FDA Approval Summary: Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer.

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy, an anti­VEGF therapy, and, if RAS wild­type and medically appropriate, an anti EGFR therapy. Approval was based on Study FRESCO-2, a globally-conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival (PFS). A total of 691 patients were randomized (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 (95% CI: 0.55, 0.80; p<0.001). The median OS was 7.4 months (95% CI: 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI: 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with inhibition of the VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI: 0.51, 0.83; p<0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild­type and medically appropriate, an anti-EGFR therapy.

Identification and genetic characterization of an isolate of bovine adenovirus 7 from the United States, a putative member of a new species in the genus Atadenovirus.

The bovine adenovirus 7 (BAdV-7) isolate SD18-74 was recovered from lung tissue of calves in South Dakota. The 30,043-nucleotide (nt) genome has the typical organization of Atadenovirus genus members. The sequence shares over 99% nt sequence identity with two Japanese BAdV-7 sequences, followed by 74.9% nt sequence identity with the ovine adenovirus 7 strain OAV287, a member of the species Ovine atadenovirus D. SD18-74 was amplified in both bovine and ovine primary nasal turbinate cells, demonstrating greater fitness in bovine cells. The genomic and biological characteristics of BAdV-7 SD18-74 support the inclusion of the members of the BAdV-7 group in a new species in the genus Atadenovirus.

A modelling framework for simulation of ultrasonic guided wave-based inspection of welded rail tracks.

A modelling framework for ultrasonic inspection of waveguides with arbitrary discontinuities, excited using piezoelectric transducers, is developed. The framework accounts for multi-modal, dispersive and damped one dimensional propagation over long distances. The proposed model is applied to simulate a realistic guided wave-based inspection of a welded rail. The framework models the excitation, propagation and scattering of guided waves from welds by respectively employing a hybrid model that couples a 3D FEM model of a piezoelectric transducer with a 2D SAFE model of the rail; a 2D SAFE model of the rail; and another hybrid method which couples a 3D FEM model of the arbitrary discontinuity (weld) with two SAFE models of the rail to represent the semi-infinite incoming and outgoing waveguides. Optimal damping parameters for hysteretic and viscous damping, respectively, are determined using a model updating procedure to approximate attenuation in the rail. Good agreement between the experimental measurement and simulation is demonstrated, even for weld reflections originating over 640 m from the transducer location. The proposed physics-based framework can be used to efficiently perform multiple analyses considering different numbers and locations of welds, different excitation signals or to investigate the effects of changes in parameters such as transducer geometry, or material property variations caused by temperature fluctuations. The framework could therefore be used in future to set up a digital twin of a section of rail track, or in the development of a rail monitoring system by predicting reflections from defects which cannot readily be measured, but which can be simulated.

Association of Ultraviolet Radiation Exposure With Dermatomyositis in a National Myositis Patient Registry.

OBJECTIVE: Dermatomyositis (DM) has been associated with geospatial differences in ultraviolet (UV) radiation, but the role of individual determinants of UV exposure prior to diagnosis is unknown. The objective was to examine the role of those individual determinants. METHODS: We analyzed questionnaire data from 1,350 adults in a US national myositis registry (638 with DM, 422 with polymyositis [PM], and 290 with inclusion body myositis [IBM] diagnosed at ages 18-65 years), examining the likelihood of DM compared with PM and IBM diagnosis, in relation to self-reported sunburn history and job- and hobby-related sun exposures in the year prior to diagnosis. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression adjusted for age, skin tone, and sex, to determine the association of individual UV exposures with DM diagnosis. We also evaluated the proportion of DM by maximum daily ambient UV exposure, based on UVB erythemal irradiances for participant residence in the year prior to diagnosis. RESULTS: DM was associated with sunburn in the year before diagnosis (2 or more sunburns OR 1.77 [95% CI 1.28-2.43] versus PM/IBM; 1 sunburn OR 1.44 [95% CI 1.06-1.95]) and with having elevated job- or hobby-related sun exposure (high exposure OR 1.64 [95% CI 1.08-2.49] or moderate exposure OR 1.35 [95% CI 1.02-1.78] versus low or no exposure). Ambient UV intensity was associated with DM in females (ß = 3.97, P = 0.046), but not overall. CONCLUSION: Our findings suggest that high or moderate personal exposure to intense sunlight is associated with developing DM compared with other types of myositis. Prospective research on UV exposure as a modifiable risk factor for DM is warranted.

Correction: Survival of viral pathogens in animal feed ingredients under transboundary shipping models.

[This corrects the article DOI: 10.1371/journal.pone.0194509.].

Association of Short-Term Ultraviolet Radiation Exposure and Disease Severity in Juvenile Dermatomyositis: Results From the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry.

OBJECTIVE: Ultraviolet (UV) radiation is considered to be an important environmental factor in the clinical course of children with juvenile dermatomyositis (DM). We aimed to evaluate the association between UV radiation and severe disease outcomes in juvenile DM. METHODS: This is a cross-sectional study of patients with juvenile DM enrolled in the US multicenter Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry from 2010 to 2015. The mean UV index (UVI) in the calendar month prior to symptom onset in each subject's zip code was calculated from daily satellite solar noon measurements. Multivariable logistic regression was used to model the relationship between the mean UVI and calcinosis as well as other outcomes of severe disease. Covariates included sex, race, age, time to diagnosis, disease duration, and latitude. RESULTS: In a multivariable model, there was no association between the mean UVI and calcinosis. African American race was associated with a 3-fold greater odds of calcinosis. However, there was a significant statistical interaction between race and mean UVI. Accounting for this interaction, the odds of calcinosis markedly decreased in African American subjects and steadily increased in non-African American subjects over a range of increasing the mean UVI. Higher mean UVI was associated with decreased odds of using biologics or nonmethotrexate disease-modifying antirheumatic drugs and skin ulceration. CONCLUSION: We described a novel association between UV radiation, calcinosis, and race in a large cohort of patients with juvenile DM. This study furthers our knowledge of the role of UV radiation in the clinical course of juvenile DM and highlights the complex interplay between genes and environment in the clinical phenotypes and development of calcinosis in children with juvenile DM.

Estimation of rail properties using semi-analytical finite element models and guided wave ultrasound measurements.

Guided wave based monitoring systems require accurate knowledge of mode propagation characteristics such as wavenumber and group velocity dispersion curves. These characteristics may be computed numerically for a rail provided that the material and geometric properties of the rail are known. Generally, the rail properties are not known with sufficient accuracy and these properties also change due to temperature, rail wear and rail grinding. An automated procedure is proposed to estimate material and geometric properties of a rail by finding the properties which, when input into a Semi-Analytical Finite Element (SAFE) model, accurately reproduce measured dispersion characteristics. Pulse-echo measurements were performed and spectrograms show the reflections from aluminothermic welds of three modes of propagation. The SAFE method was used to solve the forward problem of predicting the dispersion characteristics for specified rail properties. Dispersion curves are computed for different combinations of Poisson's ratio and three geometric parameters. These dispersion curves are scaled to cover a range of longitudinal speeds of sound of the rail material. A technique is developed to determine which SAFE model provided the best fit to the experimental measurements. The technique does not require knowledge of the distances to the reflectors; rather these distances are estimated as part of the proposed procedure. A SAFE model with the estimated rail parameters produced dispersion curves and distances in very good agreement with the measured spectrograms. In addition, the estimated mean geometric parameters agreed with the measured profile of the rail head.

Correction: Survival of viral pathogens in animal feed ingredients under transboundary shipping models.

[This corrects the article DOI: 10.1371/journal.pone.0194509.].

Survival of viral pathogens in animal feed ingredients under transboundary shipping models.

The goal of this study was to evaluate survival of important viral pathogens of livestock in animal feed ingredients imported daily into the United States under simulated transboundary conditions. Eleven viruses were selected based on global significance and impact to the livestock industry, including Foot and Mouth Disease Virus (FMDV), Classical Swine Fever Virus (CSFV), African Swine Fever Virus (ASFV), Influenza A Virus of Swine (IAV-S), Pseudorabies virus (PRV), Nipah Virus (NiV), Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), Swine Vesicular Disease Virus (SVDV), Vesicular Stomatitis Virus (VSV), Porcine Circovirus Type 2 (PCV2) and Vesicular Exanthema of Swine Virus (VESV). Surrogate viruses with similar genetic and physical properties were used for 6 viruses. Surrogates belonged to the same virus families as target pathogens, and included Senecavirus A (SVA) for FMDV, Bovine Viral Diarrhea Virus (BVDV) for CSFV, Bovine Herpesvirus Type 1 (BHV-1) for PRV, Canine Distemper Virus (CDV) for NiV, Porcine Sapelovirus (PSV) for SVDV and Feline Calicivirus (FCV) for VESV. For the remaining target viruses, actual pathogens were used. Virus survival was evaluated using Trans-Pacific or Trans-Atlantic transboundary models involving representative feed ingredients, transport times and environmental conditions, with samples tested by PCR, VI and/or swine bioassay. SVA (representing FMDV), FCV (representing VESV), BHV-1 (representing PRV), PRRSV, PSV (representing SVDV), ASFV and PCV2 maintained infectivity during transport, while BVDV (representing CSFV), VSV, CDV (representing NiV) and IAV-S did not. Notably, more viruses survived in conventional soybean meal, lysine hydrochloride, choline chloride, vitamin D and pork sausage casings. These results support published data on transboundary risk of PEDV in feed, demonstrate survival of certain viruses in specific feed ingredients ("high-risk combinations") under conditions simulating transport between continents and provide further evidence that contaminated feed ingredients may represent a risk for transport of pathogens at domestic and global levels.

Mode repulsion of ultrasonic guided waves in rails.

Accurate computation of dispersion characteristics of guided waves in rails is important during the development of inspection and monitoring systems. Wavenumber versus frequency curves computed by the semi-analytical finite element method exhibit mode repulsion and mode crossing which can be difficult to distinguish. Eigenvalue derivatives, with respect to the wavenumber, are used to investigate these regions. A term causing repulsion between two modes is identified and a condition for two modes to cross is established. In symmetric rail profiles the mode shapes are either symmetric or antisymmetric. Symmetric and antisymmetric modes can cross each other while the modes within the symmetric and antisymmetric families do not appear to cross. The modes can therefore be numbered in the same way that Lamb waves in plates are numbered, making it easier to communicate results. The derivative of the eigenvectors with respect to wavenumber contains the same repulsion term and shows how the mode shapes swop during a repulsion. The introduction of even a small asymmetry appears to lead to repulsion forces that prevent any mode crossings. Measurements on a continuously welded rail track were performed to illustrate a mode repulsion.

Assessment of upper tropospheric and stratospheric water vapor and ozone in reanalyses as part of S-RIP.

Reanalysis data sets are widely used to understand atmospheric processes and past variability, and are often used to stand in as "observations" for comparisons with climate model output. Because of the central role of water vapor (WV) and ozone (O3) in climate change, it is important to understand how accurately and consistently these species are represented in existing global reanalyses. In this paper, we present the results of WV and O3 intercomparisons that have been performed as part of the SPARC (Stratosphere-troposphere Processes and their Role in Climate) Reanalysis Intercomparison Project (S-RIP). The comparisons cover a range of timescales and evaluate both inter-reanalysis and observation-reanalysis differences. We also provide a systematic documentation of the treatment of WV and O3 in current reanalyses to aid future research and guide the interpretation of differences amongst reanalysis fields. The assimilation of total column ozone (TCO) observations in newer reanalyses results in realistic representations of TCO in reanalyses except when data coverage is lacking, such as during polar night. The vertical distribution of ozone is also relatively well represented in the stratosphere in reanalyses, particularly given the relatively weak constraints on ozone vertical structure provided by most assimilated observations and the simplistic representations of ozone photochemical processes in most of the reanalysis forecast models. However, significant biases in the vertical distribution of ozone are found in the upper troposphere and lower stratosphere in all reanalyses. In contrast to O3, reanalysis estimates of stratospheric WV are not directly constrained by assimilated data. Observations of atmospheric humidity are typically used only in the troposphere, below a specified vertical level at or near the tropopause. The fidelity of reanalysis stratospheric WV products is therefore mainly dependent on the reanalyses' representation of the physical drivers that influence stratospheric WV, such as temperatures in the tropical tropopause layer, methane oxidation, and the stratospheric overturning circulation. The lack of assimilated observations and known deficiencies in the representation of stratospheric transport in reanalyses result in much poorer agreement amongst observational and reanalysis estimates of stratospheric WV. Hence, stratospheric WV products from the current generation of reanalyses should generally not be used in scientific studies.

Laser vibrometer measurement of guided wave modes in rail track.

The ability to measure the individual modes of propagation is very beneficial during the development of guided wave ultrasound based rail monitoring systems. Scanning laser vibrometers can measure the displacement at a number of measurement points on the surface of the rail track. A technique for estimating the amplitude of the individual modes of propagation from these measurements is presented and applied to laboratory and field measurements. The method uses modal data from a semi-analytical finite element model of the rail and has been applied at frequencies where more than twenty propagating modes exist. It was possible to measure individual modes of propagation at a distance of 400 m from an ultrasonic transducer excited at 30 kHz on operational rail track and to identify the modes that are capable of propagating large distances.

The mystery of recent stratospheric temperature trends.

A new data set of middle- and upper-stratospheric temperatures based on reprocessing of satellite radiances provides a view of stratospheric climate change during the period 1979-2005 that is strikingly different from that provided by earlier data sets. The new data call into question our understanding of observed stratospheric temperature trends and our ability to test simulations of the stratospheric response to emissions of greenhouse gases and ozone-depleting substances. Here we highlight the important issues raised by the new data and suggest how the climate science community can resolve them.

Enzymatic hydrolysis and simultaneous saccharification and fermentation of soybean processing intermediates for the production of ethanol and concentration of protein and lipids.

Carbohydrates in soybeans are generally undesirable due to their low digestibility and because they "dilute" more valuable components (proteins, lipids). To remove these carbohydrates and raise the titer of more valuable components, ethanol production was investigated. Commercial enzymes (Novozyme cellulase, ß -glucosidase, and pectinase) were added to ground soybeans (SB), soybean meal (SBM), soybean hulls (SH), and soybean white flakes (WF) at a 10% solids loading rate to quantify hydrolyzed glucan. Saccharification resulted in glucan reductions of 28%, 45%, 76%, and 80% (SBM, SB, SH, WF, resp.). Simultaneous saccharification and fermentation (SSF) trials were conducted at 5%, 10%, 15%, and 20% solids loading with Saccharomyces cerevisiae NRRL Y-2034 and Scheffersomyces stipitis NRRL Y-7124, with protein, fiber, and lipids analyzed at SSF 10% solids and saccharification trials. S. cerevisiae and S. stipitis produced ~3-12.5 g/L ethanol and ~2.5-8.6 g/L ethanol, respectively, on SB, SBM, and WF over all solid loading rates. SH resulted in higher ethanol titers for both S. cerevisiae (~9-23 g/L) and S. stipitis (~9.5-14.5 g/L). Protein concentrations decreased by 2.5-10% for the SB, SBM, and WF, but increased by 53%-55% in SH. Oil concentrations increased by ~50% for SB; by ~500%-1300% for the others.

Vascular anomaly causing subclavian steal and cervical myelopathy in a dog: diagnosis and endovascular management.

A 3-year-old dog with cervical myelopathy resulting from a vascular anomaly is described. Marked intradural-extramedullary spinal cord compression was observed, in association with multilevel ectatic anastomotic radicular arterial branches connecting the left and right vertebral arteries. A nonpatent proximal segment of the right subclavian artery had resulted in compensatory enlargement of the left vertebral artery. Flow within the right vertebral artery was retrograde and fed into the patent distal segment of the right subclavian artery. Multiple imaging techniques including myelography, computed tomography, magnetic resonance imaging, and selective digital angiography were used to document this anomaly. To reduce spinal cord compression the largest collateral vessel was embolized without complication. Good clinical response was observed within 6 weeks and improved clinical neurologic function was maintained at the time of a 12-month re-evaluation.

Ultrasonographic evaluation of brachial plexus tumors in five dogs.

Five dogs with unilateral thoracic limb lameness, neurologic deficits, muscle atrophy, and pain, or a combination of these signs, were examined using ultrasonograghy. Large, hypoechoic tubular masses that displaced vessels and destroyed the normal architecture were found in each dog. The affected axilla of each patient was then imaged with computed tomography or magnetic resonance to fully assess the extent of the masses. We describe the use of ultrasound in screening patients for brachial plexus tumors.

Use of a jugular vein autograft for reconstruction of the cranial vena cava in a dog with invasive thymoma and cranial vena cava syndrome.

A spayed female dog was evaluated because of edema of the ventral cervical region, lethargy, cough, and reduced exercise tolerance. Invasive thymoma and cranial vena cava syndrome were diagnosed by use of ultrasound-guided fine-needle biopsy and contrast-enhanced helical computed tomography. Resection of the cranial vena cava and an autogenous jugular vein graft were used for restoration of normal venous return to the right atrium and alleviation of the cranial vena cava syndrome.

Sensitivity of radiographic evaluation of radio-ulnar incongruence in the dog in vitro.

OBJECTIVE: To determine the sensitivity and specificity of radiographic evaluation of radio-ulnar incongruence in canine elbow joints in vitro. STUDY DESIGN: Radiographic evaluation of induced radio-ulnar incongruence in canine cadaveric forelimbs by radiologists blinded to study design. SAMPLE POPULATION: Six cadaveric canine left forelimbs. METHODS: Extended lateral, 90 degrees flexed lateral, and cranio-caudal projections were taken of the elbow joint of six cadaveric canine forelimbs. A four-pin, type I external skeletal fixator (ESF) with a linear motor side bar was attached to the medial aspect of the radius, and a 2-cm segment of bone was removed from the mid-diaphysis. A 3.5-mm cortical bone screw placed from the medial to lateral styloid processes prevented relative movement between the distal radius and ulna during radial shortening. The ESF was used to progressively shorten the radius in increments of 0.5 mm to a total of 4 mm. The three radiographic projections were repeated after each incremental change of length. After the study, each elbow joint was disarticulated to confirm the presence of a step defect. The original radiographs and three copies were randomized and then evaluated by four radiologists blinded to the study design. Radiologists were asked to evaluate whether the joint was normal or abnormal and if there was evidence of radio-ulnar incongruence. The ability of each radiologist to correctly identify congruent elbows (specificity) and incongruent elbows (sensitivity) was calculated. RESULTS: The median specificity was 86% using the lateral projection and 82% using the cranio-caudal projection. The median sensitivities using the lateral and cranio-caudal radiographic projections were 78% and 79%, respectively. The degree of radial shortening required for individual radiologists to achieve a sensitivity of 90% ranged from 1.5 mm to greater than 4 mm. CLINICAL RELEVANCE: Standard radiographic evaluation for radio-ulnar incongruence in the dog may be associated with relatively poor sensitivity and specificity. Invasive surgical procedures and screening programs that rely on radiographic diagnosis of radio-ulnar incongruence should be discouraged until a more reliable method of diagnosis of this type of elbow joint incongruence is available.