Herein we report the use of next generation maleimides (NGMs) for the construction of a potent antibody-drug conjugate (ADC) via functional disulfide bridging. The linker has excellent stability in ...blood serum and the ADC, armed with monomethyl auristatin E (MMAE), shows excellent potency and cancer cell selectivity in vitro.
The purpose of this article is to evaluate the effect of sinogram-affirmed iterative reconstruction (SAFIRE) on contrast-to-noise ratio (CNR) compared with filtered back projection (FBP) and to ...determine whether SAFIRE improves low-contrast object detection or conspicuity in a low-contrast object phantom and in the liver on full- and low-dose examinations.
A low-contrast object phantom was scanned at 100%, 70%, 50%, and 30% dose using a single-source made of a dual-source MDCT scanner, with the raw data reconstructed with SAFIRE and FBP. Unenhanced liver CT scans in 22 patients were performed using a dual-source MDCT. The raw data from both tubes (100% dose) were reconstructed using FBP, and data from one tube (50% dose) were reconstructed using both FBP and SAFIRE. CNR was measured in the phantom and in the liver. Noise, contrast, and CNR were compared using paired Student t tests. Six readers assessed sphere detection and conspicuity in the phantom and liver-inferior vena cava conspicuity in the patient data. The phantom and patient data were assessed using multiple-variable logistic regression.
The phantom at 70% and 50% doses with SAFIRE had decreased noise and increased CNR compared with the 100% dose with FBP. In the liver, the mean CNR improvement at 50% dose with SAFIRE compared with FBP was 31.4% and 88% at 100% and 50% doses, respectively (p < 0.001). Sphere object detection and conspicuity improved with SAFIRE (p < 0.001). However, smaller spheres were obscured on both FBP and SAFIRE images at lower doses. Liver-vessel conspicuity improved with SAFIRE over 50%-dose FBP in 67.4% of cases (p < 0.001), and versus 100%-dose FBP, improved in 38.6% of cases (p = 0.085). As a predictor for detection, CNR alone had a discriminatory ability (c-index, 0.970) similar to that of the model that analyzed dose, lesion size, attenuation difference, and reconstruction technique (c-index, 0.978).
Lower dose scans reconstructed with SAFIRE have a higher CNR. The ability of SAFIRE to improve low-contrast object detection and conspicuity depends on the radiation dose level. At low radiation doses, low-contrast objects are invisible, regardless of reconstruction technique.
For over 40 years, restorative proctocolectomy has been used in patients with ulcerative colitis or familial adenomatous polyposis undergoing proctocolectomy. Radiologists are now encountering an ...increasing number of patients with an ileal pouch and therefore need to understand the clinical issues and concerns in these patients. This review is the introduction of a special issue on the ileal pouch and was written with both surgeon and gastroenterology input. The intent is to assist the radiologist in understanding the clinical questions posed by both the patients and their physicians. Subsequent sessions will address specific imaging modalities and techniques, how the gastroenterologists and surgeons address issues with these patients, and a final session summarizing the sessions and speculating on future investigations and approaches.
IMPORTANCE: A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis. ...OBJECTIVE: To characterize the exposure characteristics and clinical manifestations of PPS–associated maculopathy. DESIGN, SETTING, AND PARTICIPANTS: In this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed. Data were collected from August 1, 2012, to October 1, 2018, and data were analyzed from October 2018 to January 2019. MAIN OUTCOMES AND MEASURES: Drug exposure, visual acuity, and retinal imaging characteristics. RESULTS: Of the 35 included patients (70 eyes), 34 (97%) were female, and the median (range) age was 60 (37-79) years. The median (range) duration of PPS intake was 15 (3-22) years, and the median (range) cumulative exposure was 1.61 (0.44-4.31) kg. The leading visual symptoms were metamorphopsia, blurred vision, and prolonged dark adaptation. Median (range) logMAR visual acuity of all eyes was 0.10 (−0.12 to 1.18). Fundus examination often revealed hyperpigmented macular spots (34 of 64 eyes 53%) with interspersed pale-yellow deposits, although less commonly in eyes that exhibited retinal pigment epithelial atrophy (6 of 26 eyes 23%; P < .001). Optical coherence tomography showed foci of retinal pigment epithelium elevation or thickening associated with hyperreflectance on near-infrared reflectance imaging. Fundus autofluorescence imaging typically revealed a symmetric, confluent pattern of hyperautofluorescent and hypoautofluorescent spots that involved the fovea in all eyes and extended to the retinal periphery in 24 eyes (36%). Longitudinal evaluation demonstrated dynamic changes in pigmentary abnormalities. CONCLUSIONS AND RELEVANCE: These findings suggest that PPS–associated maculopathy is a vision-threatening condition that can manifest in the setting of long-term exposure to the drug. Multimodal imaging posits a distinctive clinical phenotype, characterized in this cohort by dynamic alterations within the retinal pigment epithelium and at the retinal pigment epithelium–photoreceptor interface. Ongoing work might explore causality and direct screening guidelines.
Stenosis is a common complication of Crohn’s disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed ...tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD.
We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system.
We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed.
In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.
Digital interventions that deliver psychological self-help provide the opportunity to reach individuals at risk of suicide who do not access traditional health services. Our primary objective was to ...test whether direct (targeting suicidality) and indirect (targeting depression) digital interventions are effective in reducing suicidal ideation and behaviours, and our secondary analyses assessed whether direct interventions were more effective than indirect interventions.
In this systematic review and meta-analysis, we searched online databases MEDLINE, PubMed, PsycINFO, and Cochrane CENTRAL for randomised controlled trials published between database inception to May 21, 2019. Superiority randomised controlled trials of self-guided digital interventions (app or web based, which delivered theory-based therapeutic content) were included if they reported suicidal ideation, suicidal plans, or suicide attempts as an outcome. Non-inferiority randomised controlled trials were excluded to ensure comparability of the effect. Data were extracted from published reports, and intention-to-treat data were used if available. The primary outcome was the difference in mean scores of validated suicidal ideation measures (Hedges'g) with the associated 95% CI for the analysis of digital intervention effectiveness on suicidal ideation. We also present funnel plots of the primary outcome measure (suicidal ideation) for direct and indirect interventions to assess for publication bias. We calculated I2 (with I2 CI) values to test heterogeneity. We used random-effects modelling for the meta-analyses to assess the primary and secondary outcomes. This study is registered with PROSPERO, CRD42018102084.
The literature search yielded 739 articles (including manual searching) for suicidality and 8842 articles for depression. After screening, 14 papers reporting on 16 studies were included in the narrative review and meta-analysis. The 16 studies (ten on direct interventions and six on indirect interventions) provided baseline data for 4398 participants. The primary outcome of overall post-intervention effect for suicidal ideation was small but significant immediately following the active intervention phase (Hedges'g −0·18, 95% CI −0·27 to −0·10, p<0·0001; I2=0%, I2 CI 0·0–47·9). The secondary objective, comparing direct and indirect interventions, showed that direct interventions (targeting suicidality) significantly reduced suicidal ideation at post-intervention (g −0·23, 95% CI −0·35 to −0·11, p<0·0001; I2=17·6%, I2 CI 0·0–58·6), but indirect interventions (targeting depression) failed to reach significance (g −0·12, 95% CI −0·25 to 0·01, p=0·071; I2=0%, I2 CI 0·0–30·7).
Self-guided digital interventions directly targeting suicidal ideation are effective immediately post-intervention. Indirect interventions were not significant for reducing suicidal ideation. Our findings suggest that digital interventions should be promoted and disseminated widely, especially where there is a lack of, or minimal access to, health services.
Australian National Health and Medical Research Council.
The 18F-JNJ-64326067-AAA (18F-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) ...participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a 11C-PIB amyloid PET scan, and a tau 18F-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The 18F-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. 18F-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of 18F-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests 18F-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.
The introduction of non-natural entities into proteins by chemical modification has numerous applications in fundamental biological science and for the development and manipulation of peptide and ...protein therapeutics. The reduction of native disulfide bonds provides a convenient method to access two nucleophilic cysteine residues that can serve as ideal attachment points for such chemical modification. The optimum bioconjugation strategy utilizing these cysteine residues should include the reconstruction of a bridge to mimic the role of the disulfide bond, maintaining structure and stability of the protein. Furthermore, the bridging chemical modification should be as rapid as possible to prevent problems associated with protein unfolding, aggregation, or disulfide scrambling. This study reports on an in situ disulfide reduction-bridging strategy that ensures rapid sequestration of the free cysteine residues in a bridge, using dithiomaleimides. This approach is then used to PEGylate the peptide hormone somatostatin and retention of biological activity is demonstrated.
Disulfide bridging offers a convenient approach to generate site-selective antibody conjugates from native antibodies. To optimise the reagents available to achieve this strategy, we describe here ...the use of dibromomaleimides designed to undergo accelerated post-conjugation hydrolysis. Conjugation and hydrolysis, which serve to 'lock' the conjugates as robustly stable maleamic acids, is achieved in just over 1 h. This dramatic acceleration is also shown to infer significant improvements in homogeneity, as demonstrated by mass spectrometry analysis.
In this communication we describe a novel acid-cleavable linker strategy for antibody-drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab ...fragment yields a homogeneous antibody-drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload.
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