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Chemical vapor deposition (CVD) polymerization is a prevalent technique for fabricating conformal, defect-free, and systematically adjustable organic thin films. CVD is particularly beneficial for barrier coatings due to its ability to eliminate solvent-related environmental, health, and safety risk factors and provide a wide spectrum of post-polymerization modification strategies. This review discusses poly-p-xylylene and its functional derivatives. CVD polymerization of [2.2]paracyclophane precursors has undergone a recent renaissance due to advancements in chemical and morphological surface manipulation. This review summarizes emerging trends based on the following outline:Table of content:1 Introduction2 CVD Polymerization as a Sustainable Coating Technology3 CVD Instrumentation4 Poly-p-xylylene Coatings: Background of Polymerization Process and Functionalized Films5 Main Applications of Poly-p-xylylenes6 Area-Selective CVD Polymerization7 Fabrication and Applications of Topological Structures8 Conclusions and Outlook

Background: Acute kidney injury (AKI) occurs frequently in septic patients and correlates with increased mortality. Because clinical studies investigating hydrocortisone, ascorbic acid, and thiamine (HAT) have demonstrated discordant results, studies were performed using mortality stratification for therapy to identify candidates for therapy and determine mechanisms of organ injury. Methods: Sepsis was induced using the cecal ligation and puncture (CLP) model of sepsis with fluid and antibiotic support. Heart rate (HR) measurements obtained 6 hours after CLP stratified mice into live predicted (P-Live) or die predicted (P-Die). Stratified mice were then randomized for treatment with HAT or vehicle given 7 hours after CLP. Physiologic measurements were taken again at 24 hours, and mice were killed to collect blood and organs. Results: The following five groups were created: (1) P-Live vehicle, (2) P-Live HAT, (3) P-Die vehicle, (4) P-Die HAT, and (5) naive mice. Comparisons were made to test the hypotheses that (1) P-Die vehicle mice will have significant deterioration compared with P-Live mice targeting the kidney and (2) HAT will correct these deleterious changes in P-Die mice. Compared with P-Live, P-Die mice had a significant decline in all measured physiologic parameters (HR, cardiac output, breath rate, and temperature), which were corrected with HAT therapy (P0.05 for all parameters). The P-Die mice had declines in the ascorbic acid within the blood, peritoneal lavage, and kidney homogenate compared with P-Live mice indicating consumption, and the decline was corrected with HAT. Elevated IL-6, KC, Macrophage Inflammatory Protein-2, and IL-1RA were found in P-Die mice and decreased with HAT. Markers of endothelial cell injury (glypican 1 and glypican 4) were elevated in the P-Die mice, and these values were decreased with HAT therapy. Low oxygen levels with subsequent oxidative stress (OS) in the kidney were visualized in histologic sections using hypoxyprobe and also with carbonyl proteins and 8-iso-prostaglandin F2α in kidney homogenates. The P-Die mice had significant elevations of renal OSs, which was ameliorated with HAT. Kidney injury was evident in the P-Die mice compared with P-Live mice with elevations in blood urea nitrogen and cystatin C, which were significantly reduced with HAT. There was no evidence of global hypoxia or organ injury because hepatic parameters remained normal. Conclusions: Our data show that in CLP-induced sepsis, P-Die mice have increased inflammation, OS, and kidney injury. Hydrocortisone, ascorbic acid, and thiamine therapy decreased renal OS and injury in the P-Die group when given after the onset of sepsis-induced physiologic changes.

The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by theKCND3-V392I was identified in an 18-year-old male with J wave syndrome/early repolarization syndrome, and a history of cardiac arrest including ventricular tachycardia/ventricular fibrillation and atrial fibrillation/atrial flutter. PathogenicKCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak IThis preclinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated J wave syndrome by inhibiting I

Previous research has adapted the use of economic production functions to estimate the scoring production of teams in professional sports. Most of these studies have focused on professional male team sports, most notably, US baseball, basketball, and association football. This study adds to the literature by utilizing a new and distinctive data set of shooting statistics from 88 men’s and 38 women’s NCAA water polo contests to estimate production functions for United States’ collegiate water polo games and identify the most important variables for predicting margin of victory in such competitions. The results show that shots on goal, average shot distance, number of counterattacks, quick shots, and efficiency in power play conversions are all significant predictors of goal differentials in men’s contests while shots on goal, average shot distance, counterattacks, and center shots are significant predictors in women’s matches. Previous season win percentage, rebounds, exclusions, and missed shots were not significant predictors in the models. These conclusions confirm and extend previous discriminatory studies of elite international water polo contests.

The aim of this study was to describe the baseline clinical features, treatment patterns and outcomes in rectal squamous cell carcinoma (SCC).This is a retrospective study of patients with rectal SCC treated at the Princess Margaret Cancer Centre (Toronto, Canada) between 1 January 1995 and 31 December 2020. Clinical factors associated with locoregional failure (LRF), distant metastases (DM), disease-free survival (DFS) and overall survival (OS), such as age, sex, HIV status, T-category, nodal status, grade and primary treatment, were investigated with univariate analysis (UVA).Twenty nine patients with rectal SCC were analysed with a median follow-up of 7.4 years (range 0.3-20.4 years). The median age at diagnosis was 52 years, with the majority presenting with clinical T3 disease or higher (n = 21, 72%) and positive regional lymph nodes (n = 16, 55%), while more than quarter of patients (28%) had metastatic disease. Definitive chemoradiation was the treatment modality of choice in more than half of all cases (n = 17, 59%) with a response rate of 100%. The 10-year cumulative incidence of LRF and DM was, respectively, 12% (95% CI 1.8%-32.9%) and 31% (95% CI: 12.0%-52.6%). The 5- and 10-year OS was 82% (95% CI 66.1%-100%). UVA revealed a trend towards an association of male gender (hazard ratio = 4.65, 95% CI 0.9%-24.1; p = 0.067) and primary surgical treatment (hazard ratio = 0.76, 95% CI 0.09-6.34; p = 0.061) with DFS.Definitive chemoradiation is an effective and preferred treatment for rectal SCC allowing for sphincter preservation with complete clinical response observed in all patients.

Current literature does not support routine testing for hereditary and acquired thrombophilia disorders in the inpatient setting. Testing in the acute setting rarely changes patient management or could lead to patient mismanagement. Despite prior educational interventions, continued overuse of inpatient testing warrants further quality improvement measures. A hard-stop best practice advisory pop-up was implemented in the electronic medical record in a multicenter academic hospital system to provide clinicians guidance on the appropriate use of thrombophilia testing at the point of care. Pre- and postintervention retrospective data were collected to assess clinical features before and after implementation. Before the intervention, 271 patients underwent inpatient hypercoagulability testing; after the intervention, 238 patients underwent inpatient hypercoagulability testing. The total number of labs ordered per patient decreased from 1185 to 910, a 13% reduction (P = 0.003). Overall, there was a savings of $23,597 in total direct cost and $123,153 in total charges when comparing the 6-month timeframes before and after the intervention (P

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy causing ventricular tachycardia following adrenergic stimulation. Pathogenic variants in RYR2-encoded ryanodine receptor 2 (RYR2) cause CPVT1 and cluster into domains I-IV, with the most N-terminal domain involving residues 77-466. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated for RYR2-F13L, -L14P, -R15P, and -R176Q variants. Isogenic control iPSCs were generated using CRISPR-Cas9/PiggyBac. Fluo-4 Ca

The multi-attribute method (MAM) was conceived as a single assay to potentially replace multiple single-attribute assays that have long been used in process development and quality control (QC) for protein therapeutics. MAM is rooted in traditional peptide mapping methods; it leverages mass spectrometry (MS) detection for confident identification and quantitation of many types of protein attributes that may be targeted for monitoring. While MAM has been widely explored across the industry, it has yet to gain a strong foothold within QC laboratories as a replacement method for established orthogonal platforms. Members of the MAM consortium recently undertook an interlaboratory study to evaluate the industry-wide status of MAM. Here we present the results of this study as they pertain to the targeted attribute analytics component of MAM, including investigation into the sources of variability between laboratories and comparison of MAM data to orthogonal methods. These results are made available with an eye toward aiding the community in further optimizing the method to enable its more frequent use in the QC environment.

Imaging diagnosis of clival cancer may be difficult, in part because of normal variation in marrow signal with aging. Identifying whether clival cancer has damaged the sixth cranial nerve is a further challenge because minimal clival abnormalities could impinge on the nerve, which travels very close to the clivus.Two neuroradiologists, who were unaware of previous imaging and clinical diagnoses, reviewed MRI studies of 25 patients with cancer but no clival involvement and no sixth nerve palsy, 24 patients with clival cancer but without sixth nerve palsy, and 31 patients with clival cancer and sixth nerve palsy. The radiologists were tasked with determining whether there was clival cancer, whether there was a sixth nerve palsy and its laterality, and with indicating the pulse sequences used to make those determinations.Both neuroradiologists correctly identified all 25 cases with a normal clivus. In about half of those cases, they depended on finding a homogeneously bright marrow signal; in the remaining cases, they excluded cancer by determining that the clivus was not expanded and that there were no focal signal abnormalities. Both neuroradiologists correctly identified clival cancer in 54 (98%) of the 55 cases with and without sixth nerve palsy. In doing so, they relied mostly on clival expansion but also on focal signal abnormalities. Both neuroradiologists were at least 80% correct in identifying a sixth nerve palsy, but they often incorrectly identified a palsy in patients who did not have one. When there was a one-sided signal abnormality or the clivus was expanded in one direction, both neuroradiologists were accurate in identifying the side of the sixth nerve palsy.Current MRI pulse sequences allow accurate differentiation of a normal from a cancerous clivus. When the marrow signal is not homogeneously bright in adults, cancer can be diagnosed on the basis of clival expansion or focal signal abnormalities. MRI is less accurate in predicting the presence of a sixth nerve palsy. However, the side of a unilateral palsy can be predicted when the clivus is clearly expanded in one direction or there is a focal signal abnormality on one side.

IntroductionGrowing data support the safe and efficacious use of ablative radiotherapy in the setting of liver metastases, with some studies suggesting that patients with metastatic breast cancer (MBCa) do better than patients with metastases from other cancers. This study aims to retrospectively review clinical outcomes of patients with MBCa following liver radiotherapy (RT).Materials and MethodsPatients with MBCa who received liver hypo fractionated ablative RT between 2004 – 2020 were classified according to metastatic classification and treatment intent (i.e., oligo-metastatic (OM) or oligo-progressive (OP)). Demographics, disease characteristics and treatment characteristics were collated. Primary outcome was local control (LC) of treated metastases. Secondary outcomes included overall survival (OS), progression-free survival (PFS), and time to next line systemic therapy (ST), analyzed by univariate (UVA) and multi-variable analysis (MVA).ResultsThirty MBCa patients with 50 liver metastases treated with 5 – 10 fraction ablative intent RT were identified for analysis. Median follow-up was 14.6 months (range 0.9 - 156.2 months). Mean age was 55.6 years (range 32.1 - 79.3 years); 53% were ER+/HER2-ve and 33% HER2+ve. Class of metastatic disease was described as – induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (3 patients, 10%) (1 synchronous, 2 metachronous). Indication of treatment was OP (73%) and OM (27%). Median size of treated liver metastases (LM) was 3.1 cm (range 1cm – 8.8 cm) and the median dose delivered was 40Gy (range 30Gy-60Gy). 1 and 3-year LC rates were 100%. Median OS was 57.7-months with size of treated liver metastases predictive of overall survival (HR 1.35, p=0.023) on UVA. Median time to progression post treatment was 4.8 months (0.8 – 114.7). Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p=0.01) on UVA compared to others, which trended to significance on MVA (HR 3.23, p=0.051).ConclusionHypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC. Further studies assessing the impact, ideal sequencing, and indications of RT in each metastatic class in MBCa are required.

The glycocalyx (GC) is a semi-solid layer lining the endothelium that plays a key role in maintaining barrier function and mechanosensing shear forces. With advanced age and pathological conditions, the GC deteriorates, and this is accompanied by arterial dysfunction characterized by impaired endothelial-dependent dilation (EDD) and large elastic artery stiffening. Alterations in hyaluronan (HA), a primary component of the GC, may contribute to the development of a dysfunctional artery phenotype. Here, we sought to determine the role of HA in GC integrity and arterial function. We have generated a tamoxifen-inducible, endothelial cell-specific, knockout mouse model of the hyaluronan producing enzyme, hyaluronan synthase 2 (HAS2, HAS2 f/f- Vecad-CreERT2). Endothelial HAS2 knockout (HAS2 f/f- Vecad-creERT2+: ecHAS2 KO, n=10) and wildtype (HAS2 +/+- Vecad-creERT2+: ecHAS2 WT, n=10) young mice were injected intraperitoneally with 4 mg of tamoxifen for 5 consecutive days. HAS2 mRNA expression was reduced by ~47% in carotid endothelial cells of ecHAS2 KO mice (P=0.004). GC barrier function (perfused boundary region [PBR]) was evaluated in vivo in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. PBR was 8.9% higher in ecHAS2 KO compared to ecHAS2 WT (P0.05). Endothelial-independent dilation in response to sodium nitroprusside was not different between groups (P>0.05). Furthermore, aortic pulse wave velocity, a measure of large elastic artery stiffness, as well as systolic, diastolic, and mean arterial blood pressure were all greater in ecHAS2 KO compared to ecHAS2 WT (all P≤0.033). These results demonstrate that endothelial cell-specific impairment in HA synthesis compromises GC integrity and leads to arterial dysfunction and elevated blood pressure. Funded in part by awards from National Institutes of Health Awards R01 AG060395, R01 AG048366, T32 HL007576, T32 HL139451 and Veteran's Affairs Merit Review Award I01 BX004492. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Atherosclerosis, the leading cause of death in the US, is a chronic inflammatory disorder that is associated with arterial dysfunction and hyperlipidemia. Dysfunction of the endothelium, a single layer of cells lining the inside of arteries, is a primary risk factor for atherosclerosis. Endothelial dysfunction is characterized by altered cell metabolism and impaired vasodilation. MicroRNAs (miRs) are small non-coding RNAs that are key regulators of metabolic and cardiovascular diseases. miR-92 has also been shown to be a modulator of endothelial function. We hypothesized that deleting miR-92 would alter endothelial cell metabolism, cause vascular dysfunction, and worsen atherosclerosis. We utilized male and female whole-body miR-92 knockout (miR-92 KO) mice. Hyperlipidemia was induced by administering a single dose of Pcsk9 containing adeno-associated virus, after which mice were fed an atherogenic diet for 16 weeks until aortas were collected to assess atherosclerotic plaque burden. We assessed measures of mitochondrial metabolism in isolated primary endothelial cells (ECs), arterial function, and aortic plaque burden. Using Seahorse technology, we found that primary ECs from miR-92 knockout mice demonstrated a 25% higher rate of oxygen consumption (p9 to 10-4 M) (maximal dilation: 72.2% vs. 38.6%, p National Institute on Aging (R01 AG048366 and R01 AG060395) and US Department of Veterans Affairs (I01 BX004492) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)-positive nasopharyngeal cancer (NPC) versus Epstein-Barr virus (EBV)-positive NPC and HPV-positive oropharyngeal cancer (OPC).Clinical characteristics and presenting signs/symptoms were compared between patients who had viral-related NPC versus viral-related OPC treated with intensity-modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005-2018 cohort to maintain 2 years of minimum follow-up. Multivariable analysis was used to evaluate the cohort effect.Similar to HPV-positive OPC (n = 1531), HPV-positive NPC (n = 29) occurred mostly in White patients compared with EBV-positive NPC (n = 422; 86% vs. 15%; p.001). Primary tumor volumes were larger in HPV-positive NPC versus EBV-positive NPC (median volume, 51 vs. 23 cmHPV-positive NPC and EBV-positive NPC seem to be mutually exclusive diseases. Patients who have HPV-positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV-positive NPC or HPV-positive OPC.

During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, a marked increase in sudden cardiac death (SCD) was observed. The p.S1103Y-SCN5A common variant, which is present in ∼8% of individuals of African descent, may be a circumstance-dependent, SCD-predisposing, proarrhythmic polymorphism in the setting of hypoxia-induced acidosis or QT-prolonging drug use.The purpose of this study was to ascertain the effects of acidosis and hydroxychloroquine (HCQ) on the action potential duration (APD) in a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of p.S1103Y-SCN5A.iPSC-CMs were generated from a 14-year-old p.S1103Y-SCN5A-positive African American male. The patient's variant-corrected iPSC-CMs (isogenic control [IC]) were generated using CRISPR/Cas9 technology. FluoVolt voltage-sensitive dye was used to assess APDUnder baseline conditions (pH 7.4), there was no difference in APDAlthough the African-specific p.S1103Y-SCN5A common variant had no effect on APD

Angiocentric gliomas (AGs) are epileptogenic low-grade gliomas in young patients. We aimed to investigate the MRI findings of AGs and systematically review previous publications and three new cases.We searched PubMed, Elsevier's abstract and citation database, and Embase databases and included 50 patients with pathologically proven AGs with analyzable preoperative MRI including 3 patients from our institution and 47 patients from 38 publications (median age, 13 years [range, 2-83 years]; 35 men). Two board-certified radiologists reviewed all images. The relationships between seizure/epilepsy history and MRI findings were statistically analyzed. Moreover, clinical and imaging differences were evaluated between supratentorial and brainstem AGs.Intratumoral T1-weighted high-intensity areas, stalk-like signs, and regional brain parenchymal atrophy were observed in 23 out of 50 (46.0%), 10 out of 50 (20.0%), and 14 out of 50 (28.0%) patients, respectively. Intratumoral T1-weighted high-intensity areas were observed significantly more frequently in patients with stalk-like signs (positive, 9/10 vs. negative, 14/40, p = .0031) and regional atrophy (13/14 vs. 10/36, p = .0001). There were significant relationships between the length of seizure/epilepsy history and presence of intratumoral T1-weighted high-intensity area (median 3 years vs. 0.5 years, p = .0021), stalk-like sign (13.5 vs. 1 year, p .0001), and regional atrophy (14 vs. 0.5 years, p .0001). Patients with brainstem AGs (n = 7) did not have a seizure/epilepsy history and were significantly younger than those with supratentorial AGs (median, 5 vs. 13 years, p .0001, respectively).Intratumoral T1-weighted high-intensity areas, stalk-like signs, and regional brain atrophy were frequent imaging features in AG. We also found that affected age was different between supratentorial and brainstem AGs.

Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined.This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma.This is a retrospective cohort study.This study was conducted at a quaternary cancer center.Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected.Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection.Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome.There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease.This study is limited by its small sample size and retrospective nature.Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO.El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo.Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal.Estudio de cohorte retrospectivo.Centro de cáncer cuaternario.Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016.Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica.Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados.Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos.Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva.Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon).

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple immunologic abnormalities and has the potential to involve the central nervous system (CNS). The prevalence of SLE seems to be growing, possibly because of earlier diagnosis and improved survival; however, the associated mortality is still high. The mortality is associated with disease-related risk factors such as lupus disease activity, young age, and organ damage or with antiphospholipid syndrome (APS). Neuropsychiatric SLE (NPSLE), which is caused by SLE-related CNS involvement, comprises a broad range of neurologic and psychiatric manifestations with varying severity, which can make this disease indistinguishable from other conditions that are unrelated to SLE. No unifying pathophysiology has been found in the etiology of NPSLE, suggesting that this condition has multiple contributors such as various immune effectors and the brain-intrinsic neuroimmune interfaces that are breached by the immune effectors. The postulated neuroimmune interfaces include the blood-brain barrier, blood-cerebrospinal fluid barrier, meningeal barrier, and glymphatic system. On the basis of the immunologic, pathologic, and imaging features of NPSLE, the underlying pathophysiology can be classified as vasculitis and vasculopathy, APS, demyelinating syndrome, or autoimmune antibody-mediated encephalitis. Each pathophysiology has different imaging characteristics, although the imaging and pathophysiologic features may overlap. Moreover, there are complications due to the immunocompromised status caused by SLE per se or by SLE treatment. Radiologists and clinicians should become familiar with the underlying mechanisms, radiologic findings, and complications of NPSLE, as this information may aid in the diagnosis and treatment of NPSLE.

Discriminating gap size (DGS) criterion shows a gap in the distribution of the expression of MHC class II expression in the IPACTR cohort. Each panel plots the rank of expression value in the cohort on the y-axis and the positive quantile transformation (PQT) value on the x-axis. Solid blue circles indicate adrenocortical carcinomas, open red circles indicate adrenocortical adenomas, and black X-marks indicate undetermined histology. In each plot, the gray rectangle highlights the large gap in the distribution that discriminates adenomas from carcinomas which was identified by the DGS criterion.

The Primary Antibodies Used for Immunohistochemistry Studies

Supplementary Fig 1. Discriminating gap size (DGS) criterion shows a gap in the distribution of the expression of MHC class II expression in the IPACTR cohort. Supplementary Fig 2. Immunohistochemical analysis of CD3, CD4, and CD8 expression.

Immunohistochemical analysis of CD3, CD4, and CD8 expression. Row: a) adenoma; b) stage I carcinoma; and c) stage III carcinoma. Note that cells with short processes are dimly positive for CD4, consistent with macrophages; cells with long process are also dimly positive for CD4, consistent with dendritic cells (Magnification, 100x; inset, 400x).

Probe-sets that Best Discriminated between Adenoma and Carcinoma in the IPACTR Cohort and Association with PFS in the COG Cohort

Clinical Data for Pediatric Adrenocortical Tumor patients

Association of HLA-DPA1 Expression with Clinical and Biological Characteristics of Uniformly Managed Pediatric Adrenocortical Carcinoma

Purpose: Histologic markers that differentiate benign and malignant pediatric adrenocortical tumors are lacking. Previous studies have implicated an association of MHC class II expression with adrenocortical tumor prognosis. Here, we determined the expression of MHC class II as well as the cell of origin of these immunologic markers in pediatric adrenocortical tumor. The impact of MHC class II gene expression on outcome was determined in a cohort of uniformly treated children with adrenocortical carcinomas.Experimental Design: We analyzed the expression of MHC class II and a selected cluster of differentiation genes in 63 pediatric adrenocortical tumors by Affymetrix Human U133 Plus 2.0 or HT HG-U133+PM gene chip analyses. Cells expressing MHC class II were identified by morphologic and immunohistochemical assays.Results: MHC class II expression was significantly greater in adrenocortical adenomas than in carcinomas (P = 4.8 ×10−6) and was associated with a higher progression-free survival (PFS) estimate (P = 0.003). Specifically, HLA-DPA1 expression was most significantly associated with PFS after adjustment for tumor weight and stage. HLA-DPA1 was predominantly expressed by hematopoietic infiltrating cells and undetectable in tumor cells in 23 of 26 cases (88%).Conclusions: MHC class II expression, which is produced by tumor-infiltrating immune cells, is an indicator of disease aggressiveness in pediatric adrenocortical tumor. Our results suggest that immune responses modulate adrenocortical tumorigenesis and may allow the refinement of risk stratification and treatment for this disease. Clin Cancer Res; 22(24); 6247–55. ©2016 AACR.

IMPORTANCE: Patient-derived xenografts (PDXs) offer the opportunity to identify patients with oral cavity squamous cell carcinoma (OSCC) who are at risk for recurrence and optimize clinical decision-making. OBJECTIVE: To develop and validate a prediction score for locoregional failure (LRF) and distant metastases (DM) in OSCC that incorporates PDX engraftment in addition to known clinicopathological risk factors. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, PDX models were generated from patients with OSCC treated with curative intent at Princess Margaret Cancer Centre (Toronto, Canada) between 2006 and 2018. The cohort included 288 patients (aged ≥18 years) with a new diagnosis of nonmetastatic (M0) OSCC whose tumor samples were available for engraftment under the skin of xenograft mice. Patients were scored as a nonengrafter if PDX formation did not occur within 6 months. Data analysis was performed between August 2006 and May 2018. INTERVENTIONS: All patients received up-front curative-intent surgery followed by either observation or postoperative radiation with or without concurrent chemotherapy based on institutional guidelines. MAIN OUTCOMES AND MEASURES: Main outcomes were LRF, DM, and overall survival (OS). Multivariable analysis (MVA) was used to identify predictors of LRF and DM. Factors retained in the final MVA were used to construct a prediction score and classify patients into risk groups. RESULTS: Overall, 288 patients (mean [SD] age at diagnosis, 63.3 [12.3] years; 112 [39%] women and 176 [61%] men) with OSCC were analyzed. The MVA identified pT3-4, pathologic extranodal extension, and engraftment as predictors of LRF and DM. Patients whose tumors engrafted (n = 198) were more likely to develop LRF (hazard ratio [HR], 1.98; 95% CI, 1.24-3.18) and DM (HR, 2.64; 95% CI, 1.21-5.75) compared with nonengrafters. A prediction score based on the aforementioned variables identified patients at high risk and low risk for LRF (43.5% vs 26.5%), DM (38.2% vs 8.4%), and inferior OS (34% vs 66%) at 5 years. Additionally, rapid engraftment was shown to be similarly prognostic, with rapid engrafters demonstrating higher rates of relapse and poor OS. CONCLUSIONS: In this cohort study, a prediction score using OSCC PDX engraftment, in conjunction with pT3-4 and pathologic extranodal extension, was associated with improved prognostic utility of existing clinical models and predicted patients at risk for LRF, DM, and poor survival.

IMPORTANCELarge language model (LLM) artificial intelligence (AI) chatbots direct the power of large training datasets towards successive, related tasks, as opposed to single-ask tasks, for which AI already achieves impressive performance. The capacity of LLMs to assist in the full scope of iterative clinical reasoning via successive prompting, in effect acting as virtual physicians, has not yet been evaluated.OBJECTIVETo evaluate ChatGPT’s capacity for ongoing clinical decision support via its performance on standardized clinical vignettes.DESIGNWe inputted all 36 published clinical vignettes from the Merck Sharpe & Dohme (MSD) Clinical Manual into ChatGPT and compared accuracy on differential diagnoses, diagnostic testing, final diagnosis, and management based on patient age, gender, and case acuity.SETTINGChatGPT, a publicly available LLMPARTICIPANTSClinical vignettes featured hypothetical patients with a variety of age and gender identities, and a range of Emergency Severity Indices (ESIs) based on initial clinical presentation.EXPOSURESMSD Clinical Manual vignettesMAIN OUTCOMES AND MEASURESWe measured the proportion of correct responses to the questions posed within the clinical vignettes tested.RESULTSChatGPT achieved 71.7% (95% CI, 69.3% to 74.1%) accuracy overall across all 36 clinical vignettes. The LLM demonstrated the highest performance in making a final diagnosis with an accuracy of 76.9% (95% CI, 67.8% to 86.1%), and the lowest performance in generating an initial differential diagnosis with an accuracy of 60.3% (95% CI, 54.2% to 66.6%). Compared to answering questions about general medical knowledge, ChatGPT demonstrated inferior performance on differential diagnosis (β=-15.8%, pCONCLUSIONS AND RELEVANCEChatGPT achieves impressive accuracy in clinical decision making, with particular strengths emerging as it has more clinical information at its disposal.