Next generation sequencing identifies WNT signalling as a significant pathway in Autosomal Recessive Polycystic Kidney Disease (ARPKD) manifestation and may be linked to disease severity.

INTRODUCTION: Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by sequence variants in PKHD1. ARPKD presents with considerable clinical variability relating to the type of PKHD1 sequence variant, but not its position. Animal models of Polycystic Kidney Disease (PKD) suggest a complex genetic landscape, with genetic modifiers as a potential cause of disease variability. METHODS: To investigate in an unbiased manner the molecular mechanisms of ARPKD and identify potential indicators of disease severity, Whole Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) were employed on human ARPKD kidneys and age-matched healthy controls. RESULTS: WES confirmed the clinical diagnosis of ARPKD in our patient cohort consisting of ten ARPKD kidneys. Sequence variant type, nor position of PKHD1 sequence variants, was linked to disease severity. Sequence variants in genes associated with other ciliopathies were detected in the ARPKD cohort, but only PKD1 could be linked to disease severity. Transcriptomic analysis on a subset of four ARPKD kidneys representing severe and moderate ARPKD, identified a significant number of genes relating to WNT signalling, cellular metabolism and development. Increased expression of WNT signalling-related genes was validated by RT-qPCR in severe and moderate ARPKD kidneys. Two individuals in our cohort with the same PKHD1 sequence variants but different rates of kidney disease progression, with displayed transcriptomic differences in the expression of WNT signalling genes. CONCLUSION: ARPKD kidney transcriptomics highlights changes in WNT signalling as potentially significant in ARPKD manifestation and severity, providing indicators for slowing down the progression of ARPKD.

The balance of n-6 and n-3 fatty acids in canine, feline, and equine nutrition: exploring sources and the significance of alpha-linolenic acid.

Both n-6 and n-3 fatty acids (FA) have numerous significant physiological roles for mammals. The interplay between these families of FA is of interest in companion animal nutrition due to the influence of the n-6:n-3 FA ratio on the modulation of the inflammatory response in disease management and treatment. As both human and animal diets have shifted to greater consumption of vegetable oils rich in n-6 FA, the supplementation of n-3 FA to canine, feline, and equine diets has been advocated for. Although fish oils are commonly added to supply the long-chain n-3 FA eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), a heavy reliance on this ingredient by the human, pet food, and equine supplement industries is not environmentally sustainable. Instead, sustainable sourcing of plant-based oils rich in n-3 α-linolenic acid (ALA), such as flaxseed and camelina oils, emerges as a viable option to support an optimal n-6:n-3 FA ratio. Moreover, ALA may offer health benefits that extend beyond its role as a precursor for endogenous EPA and DHA production. The following review underlines the metabolism and recommendations of n-6 and n-3 FA for dogs, cats, and horses and the ratio between them in promoting optimal health and inflammation management. Additionally, insights into both marine and plant-based n-3 FA sources will be discussed, along with the commercial practicality of using plant oils rich in ALA for the provision of n-3 FA to companion animals.

In the realm of companion animal nutrition, the balance between the n-6 and n-3 fatty acids (FA) is important. The shared metabolic pathway of these two FA families and the respective signaling molecules produced have implications for the well-being of companion animals such as dogs, cats, and even horses. The n-6:n-3 FA ratio of the diet can directly influence inflammatory responses, disease management, and overall health. Given the prevalent use of n-6 FA-rich vegetable oils in both human and animal diets, there is a growing need to supplement these animals' diets with n-3 FA. While fish oils containing the long-chain n-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been the conventional choice, their overreliance is environmentally unsustainable. Plant-based oils abundant in the n-3 FA α-linolenic acid (ALA) such as flaxseed and camelina oils should be considered, especially given the health benefits of ALA that extend beyond its role as a precursor to EPA and DHA. This review examines the importance of n-3 FA and the n-6:n-3 FA ratio in companion animal diets on animal health while discussing environmentally sustainable alternatives to fish oil to supplement n-3 FA.

Phenylalanine requirements using the direct amino acid oxidation technique, and the effects of dietary phenylalanine on food intake, gastric emptying, and macronutrient metabolism in adult cats.

Despite Phe being an indispensable amino acid for cats, the minimum Phe requirement for adult cats has not been empirically defined. The objective of study 1 was to determine the minimum Phe requirement, where Tyr is in excess, in adult cats using the direct amino acid oxidation (DAAO) technique. Four adult male cats were used in an 8 × 4 Latin rectangle design. Cats were adapted to a basal diet for 7 d, top dressed with Phe to meet 140% of the adequate intake (NRC, 2006. Nutrient requirements of dogs and cats. Washington, DC: Natl. Acad. Press). Cats were randomly assigned to one of eight experimental Phe diets (0.29%, 0.34%, 0.39%, 0.44%, 0.54%, 0.64%, 0.74%, and 0.84% Phe in the diet on a dry matter [DM] basis). Following 1 d of diet adaptation, individual DAAO studies were performed. During each DAAO study, cats were placed into individual indirect calorimetry chambers, and 75% of the cat's daily meal was divided into 13 equal meals supplied with a dose of L-[1-13C]-Phe. Oxidation of L-[1-13C]-Phe (F13CO2) during isotopic steady state was determined from the enrichment of 13CO2 in breath. Competing models were applied using the NLMIXED procedure in SAS to determine the effects of dietary Phe on 13CO2. The mean population minimum requirement for Phe was estimated at 0.32% DM and the upper 95% population confidence limit at 0.59% DM on an energy density of 4,200 kcal of metabolizable energy/kg DM calculated using the modified Atwater factors. In study 2, the effects of a bolus dose of Phe (44 mg kg-1 BW) on food intake, gastric emptying (GE), and macronutrient metabolism were assessed in a crossover design with 12 male cats. For food intake, cats were given Phe 15 min before 120% of their daily food was offered and food intake was measured. Treatment, day, and their interaction were evaluated using PROC GLIMMIX in SAS. Treatment did not affect any food intake parameters (P > 0.05). For GE and macronutrient metabolism, cats were placed into individual indirect calorimetry chambers, received the same bolus dose of Phe, and 15 min later received 13C-octanoic acid (5 mg kg-1 BW) on 50% of their daily food intake. Breath samples were collected to measure 13CO2. The effect of treatment was evaluated using PROC GLIMMIX in SAS. Treatment did not affect total GE (P > 0.05), but cats receiving Phe tended to delay time to peak enrichment (0.05 < P ≤ 0.10). Overall, Phe at a bolus dose of 44 mg kg-1 BW had no effect on food intake, GE, or macronutrient metabolism. Together, these results suggest that the bolus dose of Phe used may not be sufficient to elicit a GE response, but a study with a greater number of cats and greater food intake is warranted.

Two studies were conducted to evaluate 1) the minimum requirement for dietary Phe and 2) the effects of Phe on gastric emptying (GE) and food intake in adult cats. In study 1, the minimum Phe requirement was estimated using the direct amino acid oxidation (DAAO) technique. Four cats were used and received all diets in random order in a Latin rectangle design (0.29%, 0.34%, 0.39%, 0.44%, 0.54%, 0.64%, 0.74%, and 0.84% Phe in the diet on a dry matter [DM] basis). The minimum Phe requirement, in the presence of excess of Tyr, for adult cats was estimated to be 0.59% DM on an energy density of 4,200 kcal of metabolizable energy/kg DM calculated using the modified Atwater factors; higher than current recommendations set in place by the National Research Council and the American Association of Feed Control Officials. In study 2, we first validated the use of the 13C-octanoic acid breath test (13C-OABT) in cats. Then, the effects of an oral bolus of Phe on food intake, GE, and macronutrient metabolism were evaluated. Phe supplementation did not influence food intake, macronutrient metabolism, or total GE, but tended to delay the time to peak GE.

Effects of dietary camelina, flaxseed, and canola oil supplementation on transepidermal water loss, skin and coat health parameters, and plasma prostaglandin E2, glycosaminoglycan, and nitric oxide concentrations in healthy adult horses.

Camelina oil is derived from a low-input, high-yield crop and, in comparison to many other dietary fat sources currently used in equine diets, provides a greater amount of α-linolenic acid [ALA; (n-3)], than linoleic acid [LA; (n-6)]. However, no research exists assessing the effects of feeding camelina oil to horses in contrast to other commonly used oils. The objective of this study was to compare the effect of supplementing camelina oil to that of flaxseed and canola oil supplementation, on outcomes related to skin and coat health in horses. Thirty adult horses [23 mares, 7 geldings; 14.9 years ±â€…5.3 years; 544 ±â€…66 kg body weight (BW) (mean ±â€…SD)] underwent a 4-week wash-in period consuming hay and sunflower oil. Following the wash-in period, horses were blocked by location, age, and BW, and assigned to one of three treatment oils for 16 weeks (370 mg oil/kg BW): camelina (CAM), canola (OLA), or flaxseed (FLX) oil. Blood samples were collected and plasma prostaglandin E2 (PGE2; ELISA), nitric oxide (NO; Griess Reaction), and glycosaminoglycan (GAG; DMMB) concentrations were measured on weeks 0 (n = 30), 14 (n = 24), and 16 (n = 30). On weeks 0, 2, 4, 8, and 16, transepidermal water loss (TEWL) was measured pre- and post-acetone application using a VapoMeter (n = 26), and a 5-point-Likert scale was used to assess skin and coat characteristics on the side and rump of the horses (n = 30). All data were analyzed with repeated measures ANOVA using PROC GLIMMIX in SAS. Independent of treatment, coat color, and quality increased from baseline. There were no differences in the outcomes assessed between the horses supplemented camelina oil and those supplemented canola or flaxseed oil. These results suggest that independent of treatment, all oil supplements improved coat color and quality in horses. This provides indication that camelina oil is comparable to existing plant-based oil supplements in supporting skin and coat health and inflammation in horses.

Horses cannot produce omega-3 α-linolenic acid or omega-6 linoleic acid in the body, and as a result, these fatty acids are required in the diet. Camelina oil contains a lower ratio of omega-6 to omega-3 fatty acids (1:1.8) in comparison to alternative fat ingredients commonly included in many horse diets, such as soybean oil (1:0.12). Omega-3 fatty acids from flaxseed oil or marine-based oils can support skin and coat health and lower inflammation in horses; however, there is a lack of research investigating camelina oil supplementation and its benefits in horses. Thus, the objective of this study was to determine the effects of camelina oil on skin and coat health in horses. Horses were supplemented with sunflower oil for 4 weeks before being assigned to one of three treatment oils (camelina, canola, or flaxseed) for 16 weeks. Skin barrier function was assessed by measuring the transepidermal water loss of the chest, inner elbow, withers, and rump. Blood markers, including prostaglandin E2, nitric oxide, and glycosaminoglycan, were measured. Skin and coat parameters, including shine, softness, hair quality, color intensity, and moisture, were assessed using a 5-point scale on the rump and side of the horses. No differences in transepidermal water loss, blood markers, or skin and coat parameters were observed among treatments. Our results suggest that camelina oil is comparable to existing oil supplements in supporting skin and coat health and inflammation in horses.

Effects of dietary camelina, flaxseed, and canola oil supplementation on inflammatory and oxidative markers, transepidermal water loss, and coat quality in healthy adult dogs.

Introduction: Camelina oil contains a greater concentration of omega-3 (n-3) a-linolenic acid (C18:3n-3; ALA) than omega-6 (n-6) linoleic acid (C18:2n-6; LA), in comparison to alternative fat sources commonly used to formulate canine diets. Omega-3 FAs are frequently used to support canine skin and coat health claims and reduce inflammation and oxidative stress; however, there is a lack of research investigating camelina oil supplementation and its effects on these applications in dogs. The objective of this study was to evaluate the effects of camelina oil supplementation on coat quality, skin barrier function, and circulating inflammatory and oxidative marker concentrations. Methods: Thirty healthy [17 females; 13 males; 7.2 ± 3.1 years old; 27.4 ± 14.0 kg body weight (BW)] privately-owned dogs of various breeds were used. After a 4-week wash-in period consuming sunflower oil (n6:n3 = 1:0) and a commercial kibble, dogs were blocked by age, breed, and size, and randomly assigned to one of three treatment oils: camelina (n6:n3 = 1:1.18), canola (n6:n3 = 1:0.59), flaxseed (n6:n3 = 1:4.19) (inclusion level: 8.2 g oil/100 g of total food intake) in a randomized complete block design. Transepidermal water loss (TEWL) was measured using a VapoMeter on the pinna, paw pad, and inner leg. Fasted blood samples were collected to measure serum inflammatory and oxidative marker concentrations using enzyme-linked immunosorbent assay (ELISA) kits and spectrophotometric assays. A 5-point-Likert scale was used to assess coat characteristics. All data were collected on weeks 0, 2, 4, 10, and 16 and analyzed using PROC GLIMMIX in SAS. Results: No significant changes occurred in TEWL, or inflammatory and oxidative marker concentrations among treatments, across weeks, or for treatment by week interactions. Softness, shine, softness uniformity, color intensity, and follicle density of the coat increased from baseline in all treatment groups (P < 0.05). Discussion: Outcomes did not differ (P > 0.05) among treatment groups over 16-weeks, indicating that camelina oil is comparable to existing plant-based canine oil supplements, flaxseed, and canola, at supporting skin and coat health and inflammation in dogs. Future research employing an immune or exercise challenge is warranted, as the dogs in this study were not subjected to either.

The genetics of Autosomal Recessive Polycystic Kidney Disease (ARPKD).

ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of individuals dying early on and the majority having good prognosis if they survive the first year of life. The reasons for this variability remain unclear. Two genes have been shown to cause ARPKD when mutated, PKHD1, mutations in which lead to most of ARPKD cases and DZIP1L, which is associated with moderate ARPKD. This mini review will explore the genetics of ARPKD and discuss potential genetic modifiers and phenocopies that could affect diagnosis.

Evaluation of Coronary Plaques and Stents with Conventional and Photon-counting CT: Benefits of High-Resolution Photon-counting CT.

PURPOSE: To compare the performance of energy-integrating detector (EID) CT, photon-counting detector CT (PCCT), and high-resolution PCCT (HR-PCCT) for the visualization of coronary plaques and reduction of stent artifacts in a phantom model. MATERIALS AND METHODS: An investigational scanner with EID and PCCT subsystems was used to image a coronary artery phantom containing cylindrical probes simulating different plaque compositions. The phantom was imaged with and without coronary stents using both subsystems. Images were reconstructed with a clinical cardiac kernel and an additional HR-PCCT kernel. Regions of interest were drawn around probes and evaluated for in-plane diameter and a qualitative comparison by expert readers. A linear mixed-effects model was used to compare the diameter results, and a Shrout-Fleiss intraclass correlation coefficient was used to assess consistency in the reader study. RESULTS: Comparing in-plane diameter to the physical dimension for nonstented and stented phantoms, measurements of the HR-PCCT images were more accurate (nonstented: 4.4% ± 1.1 [standard deviation], stented: -9.4% ± 4.6) than EID (nonstented: 15.5% ± 4.0, stented: -19.5% ± 5.8) and PCCT (nonstented: 19.4% ± 2.5, stented: -18.3% ± 4.4). Our analysis of variance found diameter measurements to be different across image groups for both nonstented and stented cases (P < .001). HR-PCCT showed less change on average in percent stenosis due to the addition of a stent (-5.5%) than either EID (+90.5%) or PCCT (+313%). For both nonstented and stented phantoms, observers rated the HR-PCCT images as having higher plaque conspicuity and as being the image type that was least impacted by stent artifacts, with a high level of agreement (interclass correlation coefficient = 0.85). CONCLUSION: Despite increased noise, HR-PCCT images were able to better visualize coronary plaques and reduce stent artifacts compared with EID or PCCT reconstructions.Keywords: CT-Spectral Imaging (Dual Energy), Phantom Studies, Cardiac, Physics, Technology Assessment© RSNA, 2021.

Effect of Total Starch and Resistant Starch in Commercial Extruded Dog Foods on Gastric Emptying in Siberian Huskies.

Gastric emptying rate (GER) may impact diabetes and obesity in humans and could provide a method to reduce canine weight gain. Starch, the most common source of carbohydrates (CHOs) in pet food, is classified as rapidly or slowly digestible, or resistant to digestion. This study investigated starch source effects in commercial extruded dog foods on the GER of 11 healthy adult Siberian Huskies. Test diets were classified as traditional, grain-free, whole-grain, and vegan. Dogs received each diet once, a glucose control twice, and acetaminophen (Ac) as a marker for GER in a randomized, partially replicated, 6 × 6 Latin square design. Pre- and post-prandial blood samples were collected at 16 timepoints from -15 to 480 min. Serum Ac concentrations were assessed via standard spectrophotometric assays and fitted with a mathematical model to estimate parameters of GER. Parameter values were subjected to ANOVA, with period and treatment as fixed effects and dog as a random effect. More total emptying (p = 0.074) occurred at a faster rate (p = 0.028) in dogs fed the grain-free diet, which contained the lowest total starch (34.03 ± 0.23%) and highest resistant starch (0.52 ± 0.007%). This research may benefit future diet formulations to reduce the prevalence of canine weight gain.

Safety of Dietary Camelina Oil Supplementation in Healthy, Adult Dogs.

This study aimed to determine whether camelina oil is safe for use in canine diets, using canola oil and flax oil as controls, as they are similar and generally regarded as safe (GRAS) for canine diets. A total of thirty privately-owned adult dogs of various breeds (17 females; 13 males), with an average age of 7.2 ± 3.1 years (mean ± SD) and a body weight (BW) of 27.4 ± 14.0 kg were used. After a 4-week wash-in period using sunflower oil and kibble, the dogs were blocked by breed, age, and size and were randomly allocated to one of three treatment oils (camelina (CAM), flax (FLX), or canola (OLA)) at a level of 8.2 g oil/100 g total dietary intake. Body condition score (BCS), BW, food intake (FI), and hematological and select biochemical parameters were measured at various timepoints over a 16-week feeding period. All of the data were analyzed with ANOVA using the PROC GLIMMIX of SAS. No biologically significant differences were seen between the treatment groups in terms of BW, BCS, FI, and hematological and biochemical results. Statistically significant differences noted among some serum biochemical results were considered small and were due to normal biological variation. These results support the conclusion that camelina oil is safe for use in canine nutrition.

The cellular pathways and potential therapeutics of Polycystic Kidney Disease.

Polycystic Kidney Disease (PKD) refers to a group of disorders, driven by the formation of cysts in renal tubular cells and is currently one of the leading causes of end-stage renal disease. The range of symptoms observed in PKD is due to mutations in cilia-localising genes, resulting in changes in cellular signalling. As such, compounds that are currently in preclinical and clinical trials target some of these signalling pathways that are dysregulated in PKD. In this review, we highlight these pathways including cAMP, EGF and AMPK signalling and drugs that target them and may show promise in lessening the disease burden of PKD patients. At present, tolvaptan is the only approved therapy for ADPKD, however, it carries several adverse side effects whilst comparatively, no pharmacological drug is approved for ARPKD treatment. Aside from this, drugs that have been the subject of multiple clinical trials such as metformin, which targets AMPK signalling and somatostatins, which target cAMP signalling have shown great promise in reducing cyst formation and cellular proliferation. This review also discusses other potential and novel targets that can be used for future interventions, such as ß-catenin and TAZ, where research has shown that a reduction in the overexpression of these signalling components results in amelioration of disease phenotype. Thus, it becomes apparent that well-designed preclinical investigations and future clinical trials into these pathways and other potential signalling targets are crucial in bettering disease prognosis for PKD patients and could lead to personalised therapy approaches.

Task-dependent estimability index to assess the quality of cardiac computed tomography angiography for quantifying coronary stenosis.

Purpose: Quantifying stenosis in cardiac computed tomography angiography (CTA) images remains a difficult task, as image noise and cardiac motion can degrade image quality and distort underlying anatomic information. The purpose of this study was to develop a computational framework to objectively assess the precision of quantifying coronary stenosis in cardiac CTA. Approach: The framework used models of coronary vessels and plaques, asymmetric motion point spread functions, CT image blur (task-based modulation transfer functions) and noise (noise-power spectrums), and an automated maximum-likelihood estimator implemented as a matched template squared-difference operator. These factors were integrated into an estimability index ( e ' ) as a task-based measure of image quality in cardiac CTA. The e ' index was applied to assess how well it can to predict the quality of 132 clinical cases selected from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain trial. The cases were divided into two cohorts, high quality and low quality, based on clinical scores and the concordance of clinical evaluations of cases by experienced cardiac imagers. The framework was also used to ascertain protocol factors for CTA Biomarker initiative of the Quantitative Imaging Biomarker Alliance (QIBA). Results: The e ' index categorized the patient datasets with an area under the curve of 0.985, an accuracy of 0.977, and an optimal e ' threshold of 25.58 corresponding to a stenosis estimation precision (standard deviation) of 3.91%. Data resampling and training-test validation methods demonstrated stable classifier thresholds and receiver operating curve performance. The framework was successfully applicable to the QIBA objective. Conclusions: A computational framework to objectively quantify stenosis estimation task performance was successfully implemented and was reflective of clinical results in the context of a prominent clinical trial with diverse sites, readers, scanners, acquisition protocols, and patients. It also demonstrated the potential for prospective optimization of imaging protocols toward targeted precision and measurement consistency in cardiac CT images.

Minimum perceivable size difference: how well can radiologists visually detect a change in lung nodule size from CT images?

OBJECTIVE: The purpose of this study was to determine how well radiologists could visually detect a change in lung nodule size on the basis of visual image perception alone. SUBJECTS AND METHODS: Under IRB approval, 109 standard chest CT image series were anonymized and exported from PACS. Nine hundred forty virtual lung nodule pairs (six baseline diameters, six relative volume differences, two nodule types-solid and ground glass-and 14 repeats) were digitally inserted into the chest CT image series (same location, different sizes between the pair). These digitally altered CT image pairs were shown to nine radiologists who were tasked to visually determine which image contained the larger nodule using a two-alternative forced-choice perception experimental design. These data were statistically analyzed using a generalized linear mixed effects model to determine how accurately the radiologists were able to correctly identify the larger nodule. RESULTS: Nominal baseline nodule diameter, relative volume difference, and nodule type were found to be statistically significant factors (p < 0.001) in influencing the radiologists' accuracy. For solid (ground-glass) nodules, the baseline diameter needed to be at least 6.3 mm (13.2 mm) to be able to visually detect a 25% change in volume with 95 ± 1.4% accuracy. Accuracy was lowest for the nodules with the smallest baseline diameters and smallest relative volume differences. Additionally, accuracy was lower for ground-glass nodules compared to solid nodules. CONCLUSIONS: Factors that impacted visual size assessment were baseline nodule diameter, relative volume difference, and solid versus non-solid nodule type, with larger and more solid lesions offering a more precise assessment of change. KEY POINTS: • For solid nodules, radiologists could visually detect a 25% change in volume with 95% accuracy for nodules having greater than 6.3-mm baseline diameter. • For ground-glass nodules, radiologists could visually detect a 25% change in volume with 95% accuracy for nodules having greater than 13.2-mm baseline diameter. • Accuracy in detecting a change in nodule size began to stabilize around 90-100% for nodules with larger baseline diameters (> 8 mm for solid nodules, > 12 mm for ground-glass nodules) and larger relative volume differences (>15% for solid nodules, > 25% for ground-glass nodules).

Current Progress and Perspective: Clinical Imaging of Islet Transplantation.

Islet transplantation has great potential as a cure for type 1 diabetes. At present; the lack of a clinically validated non-invasive imaging method to track islet grafts limits the success of this treatment. Some major clinical imaging modalities and various molecular probes, which have been studied for non-invasive monitoring of transplanted islets, could potentially fulfill the goal of understanding pathophysiology of the functional status and viability of the islet grafts. In this current review, we summarize the recent clinical studies of a variety of imaging modalities and molecular probes for non-invasive imaging of transplanted beta cell mass. This review also includes discussions on in vivo detection of endogenous beta cell mass using clinical imaging modalities and various molecular probes, which will be useful for longitudinally detecting the status of islet transplantation in Type 1 diabetic patients. For the conclusion and perspectives, we highlight the applications of multimodality and novel imaging methods in islet transplantation.

A Simulation Paradigm for Evaluation of Subtle Liver Lesions at Pediatric CT: Performance and Confidence.

Purpose: To create and validate a systematic observer performance platform for evaluation of simulated liver lesions at pediatric CT and to test this paradigm to measure the effect of radiation dose reduction on detection performance and reader confidence. Materials and Methods: Thirty normal pediatric (from patients aged 0-10 years) contrast material-enhanced, de-identified abdominal CT scans obtained from July 1, 2012, through July 1, 2016, were retrospectively collected from the clinical database. The study was exempt from institutional review board approval. Zero to three simulated, low-contrast liver lesions (≤6 mm) were digitally inserted by using software, and noise was added to simulate reductions in volume CT dose index (representing radiation dose estimation) of 25% and 50%. Pediatric, abdominal, and resident radiologists (three of each) reviewed 90 data sets in three sessions using an online interface, marking each lesion location and rating confidence (scale, 0-100). Statistical analysis was performed by using software. Results: Mixed-effects models revealed a significant decrease in detection sensitivity as radiation dose decreased (P < .001). The mean confidence of the full-dose and 25% dose reduction examinations was significantly higher than that of the 50% dose reduction examinations (P = .011 and .012, respectively) but not different from one another (P = .866). Dose was not a significant predictor of time to complete each case, and subspecialty was not a significant predictor of sensitivity or false-positive results. Conclusion: Sensitivity for lesion detection significantly decreased as dose decreased; however, confidence did not change between the full-dose and 25% reduced-dose scans. This suggests that readers are unaware of this decrease in performance, which should be accounted for in clinical dose reduction efforts.Keywords: Abdomen/GI, CT, Liver, Observer Performance, Pediatrics, Perception Image© RSNA, 2019.

Atmin modulates Pkhd1 expression and may mediate Autosomal Recessive Polycystic Kidney Disease (ARPKD) through altered non-canonical Wnt/Planar Cell Polarity (PCP) signalling.

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a genetic disorder with an incidence of ~1:20,000 that manifests in a wide range of renal and liver disease severity in human patients and can lead to perinatal mortality. ARPKD is caused by mutations in PKHD1, which encodes the large membrane protein, Fibrocystin, required for normal branching morphogenesis of the ureteric bud during embryonic renal development. The variation in ARPKD phenotype suggests that in addition to PKHD1 mutations, other genes may play a role, acting as modifiers of disease severity. One such pathway involves non-canonical Wnt/Planar Cell Polarity (PCP) signalling that has been associated with other cystic kidney diseases, but has not been investigated in ARPKD. Analysis of the AtminGpg6 mouse showed kidney, liver and lung abnormalities, suggesting it as a novel mouse tool for the study of ARPKD. Further, modulation of Atmin affected Pkhd1 mRNA levels, altered non-canonical Wnt/PCP signalling and impacted cellular proliferation and adhesion, although Atmin does not bind directly to the C-terminus of Fibrocystin. Differences in ATMIN and VANGL2 expression were observed between normal human paediatric kidneys and age-matched ARPKD kidneys. Significant increases in ATMIN, WNT5A, VANGL2 and SCRIBBLE were seen in human ARPKD versus normal kidneys; no substantial differences were seen in DAAM2 or NPHP2. A striking increase in E-cadherin was also detected in ARPKD kidneys. This work indicates a novel role for non-canonical Wnt/PCP signalling in ARPKD and suggests ATMIN as a modulator of PKHD1.

3D task-transfer function representation of the signal transfer properties of low-contrast lesions in FBP- and iterative-reconstructed CT.

PURPOSE: The purpose of this study was to investigate how accurately the task-transfer function (TTF) models the signal transfer properties of low-contrast features in a non-linear commercial CT system. METHODS: A cylindrical phantom containing 24 anthropomorphic "physical" lesions was 3D printed. Lesions had two sizes (523, 2145 mm3 ), and two nominal radio-densities (80 and 100 HU at 120 kV). CT images were acquired on a commercial CT system (Siemens Flash scanner) at four dose levels (CTDIvol , 32 cm phantom:1.5, 3.0, 6.0, 22.0 mGy) and reconstructed using FBP and IR kernels (B31f, B45f, I31f\2, I44f\2). Low-contrast rod inserts (in-plane) and a slanted edge (z-direction) were used to estimate 3D-TTFs. CAD versions of lesions were blurred by the 3D-TTFs, virtually superimposed into corresponding phantom images, and compared to the physical lesions in terms of (a) a 4AFC visual assessment, (b) edge gradient, (c) size, and (d) shape similarity. Assessments 2 and 3 were based on an equivalence criterion D ¯ ≥ COV ¯ to determine if the natural variability COV ¯ in the physical lesions was greater or equal to the difference D ¯ between physical and simulated. Shape similarity was quantified via Sorensen-Dice coefficient (SDC). Comparisons were done for each lesion and for all imaging conditions. RESULTS: The readers detected simulated lesions at a rate of 37.9 ± 3.1% (25% implies random guessing). Lesion edge blur and volume differences D ¯ were on average less than physical lesions' natural variability COV ¯ . The SDC (average ± SD) was 0.80 ± 0.13 (max of 1 possible). CONCLUSIONS: The visual appearance, edge blur, size, and shape of simulated lesions were similar to the physical lesions, which suggests 3D-TTF models the low-contrast signal transfer properties of this non-linear CT system reasonably well.

Quantification of uncertainty in the assessment of coronary plaque in CCTA through a dynamic cardiac phantom and 3D-printed plaque model.

The purpose of this study was to develop a dynamic physical cardiac phantom with a realistic coronary plaque to investigate stenosis measurement accuracy under clinically relevant heart-rates. The coronary plaque model (5 mm diameter, 50% stenosis, and 32 mm long) was designed and 3D-printed with tissue equivalent materials (calcified plaque with iodine-enhanced lumen). Realistic cardiac motion was modeled by converting computational cardiac motion vectors into compression and rotation profiles executed by a commercial base cardiac phantom. The phantom was imaged on a dual-source CT system applying a retrospective gated coronary CT angiography (CCTA) protocol using synthesized motion-synchronized electrocardiogram (ECG) waveforms. Multiplanar reformatted images were reconstructed along vessel centerlines. Enhanced lumens were segmented by five independent operators. On average, stenosis measurement accuracy was 0.9% positively biased for the motion-free condition. Average measurement accuracy monotonically decreased from 0.9% positive bias for the motion-free condition to 18.5% negative bias at 90 beats per minute. Contrast-to-noise ratio, lumen circularity, and segmentation conformity also decreased monotonically with increasing heart-rate. These results demonstrate successful implementation of a base cardiac phantom with a 3D-printed coronary plaque model, relevant motion profile, and coordinated ECG waveform. They further show the utility of the model to ascertain metrics of CCTA accuracy and image quality under realistic plaque, motion, and acquisition conditions.

Clinically Significant Differences in Ki-67 Proliferation Index Between Primary and Metastases in Resected Pancreatic Neuroendocrine Tumors.

OBJECTIVE: Pancreatic neuroendocrine tumors (NETs) (pNETs) have a varied prognosis according to their grade. The European Neuroendocrine Tumor Society grading system uses assessment of the proliferation index via Ki-67 immunohistochemistry to aid prognosis. There is evidence that the proliferation index can vary significantly within a single tumor, but it is not fully understood to what extent heterogeneity occurs between the primary and metastatic sites and how this may affect the grade. The aim of this study is to determine whether the grade assigned to a pNET varies depending on which site is selected for Ki-67 immunolabeling. METHODS: Patients were selected from our institution's NET database. Patients were included if they had a confirmed pNETs, had multiple resection specimens, and had consented to research being performed on their specimens. Ki-67 immunohistochemistry was performed on all resected specimens meeting the inclusion criteria. RESULTS: Pancreatic neuroendocrine tumors specimens resected from 16 patients were analyzed. There was no trend to higher Ki-67 in metastatic than primary disease. Ki-67 was on average 3% higher in liver metastases than lymph node metastases (P < 0.001). CONCLUSIONS: The grade of pNETs varies according to the tumor selected for Ki-67 immunolabeling. Useful information can be gained by performing Ki-67 PI on liver metastases.

The Synthesis of Trifluoromethyl-sulfonimidamides from Sulfinamides.

A general synthesis of CF3-sulfonimidamides from sulfinamides under both batch and continuous flow conditions is described. The reaction proceeds via a sulfonimidoyl fluoride intermediate. A reaction scope showing good group variation on the substituents of both nitrogen atoms is also presented.