Counting Function Research Articles

Clinical Characteristics, Genetic Profile and Prognosis of Adult Acute Myeloid Leukemia with NUP98 Rearrangement

Introduction: Nucleoporin 98 ( NUP98) rearrangement has been proposed in 2022 as one type of acute myeloid leukemia (AML) with defining genetic abnormalities. It occurred more often in pediatric leukemia with poor outcome. However, in adult AML with NUP98 rearrangement, patients may show different clinical characteristics, genetic profile and outcome, as we reported here. Method: We retrospectively collected and analyzed the data of adult AML patients with NUP98 rearrangement who were diagnosed at Shanghai Institute of Hematology from May 2019 to December 2022, including clinical characteristics, laboratory examination, genetic abnormalities, treatment strategies and outcome. All patients underwent next generation sequencing and RNA sequencing. Result: A total of 21 AML patients with NUP98 rearrangement were included in this study, counting for 2.3% of all AML patients (930 cases). The median age was 40 (19-64) years old. The median white blood cell and platelet count was 31.1 (1.5-313.6) and 48 (15-140) ×10 9/L, respectively. Interestingly, 11 (52.4%) patients suffered from severe or fatal hemorrhage irrelative with platelet count or coagulative function, including 4 cerebral bleeding (3 died), 1 urgent uterine bleeding, 1 gastro-intestinal bleeding, 1 retina bleeding and 4 massive bleeding of subcutaneous soft tissue or mucous membranes. The FAB types involved M2, M4 and M5. Eight patients carried normal karyotype, 6 were found with t(7;11)(p15;p15), all of whom had NUP98::HOXA9 fusion gene, 2 with +8 and 1 complex karyotype. According to ELN 2022 risk classification, 14 (66.7%) were at intermediate risk and 6 (28.6%) at adverse risk, 1 unclassified. Five fusion partners with NUP98 were detected: NUP98::NSD1 (11 cases), NUP98::HOXA9 (7 cases), NUP98::HOXA11, NUP98::HMGB3 and NUP98::TNRC18 (each with 1 case). Of which NUP98::TNRC18 was first reported by our center (see Cheng WY, et al. Proc Natl Acad Sci U S A. 2022;119(49):e2211429119). NUP98 rearrangement also co-existed with several mutations. FLT3-ITD (12 cases, of which 10 were co-existed with NUP98::NSD1) and WT1 (7 cases) were most frequently occurred. Patients with relapse/refractory disease had more additional mutations than de novo status (Figure 1). Nineteen patients were treated with standard dose of “7+3” induction therapy, and 2 with hypomethylating agents (HMA) plus venetoclax (VEN). Complete remission (CR) was achieved by 8 (38.1%) patients after first induction, 2 (9.5%) early deaths were both due to cerebral hemorrhage. Salvage induction varied from intensive chemotherapy (IC, including “7+3” and CLAG±M) to low-intensity therapy (LIT, including priming chemotherapy±HMA and HMA+VEN). FLT3 inhibitors (FLT3i) were added to 5 patients carrying FLT3-ITD, and they all achieved CR. A total of 15 (71.4%) patients achieved CR after 1-2 courses of induction (8 mainly benefited from IC, 7 mainly benefited from LIT±FLT3i), 1 survived from allogeneic hematopoietic stem cell transplantation (allo-HSCT) without reaching remission before, and 3 died from refractory disease within 6 months. Three patients relapsed after CR, 2 died without allo-HSCT, and the other one survived after CR2 and sequential allo-HSCT. A total of 14 patients underwent allo-HSCT after CR, 7 were measurable residual disease (MRD) negative and 7 were positive by flow cytometry before HSCT, none of them relapsed till the last follow-up. With a median follow-up time of 19.2 months, the median overall survival (OS) and event-free survival (EFS) were not reached, estimated 2-year OS and EFS rate were 66.7% and 57.1%, respectively. For patients achieving CR or not, the median OS were not reached vs 3.2 months (95% CI 0-8.361, P<0.001, Figure 2). Ten patients were diagnosed with NUP98::NSD1 co-occurring with FLT3-ITD (once considered as unfavorable prognosis), ending up with a CR rate of 70%, and a 2-year OS and EFS rate of 80% and 60%, respectively, making no significant difference compared to others ( P=0.236 and 0.725, respectively). Conclusion: Adult AML with NUP98 rearrangement may combine with a set of partner fusion genes and mutations, with NUP98::NSD1 and FLT3-ITD as the most common combination. Both IC an LIT can induce CR, and FLT3i will benefit those with FLT3 mutations, also prevention of fatal bleeding should be paid attention to. After achieving CR with whatever method and whatever MRD status, allo-HSCT is the key to long-term survival.

Exponential moments for disk counting statistics at the hard edge of random normal matrices

We consider the multivariate moment generating function of the disk counting statistics of a model Mittag-Leffler ensemble in the presence of a hard wall. Let n be the number of points. We focus on two regimes: (a) the “hard edge regime” where all disk boundaries are at a distance of order \frac{1}{n} from the hard wall, and (b) the “semi-hard edge regime” where all disk boundaries are at a distance of order \frac{1}{\sqrt{n}} from the hard wall. As n \to + \infty , we prove that the moment generating function enjoys asymptotics of the form \exp (C_{1}n + C_{2}\ln n + C_{3} + \frac{C_{4}}{\sqrt{n}} + \mathcal{O}(n^{-\frac{3}{5}})) for the hard edge, \exp (C_{1}n + C_{2}\sqrt{n} + C_{3} + \frac{C_{4}}{\sqrt{n}} + \mathcal{O}(\frac{(\ln n)^{4}}{n})) for the semi-hard edge. In both cases, we determine the constants C_{1},\dots,C_{4} explicitly. We also derive precise asymptotic formulas for all joint cumulants of the disk counting function, and establish several central limit theorems. Surprisingly, and in contrast to the “bulk”, “soft edge”, and “semi-hard edge” regimes, the second and higher order cumulants of the disk counting function in the “hard edge” regime are proportional to n and not to \sqrt{n} .

The correlation between periodontitis and uncontrolled hypertension is mediated by inflammatory markers: results from a cross-sectional study of urban elderly population in southeast China

BackgroundPeriodontal diseases is considered the most important global oral health burden according to the world health organization (WHO) (Oral health. https://www.who.int/news-room/fact-sheets/detail/oral-health#Overviewth (who.int). Accessed 21 Sep 2023). It is a common local inflammatory disease associated with hypertension, this study aims to explore the relationship between periodontitis and uncontrolled hypertension and whether inflammation indication such as white blood cell (WBC) count or neutrophil count is a mediator of this relationship.MethodsOne thousand four hundred eighty-eight elders attending annual physical and oral examinations in Zhejiang province were included in this study. The staging of Periodontitis was classified as none, mild-moderate and severe. Participants are categorized into two groups based on blood pressure: hypertensive( positive high blood pressure( HBP) history or underwent HBP medication or blood pressure( BP) ≥ 140/90 mmHg) and uncontrolled hypertensive (systolic blood pressure( SBP) ≥ 140 mmHg or distolic blood pressure( DBP) ≥ 90 mmHg). Peripheral blood samples were collected, information on hypertension history and potential confounders (age, sex, smoking, alcohol consumption, exercise frequency, diabetes) was collected in questionnaires. The correlation between periodontitis and hypertension was investigated using logistics regression analyses, mediation analysis was assessed for the effect of inflammation on hypertension.ResultsThe study population includes 1,488 participants aged 55–90 years. Odds of uncontrolled hypertension increased significantly along with periodontitis in the regression models both in unadjusted model (odds ratio( OR): 1.407, 95% confidence intervals( CI): 1.037 ~ 1.910) and fully adjusted model (OR: 1.950, 95% CI: 1.127 ~ 3.373). Mediation analysis confirmed that WBC and neutrophic count function as a full mediator of the association between periodontitis and uncontrolled hypertension either in the unadjusted or the adjusted model.ConclusionsIn a study of urban elderly population in southeast China, periodontitis is found to be significantly associated with uncontrolled hypertension, such relation is mediated by WBC and neutrophil count. Periodontitis can increase the difficulty of controlling hypertension. Promotion of periodontal health strategies in the dental setting could help reduce the burden of hypertension and its complications.

ADDITIVE COMPLETION OF THIN SETS

AbstractTwo sets $A,B$ of positive integers are called exact additive complements if $A+B$ contains all sufficiently large integers and $A(x)B(x)/x\rightarrow 1$ . For $A=\{a_1<a_2<\cdots \}$ , let $A(x)$ denote the counting function of A and let $a^*(x)$ denote the largest element in $A\bigcap [1,x]$ . Following the work of Ruzsa [‘Exact additive complements’, Quart. J. Math.68 (2017) 227–235] and Chen and Fang [‘Additive complements with Narkiewicz’s condition’, Combinatorica39 (2019), 813–823], we prove that, for exact additive complements $A,B$ with ${a_{n+1}}/ {na_n}\rightarrow \infty $ , $$ \begin{align*}A(x)B(x)-x\geqslant \frac{a^*(x)}{A(x)}+o\bigg(\frac{a^*(x)}{A(x)^2}\bigg) \quad\mbox{as } x\rightarrow +\infty.\end{align*} $$ We also construct exact additive complements $A,B$ with ${a_{n+1}}/{na_n}\rightarrow \infty $ such that $$ \begin{align*}A(x)B(x)-x\leqslant \frac{a^*(x)}{A(x)}+(1+o(1))\bigg(\frac{a^*(x)}{A(x)^2}\bigg)\end{align*} $$ for infinitely many positive integers x.

The Impact of Modern Anti-Diabetic Treatment on Endothelial Progenitor Cells.

Diabetes is one of the leading chronic diseases globally with a significant impact on mortality. This condition is associated with chronic microvascular and macrovascular complications caused by vascular damage. Recently, endothelial progenitor cells (EPCs) raised interest due to their regenerative properties. EPCs are mononuclear cells that are derived from different tissues. Circulating EPCs contribute to regenerating the vessel's intima and restoring vascular function. The ability of EPCs to repair vascular damage depends on their number and functionality. Diabetic patients have a decreased circulating EPC count and impaired EPC function. This may at least partially explain the increased risk of diabetic complications, including the increased cardiovascular risk in these patients. Recent studies have confirmed that many currently available drugs with proven cardiovascular benefits have beneficial effects on EPC count and function. Among these drugs are also medications used to treat different types of diabetes. This manuscript aims to critically review currently available evidence about the ways anti-diabetic treatment affects EPC biology and to provide a broader context considering cardiovascular complications. The therapies that will be discussed include lifestyle adjustments, metformin, sulphonylureas, gut glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor analogs, sodium-glucose transporter 2 inhibitors, and insulin.

Leukemia Inhibitory Factor, Tissue Factor, Thrombomodulin, P-Selectine, D-Dimer, Thrombin Generation and Procoagulant Phospholipid Dependent Clotting Time Are Predictive for in Vitro Fertilization Outcome. the Prospective Roadmap-IVF Study

Background The link between blood hypercoagulability, endothelial cell activation and infertility or in vitro fertilization (IVF) failure is a puzzling issue. Activation of platelets, endothelial cells and blood coagulation, proinflammatory and angiogenetic potential play important role in implantation and early embryonic development. Biomarkers of cellular hypercoagulability are associated with high risk of IVF failure. Soluble Leukemia Inhibitory Factor (LIF), an interleukin 6 class cytokine expressed in the trophectoderm of the developing embryo is an important regulator in the establishment of pregnancy. Endoglin (Eng), a co-receptor for TGF-β1 and TGF-β3 is implicated in vascular complications of pregnancy and particularly in preeclampsia. Aim: The prospective longitudinal monocentric observational cohort study ROADMAP-IVF, evaluated the synergistic prognostic value of LIF and Eng with the biomarkers of cellular hypercoagulability in predicting the endometrial receptivity of fresh IVF cycles. Materials and Methods. The ROADMAP-IVF enrolled 40 women eligible for IVF with normal blood count, PT, aPTT, Fg, renal and liver function. The control group (CG) consisted of 30 healthy women with history of uncomplicated pregnancies. Exclusion criteria: Use of anticoagulant or antiplatelet agents during the last 30 days before inclusion. Known cardiovascular disease, active cancer. Active corticosteroid treatment. Primary end-point: Echographically documented pregnancy at 7 weeks from implantation. Blood was collected on day 2 (D2) from the natural cycle and 6 days after hormone treatment initiation corresponding to D8 of the cycle. Procoagulant phospholipid-dependent clotting time (PPL-ct), tissue factor (TF), thrombomodulin (TM), von Willebrand factor (vWF) and D-Dimers (DDi) were measured with assays from Diagnostica Stago (Asnieres, France). P- and E-Selectin, LIF and Eng were measured with ELISA. Thrombin generation (TG) with the TF 5 pM PPP-Reagent ® was assessed on Calibrated Automated Thrombogram (Stago, France). The cut-off values for studied biomarkers have been selected on the basis of ROC analysis. Univariate and multivariate logistic regression analysis examined the associations between the biomarkers and the study outcome. Results: 40 women were enrolled in the study. In 11 women pregnancy was confirmed with ultrasound and in 23 women no pregnancy was echographically documented. Age was not significantly different between the IVF (41 ys; range 22 - 48 ys) and the control group (40 ys; range 20 - 46 ys). At D2 and D8 the DDi and LIF were significantly higher in IVFG as compared to the CG. At D2 most of the patients had PPL-ct, DDi and MRI of TG higher than the upper normal limit (UNL). At D8 only TF was significantly increased as compared to the CG. Analytical data are presented in Table 1. Age did not correlate with the levels of the studied biomarkers. Significant correlations (p<0.05) were found between DDi and ETP (r=0.35); TM, TF and P-Selectin (r=0.4) at D2; TF, LIF and Eng (r=0.5) at D2 and D8; P-Selectin and PPL-ct (r=-0.4) at D2; P-Selectin and TM (r=0.4), E-Selectin (r=0.5), LIF (0.4) at D2; E-Selectin and P-Selectin (r=0.5), TF (r=0.3), and LIF (r=0.4) at D2. The ROC analysis showed that IVF failure was associate with DDi increase at D2 (AUC = 0.64); P-Selectin increase at D2(AUC = 0.57) and D8 (AUC = 0.61); TM increase at D8 (AUC = 0.61); TF increase at D8 (AUC = 0.57); LIF increase at D8 (AUC = 0.59); ETP increase at D2 (AUC = 0.67) and D8 (AUC = 0.67); Peak increase at D2 (AUC = 0.64) and D8 (AUC = 0.61). Prolongation of PPL-ct on D8 was predictive for positive pregnancy outcome(AUC 0.64). Conclusion The ROADMAP-IVF study showed that at least one out of four women eligible for IVF present biological evidence of activation of platelets, endothelial cells, blood coagulation or LIF upregulation. Hormone treatment administration does not significantly alter the proinflammatory or the hypercoagulable state. Among the studied biomarkers the levels of LIF, DDi, P-Selectine, TM and TF as well as the status of thrombin generation and PPL-ct showed a significant predictive value for the IVF outcome, particularly when measured at 6 days after hormone treatment administration. These findings will lead to the elaboration of an risk assessment model for IVF failure combining the selected biomarkers of hypercoagulability with LIF.

Gaps labeling theorem for the bubble-diamond self-similar graphs

Motivated by the appearance of fractals in several areas of physics, especially in solid state physics and the physics of aperiodic order, and in other sciences, including the quantum information theory, we present a detailed spectral analysis for a new class of fractal-type diamond graphs, referred to as bubble-diamond graphs, and provide a gap-labeling theorem in the sense of Bellissard for the corresponding probabilistic graph Laplacians using the technique of spectral decimation. Labeling the gaps in the Cantor set by the normalized eigenvalue counting function, also known as the integrated density of states, we describe the gap labels as orbits of a second dynamical system that reflects the branching parameter of the bubble construction and the decimation structure. The spectrum of the natural Laplacian on limit graphs is shown generically to be pure point supported on a Cantor set, though one particular graph has a mixture of pure point and singularly continuous components.

The Statistical Uncertainties on X-Ray Flux and Spectral Parameters from Chandra ACIS-I Observations of Faint Sources: Application to the Cygnus OB2 Association

We investigate the uncertainties of fitted X-ray model parameters and fluxes for relatively faint Chandra ACIS-I source spectra. Monte Carlo (MC) simulations are employed to construct a large set of 150,000 fake X-ray spectra in the low photon count statistics regime (from 10 to 350 net counts) using the XSPEC spectral model-fitting package. The simulations employed both absorbed thermal (APEC) and nonthermal (power-law) models, in concert with the Chandra ACIS-I instrument response and interstellar absorption. Simulated X-ray spectra were fit assuming a wide set of different input parameters and C-statistic minimization criteria to avoid numerical artifacts in the accepted solutions. Results provide an error estimate for each parameter (absorption, N H, plasma temperature, kT, or power-law slope, Γ, and flux) and for different background contamination levels. The distributions of these errors are studied as a function of the 1σ quantiles, and we show how these correlate with different model parameters, net counts in the spectra, and relative background level. Maps of uncertainty in terms of the 1σ quantiles for parameters and flux are computed as a function of spectrum net counts. We find very good agreement between our estimated X-ray spectral parameter and flux uncertainties and those recovered from spectral fitting for a subset of the X-ray sources detected in the Chandra Cygnus OB2 Legacy Survey diagnosed to be association members and that have between 20 and 350 net counts. Our method can provide uncertainties for spectral parameters whenever formal X-ray spectral fits cannot be well constrained, or are unavailable, and predictions useful for computing Chandra ACIS-I exposure times for observation planning.

Inequalities concerning maximum modulus and zeros of random entire functions

AbstractLet $f(z)=\sum\limits_{j=0}^{\infty} a_j z^j$ be a transcendental entire function and let $f_\omega(z)=\sum\limits_{j=0}^{\infty}\chi_j(\omega) a_j z^j$ be a random entire function, where $\chi_j(\omega)$ are independent and identically distributed random variables defined on a probability space $(\Omega, \mathcal{F}, \mu)$. In this paper, we first define a family of random entire functions, which includes Gaussian, Rademacher and Steinhaus entire functions. We prove that, for almost all functions in the family and for any constant C > 1, there exist a constant $r_0=r_0(\omega)$ and a set $E\subset [e, \infty)$ of finite logarithmic measure such that, for $r \gt r_0$ and $r\notin E$, \begin{equation*} |\log M(r, f)- N(r,0, f_\omega)|\le (C/A)^{\frac1{B}}\,\log^{\frac1{B}}\,\log M(r,f) +\log\,\log M(r, f), \qquad a.s. \end{equation*}where $A, B$ are constants, $M(r, f)$ is the maximum modulus and $N(r, 0, f)$ is the integrated zero-counting function of f. As a by-product of our main results, we prove Nevanlinna’s second main theorem for random entire functions. Thus, the characteristic function of almost all functions in the family is bounded above by an integrated counting function, rather than by two integrated counting functions as in the classical Nevanlinna theory. For instance, we show that, for almost all Gaussian entire functions fω and for any ϵ > 0, there is r0 such that, for $r \gt r_0$, \begin{equation*} T(r, f) \le N(r,0, f_\omega)+\left(\tfrac12+\epsilon\right) \log T(r, f). \end{equation*}

Advanced morphological characterization of DC sputtered copper thin films

In this paper, Cu thin films were successfully deposited on glass substrates using DC magnetron sputtering at varying deposition times. The deposition time was varied as 5, 9, 11 and 17[Formula: see text]min. The obtained Cu thin films were analyzed for morphology and topography using atomic force microscopy (AFM). The size of the surface structures/grains was seen to evolve with deposition time. The conventional/statistical, fractal and multifractal analyses were carried out on AFM images using existing imaging algorithms. The arithmetic roughness and interface width parameters were seen to evolve with the sputtering time. The autocorrelation and height–height correlation functions revealed that the surfaces of all the Cu thin films exhibited self-affine character, but were not mounded properties. The fractal dimensions computed using box counting and power spectral density functions revealed that larger dimensions were associated with larger surface features. The lacunarity coefficients were too small indicating that the surfaces were generally deficient in porosity and other defects. The multifractal analyses revealed that spatial roughness does not exhibit linear relationship with the deposition time. The study reveals that surface evolution and nanoscale behavior is significantly influenced by the deposition time although a linear relationship is not established.

Coronavirus disease 2019-associated thrombotic microangiopathy treated with plasma exchange and antihypertensive therapy in a patient with HIV: A case report with literature review.

Coronavirus disease 2019 (COVID-19) is an infectious disease that often causes complications in multiple organs and thrombosis due to abnormal blood coagulation. This case report aimed to describe the clinical course of COVID-19-associated thrombotic microangiopathy (TMA) and reviewed the comprehensive information on TMA, thrombotic thrombocytopenic purpura (TTP), and atypical hemolytic uremic syndrome associated with COVID-19 in the past literature. A 46-year-old Japanese man was diagnosed with human immunodeficiency virus infection 10 years ago and treated with antiretroviral therapy. The patient presented with fever, malaise, hematuria, and bilateral upper abdominal discomfort for the past 4 days. COVID-19-associated TMA was diagnosed based on a positive polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 and laboratory findings such as thrombocytopenia, acute kidney injury, and hemolytic anemia. Malignant hypertension and human immunodeficiency virus infection were also considered as differential diagnoses of TMA. Considering the possibility of TTP, plasma exchange was performed, and glucocorticoids were administered. Hemodialysis was performed for acute kidney injury. Antihypertensive drugs were administered to control the high blood pressure. Platelet count and renal function improved, and hemodialysis was no longer required. The patient was in good general condition and was discharged from the hospital. COVID-19-associated TMA should be considered as a differential diagnosis during the COVID-19 epidemic. Excessive inflammation and severe COVID-19 are not essential for TMA development. Early intervention using conventional TMA treatments, such as plasma exchange and corticosteroids, might be important in improving prognosis while differentiating between TTP and atypical hemolytic uremic syndrome. Antihypertensive therapy may be helpful in the treatment of COVID-19-associated TMA.

THU298 Effect Of SGLT2 Inhibition On Metabolic, Cardiac And Renal Outcomes In Heart Transplant Recipients (EMPA-HTx study): Protocol And Study Design

Abstract Disclosure: L.M. Raven: None. C.A. Muir: None. C. Kessler Iglesias: None. E. Kotlyar: None. K. Muthiah: None. N.K. Bart: Advisory Board Member; Self; Bristol-Myers Squibb. Grant Recipient; Self; Pfizer, Inc. Speaker; Self; Pfizer, Inc. P.S. Macdonald: Speaker; Self; Boehringer Ingelheim, AstraZeneca. C.S. Hayward: None. A. Jabbour: None. J.R. Greenfield: Speaker; Self; Boehringer Ingelheim, AstraZeneca. Background: Heart transplantation (HTx) is standard of care for treatment of end-stage heart failure. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant post-transplant complications include metabolic (diabetes, weight gain), renal impairment and cardiac disease, such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 inhibitors (SGLT2i) may have positive effects on all of these post-transplant complications. SGLT2i have been observed to improve metabolic parameters in patients with type 2 diabetes following cardiac and renal transplantation, but their benefit and safety in HTx has not been evaluated in randomised prospective studies. Aims: The overall aim of this project is to study the safety and efficacy of empagliflozin in HTx recipients. The primary end point will be improvement in glycaemic control assessed by change in glycosylated hemoglobin (HbA1c) and/or fructosamine, with secondary endpoints of cardiac fibrosis assessed by cardiac magnetic resonance, and renal function assessed by serum creatinine. Methods: Randomised, placebo-controlled trial of empagliflozin 10 mg daily versus placebo in recent HTx recipients. One hundred participants will be randomised 1:1. They will commence the study medication within 6-8 weeks of transplantation. Follow up will be 12 months after transplantation. Results from routine pre-HTx assessment will be reviewed to assess for pre-HTx diagnosis of diabetes. Routine laboratory tests, including full blood count, biochemistry, glucose, lipids and liver function as well as HbA1c, fructosamine, beta-hydroxybutyrate and urine albumin creatinine ratio, will be measured at baseline prior to receipt of study drug or placebo. Patients will be reviewed monthly during the study until 12 months post-HTx and data will be collected for each patient at each study visit. Cardiovascular magnetic resonance will be measured at baseline and 12 months after HTx. This study has been approved by St Vincent’s Hospital Human Research Ethics Committee (2021/ETH12184). Trial registration: ACTRN12622000978763. Discussion: This study will, for the first time, determine the efficacy and safety of SGLT2i in HTx recipients. Presentation: Thursday, June 15, 2023

THU470 Blood - Bone Connection? A Case Of A Young Woman With Bilateral Hip Osteonecrosis And Prothrombin Mutation

Abstract Disclosure: A. Sliwinska: None. C. Vanek: None. Introduction: Osteonecrosis of the femoral head (ONFH) is a localized bone disease responsible for 10% of total hip replacements in the United States. Although the condition is a separate entity from osteoporosis, it may co-occur representing underlying systemic bone disease. Many risk factors (steroids, trauma, infections, thrombophilia, blood cell dyscrasias) can predispose to ONFH, therefore, diligent evaluation is required to reveal the underlying cause. There are no FDA approved therapies. Here, we present a case of young woman with bilateral osteonecrosis of femoral head who was found to have prothrombin gene mutation, severe osteoporosis, and was successfully treated with PTH analog therapy with abaloparatide. Case Description: 33-year-old Asian female with no past medical history presented to the Endocrinology clinic for a metabolic bone disease assessment. Two years prior, she developed progressive bilateral hip pain which prompted radiographic evaluation, discovering bilateral ONFH. She was managed non-surgically with a 6-month trial of oral alendronate. Worsening pain prompted left hip decompression surgery with stem cell transfer. Patient had no history of fragility fractures nor family history of bone disease. A bone density revealed Z scores of -3.9 and -3.5 in lumbar spine and total hip, respectively. She was taking 2000 IU vitamin D3 and 600 mg of elemental calcium daily. Her blood tests revealed normal basic metabolic panel, normal complete blood count and liver function tests. Calcium was 9.0 mg/dl (ref:8.6-10.2), albumin 4.6 mg/dl (3.5-4.7 mg/dl), phosphorus 4.0 mg/dl (2.4-4.7 mg/dl), PTH of 28 pg/ml (18-88 pg/ml), Vitamin D 25-hydroxy 41.3 ng/ml (30-80 ng/ml), and TSH was 1.66 mIU/L (0.39-4.17 mIU/L). Patient had an infectious, metabolic and rheumatological work-up that was negative. A thrombosis workup showed a heterozygous prothrombin gene (G20210A) mutation. Factor V Leiden mutation was negative. Repeat Hip MRI showed progression of her ONFH with marked bone marrow edema in femoral head bilaterally. Patient was then started on abaloparatide. After 6 months, hip MRI showed marked improvement with no bone marrow edema. Discussion: Osteonecrosis of the femoral head is a complex disease that can affect young individuals. Bilateral ONFH suggests systemic disease and a thorough work-up is necessary. Although the exact mechanism is unclear, it has been hypothesized that thrombin plays a role in bone homeostasis therefore hematologic disorders may predispose patients to both ONFH and osteoporosis. Medical treatment of ONFH, including bisphosphonates, statins, or anticoagulants, have been suggested. Recently the PTH analog, teriparatide, has shown promising results and found to be beneficial in treating osteonecrosis. Our case highlights importance of thorough work-up for patients with bilateral ONFH and successful use of anabolic agent in this population. Presentation: Thursday, June 15, 2023

THU371 Empagliflozin Associated Pancreatitis: A Case Report

Abstract Disclosure: A. Poloju: None. P. Majety: None. A.Y. Groysman: None. Background/Objective: Sodium glucose cotransporter 2 (SGLT2) inhibitors are increasingly being used in the treatment of type 2diabetes mellitus (T2DM). With the recent FDA approval of these medications for treatment of heart failure, their use is expected to increase further. Common adverse events associated with SGLT2 inhibitors are genitourinary infections, hypotension, acute kidney injury and euglycemic diabetic ketoacidosis. Recently, SGLT2 inhibitors are increasingly associated with drug induced acute pancreatitis (DIAP). We present a case of empagliflozin associated DIAP, with the intent to add to the limited data on this possible adverse effect. Clinical Case: A 57-year-old woman with a history of T2DM presented to the hospital with severe abdominal pain. She had no recent alcohol use or prior episodes of pancreatitis. There was no history of trauma. Home medications include metformin, glipizide, empagliflozin, and lisinopril. Exam showed epigastric tenderness to palpation without guarding or rebound tenderness. Labs were notable for elevated white blood cell count, normal lipase, calcium, triglycerides, and liver function tests. CT abdomen showed induration of the peri-pancreatic fat, suggestive of pancreatitis. After ruling out common causes of pancreatitis, DIAP and idiopathic pancreatitis were considered possible etiologies. Obtaining further history revealed that patient was started on empagliflozin two weeks prior to this presentation. The only other medication that is known to cause pancreatitis is lisinopril but our patient was on this medication for several years. The Naranjo probability scale for empagliflozin showed a possible association between the drug and side effect. Empagliflozin was discontinued and the patient was discharged on metformin and glipizide. Conclusions: Pancreatitis is a common diagnosis requiring hospital admission and is associated with significant costs to the healthcare system. Although pancreatitis is a known side-effect with other medications used in treatment of T2DM, such as GLP1RAs and DPP-4inhibitors, it has not been well described with SGLT2 inhibitors. The prevalence of DIAP is difficult to assess since most of the existing data comes from individual case reports. Our patient had no known risk factors for pancreatitis. It is yet to be studied if genetic predisposition has a role in the development of pancreatitis with SGLT-2 inhibitors. With the increasing use of these medications in the treatment of type 2diabetes mellitus and heart failure, more cases of DIAP are being reported. It is important for physicians to consider SGLT2 inhibitors as a cause of pancreatitis after excluding other common etiologies. This may reduce episodes of recurrent pancreatitis and the burden of extensive workup for idiopathic pancreatitis. Presentation: Thursday, June 15, 2023

Charcot arthropathy and acro-osteolysis in a 5-year-old girl with hereditary sensory and autonomic neuropathy type II: A case report

Charcot neuropathic arthropathy is a destructive process that can occur in patients with neuropathy associated with medical diseases such as diabetes. A rare cause of neuropathic arthropathy is congenital insensitivity to pain (CIP) which includes varying degrees of sensory loss and lack of pain perception contributing to absent withdrawal responses. The clinical manifestations of CIP include delayed diagnosis of fractures, joint dislocations, acro-osteolysis, avascular necrosis, osteomyelitis, heterotopic ossification, and Charcot arthropathy. We herein report a case of Charcot arthropathy of ankle joints in a 5-year-old girl with CIP due to underlying hereditary sensory and autonomic neuropathy who had recurrent upper and lower limb fractures with acro-osteolysis. She had an inability to perceive pain from the first year of her life. She also had mild developmental delay. Family history was unremarkable. Blood count, liver and thyroid function tests, erythrocyte sedimentation rate, C-reactive protein, blood electrolytes, blood sugar and other laboratory tests were normal. Charcot neuropathic arthropathy in children is rare and can be a part of congenital diseases like CIP. A high degree of suspicion may lead to early detection and can prevent joint and bone destruction and deformities.

Restoration of von Willebrand factor after transcatheter aortic valve replacement-A possible cause for posttranscatheter aortic valve replacement thrombocytopenia?

The aim of the current study was to analyze the clinical and procedural predictors of thrombocytopenia and the relationship between the decrease in platelet count (DPC) and change in vWF function (ΔvWF) after transcatheter aortic valve replacement (TAVR). TAVR often causes temporary thrombocytopenia. At the same time, TAVR leads to a restoration of von Willebrand factor (vWF) function. One hundred and forty-one patients with severe aortic stenosis undergoing TAVR were included in the study. Platelet count and vWF function (vWF:Ac/Ag ratio) were assessed at baseline and 6 h after TAVR. Thrombocytopenia was defined as platelet count <150/nL. Median platelet count at baseline was 214/nL (interquartile range [IQR]: 176-261) and decreased significantly to 184/nL (IQR: 145-222) 6 h after TAVR. The number of patients with thrombocytopenia increased from 12.8% at baseline to 29.1% after 6 h. DPC 6 h after TAVR showed a significant correlation with ΔvWF (r = - 0.254, p = 0.002). Patients with DPC > 20% had significantly higher ΔvWF (10.9% vs. 6.5%, p = 0.021). Obese patients showed a significantly lower DPC (11.8% vs. 19.9%, p = 0.001). In multivariate analysis, ΔvWF 6 h after TAVR was the only significant predictor for DPC > 20% (p = 0.017). The restoration of vWF after TAVR is a significant predictor for DPC after TAVR. An increased platelet consumption due to vWF restoration could play a key role in the development of thrombocytopenia after TAVR.

Asymptotic of the dissipative eigenvalues of Maxwell’s equations

Let Ω = R 3 ∖ K ¯, where K is an open bounded domain with smooth boundary Γ. Let V ( t ) = e t G b , t ⩾ 0, be the semigroup related to Maxwell’s equations in Ω with dissipative boundary condition ν ∧ ( ν ∧ E ) + γ ( x ) ( ν ∧ H ) = 0, γ ( x ) &gt; 0, ∀ x ∈ Γ. We study the case when γ ( x ) ≠ 1, ∀ x ∈ Γ, and we establish a Weyl formula for the counting function of the eigenvalues of G b in a polynomial neighbourhood of the negative real axis.

Blood eosinophils and clinical features of pneumoconiosis complicated with chronic obstructive pulmonary disease: A cross-sectional study

Objective: To analyze the correlation between peripheral blood eosinophil (EOS) level and clinical characteristics of patients with pneumoconiosis complicated with chronic obstructive pulmonary disease (COPD) . Methods: From January 2007 to November 2020, newly diagnosed patients with pneumoconiosis complicated with COPD in Beijing Chaoyang Hospital, were retrospectively analyzed. These patients were stratified into EOS<100 cells/μl group and EOS≥100 cells/μl group, taking 100 cells/μl as the cut-off value. Demographic characteristics, clinical symptoms, lung function and laboratory indexes were compared between the two groups. Results: The median EOS count of patients with pneumoconiosis complicated with COPD was 100 (40, 180) cells/μl. 50.2% (160/319) had blood eosinophil counts ≥100 cells/μl, and 11.0% (35/319) had blood eosinophil counts ≥300 cells/μl. In comparison with EOS<100 cells/μl group, EOS≥100 cells/μl group were older (P=0.035), had higher body mass index (P=0.008), and had lower forced respiratory volume in the first second (P=0.017), had higher the ratio of residual volume to total lung volume (P=0.010), and had lower diffusing capacity of the lung for carbon monoxide (P=0.008). Arterial partial pressure of oxygen was significantly reduced in EOS≥100 cells/μl group (P=0.039). The peripheral blood EOS count was negatively correlated with forced vital capacity, forced breathing volume in the first second, carbon monoxide diffusion, peak expiratory flow, and maximum mid expiratory flow as a percentage of expected values (r(s)=-0.22, -0.18, -0.19, -0.19, -0.19, P=0.000, 0.001, 0.003, 0.008, 0.002), and positively correlated with the ratio of residual air volume to total lung volume (r(s)=0.17, P=0.002) . Conclusion: There was a correlation between blood EOS count and pulmonary function parameters, can proide reference for the diagnosis and treatment of chnoric obstuctive pulmmory disease in clinical practice.

Measurability, spectral densities, and hypertraces in noncommutative geometry

We introduce, in the dual Macaev ideal of compact operators of a Hilbert space, the spectral weight \rho(L) of a positive, self-adjoint operator L having discrete spectrum away from zero. We provide criteria for its measurability and unitarity of its Dixmier traces ( \rho(L) is then called spectral density) in terms of the growth of the spectral multiplicities of L or in terms of the asymptotic continuity of the eigenvalue counting function N_L . Existence of meromorphic extensions and residues of the \zeta -function \zeta_L of a spectral density are provided under summability conditions on spectral multiplicities. The hypertrace property of the states \Omega_L(\cdot)=\mathrm{Tr}_\omega(\cdot\rho(L)) on the norm closure of the Lipschitz algebra \mathcal{A}_L follows if the relative multiplicities of L vanish faster than its spectral gaps or if N_L is asymptotically regular.

Risk Factors of Multiple Myeloma Complicated with Venous Thromboembolism

To analyze the clinical characteristics of venous thromboembolism (VTE) in patients with multiple myeloma (MM) and to identify the risk factors of VTE in MM patients. 179 newly diagnosed MM (NDMM) patients admitted to The Second Hospital of Shanxi Medical University from January 2014 to December 2020 who were followed up for more than 6 months were collected, and they were divided into VTE group and control group according to whether combined with VTE. The clinical and laboratory data were compared between the two groups. Mann-whitney U test was used for inter-group comparison of measurement data, Chi-square test or Fisher's exact test was used for inter-group comparison of count data, and multivariate logistic regression analysis was performed to explore the risk factors of VTE in MM patients. Compared with control group, the serum albumin (ALB) level in VTE group was significantly lower (P =0.033), the fibrinogen (FIB) level was significantly higher (P =0.016), and the proportion of patients with D-dimer≥2 000 ng/ml was significantly higher than that in the control group (26.3% vs 4.4%, P =0.002). There was a significant difference in M-component type between the two groups (P =0.028), and the proportion of IgG type in VTE group was higher. There were no statistically significant differences between two groups in age, sex, body mass index (BMI), the proportions of patients with hypertension, diabetes, coronary heart disease and cerebral infarction, white blood cell (WBC) count, platelet (PLT) count, liver and kidney function, plasma cells ratio in bone marrow, serum globulin (GLO), lactate dehydrogenase (LDH), β2-microglobulin (β2-MG) level, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), prothrombin time (PT), activated partial thromboplastin time (APTT), disease stage, thrombosis prevention and the use of immunomodulators (P >0.05). Multivariate logistic regression analysis showed that FIB level (OR=1.578, 95%CI:1.035-2.407, P =0.034), D-dimer≥2 000 ng/ml (OR=5.467, 95%CI:1.265-23.621, P =0.023) and IgG type (OR=4.780, 95%CI: 1.221-18.712, P =0.025) were independent risk factors for VTE in MM patients. MM patients are prone to VTE, and FIB level, D-dimer≥2 000 ng/ ml and IgG type are independent risk factors for VTE in MM patients.