Objectives:Up to 50% of small fiber neuropathy (SFN) cases are idiopathic, but novel antibodies to Trisulfated Heparin Disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been implicated in half of these cases; the role of anti-Plexin D1 is less clear. We aimed to clarify presentation and management of these patients. Methods:An 18-month retrospective analysis revealed 54 cases of cryptogenic SFN who had testing for the 3 autoantibodies. Demographics, clinical features, epidermal nerve fiber density, and Quantitative Sudomotor Axon Reflex Test results were analyzed. Intravenous immunoglobulin (IVIG) treatment response was assessed. Results:In total, 44.4% of patients had antibodies (62.5% TS-HDS, 29.2% FGFR-3, and 20.8% Plexin D1). Male patients were more likely to be FGFR-3 positive (P ¼ 0.014). Facial involvement was more common in seropositive patients (P ¼ 0.034), and patients with a higher Utah Early Neuropathy Scale score had a higher TS-HDS titer (P ¼ 0.0469), but other clinical features were not significantly different. Seropositive patients trended toward a higher SFN screening list score (P ¼ 0.16), abnormal Quantitative Sudomotor Axon Reflex Test (P ¼ 0.052), and prior erroneous diagnosis (P ¼ 0.19). In patients who completed IVIG, examinations and questionnaires improved and mean epidermal nerve fiber density increased by 297%.Conclusions: TS-HDS, FGFR-3, and Plexin D1 antibodies are present in a high proportion of cryptogenic SFN cases with more facial involvement, and greater disease severity is associated with higher antibody titers.They are often misdiagnosed but may respond subjectively and objectively to IVIG.

Burn patients experience erythropoietin resistant anemia in which early commitment and late maturation of erythroblasts are defective. We previously showed that propranolol (Prop) treatment restores erythroid committed progenitors, but terminal maturation remains impaired. Hemoglobinization and maturation occurs during terminal erythropoiesis and these processes are aided by an erythroblast intrinsic functional protein called alpha hemoglobin stabilizing protein (AHSP). We evaluated the role of AHSP in PBMC (peripheral blood mono nuclear cell) derived erythroblasts and the implications of Prop in burn patients. Blood samples were collected at three time points from seventeen patients receiving standard burn care (SBC) or Prop. Five healthy volunteers provided control plasma (CP). PBMCs were placed in biphasic cultures with 5% autologous plasma (BP) or CP. Erythroblasts were harvested during mid and late maturation stages; the percentage of AHSP + erythroblasts, AHSP expression, and relative distribution of reticulocytes and polychromatophilic erythroblasts (PolyE) were determined by cytometry. During the second time point (7-10 days post burn), Prop cohort required 35% less transfusions. At mid maturation, PBMCs from Prop treated patients cultured in BP had 33% more AHSP + erythroblasts and 40% more AHSP expression compared to SBC. Furthermore, at late maturation, Prop had 50% more reticulocytes and 30% less PolyEs in CP versus BP compared to SBC (11% and 6% respectively). AHSP is positively associated with late stage maturation of PBMC derived erythroblasts in the presence of CP. Albeit transiently, this is more pronounced in Prop than SBC. Early administration of propranolol in burn patients supports erythropoiesis via the chaperone AHSP.

Introduction During anemia of critical illness such as burn injury, erythropoietin (Epo) resistance is accompanied by impaired bone marrow (BM) erythropoiesis. The non-selective β1, β2 -adrenergic receptor (AR) blocker propranolol was effective in mitigating MafB expression in multi potential progenitors and rescuing their erythrocyte commitment in burn patients. However, peripheral HGB levels did not reflect the effect of propranolol perhaps due to defective maturation of late erythroblasts, not regulated by propranolol. Subsequently, we reported that early commitment and late maturation stages are independently orchestrated via discrete β2- and β3-AR mechanisms respectively in the BM of mice with a parallel increase in blood HGB levels. Nonetheless, it is not clear whether commitment of progenitors or maturation of erythroblasts is essential to restore erythropoietic homeostasis after burn injury. In adult mice, the spleen serves as an extra medullary erythropoietic organ under hypoxia and also functions as a primary organ of erythropoietic homeostasis (Bozzini CE et al. Am J Physiol. 1970; 219(3):724). We examined in mice, erythropoietic responses to burn injury in two organs, the spleen and BM to understand the reciprocal relationship, if any, in erythropoiesis between the two adrenergically innervated organs in response to propranolol, and selective β2- and β3- AR blockers. As variation in the size of RBCs is an indication of ineffective maturation, we also evaluated coefficient of variation of RBC size (RDW) in peripheral blood from mice. To validate our animal studies, we also measured RBC parameters in human burn patients. Methods Animal study: B6D2F1 mice were randomized into 2 groups, 15% TBSA (total burn surface area) scald burn and sham burn. Burn mice were given β-AR blockers or saline either via Alzet pumps eight hours after injury or by daily injections. All treatments were terminated 24 hours before harvest. Animals were euthanized to obtain spleen, femurs and blood on post burn days (PBD) as specified in results. Single cell suspensions from spleen and BM were characterized for early erythroblasts (CD71+Ter119neg), orthochromatic erythroblasts (Ter119+CD71+Syto16+), reticulocytes (Ter119+CD71+Syto16neg), erythrocytes (Ter119+), and non-erythroid cells (Ter119neg CD71neg) by flow cytometry, and expressed as 103/106 total splenocytes or total BM cells. RDW was measured using HemaTrue analyzer. Human study: Retrospective analysis was done on 19 adult burn patients enrolled in IRB approved study. All patients received standard burn care (SBC) during the study period of seven weeks. As part of another clinical trial, 9/19 patients had received propranolol along with SBC (SBC+PR). Cohorts matched for age, gender and %TBSA. Results Animal study: Splenic erythropoiesis was increased after burn injury on PBD 3, 7, 14 and 21 as measured by erythrocyte and erythroblast production. Propranolol treatment for 14 days via Alzet pump alone or in combination with Epo was not sufficient to reduce splenic erythrocytes and erythroblasts that were elevated after burn injury. Between the selective blockers, only SR59320A (β3-AR) and not butoxamine (β2-AR) significantly reduced splenic erythropoiesis. This was accompanied by a decrease in splenomegaly and a reciprocal increase in BM erythropoiesis only with SR59230A treatment. RDW was significantly increased in blood after burn injury, while MCV remained within normal range. Interestingly, only SR59230A treatment and not propranolol or butoxamine reversed RDW to sham levels. Human study: Hemoglobin levels were higher at PBD 1-3 (due to hemo concentration) and decreased significantly in both groups through PBD 30-48. Mean RDW was normal at PBD 1-3 (Normal range =11.5% -14.5%) in all burn patients. Although RDW seemed to stabilize initially in SBC+PR treated patients at PBD 7-10, it increased to SBC levels by PBD 30-48. Mean corpuscular volume (MCV) remained within normal limits. Conclusion Effective maturation of late erythroblasts in BM is essential for the spleen to sense erythropoietic homeostasis, which is reestablished with β3-AR blockade after burn injury. Results emphasize only β3-AR antagonist restores RDW to sham levels and not β1/ β2-AR blocker. Increased RDW in burn patients corroborates with animal studies. Overall, this model system is suitable to study mechanisms of early and late erythropoiesis after burn injury. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Introduction: Predicting outcome after mechanical thrombectomy (MT) for ischemic stroke due to LVO can inform prognosis and guide early management. Prior studies report heterogeneity in risk factors for poor outcome. Machine learning may identify patterns of poor outcome from diverse variables that are difficult to discern with conventional statistical methods. Methods: Using a retrospective database of 233 stroke patients (2015-20) who had MT for LVO, we created machine learning predictive models with clinical and imaging variables for the following 4 outcomes: decompressive craniectomy, discharge mRS ≥4, development of post-stroke cerebral edema with mass effect, and in-hospital mortality. We compared 10 learner models: AdaBoost, Tree, Random Forest, Neural Network, CN2 Rule Induction, Logistic Regression, Naïve Bayes, kNN, Stochastic Gradient Descent, and Support Vector Machine. Variables were ranked by 5 scoring methods: information gain, information gain ratio, gini decrease, chi-square, ReliefF, and fast correlation-based filter. A prediction model was created using the top 5 variables to maximize the area under the receiver operating characteristic curve and classification accuracy. Models were 5-fold cross validated. Analyses were conducted via Stata and Orange Data Mining. Results: Prediction model sets of 5 variables were generated for the 4 outcomes of interest. Infarction volume was most important for predicting decompressive craniectomy, discharge mRS ≥4, and in-hospital mortality. Cerebral edema was important for decompressive craniectomy, discharge mRS ≥4, and in-hospital mortality. Initial NIHSS was important for decompressive craniectomy, discharge mRS ≥4, and in-hospital mortality. Contrast staining on post-procedural CT was important for cerebral edema (χ 2 11.9) and in-hospital mortality (χ 2 21.8). Patient age was important for discharge mRS ≥4 and decompressive craniectomy. Conclusion: We identified prediction models consistent with established prognostic variables. Post-MT contrast staining is a novel and important predictor of poor outcome, which merits further research. In conclusion, machine learning can be used to create accurate prediction models for outcome after MT for ischemic stroke with LVO.