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1.
Ann Am Thorac Soc ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33413026

RESUMO

RATIONALE: Much is known about the acute infective process of SARS-CoV-2, the causative virus of the COVID-19 pandemic. The marked inflammatory response and coagulopathic state in acute SARS-CoV-2 may promote pulmonary fibrosis. However, little is known of the incidence and seriousness of post-COVID pulmonary pathology. OBJECTIVES: We describe respiratory recovery and self-reported health following infection at time of outpatient attendance. METHODS: Infection severity was graded into three groups: (i) not requiring admission, (ii) requiring hospital admission, and (iii) requiring ICU care. Participants underwent chest radiography and six-minute-walk test (6MWT). Fatigue and subjective return to health were assessed and levels of C-reactive protein (CRP), interleukin-6, soluble CD25 and D-dimer were measured. The association between initial illness and abnormal chest x-ray, 6MWT distance and perception of maximal exertion was investigated. RESULTS: 487 patients were offered an outpatient appointment, of which 153 (31%) attended for assessment at a median of 75 days after diagnosis. 74 (48%) had required hospital admission during acute infection. Persistently abnormal chest x-rays were seen in 4%. The median 6MWT distance covered was 460m. Reduced distance covered was associated with frailty and length of inpatient stay. 95 (62%) felt that they had not returned to full health, while 47% met the case definition for fatigue. Ongoing ill-health and fatigue were associated with increased perception of exertion. None of the measures of persistent respiratory disease were associated with initial disease severity. CONCLUSIONS: This study highlights the rates of objective respiratory disease and subjective respiratory symptoms following COVID-19 and the complex multifactorial nature of post-COVID ill-health.

2.
Org Lett ; 23(1): 60-65, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33351641

RESUMO

The use of the unprecedented annulating reagents methyl N-(tert-butylsulfinyl)-4-chlorobutanimidate and methyl N-(tert-butylsulfinyl)-5-bromopentanimidate enables the diastereoselective preparation of 5- and 6-membered carbocycles bearing three contiguous stereocenters. These synthons undergo cycloaddition with a variety of Michael acceptors to form cyclopentane/cyclohexane rings with excellent stereochemical control, generating only one of the eight possible diastereomers. This novel methodology has enabled the highly enantioselective and high yielding synthesis of novel chemotypes of pharmacological relevance.

3.
J Med Chem ; 63(23): 15050-15071, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33261314

RESUMO

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

4.
Bioorg Med Chem Lett ; 30(23): 127521, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882417

RESUMO

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.

5.
Skeletal Radiol ; 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32734375

RESUMO

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.

7.
Bioorg Med Chem Lett ; 30(19): 127466, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763309

RESUMO

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.

8.
ACS Med Chem Lett ; 11(7): 1402-1409, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32676146

RESUMO

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.

10.
Radiol Case Rep ; 15(4): 424-426, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32082463

RESUMO

We present the case of a 17 year old football player with a 2 week history of left leg weakness and difficulty weight-bearing. Magnetic resonance imaging revealed a well-circumscribed lesion deep to the left iliacus muscle. The patient proceeded to computed tomography-guided biopsy. The likely diagnosis was that of a subperiosteal haematoma of the iliac wing, which was exerting mass effect upon the left femoral nerve resulting in leg pain and weakness. Imaging was repeated at an interval of 1 month, at which time the lesion had almost entirely resolved. Subperiosteal haematoma of the iliac bone is a rare entity but should be considered as a potential diagnosis in young adults, particularly where there is a history of trauma or recent sports injury.

12.
Ir J Med Sci ; 189(1): 333-336, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31292918

RESUMO

AIMS: To rationalize the ordering of trauma cervical spine radiographs via the institution of electronic clinical decision support criteria. METHODS: In February 2017, we added evidence-based criteria to the electronic imaging ordering system so that requesting clinicians had to indicate which criteria the patient met. We subsequently compared numbers of cervical spine trauma films requested by the ED in comparable months prior to and after the intervention. RESULTS: The total number of ED trauma cervical spine radiographs reduced by 30.7%, from 182 (in March and April 2016) to 126 (in March and April 2017). The proportion of requests clinically indicated increased from 76.7% (140/182) to 99.2% (125/126). There were no fractures in the 2016 period. 1.6% (2/126) had fractures in the 2017 group. CONCLUSION: Introduction of clinical indication criteria to the electronic ordering system for cervical spine radiographs in trauma patients reduced the total number of requests by 30.7% while increasing the proportion which were indicated to 99.2%.


Assuntos
Vértebras Cervicais/lesões , Sistemas de Apoio a Decisões Clínicas/normas , Traumatismos da Coluna Vertebral/diagnóstico por imagem , Feminino , Humanos , Masculino
13.
J Med Chem ; 62(21): 9931-9946, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.


Assuntos
Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Animais , Humanos , Células Jurkat , Camundongos , Modelos Moleculares , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
14.
Org Lett ; 21(22): 9198-9202, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31647672

RESUMO

This communication highlights the use of chiral sulfinamides as nitrogen nucleophiles in intermolecular aza-Michael reactions. When chiral sulfinamides are coupled to a chloroethyl group, the corresponding novel annulating reagents can be used to streamline the stereoselective synthesis of complex pyrrolidine-containing molecules. As a result, it has enabled a medicinal chemistry campaign for the synthesis of biologically active RORγt inverse agonists.

15.
J Magn Reson Imaging ; 50(6): 1687-1701, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31016800

RESUMO

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.


Assuntos
Doenças da Medula Óssea/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Imagem Corporal Total/métodos , Medula Óssea/diagnóstico por imagem , Humanos
16.
Artigo em Inglês | MEDLINE | ID: mdl-30553974

RESUMO

INTRODUCTION: Low intrinsic solubility leading to poor oral bioavailability is a common challenge in drug discovery that can often be overcome by formulation strategies, however, it remains a potential limitation that can pose challenges for early risk assessment and represent a significant obstacle to drug development. We identified a selective inhibitor (BMS-986126) of the IL-1 receptor-associated kinase 4 (IRAK4) with favorable properties as a lead candidate, but with unusually low intrinsic solubility of <1 µg/mL. METHODS: Conventional histopathology identified the issue of crystal formation in vivo. Subsequent investigative work included confocal Raman micro-spectroscopy, MALDI-MS, polarized light microscopy of fresh wet-mount tissue scrapings and transmission electron microscopy. RESULTS: BMS-986126 was advanced into a 2-week toxicology study in rats. The main finding in this study was minimal granulomatous inflammation in the duodenum, associated with the presence of birefringent crystals at the highest dosage of 100 mg/kg/day. Considering the safety margin, and the single location of the lesion, BMS-986126 was further progressed into IND-enabling toxicology studies where tolerability deteriorated with increasing dosing duration. Birefringent crystals and granulomatous inflammation were detected in multiple organs at dosages ≥20 mg/kg/day. Raman spectroscopy confirmed the identity of the crystals as BMS-986126. Therefore, follow up investigations were conducted to further characterize drug crystallization and to evaluate detection methods for their potential to reliably detect in vivo crystallization early. DISCUSSION: The purpose of our efforts was to identify critical factors influencing in vivo drug crystallization and to provide a preliminary assessment (based on one compound) which method would be best suited for identifying crystals. Results indicated a combination of methods was required to provide a complete assessment of drug crystallization and that a simple technique, scraping of freshly collected tissue followed by evaluation under polarizing light was suitable for detecting crystals. However, dosing for 2 weeks was required for crystals to grow to a clearly detectable size.


Assuntos
Cristalização , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Animais , Disponibilidade Biológica , Descoberta de Drogas , Duodeno/patologia , Feminino , Quinases Associadas a Receptores de Interleucina-1/química , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Cultura Primária de Células , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Risco , Solubilidade , Análise Espectral Raman
17.
Semin Musculoskelet Radiol ; 22(5): 546-563, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30399619

RESUMO

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.


Assuntos
Diagnóstico por Imagem/tendências , Doenças Musculoesqueléticas/diagnóstico por imagem , Doenças Musculoesqueléticas/terapia , Ortopedia/tendências , Radiologia Intervencionista/tendências , Previsões , Humanos , Biópsia Guiada por Imagem/tendências , Cirurgia Assistida por Computador/tendências
18.
Semin Musculoskelet Radiol ; 22(5): 564-581, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30399620

RESUMO

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.


Assuntos
Diagnóstico por Imagem/tendências , Doenças Musculoesqueléticas/diagnóstico por imagem , Previsões , Humanos
19.
Semin Musculoskelet Radiol ; 22(5): 582-591, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30399621

RESUMO

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.


Assuntos
Traumatismos em Atletas/diagnóstico por imagem , Traumatismos em Atletas/terapia , Diagnóstico por Imagem/tendências , Doenças Musculoesqueléticas/diagnóstico por imagem , Doenças Musculoesqueléticas/terapia , Papel do Médico , Medicina Esportiva/tendências , Humanos
20.
Org Lett ; 20(2): 337-340, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29283585

RESUMO

The purpose of this letter is to document the use of protected chloroethyl and chloropropyl amines as conformationally unrestricted ambiphilic reagents that undergo annulation reactions with Michael acceptors. This reaction is wide in scope and utilizes reagents that are commercially available, inexpensive, and stable. Furthermore, this reaction is easy to execute and proceeds rapidly.

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