Three commercial metal artifact reduction methods were evaluated for use in computed tomography (CT) imaging in the presence of clinically realistic metal implants: Philips O-MAR, GE's monochromatic ...gemstone spectral imaging (GSI) using dual-energy CT, and GSI monochromatic imaging with metal artifact reduction software applied (MARs). Each method was evaluated according to CT number accuracy, metal size accuracy, and streak artifact severity reduction by using several phantoms, including three anthropomorphic phantoms containing metal implants (hip prosthesis, dental fillings and spinal fixation rods). All three methods showed varying degrees of success for the hip prosthesis and spinal fixation rod cases, while none were particularly beneficial for dental artifacts. Limitations of the methods were also observed. MARs underestimated the size of metal implants and introduced new artifacts in imaging planes beyond the metal implant when applied to dental artifacts, and both the O-MAR and MARs algorithms induced artifacts for spinal fixation rods in a thoracic phantom. Our findings suggest that all three artifact mitigation methods may benefit patients with metal implants, though they should be used with caution in certain scenarios.
A hallmark of severe COVID-19 pneumonia is SARS-CoV-2 infection of the facultative progenitors of lung alveoli, the alveolar epithelial type 2 cells (AT2s). However, inability to access these cells ...from patients, particularly at early stages of disease, limits an understanding of disease inception. Here, we present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 by using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. We find a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-κB signaling and loss of the mature alveolar program. Drug testing confirms the efficacy of remdesivir as well as TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in alveolar cells. Our model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development.
Display omitted
•iPSC-derived alveolar type 2 cells (iAT2s) are permissive to SARS-CoV-2 infection•SARS-CoV-2 induces an iAT2-intrinsic cytotoxicity and inflammatory response•iAT2s effectively model antiviral drug response and may be used for further drug development
Huang et al. show that human iPSC-derived alveolar type 2 cells (iAT2s) can be used to model COVID-19. They find that iAT2s in air-liquid interface culture are permissive to SARS-CoV-2 infection and show that SARS-CoV-2 induces a rapid inflammatory phenotype predominated by NF-κB signaling.
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and ...translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.
Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. The functional relationship between subchondral bone (SB) and ...articular cartilage (AC) is unclear. Here, we found that the changes of SB architecture altered the distribution of mechanical stress on AC. Importantly, the latter is well aligned with the pattern of transforming growth factor beta (TGFβ) activity in AC, which is essential in the regulation of AC homeostasis. Specifically, TGFβ activity is concentrated in the areas of AC with high mechanical stress. A high level of TGFβ disrupts the cartilage homeostasis and impairs the metabolic activity of chondrocytes. Mechanical stress stimulates talin-centered cytoskeletal reorganization and the consequent increase of cell contractile forces and cell stiffness of chondrocytes, which triggers αV integrin-mediated TGFβ activation. Knockout of αV integrin in chondrocytes reversed the alteration of TGFβ activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. Thus, SB structure determines the patterns of mechanical stress and the configuration of TGFβ activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis.
To determine whether in-house patient-specific intensity modulated radiation therapy quality assurance (IMRT QA) results predict Imaging and Radiation Oncology Core (IROC)-Houston phantom results.
...IROC Houston's IMRT head and neck phantoms have been irradiated by numerous institutions as part of clinical trial credentialing. We retrospectively compared these phantom results with those of in-house IMRT QA (following the institution's clinical process) for 855 irradiations performed between 2003 and 2013. The sensitivity and specificity of IMRT QA to detect unacceptable or acceptable plans were determined relative to the IROC Houston phantom results. Additional analyses evaluated specific IMRT QA dosimeters and analysis methods.
IMRT QA universally showed poor sensitivity relative to the head and neck phantom, that is, poor ability to predict a failing IROC Houston phantom result. Depending on how the IMRT QA results were interpreted, overall sensitivity ranged from 2% to 18%. For different IMRT QA methods, sensitivity ranged from 3% to 54%. Although the observed sensitivity was particularly poor at clinical thresholds (eg 3% dose difference or 90% of pixels passing gamma), receiver operator characteristic analysis indicated that no threshold showed good sensitivity and specificity for the devices evaluated.
IMRT QA is not a reasonable replacement for a credentialing phantom. Moreover, the particularly poor agreement between IMRT QA and the IROC Houston phantoms highlights surprising inconsistency in the QA process.
Objective
To compare fall incidence, and visual acuity and refractive status, before surgery and after first and second eye cataract surgery.
Design, setting
Prospective observational study in eight ...tertiary referral ophthalmology clinics in public hospitals in Sydney, Melbourne, and Perth.
Participants
People aged 65 years or more referred for bilateral age‐related cataract surgery during 2013–16, followed for maximum of 24 months after study entry or until six months after second eye surgery, whichever was shorter.
Main outcome measures
Primary outcome: age‐ and sex‐adjusted incidence of falls. Secondary outcomes: visual acuity and refractive error.
Results
The mean age of the 409 included participants was 75.4 years (SD, 5.4 years); 220 were women (54%). Age‐ and sex‐adjusted fall incidence prior to surgery was 1.17 (95% CI, 0.95–1.43) per year, 0.81 (95% CI, 0.63–1.04) per year after first eye surgery, and 0.41 (95% CI, 0.29–0.57) per year after second eye surgery. For the 118 participants who underwent second eye surgery and participated in all follow‐up visits, age‐ and sex‐adjusted incidence before (0.80 95% CI, 0.55–1.15 falls per year) and after first eye surgery (0.81 95% CI, 0.57–1.15 falls per year) was similar, but was lower after second eye surgery (0.32 95% CI 0.21–0.50 falls per year). Mean habitual binocular visual acuity (logMAR) was 0.32 (SD, 0.21) before surgery, 0.15 (SD, 0.17) after first eye surgery, and 0.07 (SD, 0.15) after second eye surgery.
Conclusions
First eye surgery substantially improves vision in older people with cataract, but second eye surgery is required to minimise fall incidence. Timely cataract surgery for both eyes not only optimises vision in older people with cataract, but also reduces their risk of injury from falls.
Alveolar epithelial type 2 cells (AEC2s) are the facultative progenitors responsible for maintaining lung alveoli throughout life but are difficult to isolate from patients. Here, we engineer AEC2s ...from human pluripotent stem cells (PSCs) in vitro and use time-series single-cell RNA sequencing with lentiviral barcoding to profile the kinetics of their differentiation in comparison to primary fetal and adult AEC2 benchmarks. We observe bifurcating cell-fate trajectories as primordial lung progenitors differentiate in vitro, with some progeny reaching their AEC2 fate target, while others diverge to alternative non-lung endodermal fates. We develop a Continuous State Hidden Markov model to identify the timing and type of signals, such as overexuberant Wnt responses, that induce some early multipotent NKX2-1+ progenitors to lose lung fate. Finally, we find that this initial developmental plasticity is regulatable and subsides over time, ultimately resulting in PSC-derived AEC2s that exhibit a stable phenotype and nearly limitless self-renewal capacity.
Display omitted
•Only a subset of PSC-lung progenitors maintain cell fate as they differentiate to iAEC2•NKX2-1+ progenitor plasticity allows clonal divergence into alternative non-lung fates•Continuous State Hidden Markov model predicts potential fate optimizing interventions•Modulation of Wnt results in a stable iAEC2 phenotype with near limitless self-renewal
Hurley et al. show that a combination of single-cell transcriptomics, computational modeling, and DNA barcoding can map cell-fate trajectories, predicting signaling pathways, transcription factors, and the time of activation for optimizing cell fate, as pluripotent stem cell-derived lung progenitors differentiate toward self-renewing lung alveolar epithelial cells.
Purpose
The dual‐energy CT (DECT) LiverVNC application class in the Siemens Syngo.via software has been used to perform non‐iodine material decompositions. However, the LiverVNC application is ...designed with an optional size‐specific calibration based on iodine measurements. This work investigates the effects of this iodine‐based size‐specific calibration on non‐iodine material decomposition and benchmarks alternative methods for size‐specific calibrations.
Methods
Calcium quantification was performed with split‐filter and sequential‐scanning DECT techniques on the Siemens SOMATOM Definition Edge CT scanner. Images were acquired of the Gammex MECT abdomen and head phantom containing calcium inserts with concentrations ranging from 50–300 mgCa/ml. Several workflows were explored investigating the effects of size‐specific dual‐energy ratios (DERs) and the beam hardening correction (BHC) function in the LiverVNC application. Effects of image noise were also investigated by varying CTDIvol and using iterative reconstruction (ADMIRE).
Results
With the default BHC activated, Syngo.via underestimated the calcium concentrations in the abdomen for sequential‐scanning acquisitions, leaving residual calcium in the virtual non‐contrast images and underestimating calcium in the enhancement images for all DERs. Activation of the BHC with split‐filter images resulted in a calcium over‐ or underestimation depending on the DER. With the BHC inactivated, the use of a single DER led to an under‐ or overestimate of calcium concentration depending on phantom size and DECT modality. Optimal results were found with BHC inactivated using size‐specific DERs. CTDIvol levels and ADMIRE had no significant effect on results.
Conclusion
When performing non‐iodine material decomposition in the LiverVNC application class, it is important to understand the implications of the BHC function and to account for patient size appropriately. The BHC in the LiverVNC application is specific to iodine and leads to inaccurate quantification of other materials. The inaccuracies can be overcome by deactivating the BHC function and using size‐specific DERs, which provided the most accurate calcium quantification.
Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared ...transcriptional changes at single-cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell-derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of datasets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors.
Display omitted
•Alveolar epithelial progenitor cells are transcriptionally distinct upon KRAS expression•Alveolar epithelial organoids recapitulate early-stage lung adenocarcinoma•Oncogenic KRAS leads to loss of lineage identity in AT2 cells•Bulk, scRNA-seq, and proteomics data from murine and human KRAS mutant AT2 cells
Early-stage lung cancer is poorly understood. Dost, Moye et al. introduce new organoid systems to model lung cancer. KRAS-expressing alveolar progenitor cells had reduced expression of lineage genes in mouse and organoid models and stage IA cancers. This is the first report of loss of differentiation in early-stage lung cancer.
Purpose:
Dose calculation errors near metal implants are caused by limitations of the dose calculation algorithm in modeling tissue/metal interface effects as well as density assignment errors caused ...by imaging artifacts. The purpose of this study was to investigate two strategies for reducing dose calculation errors near metal implants: implementation of metal-based energy deposition kernels in the convolution/superposition (C/S) dose calculation method and use of metal artifact reduction methods for computed tomography (CT) imaging.
Methods:
Both error reduction strategies were investigated using a simple geometric slab phantom with a rectangular metal insert (composed of titanium or Cerrobend), as well as two anthropomorphic phantoms (one with spinal hardware and one with dental fillings), designed to mimic relevant clinical scenarios. To assess the dosimetric impact of metal kernels, the authors implemented titanium and silver kernels in a commercial collapsed cone C/S algorithm. To assess the impact of CT metal artifact reduction methods, the authors performed dose calculations using baseline imaging techniques (uncorrected 120 kVp imaging) and three commercial metal artifact reduction methods: Philips Healthcare’s o-mar, GE Healthcare’s monochromatic gemstone spectral imaging (gsi) using dual-energy CT, and gsi with metal artifact reduction software (mars) applied. For the simple geometric phantom, radiochromic film was used to measure dose upstream and downstream of metal inserts. For the anthropomorphic phantoms, ion chambers and radiochromic film were used to quantify the benefit of the error reduction strategies.
Results:
Metal kernels did not universally improve accuracy but rather resulted in better accuracy upstream of metal implants and decreased accuracy directly downstream. For the clinical cases (spinal hardware and dental fillings), metal kernels had very little impact on the dose calculation accuracy (<1.0%). Of the commercial CT artifact reduction methods investigated, the authors found that o-mar was the most consistent method, resulting in either improved dose calculation accuracy (dental case) or little impact on calculation accuracy (spine case). gsi was unsuccessful at reducing the severe artifacts caused by dental fillings and had very little impact on calculation accuracy. gsi with mars on the other hand gave mixed results, sometimes introducing metal distortion and increasing calculation errors (titanium rectangular implant and titanium spinal hardware) but other times very successfully reducing artifacts (Cerrobend rectangular implant and dental fillings).
Conclusions:
Though successful at improving dose calculation accuracy upstream of metal implants, metal kernels were not found to substantially improve accuracy for clinical cases. Of the commercial artifact reduction methods investigated, o-mar was found to be the most consistent candidate for all-purpose CT simulation imaging. The mars algorithm for gsi should be used with caution for titanium implants, larger implants, and implants located near heterogeneities as it can distort the size and shape of implants and increase calculation errors.
PDF
