiology.

Musculoskeletal Imaging: Current Practice and Future Directions.

Musculoskeletal (MSK) radiology plays a crucial role in the diagnosis and management of MSK disorders and has rapidly expanded in tandem with advances in technology and improved access to imaging. Although anatomical imaging remains the mainstay of MSK radiology, significant progress has been made in functional and molecular imaging as well as in hybrid imaging with an expanding armament of technologies becoming available or in development. A vast array of research is occurring in MSK imaging, and this review article highlights some of the most promising current and future clinical applications in development in each of the major imaging modalities. Identifying the clinical utility of these technologies in an era of rising health care costs is an important challenge for MSK radiologists.

Identification of highly potent and selective PI3Kδ inhibitors.

Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.

Discovery of highly potent, selective, covalent inhibitors of JAK3.

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.

Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

Synthesis and characterization of tritium labeled N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide.

N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide is a potent C-C chemokine receptor 1 (CCR1) antagonist. The compound, possessing benzamide functionality, successfully underwent tritium/hydrogen (T/H) exchange with an organoiridium catalyst (Crabtree's catalyst). The labeling pattern in the product was studied with liquid chromatography-mass spectrometry, time-of-flight mass spectrometry, and (3) H-NMR. Overall, multiple labeled species were identified. In addition to the anticipated incorporation of tritium in the benzamide moiety, tritium labeling was observed in the valine portion of the molecule including substitution at its chiral carbon. Using authentic standards, liquid chromatography analysis of the labeled compound showed complete retention of stereochemical configuration.

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.

Percutaneous image-guided treatment of mucoid degeneration of the ACL in advanced knee osteoarthritis-Preliminary observations.

OBJECTIVES: To describe the percutaneous image-guided treatment of mucoid degeneration of the ACL causing deep knee pain on flexion in patients with advanced knee osteoarthritis. METHODS: Five patients with mucoid degeneration of the ACL complicating knee osteoarthritis underwent percutaneous image-guided steroid bupivacaine ACL sleeve injections over a 3-year period. RESULTS: There were four males and one female of mean age 54 (range 48-59 years). Each patient had Kellgren and Lawrence grade 4 medial compartment knee osteoarthritis with coexistent mucoid degeneration of the ACL sleeve. Each patient complained of deep knee pain on flexion as a dominant symptom. Each patient underwent image-guided (CT or ultrasound) steroid bupivacaine injection of the ACL sleeve resulting in symptom resolution and improved mobility for a mean duration of 8 months, (range 6-15 months.) CONCLUSION: Mucoid degeneration of the ACL should be sought in patients with osteoarthritis presenting with deep knee pain on flexion. Image-guided ACL sleeve injection in affected patients may result in symptom resolution and potential deferral of planned knee replacement surgery. ADVANCES IN KNOWLEDGE: Emphasises Image guided percutaneous treatment of Mucoid degeneration of ACL in patients with knee osteoarthritis.