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The purpose of this study is to determine whether a deep convolutional neural network (DCNN) trained on a dataset of limited size can accurately diagnose traumatic pediatric elbow effusion on lateral radiographs.A total of 901 lateral elbow radiographs from 882 pediatric patients who presented to the emergency department with upper extremity trauma were divided into a training set (657 images), a validation set (115 images), and an independent test set (129 images). The training set was used to train DCNNs of varying depth, architecture, and parameter initialization, some trained from randomly initialized parameter weights and others trained using parameter weights derived from pretraining on an ImageNet dataset. Hyperparameters were optimized using the validation set, and the DCNN with the highest ROC AUC on the validation set was selected for further performance testing on the test set.The final trained DCNN model had an ROC AUC of 0.985 (95% CI, 0.966-1.000) on the validation set and 0.943 (95% CI, 0.884-1.000) on the test set. On the test set, sensitivity was 0.909 (95% CI, 0.788-1.000), specificity was 0.906 (95% CI, 0.844-0.958), and accuracy was 0.907 (95% CI, 0.843-0.951).Accurate diagnosis of traumatic pediatric elbow joint effusion can be achieved using a DCNN.

The 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as "day 14 [D14] marrow"). Those who do not achieve a hypoplastic marrow, with cellularity 20% and blasts 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results.Patients aged 18 to 70 years undergoing induction therapy with standard "7 + 3" regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS.A total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts 5% were predictive of CR/CR with incomplete count recovery (P .001). Cytogenetic risk (P .001), age 60 years (P = .001), and D14 blasts 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS.The results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.

Background: Myeloproliferative neoplasms (MPNs) are a heterogenous group of chronic hematologic malignancies that lead to morbidity and early mortality primarily due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs, and are used commonly to guide therapeutic decisions (including allogenic stem cell transplant) in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients, and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively reported in this population. Methods: We conducted a retrospective review of patients evaluated at the Princess Margaret Cancer Centre (PMCC) between 1/1/2000 and 30/6/2021 for an MPN diagnosed at ≤45 years of age. Diagnoses were defined per 2016 WHO criteria using available information on chart review. Targeted mutational profiling of clinically relevant myeloid genes (49- or 54-gene panel) was previously performed on peripheral blood or bone marrow samples. Pathologic variants in ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1 Q157 were categorized as high-molecular risk (HMR). Categorical variables were compared using the χ2 test. Kaplan-Meier method was used for overall survival (OS) and time-to-event analysis; and were compared using the log-rank test. Results: A total of 237 patients with initial MPN diagnosis ≤45 years were included in the study, with median age of diagnosis 35 (range 12-45) years. MPN diagnosis included: essential thrombocythemia (ET, n=100), polycythemia vera (PV, n=75), prefibrotic primary myelofibrosis (Pre-PMF, N=29), overt PMF (n=24), and MPN-unclassifiable (MPN-u, n=9). Driver mutation data, available for 230 (97%) patients, were: JAK2 in 134 (56%), CALR in 70 (30%), MPL in 6 (2.5%), and triple-negative in 20 (8.4%) patients. Median follow-up was 10.2 (range 0.3-45.3) years, and median OS was the shortest for those with overt PMF (21.4 years, P=0.001) compared with PV (33.0 years), ET (31.4 years), and Pre-PMF (median OS not reached). No difference in OS based on driver mutation was observed. Progression to a secondary MF (SMF) was observed in 84 patients (47% of ET, 48% of PV) after median time of 19.7 years; with no difference in time to progression due to diagnosis or driver mutation. Progression to an accelerated/blast phase (AP/BP) was observed in 26 patients and was associated with diagnosis of overt PMF (P=0.04) and triple-negative for driver mutation (P=0.04). Thrombosis was observed in 61 (26%) patients: 34 (14%) patients with thrombosis prior to/concurrent with MPN diagnosis, and 34 (14%) patients with thrombosis after diagnosis. Splanchnic circulation thrombosis was found in 29 (12%) patients and 12 (5%) patients had Budd-Chiari syndrome. Portal hypertension was reported in 37 (16%) patients. CALR type-2 mutations were associated with the lowest frequency of total thrombosis (4%, P=0.02); while JAK2 had the greatest frequency of splanchnic circulation clot (17%, P=0.03). Targeted mutational profile was obtained for 202 (85%) of patients: 135 samples obtained during the initial disease phase, 51 samples during a secondary MF phase, and 16 during an AP/BP. For the patients with mutation analysis in the initial phase, 24 pathogenic mutations were observed in 16 (12%) patients including 3 patients with HMR mutations. The most frequent mutations observed were in TET2 (n=12, 9%), and ASXL1 (n=3, 2%). Presence of additional mutations did not predict OS, AP/BP progression, or thrombosis; though TET2 mutation was associated with shorter time to SMF progression in patients with PV/ET (P=0.002). Additional mutations were found in 34/51 (67%) patients in whom mutational analysis was first performed during a SMF disease phase. Conclusions: A long-term follow-up study of a large molecularly annotated cohort of AYA patients with MPN demonstrated excellent long-term survival for these patients. Overt PMF is associated with the lower OS and higher risk of AP/BP transformation. Thrombotic complications including splanchnic circulation thrombosis are frequent complications. Mutations aside from JAK2/MPL/CALR are uncommon and HMR mutations rare in the initial phase of MPN in the AYA population. Figure 1 Figure 1. Disclosures Gupta: Roche: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Constellation Pharma: Consultancy, Honoraria. Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding.

The natural history of BCR-ABL1 negative myeloproliferative neoplasms (MPNs) is progression towards an overt myelofibrotic (MF) phase with variable risk to develop secondary acute myeloid leukemia. Current treatments include Janus kinase inhibitors (JAKi) which can temporarily alleviate MF-related symptoms but are non-curative and most patients eventually progress to a more advanced stage. Given the negative prognostic impact of bone marrow fibrosis in MPNs and generally poor outcome post JAKi failure, it would be important to identify in situ biomarkers that address the initiation, perpetuation and early reversal of the fibrotic reaction. The current clinical standard for bone marrow fibrosis assessment involves reticulin/trichrome stains that detect relatively static extracellular matrix products rather than the fibrosis driving cells directly. To address this, we have developed a smooth muscle actin stromal-vascular (SMA-CD34) dual immunohistochemical (IHC) technique amenable to morphologic scoring and complemented with a CellProfiler image analysis pipeline. SMA was prioritized over other validated stromal IHC markers given work by others in experimental models demonstrating SMA+ myofibroblasts to be the differentiated output of critical fibrosis inducing Gli1+ 'driver' mesenchymal stem/progenitor cells in MPN. Herein, we demonstrate the feasibility of our translational approach using a clinically annotated cohort of MF patients from the Princess Margaret Cancer Centre MPN Registry. After selecting for high quality (>1.0 cm) paired pre and post JAKi biopsies amenable to image and transcriptome-based analysis, the pilot cohort was comprised of 13 cases with 38% high-risk, 54% intermediate-2 and 8% intermediate-1 risk by DIPSS. Driver mutations were JAK2 V617F (77%), CALR (15%) and other (8%). JAKi therapies included ruxolitinib (31%) + pelabresib (23%), momelotinib (15%), itacitinib (15%) and pacritinib (8%). The SMA-CD34 stromal assessment at baseline revealed distinct interstitial myofibroblast patterns and vascular perturbations not captured by conventional clinical hematopathology assessment (e.g. SMA+ dilated sinusoids). A SMA-CD34 scoring system was developed using a 4-point scale representing normal (0 pts), increased vascularity (1 pt), focal interstitial SMA (2 pts), multifocal interstitial SMA (3 pts) and diffuse SMA (4 pts). Scoring was then performed by blinded hematopathologists. A trend towards JAK2 mutated MF cases demonstrating higher SMA grade at baseline was noted. Interestingly, variable trajectories in SMA scores emerged following treatment with JAKi. Specifically, SMA signals had increased in 15%, decreased in 46% and were stable in 38% post-JAKi when using a morphologic SMA grading scheme. When compared to reticulin fibrosis, the severity of SMA signals had diverged in 1/3 of the cases (e.g. SMA grade decreased, reticulin grade stable). To further complement the SMA-CD34 morphologic grading, a CellProfiler image analysis pipeline was developed yielding a non-vessel associated normalized SMA area metric as a supervised correlate of the clinical SMA scoring system (R 2 = 0.68). Additional supervised and unsupervised bioinformatic approaches for clustering of relevant SMA-CD34 features including an algorithm that informs SMA spatial patterns with respect to niche elements such as arterioles (CD34+SMA+), sinusoids (CD34+) and adipocytes is in development. Lastly, Nanostring Fibrosis V2 panel was employed on a subset that met RNA concentration and quality metrics. Exploratory interpretation showed significant differentially expressed genes in pre vs. post JAKi specimens related to lipid metabolism such as ADIPOR1, SCD, ELOVL6 as well as the chemokine CXCL16. This may suggest a link between fatty acid metabolism and inflammatory differentiation along the SMA-vascular axis in the bone marrow modulated by JAKi treatment. SMA-CD34 IHC stratifies MF bone marrow biopsies differentially from standard WHO reticulin/trichome grading providing a practical formalin-fixed paraffin embedded (FFPE) tissue-based biomarker for assessing fibrosis related bone marrow niche elements from archived clinical samples. While our pilot numbers precluded statistical evaluation by JAKi-type, clinical response and NGS mutational profile at this time, further studies are underway to validate the SMA-CD34 signature on a larger MF cohort. Figure 1 Figure 1. Disclosures Gupta: Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Incyte: Honoraria, Research Funding; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy.

Referral to hematology for anemia is common. In paroxysmal nocturnal hemoglobinuria (PNH), cells deficient in the glycosylphosphatidyl inositol (GPI) anchor are lysed by complement. Eculizumab improves overall survival and quality of life while reducing hemolysis, transfusion requirements, and thrombosis. We evaluated the frequency of screening for PNH in patients with unexplained anemia. Key clinical features, laboratory data, and investigations were recorded for patients referred for anemia since 2010, without a specific cause found. PNH testing was done by flow cytometry. 540 patients had: anemia not yet diagnosed (NYD, n=318 (including unexplained iron deficiency, n=92; DAT-negative hemolysis, n=9)); anemia of chronic disease, n=173; and pancytopenia NYD, n=49. 82.4% had LDH testing done; 85.0% total bilirubin; 78.7% reticulocyte counts; and 40.6% haptoglobin level; 131 (24.2%) had possible hemolysis. PNH testing was done in 56 (10.4%). Those screened for PNH were more likely to have: younger age (P=0.04); a history of thrombosis (P

Mechanical forces in the cell’s natural environment have a crucial impact on growth, differentiation and behaviour. Few areas of biology can be understood without taking into account how both individual cells and cell networks sense and transduce physical stresses. However, the field is currently held back by the limitations of the available methods to apply physiologically relevant stress profiles on cells, particularly with sub-cellular resolution, in controlled in vitro experiments. Here we report a new type of active cell culture material that allows highly localized, directional and reversible deformation of the cell growth substrate, with control at scales ranging from the entire surface to the subcellular, and response times on the order of seconds. These capabilities are not matched by any other method, and this versatile material has the potential to bridge the performance gap between the existing single cell micro-manipulation and 2D cell sheet mechanical stimulation techniques., United States. Department of Energy (DE-SC0005247), United States. Office of Naval Research (N00014-15-1-2157)

Deterioration of hematologic parameters in lymphoma patients is often attributed to disease progression, comorbidities, or treatment effects. Second primary malignancies occur at increased frequency in CLL and must also be considered.

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a “Cytokine Storm Syndrome” (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

Lymphoproliferative disorders are prevalent in HIV-positive patients and the majority are aggressive [1]. The success of highly active antiretroviral therapy (HAART) has resulted in a substantial i...

We examined the prognostic impact of SES, estimated by census median household income, in 312 adult MDS patients. Age, progression to AML, use of recombinant erythropoietin, WHO diagnosis and IPSS risk category were independent predictors of survival but there was no association between SES and survival. Unexpectedly, progression to AML was more prevalent in the highest income quartile (HR 3.96 for highest vs. lowest; p = 0.0032). The previously demonstrated association of low SES with poor outcome MDS in the United States may have been driven primarily by reduced access to care rather than other SES-linked factors such as co-morbidity.

A quantitative risk assessment model was developed to estimate the frequency with which meat waste from ships or aircraft might expose British livestock to infection with foot-and-mouth disease (fmd), and investigate the factors that might contribute to the risk. In the model, the total weight of waste introduced that was contaminated with fmd was estimated to be 26 kg per year, with 90 per cent certainty that it would be between 10 and 53 kg. As a result, it was estimated that there would be a mean of 1429 years between outbreaks of fmd due to ship and aircraft waste, with a 90 per cent certainty that the interval would be between 500 and 10,000 years. These estimates were affected by three principal uncertainties: first, the prevalence of fmd; secondly, the probability of the waste being removed and fed to pigs; and thirdly, the probability that overboard dumping of contaminated waste might expose livestock to fmd. The effect of these uncertainties on the model was investigated in a sensitivity analysis.

Brucellosis is a widespread, economically devastating and highly infectious zoonosis. In cattle, infection predominantly is caused by Brucella abortus, and is usually detected in pregnant females through abortions. Great Britain (GB) has been declared free from brucellosis (officially brucellosis free (OBF)) since 1993 and as such is required by European Union (EU) regulations to testor =20% of both beef and dairy cattle24 months old routinely. Currently, however, GB serologically tests more cattle than required and the issue of reducing the level of testing has come under consideration. We developed a simulation model to determine the rate of spread of brucellosis under a variety of testing regimes. For dairy herds, we found that reducing the level of testing would have a major effect on the rate of spread of infection, should it be imported. For beef herds, reducing the level of testing would have much less effect. We also found that abortion notification is a very-important additional means of surveillance. As a result of our predictions, policy-makers decided not to reduce the level of testing and actively to promote abortion notification.

The human anterior cruciate ligament is ruptured 200,000 times per year in the United States, resulting in medical costs of $1 billion. The standard treatment is patellar tendon autograft, but this treatment is suboptimal because of lengthy recovery time, arthritis, donor site morbidity, and degenerative joint disease. This study aimed to engineer scaffold-free ligament analogs from a clinically relevant cell source and to examine mechanical and histological properties of the resulting engineered tissue. Porcine bone marrow stromal cells were seeded on laminin-coated substrates with silk suture segments as anchor points. Cells developed into monolayers that subsequently delaminated and self-organized into cohesive rod-like tissues that were held in tension above the substrate. After 14 days of maturation, scanning electron microscopy revealed a well-organized extracellular matrix, aligned collagen fibers, and a collagen fibril diameter of 51.1+/-77 nm. Histological evaluation showed that constructs were composed of approximately 60% collagen. During tensile tests to failure, constructs had a stress of 2.11 +/- 0.13 MPa, a strain of 28.8 +/- 0.95%, a force of 0.26 +/- 0.02 N, and a tangent modulus of 15.4+/-1.04 MPa. Mechanically and histologically, engineered ligament resembled native embryonic connective tissue and had an ultimate stress approximately 15% of native adult mouse tissue.

A method is described for the separation of fecal porphyrins by the principle of counter-current distribution, using ether and 0.1 N HCl as upper and lower phase, respectively. Porphyrins in the feces of human subjects were first extracted with an ether and acetic acid mixture. The mixture of porphyrins removed from this with 5% ( w v ) HCl yielded 5 distinct porphyrins which were identified as coproporphyrin, deuteroporphyrin, mesoporphyrin, and protoporphyrin, together with a fifth porphyrin which may be a compound intermediate between protoporphyrin and deuteroporphyrin. This porphyrin has not previously been described in feces, and pending elucidation of its structure the name “pemptoporphyrin” is suggested. The method gives good qualitative resolution and shows good quantitative reproducibility.

Under preparative conditions, 2-chloropteridine is shown to react with t-butylamine about 20,000 times faster than does 2-chloropyrimidine, but 2-chloro-6,9-dimethylpurine is butylaminated a little more slowly than is the corresponding 2-chloro-4,6-dimethylpyrimidine. The formation of twelve new alkylaminopteridines and purines are recorded; their ionisation constatns and ultraviolet spectra are compared with those of twanty analogous pyrimidines. Syntheses of three 2-carboxypyrimidines are recorded.