Analytic Morphomics in Myositis-Related Interstitial Lung Disease.

PURPOSE: Interstitial lung disease (ILD) is the most common non-musculoskeletal manifestation of idiopathic inflammatory myopathies (IIM). Identification of body composition change may enable early intervention to improve prognosis. We investigated muscle quantity and quality derived from cross-sectional imaging in IIM, and its relationship to ILD severity. METHODS: A retrospective cohort study assessing IIM of ILD patients (n = 31) was conducted. Two datasets separated in time were collected, containing demographics, biochemical data, pulmonary function testing and thoracic CT data. Morphomic analysis of muscle quantity (cross-sectional area) and quality (density in Hounsfield Units) on thoracic CT were analysed utilising a web-based tool allowing segmentation of muscle and fat. Bilateral erector spinae and pectoralis muscle (ESM&PM) were measured at defined vertebral levels. RESULTS: FVC and DLCO decreased but within acceptable limits of treatment response (FVC: 83.7-78.7%, p < 0.05, DLCO 63.4-60.6%, p < 0.05). The cross-sectional area of the PM and ESM increased (PM: 39.8 to 40.7 cm2, p = 0.491; ESM: 35.2 to 39.5 cm2, p = 0.098). Density significantly fell for both the PM and ESM (PM: 35.3-31 HU, p < 0.05; ESM: 38-33.7, p < 0.05). Subcutaneous fat area increased from 103.9 to 136.1 cm2 (p < 0.05), while the visceral fat area increased but not reaching statistical significance. The change in PM density between time points demonstrated an inverse correlation with DLCO (p < 0.05, R = - 0.49). CONCLUSION: Patients with IIM ILD demonstrated significant body composition changes on CT imaging unlikely to be detected by traditional measurement tools. An increase in muscle area with an inverse decrease in density suggests poor muscle quality.

Multifaceted Bioanalytical Methods for the Comprehensive Pharmacokinetic and Catabolic Assessment of MEDI3726, an Anti-Prostate-Specific Membrane Antigen Pyrrolobenzodiazepine Antibody-Drug Conjugate.

Complex biotherapeutic modalities, such as antibody-drug conjugates (ADC), present significant challenges for the comprehensive bioanalytical characterization of their pharmacokinetics (PK) and catabolism in both preclinical and clinical settings. Thus, the bioanalytical strategy for ADCs must be designed to address the specific structural elements of the protein scaffold, linker, and warhead. A typical bioanalytical strategy for ADCs involves quantification of the Total ADC, Total IgG, and Free Warhead concentrations. Herein, we present bioanalytical characterization of the PK and catabolism of a novel ADC. MEDI3726 targets prostate-specific membrane antigen (PMSA) and is comprised of a humanized IgG1 antibody site-specifically conjugated to tesirine (SG3249). The MEDI3726 protein scaffold lacks interchain disulfide bonds and has an average drug to antibody ratio (DAR) of 2. Based on the structural characteristics of MEDI3726, an array of 4 bioanalytical assays detecting 6 different surrogate analyte classes representing at least 14 unique species was developed, validated, and employed in support of a first-in-human clinical trial (NCT02991911). MEDI3726 requires the combination of heavy-light chain structure and conjugated warhead to selectively deliver the warhead to the target cells. Therefore, both heavy-light chain dissociation and the deconjugation of the warhead will affect the activity of MEDI3726. The concentration-time profiles of subjects dosed with MEDI3726 revealed catabolism of the protein scaffold manifested by the more rapid clearance of the Active ADC, while exhibiting minimal deconjugation of the pyrrolobenzodiazepine (PBD) warhead (SG3199).

Cumulative Radiation Dose from Medical Imaging in Children with Congenital Heart Disease: A Systematic Review.

Children with congenital heart disease are exposed to repeated medical imaging throughout their lifetime. Although the imaging contributes to their care and treatment, exposure to ionising radiation is known to increase one's lifetime attributable risk of malignancy. A systematic search of multiple databases was performed. Inclusion and exclusion criteria were applied to all relevant papers and seven were deemed acceptable for quality assessment and risk of bias assessment. The cumulative effective dose (CED) varied widely across the patient cohorts, ranging from 0.96 mSv to 53.5 mSv. However, it was evident across many of the included studies that a significant number of patients were exposed to a CED >20 mSv, the current annual occupational exposure limit. Many factors affected the dose which patients received, including age and clinical demographics. The imaging modality which contributed the most radiation dose to patients was cardiology interventional procedures. Paediatric patients with congenital heart disease are at an increased risk of receiving an elevated cumulative radiation dose across their lifetime. Further research should focus on identifying risk factors for receiving higher radiation doses, keeping track of doses, and dose optimisation where possible.

Replacing Plain Radiograph with ultra-low dose CT thorax in cystic fibrosis (CF) in the era of CFTR modulation and its impact on cumulative effective dose.

BACKGROUND: Medical radiation exposure is of increasing concern in patients with cystic fibrosis (PWCF) due to improving life expectancy. We aimed to assess and quantify the cumulative effective dose (CED) in PWCF in the context of CFTR-modulator therapy and the advancement of dose reduction techniques. METHODS: We performed a retrospective observational study in a single University CF centre over a 11-year period. We included PWCF, aged over 18 years who exclusively attended our institution. Relevant clinical data (demographics, transplantation history and modulator status) and radiological data (modality, quantity, and radiation exposure measured as CED) were collected. For those on modulator therapy the quantified imaging and radiation data was dichotomised into pre-and-post therapy periods. RESULTS: The study included 181 patients: 139 on CFTR modulator therapy, 15 transplant recipients and 27 with neither exposure. 82% of patients received <25 mSv over the study period. Mean study duration was 6.9 ± 2.6 years pre-modulation and 4.2 ± 2.6 years post-modulation. Pre-modulation CT contributed 9.6% of total chest imaging (n = 139/1453) and 70.9% of the total CED. Post-modulation CT use increased contributing 42.7% of chest imaging (n = 444/1039) and comprised 75.8% of CED. Annual CED was 1.55 mSv pre and 1.36 mSv post modulation (p = 0.41). Transplant recipients had an annual CED of 64 ± 36.1mSv. CONCLUSION: Chest CT utilisation for PWCF is rising in our institution, replacing chest radiography amidst CFTR-modulation. Despite the increasing use of CT, no significant radiation dose penalty was observed with a reduction in mean annual CED, primarily due to the influence of CT dose reduction strategies.

Barrier materials for prevention of surgical adhesions: systematic review.

BACKGROUND: Postoperative surgical adhesions constitute a major health burden internationally. A wide range of materials have been evaluated, but despite constructive efforts and the obvious necessity, there remains no specific barrier widely utilized to prevent postoperative adhesion formation. The aim of this study was to highlight and characterize materials used for prevention of postoperative surgical adhesions in both animal and human studies. METHODS: A systematic review was performed of all original research articles presenting data related to the prevention of postoperative adhesions using a barrier agent. All available observational studies and randomized trials using animal models or human participants were included, with no restrictions related to type of surgery. PubMed and Embase databases were searched using key terms from inception to August 2019. Standardized data collection forms were used to extract details for each study and assess desirable characteristics of each barrier and success in animal and/or human studies. RESULTS: A total of 185 articles were identified for inclusion in the review, with a total of 67 unique adhesion barrier agents (37 natural and 30 synthetic materials). Desirable barrier characteristics of an ideal barrier were identified on review of the literature. Ten barriers achieved the primary outcome of reducing the incidence of postoperative adhesions in animal studies followed with positive outputs in human participants. A further 48 materials had successful results from animal studies, but with no human study performed to date. DISCUSSION: Multiple barriers showed promise in animal studies, with several progressing to success, and fulfilment of desirable qualities, in human trials. No barrier is currently utilized commonly worldwide, but potential barriers have been identified to reduce the burden of postoperative adhesions and associated sequelae.

Uterine Artery Embolisation of Fibroids and the Phenomenon of Post-Embolisation Syndrome: A Systematic Review.

Post-embolisation syndrome (PES) is a prevalent complication that occurs in patients following uterine artery embolisation (UAE) for the treatment of uterine fibroids. The aetiology of PES remains incompletely understood, although postulated to result secondary to tissue infarction resulting in release of inflammatory mediators. We followed PRISMA guidelines and performed a systematic review of studies of PES following UAE from inception to October 2022. Our published protocol was prospectively registered. Our search yielded 54 results. We reviewed 22 full texts, and nine articles were included. Observational studies comprised 6/9 relevant studies, with 5/9 retrospective design. The rate of PES was documented in 5/8 studies (excluding case report) with a reported incidence ranging from 4-34.6%. Five of the nine studies studies postulated that the aetiological basis of PES is inflammatory related. Further research is necessary to advance our understanding of PES to define the biological basis of the syndrome with more certainty and gain a consensus on peri-procedure management to reduce incidence and improve patient outcomes.

A highly sensitive and selective UPLC-MS/MS assay for the determination of enarodustat (JTZ-951) in human plasma.

Enarodustat, a potent, orally bioavailable, selective inhibitor of hypoxia inducible factor-Prolyl hydroxylase (HIF-PH), has been approved recently in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). To evaluate the pharmacokinetics of enarodustat, a bioanalytical assay in human plasma was needed for the quantitation of enarodustat for both healthy subjects and patients with CKD. The UPLC-MS/MS method for the quantitation of enarodustat was initially validated in a bioanalytical laboratory in Japan to support clinical studies conducted in Japan, and then was transferred and validated in a bioanalytical laboratory in United States to support clinical studies conducted here. A cross-validation was successfully performed between the two bioanalytical laboratories using both quality control (QC) samples and incurred study samples. Enarodustat was fortified with its isotopically labeled internal standard in a 25 µL plasma aliquot and extracted with protein precipitation. The chromatographic separation was achieved on an Acquity UPLC BEH C18 (1.7 µm, 2.1 × 50 mm) column with gradient elution. The calibration curve range for the assay was 1.00-500 ng/mL. Assay precision, accuracy, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. No interferences were observed from medications that may be co-administered along with enarodustat. The validated UPLC-MS-MS method at the US bioanalytical laboratory has been successfully applied to eight clinical studies for the determination of enarodustat concentrations in human plasma for both healthy subjects and patients with CKD.

Validation and clinical application of dried blood spot assay for quantitative assessment of edoxaban in healthy adults.

Aim: Dried blood spot (DBS) is a sampling approach that offers several advantages over plasma and whole blood (WB) sampling, but several factors, such as hematocrit and temperature, can adversely affect quantitation. Methodology & results: In an open-label, three-way crossover study in healthy subjects, we explored the correlation between DBS, WB and plasma samples, and between DBS samples from finger-prick and venipuncture blood for measuring edoxaban and its metabolite M-4 using LC-MS/MS. The methods were validated comprehensively. The incurred sample reanalysis experiments demonstrated quantitation reproducibility in all three matrices. Overall, there was a good correlation (near perfect concordance for edoxaban) among plasma, WB and DBS measurements. M-4 concentrations in DBS and WB were lower than in plasma. Conclusion: These results indicate using DBS may be used as an alternative methodology to measure edoxaban pharmacokinetics.

Multiplex LC-MS/MS Assays for Clinical Bioanalysis of MEDI4276, an Antibody-Drug Conjugate of Tubulysin Analogue Attached via Cleavable Linker to a Biparatopic Humanized Antibody against HER-2.

Bioanalysis of complex biotherapeutics, such as antibody-drug conjugates (ADCs), is challenging and requires multiple assays to describe their pharmacokinetic (PK) profiles. To enable exposure-safety and exposure-efficacy analyses, as well as to understand the metabolism of ADC therapeutics, three bioanalytical methods are typically employed: Total Antibody, Antibody Conjugated Toxin or Total ADC and Unconjugated Toxin. MEDI4276 is an ADC comprised of biparatopic humanized antibody attached via a protease-cleavable peptide-based maleimidocaproyl linker to a tubulysin toxin (AZ13599185) with an approximate average drug-antibody ratio of 4. The conjugated payload of MEDI4276 can undergo ester hydrolysis to produce the conjugated payload AZ13687308, leading to the formation of MEDI1498 (de-acetylated MEDI4276). In this report, we describe the development, validation and application of three novel multiplex bioanalytical methods. The first ligand-binding liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) method was developed and validated for simultaneous measurement of total antibody and total ADC (antibody-conjugated AZ13599185) from MEDI4276. The second LBA-LC-MS/MS assay quantified total ADC (antibody-conjugated AZ13687308) from MEDI1498. The third multiplex LC-MS/MS assay was used for simultaneous quantification of unconjugated AZ13599185 and AZ13687308. Additional stability experiments confirmed that quantification of the released warhead in the presence of high concentrations of MEDI4276 was acceptable. Subsequently, the assays were employed in support of a first-in-human clinical trial (NCT02576548).

Obscure gastrointestinal bleeding resulting from small bowel neoplasia; A case series.

INTRODUCTION: Undiagnosed gastrointestinal bleeding may originate in the small bowel. This presents a diagnostic challenge despite the advancement in contemporary imaging. We report two cases which highlight the limitations of routine investigation for obscure gastrointestinal bleeding. PRESENTATION OF CASE: Patient A presented with a history of rectal bleeding, treated with interventional embolisation of caecal angiodysplasia. A diagnosis of neuroendocrine tumour (NET) was reached two years after presentation following intraoperative right hemicolectomy resection of a presumed recurrent angiodysplastic bleed. Patient B presented with recurrent melaena labelled as non-steroidal anti-inflammatory drug (NSAID) induced gastritis. After multiple endoscopic and radiological investigations, a 4.5 cm mass was visualised on imaging after three years, which was histologically proven as gastrointestinal stromal tumour (GIST) of the small bowel. Both patients experienced a delayed diagnosis despite multiple investigations and careful follow-up. DISCUSSION: Our case series discusses the benefits and limitations of investigation for gastrointestinal bleeding and suggests a need for continued multidisciplinary input in situations where the patient presumed diagnosis remains in question. CONCLUSION: OGIB remains a diagnostic challenge and is attributable to small bowel pathology in 75% of cases. This suggests a need for continued investigation in situations where the patient presents multiple times despite adequate treatment for the presumed underlying condition.

Development and validation of HILIC-ESI/MS/MS methods for simultaneous quantitation of several antipsychotics in human plasma and blood.

BACKGROUND: Knowledge of antipsychotic drug levels at point of care (POC) may significantly aid therapeutic decision-making. To support the development of future POC devices and to validate the use of fingerstick capillary blood sampling, two robust hydrophilic interaction LC-ESI/MS/MS methods were developed and validated. Two PK studies were completed evaluating the correlation between fingerstick blood and plasma concentrations with corresponding venous blood and plasma concentrations for several commonly prescribed atypical antipsychotics and selected metabolites. Sensitive and reliable LC-MS/MS bioanalytical assays were developed to support these studies. RESULTS: Three methods, requiring only 25-µl matrix volumes, were developed using supported liquid extraction with hydrophilic interaction LC-MS/MS detection and validated according to regulatory guidance. CONCLUSION: Robust and efficient LC-MS/MS assays were established and were effective in providing antipsychotic drug matrix comparator results in the intended clinical studies.