The 2021 SIIM-FISABIO-RSNA Machine Learning COVID-19 Challenge: Annotation and Standard Exam Classification of COVID-19 Chest Radiographs.

We describe the curation, annotation methodology, and characteristics of the dataset used in an artificial intelligence challenge for detection and localization of COVID-19 on chest radiographs. The chest radiographs were annotated by an international group of radiologists into four mutually exclusive categories, including "typical," "indeterminate," and "atypical appearance" for COVID-19, or "negative for pneumonia," adapted from previously published guidelines, and bounding boxes were placed on airspace opacities. This dataset and respective annotations are available to researchers for academic and noncommercial use.

Interstitial cell network volume is reduced in the terminal bowel of ageing mice.

Ageing is associated with impaired neuromuscular function of the terminal gastrointestinal (GI) tract, which can result in chronic constipation, faecal impaction and incontinence. Interstitial cells of cajal (ICC) play an important role in regulation of intestinal smooth muscle contraction. However, changes in ICC volume with age in the terminal GI tract (the anal canal including the anal sphincter region and rectum) have not been studied. Here, the distribution, morphology and network volume of ICC in the terminal GI tract of 3- to 4-month-old and 26- to 28-month-old C57BL/6 mice were investigated. ICC were identified by immunofluorescence labelling of wholemount preparations with an antibody against c-Kit. ICC network volume was measured by software-based 3D volume rendering of confocal Z stacks. A significant reduction in ICC network volume per unit volume of muscle was measured in aged animals. No age-associated change in ICC morphology was detected. The thickness of the circular muscle layer of the anal sphincter region and rectum increased with age, while that in the distal colon decreased. These results suggest that ageing is associated with a reduction in the network volume of ICC in the terminal GI tract, which may influence the normal function of these regions.

Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation.

Objectives: The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken. Methods: This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression. Results: One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110-4220) ng/mL and the median time until level was 6 (range 5-14) days. There was a statistically significant increase in AST ( P < 0.001), ALT ( P < 0.001), alkaline phosphatase (ALK) ( P < 0.001), total bilirubin (TBILI) ( P < 0.001) and QTc ( P = 0.05) from baseline. Posaconazole levels were not associated with increases in AST [ß (SE) = -0.33 (2.2), P = 0.88], log ALT [ß (SE) = -0.02 (0.03), P = 0.63], ALK [ß (SE) = 2.2 (2.9), P = 0.46] and TBILI [ß (SE) = -0.01 (0.04), P = 0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13 mg/dL ( P = 0.02) and ALK of 7.1 U/L ( P = 0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found. Conclusions: We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.

Feasibility, Benefits, and Limitations of a Penicillin Allergy Skin Testing Service.

OBJECTIVE: To critically examine the feasibility, benefits, and limitations of an inpatient penicillin skin testing service and how pharmacists can be utilized. DATA SOURCES: A PubMed search was performed from July 2016 through September 2016 using the following search terms: penicillin skin testing, penicillin allergy, ß-lactam allergy. Additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: All English-language studies assessing the use of penicillin skin testing as well as management and clinical outcomes of patients with a ß-lactam allergy were evaluated. DATA SYNTHESIS: The prevalence of people self-identifying as penicillin allergic ranges from 10% to 20% in the United States. Being improperly labeled as penicillin allergic is associated with higher health care costs, worse clinical outcomes, and an increased prevalence of multidrug-resistant infections. Penicillin skin testing can be a tool used to clarify penicillin allergies and has been demonstrated to be a successful addition to antimicrobial stewardship programs in multiple health care settings. Prior to implementing a penicillin skin testing service, institutions will need to perform a feasibility analysis of who will supply labor and accept the financial burden as well as identify if the positive benefits of a penicillin skin testing service overcome the limitations of this diagnostic test. CONCLUSION: We conclude that institutions with high percentages of patients receiving non-ß-lactams because of penicillin allergy labels would likely benefit the most from a penicillin skin testing service.

Consequences of avoiding ß-lactams in patients with ß-lactam allergies.

BACKGROUND: The choice of empiric antibiotics for the treatment of gram-negative bacilli (GNB) bloodstream infections (BSIs) in patients presenting with a ß-lactam (BL) allergy is often a difficult decision given that these agents are first-line treatment in many guidelines. OBJECTIVE: We sought to compare rates of clinical failure between patients with a history of BL allergy who received either a BL or a non-ß-lactam (NBL). METHODS: Adult patients with a past medical history of BL allergy and receipt of antibiotics for treatment of a GNB BSI were included from 3 academic medical centers. Treatment groups were classified as BL or NBL groups based on the empiric antibiotics received. Clinical failure was assessed 72 to 96 hours after initiation of empiric antibiotics. Hypersensitivity reactions during receipt of antibiotic therapy for the index BSI were recorded. RESULTS: A total of 552 patients were included for analysis: 433 patients in the BL group and 119 patients in the NBL group. Clinical failure was higher in the NBL group compared with the BL group (38.7% vs 27.4%, P = .030). The most common cause of clinical failure was a temperature of greater than 38.0°C 72 to 96 hours after receipt of empiric antibiotics (NBL group: 22.7% vs BL group: 13.9%, P = .016). Hypersensitivity occurred in 16 (2.9%) of 552 patients. Thirteen (2.5%) of 552 patients experiencing hypersensitivity reactions were exposed to a BL during treatment for GNB BSI. CONCLUSION: Among patients with a BL allergy, use of BL antibiotics is associated with a lower rate of clinical failure. The low rate of hypersensitivity provides further evidence about the risk of cross-reactivity between BL classes. These results support the practice of using a BL from an alternative class for patients in need of gram-negative antibiotic coverage.

Impact of Cefepime Susceptible-Dose-Dependent MIC for Enterobacteriaceae on Reporting and Prescribing.

The CLSI cefepime breakpoints were revised to include a susceptible-dose-dependent (SDD) category for Enterobacteriaceae, with the intention that higher cefepime doses be used for these isolates. In this study, 1.6% of Enterobacteriaceae isolates were reported as SDD, with Escherichia coli the most common SDD organism. Cefepime was prescribed in three cases (4.8%); the majority of SDD isolates were treated with a carbapenem. Enterobacteriaceae with cefepime SDD MICs were not commonly treated with cefepime at our institution.

Analysing the influence of ground granulated blast furnace slag and steel fibre on RC beams flexural behaviour.

This study examines the effect of Ground Granulated Blast Furnace Slag (GGBS) and steel fibers on the flexural behaviour of RC beams under monotonic loading. Various percentages of GGBS were used to substitute cement, namely 0%, 20%, 40%, 60%, and 80% and fibers were added to the concrete mix as 0%, 0.5%, 1%, and 1.5% of the volume of concrete. The load-deflection behaviour of GGBS-incorporated RC beams with fibers was compared with the control RC beam. Beams were tested under load control for 28 days and 180 days. The ultimate load of the GGBS-incorporated RC beam up to 40% cement replacement was found to higher than that of the control beam. The strength of concrete is reduced by 28% and 19% when cement was partially replaced by 80% of GGBS at 28 and 180 days, respectively, compared to control concrete without fibres. Further, the analytical load-deflection response of GGBS-incorporated RC beams was determined by using several codes of practice, namely, ACI 318-11(2011), CSA A23.3-04 (2004), EC-04 (2004), and IS 456 (2000). The Codal provisions were primarily based on the effective moment of inertia, Young's modulus, and modulus of rupture, stiffness, and cracking. Average load-deflection plots obtained from experiments were compared with the computed load-deflection of analytical studies. It was found that the analytically predicted load-deflection behaviour is comparable with the corresponding average experimental load-deflection response. Moment curvature relations were also developed for RC beams.

Efficiency of Glucosamine in Treating Temporomandibular Joint Osteoarthritis: A Systematic Review.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJ OA) is a chronic disease that is a consequence of undue occlusal forces and is characterized by irreversible damage to the articular surfaces. Symptomatic slow-acting so-called nutraceutical drugs have been proposed as a treatment for osteoarthritis in comparison to non-steroidal anti-inflammatory drugs (NSAIDs). Oral glucosamine and chondroitin, slow-acting drugs, have been found to reduce pain and in- crease mouth opening in patients with TMJ OA. However, there is limited scientific evidence to confirm their clinical effectiveness. AIM: This systematic review was conducted to bolster the evidence supporting the assessment of the efficacy of glucosamine in the context of temporomandibular joint osteoarthritis (TMJ OA). METHODOLOGY: This review identified four review articles from databases like Medline (via PubMed), Web of Science, Scopus, and EMBASE till September 2023 after screening at the title, abstract, and full-text level. They were assessed for risk of bias with the JBI risk of bias assess- ment tool. RESULT: This review with meta-analysis focused on pooled estimate mean differences, revealing non-significant but discernible effects of glucosamine on maximum mouth opening (SMD = 0.288, p = 0.15) and pain reduction (SMD = 0.217, p = 0.476) in TMJ-related disorders. CONCLUSION: Compared to control groups with ibuprofen and tramadol, glucosamine showed slightly more favourable outcomes. However, the variability in methodology and study characteristics warrants further longitudinal studies to confirm its efficacy.

Endonasal Dacryocystorhinostomy: Results With or Without Stenting.

Introduction This is a comparative cross-sectional study done to compare the curative outcome of endonasal dacryocystorhinostomy (DCR) done with and without a silicon stent in patients with chronic dacryocystitis due to nasolacrimal duct obstruction. Methods This study was carried out in central India, involving 60 patients who were diagnosed with chronic dacryocystitis and underwent endonasal DCR (with zero-degree and 45-degree endoscopes from Olympus, with an Olympus camera and monitor) between October 2021 and September 2022. All patients were over the age of 18, with major exclusion criteria of previous DCR and sinonasal disease. All the surgeries were done by the same senior surgeon, in which 30 patients were stented (with a Prison silicone nasolacrimal duct stent) and 30 of them were non-stented. The follow-up duration for these was 12 months after the surgery.  Results The outcome was evaluated at the end of three months, six months, and 12 months for both groups (patients with and without stents) using the Chi-square test. The success rate at the end of six months was 90% with stented patients and 93.3% with non-stented patients (p-value - 0.64); at six months, it was also the same (p-value - 0.64); and at the end of 12 months, it was 80% and 76.6% (p-value - 0.71) for patients with and without a stent, respectively. The final endoscopy at the end of 12 months showed 93.3% of patients who underwent stenting had a patent rhinostomy opening, and 90% of those who were not stented had a patent opening. Conclusions Our observational comparative study showed that patients with chronic dacryocystitis who underwent endonasal DCR with and without stenting had almost similar results. There was no significant difference in the outcome. So, we concluded that generally all the patients should be considered for endonasal DCR without a stent, except in special cases like revision endonasal DCR, lacrimal gland cysts, fistulas, and patients with sinonasal pathology, in whom silicon stents can be preferred.

Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers.

Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS ("E26 transformation specific") family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.

Assessing Naltrexone Prescribing and Barriers to Initiation for Alcohol Use Disorder: A Multidisciplinary, Multisite Survey.

Objective: To survey barriers in prescribing naltrexone for alcohol use disorder. Methods: A 12-question survey related to naltrexone prescribing patterns, perceptions, and knowledge was sent to 770 prescribers in the departments of internal medicine, family medicine, and psychiatry across a health system with sites in Arizona, Florida, and Minnesota. Results: Responses were obtained and included for 146/770 prescribers (19.0% response rate). Most respondents were in the department of internal medicine (n = 94, 64.4%), but the departments of psychiatry (n = 22, 15.1%) and family medicine (n = 30, 20.5%) were also represented. Only 34 (23.3%) respondents indicated they had prescribed naltrexone in the previous 3 months. The most common reasons for not prescribing naltrexone were "unfamiliarity with naltrexone for treatment of alcohol use disorder" and "patients do not have appropriate follow-up or are not in a formal treatment program." Compared with those representing internal/family medicine, psychiatry respondents were more likely to prescribe naltrexone and answer knowledge questions correctly. Conclusion: In this survey among primarily non-addiction-trained prescribers, a disparity was shown for prescribing naltrexone and in knowledge barriers between staff in internal/family medicine and psychiatry. There exist opportunities for education and quality improvement that promote the prescribing of naltrexone for alcohol use disorder by non-addiction specialists.

Perceptions and practices regarding use of personal listening devices among medical students in coastal south India.

UNLABELLED: Today's generation enjoys having music at their fingertips. This has led to an increase in the usage of personal listening devices (PLDs) over the past decade. There are significant concerns regarding harmful effects of PLD use. To find out the perception and practice of medical students regarding use of PLDs. Cross-sectional study was carried out in Mangalore, Coastal south India. Data were collected using a 31 item semi structured questionnaire that was distributed among 570 medical students, of which 485 completed questionnaire were received giving an overall response rate of 86.14%. The study was approved by the departmental review board. STATISTICAL ANALYSIS USED: data were analyzed using SPSS Version 11.5, Chi-square test for association was used and P<0.05 was considered statistically significant. Of the total study participants, 83.1% of them used PLDs regularly, of whom 77.7% used it for more than 1 h a day. Overall, 18.0% of the study population was aware that prolonged use of PLDs could be harmful to their health. Majority of the study subjects (72.4%) felt that the safe duration of listening to PLDs is 3 to 5 h. Among the subjects using PLDs ≥ 1 h, 60.1% preferred ear phones and among those using PLDs <1 h, 44.1% preferred earphones. Overall, 12.4% experienced temporary hearing loss on usage of PLDs. The use of PLDs among the medical students is on the rise, and they should be made more aware of the harmful effects associated with its use.

Formulation of a mixed fruit beverage using fuzzy logic optimization of sensory data and designing its batch thermal pasteurization process.

The study aims to formulate a mixed fruit beverage through sensory analysis, and the composition was optimized using a fuzzy logic algorithm. The fuzzy optimization algorithm was developed using a modified Takagi and Sugeno's approach, polynomial mixture modeling, and nonlinear solver engine. The optimized blend consisted of amla juice, pineapple juice, and coconut water in 14.3, 63.0, and 22.7%, respectively. Further, the batch thermal treatment was carried out within 50 to 95 °C for an isothermal holding time of 1 s to 10 min, and pasteurization condition for the beverage was estimated from kinetic modeling. The concept of thermal pulse inactivation due to non-isothermal heat-up-time and cool-down-time has been introduced within the process time calculation. From the kinetic study, polyphenoloxidase enzyme appeared to be the most resistant entity towards inactivation among all the natural microbiota and quality deteriorating enzymes. Pasteurization in terms of achieving a 5D reduction of both aerobic mesophilic and yeast-mold counts was attained over a range of 80 to 95 °C for 10.2 + 1.4 to 3.1 + 2.0 min (1.4 and 2.0 min = heat-up-time + cool-down-time), respectively. The 90% inactivation of both polyphenoloxidase and peroxidase enzymes was obtained over a range of 90 to 95 °C for 12.8 + 1.7 to 8.4 + 2.0 min, respectively. While obtaining both the microbial and enzyme stability at the isothermal condition of 95 °C for 8.4 min, the corresponding retention in ascorbic acid, total phenolics, and antioxidant capacity were observed as 49.7, 63.0, and 61.4%, respectively. PRACTICAL APPLICATION: In this work, the formulation of a fruit blend was optimized through an intelligent optimization technique (fuzzy algorithm) applied to the sensory data set. The approach for calculating thermal processing time or pasteurization condition provides a new dimension with better precision. The thermal treatment condition of 95 °C for 10 min can be used for this mixed beverage to achieve both microbial stability (5-log reduction) and enzyme stability (90% reduction). The presented study can be used as a reference for other similar beverages to achieve a complete process design from basic formulation optimization to thermal (batch-type) processing conditions.

Quality of life and perceived financial implications among otorhinolaryngologists during the COVID-19 pandemic across India.

OBJECTIVE: The changing trends in medical practice, uncertainties and monetary apprehensions due to the COVID-19 pandemic may influence the sense of well-being among otorhinolaryngologists. The present study was conducted to evaluate quality of life (QOL) and perceived financial implications in otorhinolaryngologists during the COVID-19 pandemic across India. METHODS: A cross-sectional study was carried out among otorhinolaryngology specialists across India using WHOQOL-BREF and Consumer Financial Protection Bureau (CFPB) Financial Well-Being Scale questionnaires on Google Forms, which was kept open for the latter half of July 2020. RESULTS: A total of 358 responses were obtained; the response rate was 26.64%. Twenty-four percent of respondents worked exclusively in academic settings; 40.22% of specialists had over 10 years of work experience. Average monthly income in 2019 was between 1-3 lakhs Indian Rupees (INR) in 43.85%, while in 2020, 62.57% of the specialists had an average monthly income of below one lakh INR; this difference was statistically significant (p < 0.001). Mean WHOQOL-BREF scores for physical, psychological, social and environmental domains were 68.8 ± 1, 62.3 ± 0.75, 68.9 ± 1.17 and 65.8 ± 1.01, respectively; mean CFPB financial well-being scale score was 55.5 ± 0.66. QOL and financial well-being were better in otolaryngologists older than 60 years, male specialists and private consultants. CONCLUSIONS: There has been a tremendous impact on quality of life and financial well-being among otorhinolaryngologists in India during the COVID-19 pandemic. The study outcome may help otolaryngologists comprehend and perceive the extent to which it has affected their professional and personal lives, and explore ways to face and overcome the situation.

SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies.

Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse BRAFV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAFV600E-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies. SIGNIFICANCE: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade.This article is highlighted in the In This Issue feature, p. 995.

Microencapsulation techniques, factors influencing encapsulation efficiency.

Microencapsulation is one of the quality preservation techniques of sensitive substances and a method for production of materials with new valuable properties. Microencapsulation is a process of enclosing micron-sized particles in a polymeric shell. There are different techniques available for the encapsulation of drug entities. The encapsulation efficiency of the microparticle or microsphere or microcapsule depends upon different factors like concentration of the polymer, solubility of polymer in solvent, rate of solvent removal, solubility of organic solvent in water, etc. The present article provides a literature review of different microencapsulation techniques and different factors influencing the encapsulation efficiency of the microencapsulation technique.

Comparison of intravenous and oral definitive antibiotic regimens in hospitalised patients with Gram-negative bacteraemia from a urinary tract infection.

OBJECTIVES: Transitioning patients from intravenous (IV) to oral antibiotic therapy has been shown to be a successful approach for several infections. However, minimal data exist evaluating outcomes following transition from to oral antibiotics for patients with bacteraemia secondary to a urinary tract infection (UTI). This study compared treatment failures between patients treated exclusively with IV antibiotics and those transitioned from IV to oral antibiotics for bacteraemia secondary to UTI. METHODS: This single-centre, retrospective cohort study included hospitalised, non-critically ill adult patients treated with culture-susceptible antibiotic therapy for 7-21 days. Patients were divided into two cohorts based on the route of definitive antibiotic administration. Treatment failure was a composite outcome of death and recurrence of the index micro-organism within 21 days following negative blood cultures. RESULTS AND DISCUSSION: Among the 346 patients enrolled, 82 (23.7%) were in the IV cohort and 264 (76.3%) were in the IV-to-oral cohort. A total of six treatment failures occurred; 2 (2.4%) in the IV cohort and 4 (1.5%) in the oral transition cohort (hazard ratio=0.62, 95% confidence interval 0.11-3.39; P=0.58). All failures were due to recurrence of the index organism. Secondary outcomes demonstrated a significantly higher rate of IV line-associated complications in the IV cohort (P=0.03) and a favourable hospital length of stay in the oral cohort (P<0.001). Patients transitioned from IV to oral antibiotics based on culture-susceptibility data experienced similarly low rates of treatment failure as those who received exclusive IV therapy.

Disorder in Pixel-Level Edge Directions on T1WI Is Associated with the Degree of Radiation Necrosis in Primary and Metastatic Brain Tumors: Preliminary Findings.

BACKGROUND AND PURPOSE: Co-occurrence of local anisotropic gradient orientations (COLLAGE) is a recently developed radiomic (computer extracted) feature that captures entropy (measures the degree of disorder) in pixel-level edge directions and was previously shown to distinguish predominant cerebral radiation necrosis from recurrent tumor on gadolinium-contrast T1WI. In this work, we sought to investigate whether COLLAGE measurements from posttreatment gadolinium-contrast T1WI could distinguish varying extents of cerebral radiation necrosis and recurrent tumor classes in a lesion across primary and metastatic brain tumors. MATERIALS AND METHODS: On a total of 75 gadolinium-contrast T1WI studies obtained from patients with primary and metastatic brain tumors and nasopharyngeal carcinoma, the extent of cerebral radiation necrosis and recurrent tumor in every brain lesion was histopathologically defined by an expert neuropathologist as the following: 1) "pure" cerebral radiation necrosis; 2) "mixed" pathology with coexistence of cerebral radiation necrosis and recurrent tumors; 3) "predominant" (>80%) cerebral radiation necrosis; 4) predominant (>80%) recurrent tumor; and 5) pure tumor. COLLAGE features were extracted from the expert-annotated ROIs on MR imaging. Statistical comparisons of COLLAGE measurements using first-order statistics were performed across pure, mixed, and predominant pathologies of cerebral radiation necrosis and recurrent tumor using the Wilcoxon rank sum test. RESULTS: COLLAGE features exhibited decreased skewness for patients with pure (0.15 ± 0.12) and predominant cerebral radiation necrosis (0.25 ± 0.09) and were statistically significantly different (P < .05) from those in patients with predominant recurrent tumors, which had highly skewed (0.42 ± 0.21) COLLAGE values. COLLAGE values for the mixed pathology studies were found to lie between predominant cerebral radiation necrosis and recurrent tumor categories. CONCLUSIONS: With additional independent multisite validation, COLLAGE measurements might enable noninvasive characterization of the degree of recurrent tumor or cerebral radiation necrosis in gadolinium-contrast T1WI of posttreatment lesions.

EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC.

Translation initiation is orchestrated by the cap binding and 43S preinitiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX mutations are enriched in advanced thyroid cancers, where they display a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113splice variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113splice. ATF4 and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4, and mTOR kinase inhibitors. SIGNIFICANCE: Mutations of EIF1AX, a component of the translation PIC, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis. EIF1AX-A113splice drives an ATF4-induced dephosphorylation of EIF2α, resulting in increased protein synthesis. ATF4 also cooperates with c-MYC to sensitize mTOR to amino acid supply, thus generating vulnerability to mTOR kinase inhibitors. This article is highlighted in the In This Issue feature, p. 151.

Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation.

The effects of genistein on 30-day survival and delayed lung injury were examined in C57BL/6J female mice. A single subcutaneous injection of vehicle (PEG-400) or genistein (200 mg/kg) was administered 24 h before total body irradiation (7.75 Gy (60)Co, 0.6 Gy/min). Experimental groups were: No treatment + Sham (NC), Vehicle + Sham (VC), Genistein + Sham (GC), Radiation only (NR), Vehicle + Radiation (VR), Genistein + Radiation (GR). Thirty-day survivals after 7.75 Gy were: NR 23%, VR 53%, and GR 92%, indicating significant protection from acute radiation injury by genistein. Genistein also mitigated radiation-induced weight loss on days 13-28 postirradiation. First generation lung fibroblasts were analyzed for micronuclei 24 h postirradiation. Fibroblasts from the lungs of GR-treated mice had significantly reduced micronuclei compared with NR mice. Collagen deposition was examined by histochemical staining. At 90 days postirradiation one half of the untreated and vehicle irradiated mice had focal distributions of small collagen-rich plaques in the lungs, whereas all of the genistein-treated animals had morphologically normal lungs. Radiation reduced the expression of COX-2, transforming growth factor-beta receptor (TGFbetaR) I and II at 90 days after irradiation. Genistein prevented the reduction in TGFbetaRI. However, by 180 days postirradiation, these proteins normalized in all groups. These results demonstrate that genistein protects against acute radiation-induced mortality in female mice and that GR-treated mice have reduced lung damage compared to NR or VR. These data suggest that genistein is protective against a range of radiation injuries.